Since we started our case series with HIV, I figured it’d be nice to stick to the ID theme. Let’s be real. Most of us don’t like ID. But somehow, it follows us no matter where we are in our careers. Whether it’s the NAPLEX, rotations, or our jobs, infectious diseases continue to haunt us. Since we can’t seem to avoid it, let’s learn to master it. And no better way to prepare than with a case :)

P.S. If there is a specific topic that you would like us to cover in a future case, feel free to reach out to me at josef@tldrpharmacy.com.

BONUS NOTE: You hear from us every other week, but now we want to hear from YOU! In an effort to highlight and celebrate the meaningful work that pharmacists (and their learners) do, we would like to start a recurring post consisting of YOUR proudest interventions. Send a brief summary of your de-identified case stories to steph@tldrpharmacy.com for inclusion in our new pharmacy impact series! (Image)

Meet Your Patient

Patient: SS

Age: 67 years

Sex: Female

Weight: 82.1 kg

Vitals: BP (114/72 mmHg), HR (102 bpm), RR (31 breaths/min), Temp (99.3℉), O2 Saturation (94%)

Subjective: SS is a 67-year-old female who presents to your emergency department from home c/o cough, shortness of breath, fatigue, and chest pain associated with deep breathing. She denies any recent hospitalizations and exposure to sick contacts. She claims that symptoms have been ongoing for several days but appear to have gotten worse over the past 24 hours.

Objective

Past Medical History: HTN, HLD, GERD, TIA in 2020, and generalized anxiety disorder

Home Medications: Lisinopril 40 mg QD, Rosuvastatin 20 mg QD, Pantoprazole 20 mg QAM, Hydrochlorothiazide 25 mg QD, Aspirin 81 mg QD, Sertraline 50 mg QD, Hydroxyzine 50 mg TID PRN anxiety

Assessment:

• CBC: 15.4 x10^3/uL; all other levels WNL

• CMP: Sodium (135 mmol/L), K (3.4 mmol/L), Creatinine (1.28 mg/dL), BUN (22 mg/dL); all other levels WNL

• Viral Panel: pending

• Sputum Culture: pending

• MRSA PCR: negative

• Imaging (Chest X-Ray): Right lower lobe consolidation concerning for pneumonia (Image)

• EKG: normal sinus rhythm with a prolonged QTc (525 ms)

1) Based on the clinical presentation and objective data provided, which of the following is the most appropriate management strategy?

a) This patient has community-acquired pneumonia (CAP) and is appropriate for outpatient treatment with oral antibiotics

b) This patient has community-acquired pneumonia (CAP) and should be admitted for inpatient treatment with IV antibiotics

c) This patient has healthcare-associated pneumonia (HCAP) and is appropriate for outpatient treatment with oral antibiotics

d) This patient has hospital-acquired pneumonia (HAP) and should be admitted for inpatient treatment with oral antibiotics

e) This patient has hospital-acquired pneumonia (HAP) and should be admitted for inpatient treatment with IV antibiotics

2) Which empiric antimicrobial regimen is the most appropriate to start for this patient?

a) Levofloxacin

b) Cefepime + Azithromycin

c) Ciprofloxacin + Doxycycline

d) Piperacillin/Tazobactam + Vancomycin

e) Ceftriaxone + Doxycycline

3) After 48 hours, the respiratory culture comes back positive for Klebsiella pneumoniae (beta-lactamase positive). Which of the following interventions is the most appropriate at this time?

a) Stop current therapy and switch patient to monotherapy cefepime

b) Stop current therapy and switch patient to monotherapy ceftazidime

c) Stop current therapy and switch patient to monotherapy sulfamethoxazole-trimethoprim

d) Stop current therapy and switch patient to monotherapy ertapenem

e) Stop current therapy and switch patients to monotherapy daptomycin

4) According to the 2019 ATS/IDSA guideline, what is the minimum duration of treatment for community-acquired pneumonia in patients that achieve clinical stability?

a) 5 days

b) 7 days

c) 10 days

d) 14 days

e) 21 days

5) Which of the following bacterial pathogens commonly cause community-acquired pneumonia? (select all that apply)

a) Streptococcus pneumoniae

b) Pseudomonas aeruginosa

c) Chlamydia pneumoniae

d) Moraxella catarrhalis

e) Citrobacter koseri

Okay ready for the answers? Take a look below:

Answers:

1) B

2) E

3) D

4) A

5) A, C, & D

Need More Infectious Disease NAPLEX Review?

Just a heads up here. This is NOT going to be an all inclusive guide to infectious diseases. There is a lot more to ID than community-acquired pneumonia (I know, I wish it was that simple). But I have good news. Here at tl;dr, we like to have our bases covered. Here is everything infectious diseases that you may find helpful:

• For starters, go to our website. In the top right you will find a little magnifying glass. Go ahead and click it. That should take you to our search bar (which can also be found here).

  Using that search bar, you can literally type any common infectious disease topic that you can think of, and I can almost guarantee that we will have something on it. This can be anything from vancomycin dosing, UTI treatment, pneumonia, aminoglycosides, osteomyelitis, C diff, sepsis, endocarditis, and so much more. Seriously, just go ahead and search for it. I bet we have it. And if we don’t, shoot me an email at josef@tldrpharmacy.com, and I can make it happen :)

• Who doesn’t love free things? I know I do. Check out our free antibiotic cheat sheet :)

• If the cheat sheet isn’t enough, we have a whole infectious disease pocket guide that you can bring with you to rounds every day. It literally has everything you need to know about antibiotics.

• And if all that still isn’t enough, then check out our NAPLEX practice exam and private 1-on-1 NAPLEX tutoring.

Okay I digress. Let’s get into the case now.

Review Time

When it comes to pneumonia, there are 4 main topics that you’ll likely get tested on. So please put them to memory. These topics include:

• Differentiating CAP vs HAP vs VAP

• When to treat CAP inpatient with IV antibiotics vs outpatient with oral antibiotics

• Appropriate empiric treatment for CAP and which pathogens to cover

• How long to treat

Questions 1 & 5: CAP vs HAP vs VAP

There are 3 different types of pneumonia that you have to remember. Knowing the origin is important because it helps us differentiate which bugs we need to empirically cover. Community-acquired pneumonia means more narrow coverage, whereas hospital/ventilator-acquired pneumonia means broader coverage against multi-drug resistant organisms. Let’s review.

Community-acquired pneumonia (CAP)

Definition: pneumonia acquired outside the hospital setting, diagnosed on admission or within 48 hours of hospital admission

Common Causative Pathogens:

• Gram-positive: Strep pneumoniae, methicillin-sensitive Staph aureus, Strep pyogenes

• Gram-negative: Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae

• Atypical: Legionella pneumophila, Mycoplasma pneumoniae, Chlamydia pneumoniae

Hospital-acquired pneumonia (HAP)

Definition: Pneumonia not incubating at the time of hospital admission, occurring ≥48 hours after admission, and not associated with mechanical ventilation

Common Causative Pathogens: Methicillin-resistant Staph aureus, Pseudomonas aeruginosa, Acinetobacter, Enterobacteriaceae

Ventilator-associated pneumonia (VAP)

Definition: Pneumonia occurring >48 hours after endotracheal intubation

Common Causative Pathogens: Methicillin-resistant Staph aureus, Pseudomonas aeruginosa, Acinetobacter, Klebsiella, Enterobacter

Okay now back to question 1. Given the information we received, she just recently presented to the ED and denied any recent hospitalizations. Therefore, it’s pretty evident that this patient has community-acquired pneumonia as she does not carry any risk factors for HAP or VAP.

Oh, and one more thing. Health-care associated pneumonia (HCAP) is no longer a real thing. We treat those patients the same way we treat CAP. So if you see “HCAP” on an exam, you can automatically rule it out.

Now onto the second part of the question. Does she need to be admitted, or can she safely be discharged with oral antibiotics?

To determine that, we can use a couple different scoring systems. The IDSA recommends using the pneumonia severity index (PSI), which collects 20+ data points and makes an objective conclusion based on the results. However, most people use the CURB-65 score since it’s much easier and only takes into account 5 different data points. Let’s review.

CURB-65 Scoring (1 point each):

• Confusion (new-onset)

• Urea (BUN >19 mg/dL)

• Respiratory rate >30 breaths/min

• Blood pressure (SBP <90 mmHg or DBP <60 mmHg)

• Age ≥65 years

Interpretation of Scoring:

Score 0-1: Outpatient treatment

Score 2: Short hospital stay or close observation

Score 3-5: Hospitalization

Using the information above, let’s calculate our patient’s CURB-65 score to determine the best course of action. Our patient was not confused, had a BUN of 22 (+1 point), respiratory rate 31 (+1 point), stable blood pressure, and is 67 years old (+1 point). Therefore, our patient has a CURB-65 score of 3 and should be hospitalized and treated with IV antibiotics.

Now regarding question 5, since this patient has community-acquired pneumonia, therapy should be more narrow and focus on the gram-positive, gram-negative, and atypical bacteria listed above. Pseudomonas and citrobacter are multi-drug resistant organisms and do not commonly cause CAP, thus making those answers incorrect.

Questions 2, 3, & 4: CAP Treatment

Okay, we now know that our patient has community-acquired pneumonia that should be admitted and treated with IV antibiotics. The next step is figuring out which antibiotics to empirically start.

The IDSA guidelines recommend one of the following regimens for the inpatient treatment of nonsevere CAP:

• Beta-lactam (e.g., ceftriaxone, cefotaxime, ampicillin-sulbactam) PLUS a macrolide OR doxycycline

• Respiratory fluoroquinolone (e.g., levofloxacin, moxifloxacin)

P.S. This is a common question that you’ll likely be tested on at one point or another. Ciprofloxacin is NOT a respiratory fluoroquinolone because it has poor coverage against Streptococcus pneumoniae. Since CAP is commonly caused by Strep species, cipro is NOT a good empiric choice to start. Stick with levofloxacin or moxifloxacin for pneumonia.

Now let’s go through each answer for question 2 to see why it’s right or wrong.

Monotherapy levofloxacin. While levofloxacin is a respiratory fluoroquinolone that can be used to treat CAP, this patient has a prolonged QTc of 525 ms. Fluoroquinolones are known to prolong QTc, and use would not be appropriate for this patient at this time.

Cefepime + Azithromycin. First of all, cefepime is a 4th generation cephalosporin that has broad gram-negative coverage. This patient does not have any risk factors for multi-drug resistant organisms such as Pseudomonas aeruginosa, and the extra broad coverage would not be appropriate at this time. Regarding the azithromycin, this patient has a prolonged QTc of 525 ms, and macrolides should not be used since they’re known to prolong QTc.

Ciprofloxacin + Doxycycline. Ciprofloxacin is not a respiratory fluoroquinolone since it has poor coverage against Strep pneumoniae. In addition, fluoroquinolones prolong the QTc, and their use would not be appropriate in this patient since she has a prolonged QTc of 525 ms at baseline. Lastly, fluoroquinolones provide good empiric coverage against atypical bacteria, and additional use of tetracyclines or macrolides for atypical coverage is not needed.

Piperacillin/Tazobactam + Vancomycin. Like we’ve already talked about, this patient does not carry any risk factors for multi-drug resistant organisms such as Pseudomonas aeruginosa or methicillin-resistant Staphylococcus aureus. Therefore this regimen is way too broad and would not be appropriate to start as empiric therapy for CAP. This regimen is more commonly seen when treating HAP and/or VAP in patients that are at risk for these multi-drug resistant organisms. (Image)

Ceftriaxone + Doxycycline. This leaves us with the only right answer. Per the IDSA CAP guidelines, a beta-lactam PLUS macrolide OR doxycycline is recommended. Since this patient has a prolonged QTc, doxycycline is preferred over a macrolide for atypical coverage.

Now on to question #3. We now have respiratory culture results positive for beta-lactamase producing Klebsiella pneumoniae. If you see beta-lactamase positive, then you can automatically conclude that the species is ESBL. And if you don’t remember, ESBL bacteria develop extrinsic resistance to all penicillins and cephalosporins.

The treatment of choice for ESBL is carbapenems. Put that to memory. Anytime you see ESBL anything, your brain should automatically think of carbapenems. Looking through our answers, only answer D has a carbapenem (ertapenem), thus making it the correct answer.

And last but not least, question #4. According to the 2019 ATS/IDSA guidelines, the standard duration of antibiotic treatment for community-acquired pneumonia (CAP) is a minimum of 5 days, with treatment continued until the patient has been afebrile and clinically stable for at least 48 hours. Since our patient has remained hemodynamically stable and is afebrile, a total 5 day course of therapy would be appropriate.

Well folks, that’s all she wrote! I hope you learned something from this case. If you have any recommendations for future case topics, please feel free to send me an email at josef@tldrpharmacy.com. And again, send your de-identified intervention stories to steph@tldrpharmacy.com!

Quick recap: When it comes to treatment there are two big questions:

• Where is the cancer?

• What is the cancer?

To discuss treatment, we need to start with Question #1 and split breast cancer into two big broad categories. There’s early stage, and there’s advanced/metastatic stage. (Now technically, there is a whole spectrum in between these two, but because this is tl;dr, we’re simplifying it to these two categories. You’re welcome.)

Then, within each of these big buckets, we have 4 smaller buckets that separate hormone receptor (HR) status and HER2 status, which is positive (+) or negative (-).

I have been working in oncology for years, and even while writing this, I had to draw the above image on a napkin for my visual self to keep everything organized. (There’s more to fill in these circles later.) (Image) To keep this from getting too long for tl;dr, we are going to focus mainly on common first line therapies. We are going to start with the medications we use to treat specific receptors, beginning with HR-positive.

Hormones, Hormones, Hormones

The most common type of treatment for hormone receptor positive breast cancer is, you guessed it, blocking those hormones from feeding the cancer! In early-stage breast cancer, these are usually given after surgery/radiation in order to prevent the cancer from coming back. In advanced or metastatic breast cancer, these are used in combination with other medications to help shrink and stop the growth of the cancer by cutting off its fuel source.

You’ll typically hear this called endocrine therapy.

An important distinction on how we treat patients with hormones is their menopausal status. Are they pre- or post-menopausal? Why is this important?

Depending on what their menopausal status is, estrogen can be coming primarily from different places. In pre-menopausal women, most of the estrogen is produced in the ovaries with some also coming from peripheral sources, such as adipose tissue (which is why obesity is a risk factor – higher body fat equals higher estrogen levels) and adrenal glands.

In post-menopausal women, estrogen production essentially stops in the ovaries, and the body relies on peripheral estrogen. So, this is why the menopausal status helps guide our therapy choices. (Image)

Now before we dig in, remember this: if the cancer doesn’t have hormone receptors, using a drug that blocks hormones is basically like trying to starve a vegetarian by telling them they can’t have meat. It’s not going to change a thing. Cutting hormones out of a cancer’s diet is only going to kill the cancer if the cancer relies on it to grow in the first place. But if it does, we have some excellent options for treatment.

Selective Estrogen Receptor Modulators (SERMs)

These medications bind to estrogen receptors in the body, but instead of a simple "on" or "off," they act as either estrogen-like agonists or antagonists depending on the specific tissue. This leads to tissue-selective effects like blocking breast cancer growth while boosting bone strength.

Tamoxifen is the medication we use in this class. It is recommended in pre- or perimenopausal women and is most commonly used in the early-stage setting. Although not the preferred first-line choice, it can also be used in postmenopausal women and in the advanced/metastatic setting.

It is generally taken for at least 5 years but can be taken for up to 10 years. Its most common side effects include hot flashes, increased vaginal discharge, and fluid retention.

*Important Counseling Tip*: It has a black box warning for increased risk of uterine cancer, stroke, and blood clots.

Aromatase Inhibitors (AIs)

These meds block the aromatase enzyme, which normally converts androgens (like testosterone) into estrogens (like estradiol). Therefore, by blocking this enzyme, these meds significantly reduce estrogen levels circulating in the blood. These work great in postmenopausal women where peripheral tissues produce the most estrogen. In pre-menopausal women, who still get estrogen from their ovaries, they would also either need to:

1. Be on ovarian suppression therapy with GnRH agonists (so that we are making sure to cut off estrogen from all sources – more on this in a bit), OR

2. Have an oophorectomy (a surgery which removes the ovaries and with them, their estrogen supply).

We have three aromatase inhibitors that are used:

• Anastrozole (Arimidex)

• Letrozole (Femara)

• Exemestane (Aromasin)

Anastrozole and letrozole are typically preferred over exemestane in a first line setting due to better efficacy with fewer side effects. (Image) The most common side effects are fatigue, hot flashes, and muscle or joint aches and pains (similar to symptoms of menopause since we are cutting out estrogen). These are generally taken for at least 5 years and can be given up to 10 years in some patients.

Gonadotropin-Releasing Hormone (GnRH) Agonists

These are synthetic hormones that stimulate the GnRH receptors. Which you may think – don’t we want the opposite of that?

Yes. Yes, we do. Sorta.

Over time, this stimulation leads to long term desensitization and slowing down of the receptors, leading to the suppression of estrogen. (Image) As I mentioned above, we use these medications in pre-menopausal women on aromatase inhibitors to cut off estrogen coming from the ovaries.

• Leuprolide (an intramuscular injection)

• Goserelin (a subcutaneous injection)

As you can also imagine, these have similar side effects to the previous medications, since we are lowering estrogen. We commonly see hot flashes and headaches, along with some injection site pain since these are injectable.

CDK 4/6 Inhibitors

These nifty drugs work by inhibiting CDK4 and CDK6 (as you could have guessed by the name) in the cell cycle. They’re used in HR+ breast cancer because estrogen signaling directly triggers the CDK4/6 pathway, driving cell division. We use them along with endocrine therapy to prevent recurrence in early-stage breast cancer or to inhibit growth of the cancer in late-stage breast cancer.

We have three CDK 4/6 Inhibitors to consider, and they each have their own pros and cons.

They are all indicated as preferred 1st line therapy for advanced/metastatic disease along with endocrine therapy; however, ribociclib holds the category 1 recommendation in the NCCN guidelines (Category 1 means it has high-level evidence that supports its use). (Image)

Abemaciclib and ribociclib are also indicated for early-stage high risk disease to prevent recurrence, each with their own set of criteria depending on the risk features.

They all share some side effects while also having some significant differences to consider when choosing one for your patients. The most common side effects include nausea, increased risk of infection, anemia, liver changes, skin rash, and diarrhea. They can also cause hair thinning or hair loss.

Ribociclib (Kisqali)

Ribociclib is currently approved for both early-stage high risk and advanced/metastatic disease. Of note, when given in early-stage high risk breast cancer, we dose it at a slightly lower dose than we do for advanced/metastatic.

One difference with this medication compared to its sister drugs is that it can cause QTc prolongation and therefore requires EKG monitoring prior to starting therapy, 2 weeks after starting therapy, and then as clinically indicated. It is also more likely than its counterparts to cause hepatotoxicity, so monitoring those liver enzymes is very important.

Abemaciclib (Verzenio)

Abemaciclib is also currently approved for both early-stage high risk and advanced/metastatic disease and has the same dosing in both settings. Its biggest side effect is diarrhea, and you may be thinking, “Oh that’s not so bad. Diarrhea is manageable…”

But the diarrhea with abemaciclib is no joke. (Image)

I have had several patients unable to leave their house due to the severity of diarrhea with this medication. As a counseling tip, I always recommend the patient have some loperamide on hand. And although we love our friend loperamide, sometimes it just doesn’t cut it, and patients need the abemaciclib dose-reduced. Luckily the data shows that the medication is just as effective at lower doses, with some providers opting to start lower and titrate up.

Of note, it is FDA approved to be used without endocrine therapy at a higher dose in the metastatic setting after progression on other therapies; however, this is less commonly used.

Palbociclib (Ibrance)

Palbociclib was the first of the CDK 4/6 inhibitors to come to market. It is currently approved for advanced/metastatic disease only, as the clinical trials in the early-stage setting did not show significant improvement. Its trademark side effect is that it can cause some pretty bad neutropenia, and this requires close monitoring.

Overview of CDK 4/6 Inhibitors

Alright, so where are we with all this? Let’s bring back up my napkin diagram.

As we continue to fill the napkin diagram out, we will start seeing more differences. But for now, we can so far see where we use endocrine therapy and CDK4/6 inhibitors.

HER2 Targeting Agents

As we mentioned before, HER2 proteins are overly expressed on some cancer cells, making them HER2 positive. This protein promotes cell growth and tends to be more aggressive than other types of breast cancer. The good news with most cancers is that if it has an overexpression of something, we can target that.

We have two major workhorses in this area:

• Trastuzumab (Herceptin)

• Pertuzumab (Perjeta)

Trastuzumab is generally given as a part of all HER2 + breast cancer therapy, while pertuzumab is typically added for higher-risk disease, such as lymph node involvement or larger tumors. We also have a dark horse in this race, trastuzumab deruxtecan (Enhertu) – an antibody drug conjugate.

An important thing to know about anti-HER2 therapy is that inhibiting HER2 can also disrupt cardiac cells and lead to cardiac dysfunction. It’s recommended to get a baseline echocardiogram (aka, an echo), as well as every 3 months during treatment, and every 6 months after treatment is complete for up to 2 years to monitor left ventricular ejection fraction (LVEF).

BONUS LESSON 101: What is an antibody drug conjugate (ADC)?

I know you didn’t ask for it, but it’s really cool so I’m going to tell you. It’s a type of targeted cancer therapy comprised of 3 components. You have the monoclonal antibody that recognizes and binds to a specific antigen that’s expressed on tumor cells. Then you have the “payload,” which is a potent chemotherapy agent that’s attached to the antibody that gets directly deposited into the tumor cell. And then you have the linker, which connects the two together. (Image)

(Store this in the back of your brain because currently there are over 300 ADCs in development!)

Okay, so you know what we need now. Our handy dandy – Napkin Diagram! (I’m a 90s kid okay - where are my Blue’s Clues fans?) Let’s add in this new information!

Last but not least – chemotherapy (with a splash of immunotherapy)…

Chemotherapy (and Immunotherapy)

Chemotherapy can be used with any of the above options, as well as with immunotherapy, in patients with triple negative breast cancer (TNBC). The most common agents we see in the breast cancer world are:

Taxanes (Paclitaxel/Docetaxel)

These work by locking the cell’s internal “skeleton” (called microtubules) in place, which cancer cells need to divide. When the cells can’t divide normally, they stop growing and eventually die. This makes these drugs especially helpful against fast-growing breast cancer cells.

Side effects of note include low blood counts (white blood cells, red blood cells, and platelets), hair loss, neuropathy (nerve problems), and allergic-type reactions.

Carboplatin

Carboplatin works by binding to DNA in cancer cells, which prevents the cells from copying their DNA and dividing. This leads to cancer cell death.

Side effects include low blood counts, kidney toxicity, and neuropathy.

Doxorubicin

This works by damaging cancer cell DNA and stopping the cells from making new DNA, which prevents them from dividing and leads to cell death. Because breast cancer cells divide quickly, they are especially sensitive to this kind of damage.

Side effects include low blood counts, hair loss, mouth sores, and red/orange urine (or other secretions like tears!) for 2-3 days after treatment.

(Harmless! But creepy) (Image)

This medication is also very cardiotoxic, so an echocardiogram is required before starting therapy.

Cyclophosphamide

This is typically given with doxorubicin in a combination known as “AC” (not followed by DC), but we may also give it with docetaxel (TC). It also works to damage cell DNA.

Side effects include low blood counts, mouth sores, and bladder irritation.

Sacituzumab govitecan (Trodelvy)

This is another antibody-drug conjugate. It is made of an antibody that targets Trop-2 (a protein highly expressed on many breast cancer cells) linked to a chemotherapy drug.

Side effects include low white blood cells, diarrhea, and hair loss.

Pembrolizumab

This is our splash of immunotherapy in the breast cancer world! (Image) It works by helping the immune system attack cancer cells.

Normally, cancer cells can “turn off” immune cells by using a pathway called PD-1/PD-L1. Pembrolizumab blocks PD-1 on immune cells, which turns the immune response back on so the body can recognize and destroy the cancer. We typically use this in TNBC.

Side effects include skin reactions, diarrhea, fatigue, and muscle/joint pain.

There is your crash course on chemotherapy used in breast cancer! So how do we use these agents? We use these in different combinations depending on the “what/where” of the cancer.

I know! This is a LOT of information! And this is still tl;dr (and we’re getting close to the dr portion). So, to bring this all into a more digestible diagram – you know what we have to do!

Now get ready for the BCTSG! (Breast Cancer Treatment Summary Guide!)

Of course, this doesn’t cover everything that breast cancer has to offer. If it did, there’s no way I’d be able to put it on tl;dr because it would inevitably be a dr. This barely scratches the surface of all the agents and treatments we have available, but I hope this gives you a birds-eye view of the most common/standard treatments you may see!

Breast cancer treatment is changing so rapidly! Even during the making of this article, more things are switching to first line, and new combinations are being approved. But that’s one of the exciting things about being a pharmacist, right? There’s always more to learn!

Gone are the days of calculating mEq at work. Instead, we are expected to understand pharmacodynamics, pharmacokinetics, guideline directed therapy, and key clinical pearls.

Here at tl;dr pharmacy, we welcome these changes. (Image) So much so that we are testing out a brand new case of the month series. These cases are meant to provide practical, real-world learning opportunities to help you prepare for rotations, the NAPLEX, board exams, and your future career.

The format is simple:

• You’ll receive a patient case (found below)

• Followed by several multiple-choice questions

• If you keep on reading, you will see a review of the correct answers with short bullet point key takeaways

With all that being said, let’s dive in.

P.S. If there is a specific topic that you would like us to cover in a future case, feel free to reach out to me at josef@tldrpharmacy.com.

Meet Your Patient

Patient: RT

Age: 32 years

Sex: Male

Weight: 77.9 kg

Vitals: BP (118/76 mmHg), HR (96 bpm), RR (17 breaths/min), Temp (98.3 ℉), O2 Saturation (96%)

Subjective

RT is a 32-year-old male who presents to your HIV clinic for medication refill requests. He admits to poor adherence over the past several months but is motivated to “get his life back together.” He is unsure of what medications he is supposed to be taking and admits to poor adherence to his lab draws.

Objective

Past Medical History: HIV, IV Drug Misuse, Hypertension

Home Medications: unknown at this time

Assessment

• CBC: pending

• CMP: pending

• HIV Viral Load: 141,000 copies/mL (normal: undetectable)

• CD4 Count: 87 cells/uL (normal: 500-1500 cell/uL)

• Imaging (Chest X-Ray): no evidence of developing segmental infiltrates or pleural effusions

Time for the questions…

1) Antimicrobial prophylaxis should be started for which of the following opportunistic infections? (select all that apply)

a) Pneumocystis Jiroveci Pneumonia

b) Cytomegalovirus

c) Mycobacterium Avium Complex

d) Toxoplasmosis

e) Treponema pallidum

2) Which prophylactic antimicrobial should be started for this patient?

a) Azithromycin

b) Voriconazole

c) Sulfamethoxazole/Trimethoprim

d) Amphotericin B

e) Cefepime

3) How long should antimicrobial prophylaxis be continued for this patient?

a) Once CD4 count exceeds 100 cells/uL for 3 consecutive months

b) Once CD4 count exceeds 100 cells/uL for 6 consecutive months

c) Once CD4 count exceeds 200 cells/uL for 3 consecutive months

d) Once CD4 count exceeds 200 cells/uL for 6 consecutive months

e) Once CD4 count exceeds 200 cells/uL for 12 consecutive months

4) Which of the following antiretroviral regimen(s) is/are recommended to start for this patient? (select all that apply)

a) Bictegravir/emtricitabine/tenofovir alafenamide

b) Dolutegravir/abacavir/lamivudine

c) Abacavir/darunavir/atazanavir

d) Lamivudine/ritonavir/cobicistat

e) Enfuvirtide/maraviroc/cobicistat

5) Which of the following best describes the drug class and mechanism of action of dolutegravir?

a) Integrase Strand Transfer Inhibitor (INSTI); binds to the integrase active site and inhibits the strand transfer step of HIV-1 DNA integration necessary for the HIV replication cycle

b) Nucleoside Reverse Transcriptase Inhibitor (NRTI); binds to reverse transcriptase and blocks the RNA-dependent and DNA-dependent DNA polymerase activities

c) Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI); interferes with HIV viral RNA-dependent and DNA-dependent DNA polymerase resulting in inhibition of viral replication

d) Fusion Inhibitor; binds to the gp41 subunit and inhibits the fusion of HIV-1 virus with CD4 cells by blocking the conformational change in gp41 required for membrane fusion and entry into CD4 cells

e) Protease Inhibitors (PI); binds to the site of HIV-1 protease activity and inhibits cleavage of viral polyprotein precursors into individual functional proteins required for infectious HIV

6) Which best describes the seven stages of the HIV life cycle?

a) Fusion → Integration → Replication → Assembly → Binding → Reverse Transcription → Budding & Maturation

b) Integration → Reverse Transcription → Fusion → Budding & Maturation → Assembly → Binding → Replication

c) Budding & Maturation → Fusion → Assembly → Integration → Reverse Transcription → Binding → Replication

d) Binding → Reverse Transcription → Integration → Replication → Assembly → Budding & Maturation → Fusion

e) Binding → Fusion → Reverse Transcription → Integration → Replication → Assembly → Budding & Maturation

Okay ready for the answers? Don’t cheat and look down here first!

Answers:

1) A & D

2) C

3) C

4) A & B

5) A

6) E

Need more HIV NAPLEX review?

Just a heads up here. This is NOT going to be an all inclusive guide to HIV. There is a lot more to HIV that you may need to know. So if you’re looking for a full review, this is not the place. Good news though. Here at tl;dr we generally have all of our bases covered. So if you want a full in-depth review, take a peek below :)

• HIV Cheat Sheet

• Ultimate Guide to HIV for Pharmacists

• HIV Bootcamp Series can be found here, here, here, here, here, here, and here

• The Top 5 HIV Clinical Pearls for the NAPLEX

• What Every Pharmacist Should Know about HIV Pre-Exposure Prophylaxis (PrEP)

• What Every Pharmacist Should Know about HIV Post-Exposure Prophylaxis (PEP)

I wasn’t lying. We’ve literally written about every HIV topic that you will need to know for the NAPLEX. Anything to make your lives easier :). And if all that still isn’t enough, then check out our NAPLEX practice exam and private NAPLEX tutoring. (Image)

Okay I digress. Let’s get into the case now.

Time for Topic Review

There are 3 main HIV topics that you’ll likely get tested on. So please put them to memory. These topics include:

• HIV replication cycle and which step each antiretroviral class inhibits

• Opportunistic infections & treatment (specifically, PJP, toxoplasmosis, and MAC)

• HIV treatment backbone & clinical pearls of the common HIV meds

Questions 1-3: Opportunistic Infections

Very very quick review time: HIV infects and destroys CD4 lymphocytes. CD4 lymphocytes are key in helping provide immune protection. Without CD4, you become immunocompromised and prone to infections to pathogens that your body normally fights off.

Those are called opportunistic infections.

There are 3 opportunistic infections that you should know for the NAPLEX: Pneumocystis Jiroveci Pneumonia (PJP), toxoplasmosis, and Mycobacterium Avium Complex (MAC). The CD4 count is your best friend to help you determine when you need to cover for what. Once you have those memorized, the rest is easy.

CD4 <200 cells/uL:

• Cover for: PJP

• Treatment of choice: Bactrim

• When to stop prophylactic therapy: CD4 ≥200 for ≥3 months on antiretroviral and viral load suppressed

CD4 <100 cells/uL:

• Cover for: Toxoplasmosis

• Treatment of choice: Bactrim

• When to stop prophylactic therapy: CD4 ≥200 for ≥3 months on antiretroviral and viral load suppressed

CD4 <50 cells/uL:

• Cover for: MAC

• Treatment of choice: Azithromycin

• When to stop prophylactic therapy: No symptoms of MAC AND CD4 ≥100 for ≥6 months

Now that we have that info, let’s review our case. Our patient has uncontrolled HIV secondary to poor medication adherence as evident by his low CD4 count and high HIV viral load. This puts him at risk for opportunistic infections.

Step 1 is to look at the CD4 count, which resulted at 87 cells/uL. Per our algorithm above, his CD4 count is <100 cells/uL, making him at risk for both PJP and toxoplasmosis (answer to question 1). Luckily, Bactrim covers both of those infections, thus making it the treatment of choice (answer to question 2). And in regard to how long you continue prophylactic Bactrim, it’s until the patient is adherent to his HIV meds and the CD4 recovers to ≥200 for ≥3 months and viral load is suppressed (answer to question 3).

Pretty straightforward, right?

Questions 4-6: HIV Replication Cycle, Treatment, and MOA

To better understand how antiretrovirals work, I think it’s important we first review the HIV replication cycle. There are a total of 7 steps in HIV replication: Binding → Fusion → Reverse Transcription → Integration → Replication → Assembly → Budding & Maturation (answer to question 6). HIV meds inhibit one (or more) of those steps and prevent the replication of HIV, leading to viral load suppression.

There are six main antiretroviral (ART) drug classes used to treat HIV:

1. Nucleoside Reverse Transcriptase Inhibitors (NRTIs):

• MOA: block viral reverse transcriptase by chain termination

• Common agents: Typically end in “-ine” (with some exceptions)

  Examples: Abacavir (need to screen for HLA-B*5701 for hypersensitivity reactions), Lamivudine, Emtricitabine, Tenofovir disoproxil (more renal toxicity), Tenofovir alafedanamide, Zidovudine

2. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs):

• MOA: directly inhibit reverse transcriptase enzyme

• Common agents:

  Examples: Efavirenz (psychiatric conditions), Rilpivirine (can’t be used with PPIs)

3. Integrase Strand Transfer Inhibitors (INSTIs):

• MOA: prevent integration of viral DNA into host genome

• Common Agents: Typically end in “-gravir”

  Examples: elvitegravir, bictegravir, dolutegravir, raltegravir

4. Protease Inhibitors (PIs):

• MOA: Prevent maturation of new virions

• Common Agents: Typically end in “-navir”

  Examples: Darunavir, Atazanavir, Fosamprenavir

• Clinical Pearl: commonly used with cobicistat as a booster. Cobicistat has no direct activity on HIV. It acts as a pharmacokinetic enhancer (booster) by acting as a potent inhibitor of CYP3A4, leading to increased plasma concentrations of PIs

5. Entry Inhibitors (CCR5 Antagonist):

• MOA: block viral attachment/entry into CD4 cells

• Common Agents: maraviroc, ibalizumab

6. Fusion Inhibitors:

• MOA: prevent fusion of HIV envelope with host membrane

• Example: enfuvirtide

For you visual learners, take a look at the picture below. It perfectly explains the HIV replication cycle and even shows you which step each HIV antiretroviral inhibits. (Image)

Okay now back to our case to answer question 5. Dolutegravir ends in “-gravir”. Therefore it must belong to the INSTI class. And we now know that INSTIs work by preventing the integration of viral DNA into the host genome.

That leaves us with just one more question. This is the final main point that you’re going to have to remember. The HIV treatment backbone is 2 NRTIs + 1 INSTI.

Anytime you’re asked to come up with a regimen to treat HIV, your answer should always have a total of 3 agents that include two NRTIs and one INSTI. So, looking at the fourth question, only the top two regimens have 2 NRTIs and 1 INSTI. The other options don’t have that recommended backbone and are therefore incorrect.

Alright, that’s all folks! I hope you found this helpful and good practice! Again, if you have any recommended case of the month topics, please don’t hesitate to reach out to us!

Steph’s Note: As a mom of 3 kids 4 years old and younger, I’m currently in a phase of life that involves bouts of health. You read that right. Not bouts of illness…bouts of health. They say we’re building our immune libraries, but honestly, it just seems like we’re succumbing to snot and croup at every turn. (For those of you who aren’t parents who just cringed that I used the word “snot”…just wait. There’s more.)

As a pharmacist mom stuck in the seven levels of phlegmy hades, I have had soooo many instances of wishing there was more I could do for my sweet barking babies. I mean, when I was a kid, we had Robitussin (the yucky red one) and Dimetapp (the yummy purple one, IYKYK). So what happened to these options? Why are they now only recommended for older kids?

In order to answer these questions that moms (and grandmas) everywhere are asking, we’re going to turn the tables a bit today. Rather than discussing what we DO use for treatment, we’re going to talk about the medications we DON’T use in kids - and why. Let’s go.

Blacklisted Medication #1: Dextromethorphan

According to the FDA and the American Academy of Pediatrics (AAP), dextromethorphan should not be used for cough suppression in children under the age of 4 years. (UK guidelines are even more restrictive with a minimum age of 6 years.) And even between ages 4-6 years, it’s not recommended first line and should only be used under the advisement of a medical provider. Instead, they recommend honey as a first line intervention (assuming the child is over the age of 1 year given the risk of botulism).

Now, for all my fellow parents out there, have you tried honey for your child’s cough? Did it do a darn thing?

Yeah. Me neither. Batting 0 on that one. (Image)

So alas, what’s the deal with dextromethorphan. What is this medication, and why isn’t it on a list of available cough suppressants for young kids?

Dextromethorphan is a centrally acting antitussive. While its exact mechanism is still unknown, it’s thought to relieve coughing through a combination of the following:

• Action in the nucleus tractus solitarius, which is a part of the brainstem involved in the cough reflex

• Sigma-1 receptor agonist, which is involved in neuronal excitability and the cough reflex

Of note, dextromethorphan is a bit of a jack of all trades. While the above are thought to be targets for relieving coughing, it has many other targets that make it useful for treatment of other conditions as well. For example, it is a noncompetitive antagonist at NMDA receptors and also inhibits serotonin and norepinephrine transporters, which contribute to its antidepressant-like effects. It also blocks several nicotinic acetylcholine receptors and some voltage-gated calcium channels. It’s approved for pseudobulbar affect (PBA) in combination with quinidine and major depressive disorder in combination with bupropion, and it’s being studied for everything from stroke to autism.

Its NMDA antagonism at abusive doses is also what produces the “robo-tripping” high, which is why many states have enacted legislation to restrict purchase to people over the age of 18 years. For context, NMDA antagonism is how ketamine and PCP create euphoria, dissociation, and hallucinations.

Who knew it was all in a bottle in every OTC cough and cold section across the country. Isn’t it wild sometimes to think about what’s sitting on the shelves available for purchase?!

A moment about what dextromethorphan is NOT (because I used to be under this misconception too!). Dextromethorphan is NOT an opioid. It does not act on the mu, kappa, or delta opioid receptors. It is also not a codeine derivative. So when you think dextromethorphan, do not think opioid.

I think some of my own confusion surrounding this dextromethorphan-codeine situation came from its metabolism. Like codeine, which requires metabolism by CYP2D6 to produce its active metabolite (morphine), dextromethorphan also requires metabolism by CYP2D6 to produce its active metabolite (dextrorphan).

Much like the issues surrounding pediatric use of opioids, especially codeine, when CYP2D6 metabolizer phenotype is unknown (aka pretty much everybody), not every child metabolizes dextromethorphan the same way. This variability can lead to a wide spectrum of efficacy and safety. Poor metabolizers won’t make enough active metabolite to be effective, whereas extensive/rapid metabolizers risk toxicity and overdose.

Speaking of overdose, what does this look like for dextromethorphan?

At this point, we’ve pretty well established that this OTC medication has a few skeletons in the closet. But what drug doesn’t? Nothing is completely safe. We give acetaminophen and even ibuprofen to infants (albeit greater than 6 months for ibuprofen), and those meds certainly have some baggage too. So what’s the nail in the coffin for dextromethorphan in kids, if it’s not just safety issues?

The other side of the coin: effectiveness. There haven’t been any studies supporting dextromethorphan efficacy or superiority in young children. In an oft cited JAMA study from 2007, a single bedtime dose of dextromethorphan was compared with honey and no treatment in 105 children 2-18 years old (mean age 5.22 years). Parents were surveyed in a before and after fashion about cough severity, cough frequency, how bothersome the cough was, and sleep quality for child and parents. Honey produced the greatest improvements in symptom scores overall. When compared with the other 2 arms, honey was superior to no treatment, and there were no significant differences between honey and dextromethorphan.

So basically, why use dextromethorphan in kids when there’s a safer alternative that appears to be just as good, if not better?

(Again, not trying to be a Debbie Downer here, but from personal experience, if honey is the best we have, can we get hopping on developing something better? Please? But I digress. Might have some cough-induced sleep deprivation trauma at the moment from bed hopping with sick kids.)

Alright, I think that gives you the need to know on dextromethorphan. The tl;dr? Potential safety issues surrounding metabolism and toxicity combined with a lack of proven efficacy make this a no go for young coughing kids.

Blacklisted Medication #2: Brompheniramine

I titled this section brompheniramine, but in reality, this section is really about first generation antihistamines, including brompheniramine, diphenhydramine, chlorpheniramine, and doxylamine. The FDA and AAP warn of significant danger in children under the age of 2 years, and they recommend against use in kids under 6 years due to concerns surrounding lack of efficacy and safety. Let’s take a closer look.

First generation antihistamines are highly lipophilic, meaning they are able to easily cross the blood brain barrier. They antagonize both peripheral and central histamine-1 (H1) receptors, allowing them to ameliorate histamine-mediated IgE and non-IgE allergic conditions. However, they also produce (often undesirable) CNS effects, including sedation, as well as anticholinergic effects, including the following lovely rhyme:

• Can’t see: blurry vision

• Can’t spit: dry mouth

• Can’t pee: urinary retention

• Can’t *poo emoji*: constipation

So while it may be tempting to use these first generation antihistamines for their anticholinergic and CNS side effects to dry up snotty noses and sedate a poor sick kid into sleeping at night, there’s more to the story.

In this 2024 JAMA study of more than 3000 children in Korea, use of first generation antihistamines was associated with a 22% increased seizure risk (adjusted OR [AOR], 1.22 [95% CI, 1.13-1.31]). That risk was even more pronounced at 49% in children aged 6 to 24 months (AOR, 1.49 [95% CI, 1.31-1.70]). Risk in children aged 25 months to 6 years was less clear (AOR, 1.11 [95% CI, 1.00-1.24]; P = .04 for interaction).

Of note, the first generation antihistamines included in this study were chlorpheniramine maleate, mequitazine, oxatomide, piprinhydrinate (actually a combination of an H1 antagonist and a xanthine stimulant like theophylline), and hydroxyzine hydrochloride. Not all the same products as what’s available here in the US, but some are.

So strike #1 - increased seizure risk, especially in children under 2 years. (Image)

In this 2023 study of almost 2000 Korean children, use of first generation antihistamines was associated with ~20% increased risk of cardiovascular events. Even when they excluded patients who had a known cardiac condition or history, there was STILL an observed ~20% increased risk! So the risk was elevated independent of baseline cardiac status. While ischemia was observed, cardiac arrhythmias were noted to be the most prominent issue (over 95% of events).

This isn’t too awfully surprising when you think about it. Consider the warnings of QT prolongation and Torsades de Pointes (TdP) on hydroxyzine and promethazine, which are other first generation antihistamines. They’re just sharing the cardiac love with their rhinorrhea-treating cousins.

So strike #2 - increased risk of cardio toxicity, especially arrhythmias.

Then we come to the third strike, which is altered mental status. For most users of first generation antihistamines, sedation is the notable mental effect. However, in pediatrics especially, there is a subset of patients who experience paradoxical excitation and/or hyperactivity. (My mom tells the story of how my toddler brother banged his head repeatedly on the floor after receiving diphenhydramine in the 80s…no bueno.)

Beyond the risk of adverse events at therapeutic doses, there is also the risk associated with accidental or intentional overdoses when trying to get sick kids to sleep. In overdose situations, first generation antihistamines can contribute to respiratory depression - which can be fatal. According to one ABC News report from 2008, when many children’s cough and cold products were pulled from the shelves and/or relabeled, there were 69 reports of pediatric fatalities in the setting of first generation antihistamines between 1969 and 2006.

So there you have it, strike #3 - increased risk of altered mental status, both over sedation/respiratory depression and hyperactivity.

Rather than reaching for these first generation antihistamines that don’t have great efficacy data and certainly have some safety baggage, most clinicians prefer to recommend second generation antihistamines - such as cetirizine - for assistance with red, runny noses and congested chests. These second gens have longer durations of action and better safety profiles due to their selectivity for peripheral H1 receptors (rather than central). Cetirizine is approved for children 6 months and up.

Blacklisted Medication #3: Vick’s VapoRub

I know, I know…yes, I’m serious. The third blacklisted product isn’t even a “medication”? How bad could it be that it’s on the blacklist as a topical natural product?!?

Let me pull out my soapbox one more time. Natural products aren’t any safer than prescription medications just because they’re “natural”. Sunshine is natural, and it can give you cancer. At least prescriptions are regulated and studied rather than people thinking they can use as much as they want of a “natural product” just because it’s “natural”.

Again, I digress. Sorry. Putting that soapbox away now. (Image)

Vick’s VapoRub contains three main active ingredients: camphor, menthol, and eucalyptus oil. Let’s look at each of these components a little more.

Camphor is a bicyclic monoterpene ketone essential oil made from the wood from the Cinnamomum camphora tree. It is also found in several other species of plants, including lavender, rosemary, and basil. Historically, it has been utilized for its pungent aroma, including being used to fumigate rooms during the Black Death of 14th century Europe and to perfume bodies in preparation for burial. But it’s also recognized as so much more than a perfume.

Camphor has demonstrated antimicrobial, anti-inflammatory, analgesic, antioxidant, and neuroprotective properties. It repels pests and is used in plastic production. Pharmacologically, it modulates transient receptor potential (TRP) channels, which is thought to produce a counterirritant - or distraction - effect so that pain is lessened. (Interestingly, this is similar to how capsaicin works as an analgesic!) As an antitussive, it is thought to stimulate TRP cold receptors in respiratory passages, producing a cooling effect that decreases the urge to cough.

Menthol is a terpene alcohol derived from the mint family of plants, including peppermint (aka Mentha piperita). Similar to camphor, it is thought to contribute to antitussive effects through modulation of a cold-sensitive TRP receptor pathway in respiratory passages. The feeling of “breathing easier” produced by menthol is the reason it has been included in tobacco products, in addition to masking irritation from nicotine and smoke. People would - erroneously - feel like cigarettes helped them breathe better…because of menthol!

Eucalyptus oil is an essential oil produced from the leaves of the eucalyptus genus of plants, primarily Eucalyptus globulus, although there are tons and tons of different members of this native Australian myrtle tree family used to make essential oils. Clinical effects include antibacterial, anti fungal, antiviral, anti-inflammatory, antioxidant, analgesic, and assistance with wound healing. For respiratory conditions, it falls into the categories of expectorant and anti-inflammatory, making it a theoretically useful addition to camphor and menthol.

The exact mechanism of action of eucalyptus oils is unknown. However, it is thought to act as a mucolytic and also to decrease respiratory secretions by inhibiting pro-inflammatory cytokines. It may also contribute to (again) that feeling of cold that seems to improve respiratory comfort.

Phew. Ok, so those are the components of Vicks VapoRub. Lots of distilling of plant components. So what’s the problem in kids?

All 3 of these ingredients can cause adverse effects in young children, and the FDA and AAP recommend completely avoiding products containing camphor in kids less than 2 years old. What adverse effects, you might ask?

Toxicity from rubs containing these ingredients is usually from accidental ingestion, although the oils are readily absorbed through the skin and can also lead to toxicity (more rare for this route though). Clinical signs are apparent rather rapidly (especially in the case of camphor, like 5-15 min after ingestion) and include the following:

• Burning in the mouth/throat (for PO exposures)

• Nausea, vomiting, abdominal pain

• Dizziness, confusion, agitation, hallucinations, ataxia

• Seizures

• Respiratory depression

• DEATH

Sooo yeah. Friends don’t let friends use products with these ingredients in their young infants or toddlers. And even in older children, we shouldn’t be doing that oh-so-tempting trick of putting it in and around the nostrils for direct application. It’s a chest rub for a reason. You can’t lick your chest. You don’t pick your chest and put what you get in your mouth like kids do with their noses (refer to initial reference about snot and how these sweet babies can do gross things :)).

Also, there are now baby and child versions of Vick’s available for ages 3 months and up. These do not contain camphor or menthol (although they do still have eucalyptus, as well as rosemary and lavender). Parents should still pay close attention to the directions for application (aka if you’re putting it on the feet at night, babies should not have mouth access to those piggy wiggies!), and children should be monitored for any signs of irritation or discomfort.

For reference, my preschooler won’t let me get within 10 feet of him when he sees that little tub come out. He runs away yelling, “It burns!!” So even if there may be some sort of benefit from it, don’t forget to factor in actually being able to apply it. (Image)

Also, for completeness, we’ve talked about chest rubs in this section. But don’t forget that these essential oils are also used in vaporizers, inhalers, and cough drops. Check those labels and be cautious!

The tl;dr of Kids’ Cold Medicines

Now that we’ve talked about why these remedies are blacklisted in young children with colds, let’s take a quick minute to review the highlights:

• Dextromethorphan should not be used for cough suppression in children under the age of 4 years. Between ages 4-6 years, it’s still not recommended first line and should only be used under the advisement of a medical provider. Honey (for ages 1+ years) is a suitable alternative.

• First generation antihistamines (e.g., brompheniramine, chlorpheniramine, diphenhydramine, doxylamine) are especially risky for children under the age of 2 years, but they are not recommended for use in kids under 6 years. Look for second generation antihistamines (e.g., cetirizine) instead when trying to help runny noses.

• Chest rubs containing camphor, menthol, and eucalyptus pose significant risks to children under 2 years old. If additional antitussive help is needed, try rubs without camphor or menthol, following application instructions closely, and monitor the child for irritation or discomfort. Even better, plug in the humidifier instead.

Clarissa Wilkins, PharmD, BCOP is an Oncology Pharmacist in the Treatment Review and Coordination Team at Texas Oncology. She graduated from the University of the Incarnate Word pharmacy school in 2017 (despite her worst class being – ironically – Oncology) and started out as a pediatric pharmacist while gradually descending into madness as oncology continued to haunt her until she finally threw in the towel and has now been a dedicated oncology pharmacist for 7 years. Outside of work she’s a video game-aholic and an avid fantasy/sci-fi reader.

Oncology – at least for me – was the part of pharmacy school journey where I thought, “Do I actually want to be a pharmacist?” I quickly lied told myself that it was only one class, and I would never need to see it again. Nine years later here I am, a board-certified oncology pharmacist.

How did I let this happen? (Image)

Well, once you peel back the scary, hazardous, exterior layers, however many of them there may be, you find out oncology isn’t so different from every other disease state. Sure, we like to use long unpronounceable names (looking at you talimogenelaherparepvec)…and we may add 4 nonsensical letters to the end of every monoclonal antibody…and we may also need to wear a spacesuit to touch them…

Wait a second, where did I put that “but”…?

BUT (ah HA, there it is!), once you break it down, it’s not the big scary beast we make it out to be! It can be an extremely rewarding field of practice.

Luckily for you, a big starting point for all things oncology is already available here at tl;dr. Not only is there a 7300-word oncology overview (that even ends on an 80s pop song reference), but there’s also a post on chemotherapy induced nausea and vomiting (CINV) and supportive care, which are HUGE in the oncology world. I suggest you check out the awesome resources tl;dr has to offer. Since you’ve already had an introduction, I’m going to be taking you straight into my favorite area of oncology: breast cancer.

Even if you’re not in an oncology area, I’m sure you’ve had your fair share of breast cancer exposure - whether it’s on your social media account in October, a pink ribbon here and there, or those bracelets back in the 2000s that said "i ♥ boobies!" that your school tried to ban. (Image)

Unfortunately, despite my teenage-self arguing that that bracelet would cure cancer to the principal, it’s still a top player in the world of oncology.

One in 8 women in the United States will be diagnosed with breast cancer in their lifetime. While advances in screening and testing have reduced the overall risk of death, the number of people diagnosed continues to rise. In 2025, it was estimated that 316,950 women and 2,800 men would be diagnosed with invasive breast cancer, and that’s in addition to the estimated 59,080 new cases of non-invasive breast cancer (we will get to those differences in a second). An estimated 42,170 women died from breast cancer in 2025.

However, it’s not all doom and gloom. When it’s caught early, the 5-year relative survival rate is 99%! This is why advances in screening and testing are so important! There are several things that factor into breast cancer, so let’s start with risks: (Image)

• Sex: of course, being a woman, or a person assigned female at birth, is the most important risk factor.

• Age: just like other diseases, your risk of breast cancer increases the older you get. Two out of three invasive breast cancers are found in women 55 and older.

• Family History/Genetics: if you have family members who have been diagnosed with breast cancer, there is a higher risk of developing the disease yourself.

• Race: although Caucasian women are slightly more likely to develop breast cancer, African American women are more likely to develop more aggressive, more advanced-stage breast cancer diagnosed at a young age.

• Pregnancy History: the age a woman has her first child and the number of times a woman has given birth can affect your risk of developing breast cancer.

  Side note: breastfeeding can actually lower the risk of breast cancer, especially if you breastfeed for longer than one year.

• Menstrual History: women who have their first period prior to turning 12 years of age have a higher risk of breast cancer later in life.

• Hormone Therapy: this can be replacement therapy or birth control. Both may increase your risk of breast cancer.

• Dense Breast Tissue: can make finding lumps harder to detect.

• Radiation Therapy: any radiation to the chest prior to 30 years of age.

And, of course, you have the classic modifiable risk factors including lack of exercise, obesity, smoking, and alcohol.

Now, all that being said, 60-70% of people with breast cancer have no connection to these risk factors, and some people with these risk factors never develop cancer. Cancer likes to keep us guessing.

#cancersucks

We’ve thrown around a couple words like invasive and non-invasive. There are several different types of breast cancer, and these are generally decided by a couple of things:

1. The location in the breast where the tumor is growing,

2. How much the cancer has grown, and

3. Certain features that influence how the cancer behaves.

I’m going to lump the first two bullets together and call them Question #1.

Question #1: Where is the Cancer?

Non-invasive breast cancer is breast cancer that has not spread beyond the breast tissue where it originated from. There are two types: Ductal carcinoma in situ (DCIS), which means it has not spread outside the milk ducts where it started, and Lobular carcinoma in situ (LCIS), which means it has not spread outside the lobules where it started. These are generally deemed pre-cancerous and are typically treated with a lumpectomy, where the cancerous tissue and surrounding tissue is removed. Surgery is followed by radiation to keep it from coming back, and sometimes there are also medications, which we will go through later!

Invasive breast cancer is the more aggressive cancer that has spread into the surrounding breast tissue. And just like with non-invasive, we have Invasive ductal carcinoma (IDC) – you guessed it, it starts in the milk ducts - and Invasive lobular carcinoma (ILC) – guessed it again, starts in the lobules. (Image)

Then there is metastatic breast cancer, meaning that it has spread to other organs in the body. Typically, breast cancer spreads to the bones, lungs, liver, or brain.

All of these help determine what stage of breast cancer the patient has:

• Stage 0: Non-invasive, and has not spread

• Stage 1: Invasive, has spread to the surrounding normal tissue/lymph nodes

• Stage 2: Invasive, has spread but it is still contained in the breast tissue or growth has only extended to axillary lymph node

• Stage 3: Invasive, has spread out of the immediate, or local, area in the breast and into the lymph nodes or muscles close to the breast. What we call “Locally Advanced” breast cancer.

• Stage 4: Advanced breast cancer that has spread to other organs

Now I could go on and on about all the different types of breast cancer, but this is tl;dr, so we are going to focus on the ones that help determine how we treat a patient with systemic therapy. Now that we’ve discussed how ‘where’ the cancer is helps guide how we treat it, let’s get into the ‘what’.

Question #2: What is the cancer?

The characteristics of cancer cells are some of the most important aspects of deciding how we are going to treat it. The main ones we are going to talk about are hormone receptor status and HER2 status.

Hormone Receptor Status

Breast cancer can have an estrogen receptor (ER) status and a progesterone receptor (PR) status. If the cancer cell is ER-positive (ER+), this means that the cancer cell uses estrogen to grow and multiply. (Image) The higher the percentage of ER+ cells, the better the prognosis (because we have great medications to deal with this!). The same goes for PR-positive (PR+), except this is when the cancer uses progesterone. Breast cancer can be both ER/PR+, or it can be just one. Either way, we will treat these cancers with some form of hormonal therapy.

HER2 Receptor Status

Human epidermal growth factor receptor 2, or simply HER2, is a type of receptor that can be found on the surface of breast cancer cells. HER2-positive breast cancers tend to be faster growing, more aggressive, and are diagnosed at a later stage. Breast cancer can be HER2-negative, HER2-low, or HER2-positive. However, like with the ER/PR+ breast cancers, we have specific medications that can target HER2 receptors.

But Clarissa, what if the cancer has NONE of these? What do we do?

We call this Triple Negative Breast Cancer (TNBC). It’s more commonly found in younger women, African American women, or in people with a BRCA1 mutation – a genetic mutation that can lead to various aggressive cancers. In this situation, the cancer lacks estrogen, progesterone, and HER2 targets, which means we can’t use any of our targeted tactics to kill it. In these cancers, we can only stick with our classic chemotherapy agents, as well as immunotherapy.

So that’s your tl;dr introduction to the world of breast cancer! Let’s wrap it all up!

• Breast cancer is still a major player in oncology to this day.

• Where the cancer is located makes a difference in treatment.

  • Non-Invasive vs Invasive

  • Ductal vs Lobular

• Characteristics of the tumor help us determine treatment.

  • Hormone receptor status

  • HER2 status

I know you’re all thinking, “But Clarissa – you’ve told us these things help determine treatment, so what are the treatments?” Have no fear, my friends! In our next article, we will be breaking down the treatment options, so stay tuned!

Joe’s Note: This question has been debated for decades. Everyone knows fluid resuscitation is the first step in treating hypotension in patients with septic shock. Everyone remembers to give 30 mL/kg of fluids. But what should actually be in the bag remains a topic of debate. (Image) There are so many options to choose from…

For starters, you have to pick between colloids and crystalloids. And even if you decide on the type of fluid, you still have tons of options to choose from. From the colloid family, you have albumin (most common), fresh frozen plasma (please no), dextran (also please no), and hydroxyethyl starch (most definitely no). From the crystalloid family, you have dextrose (please no), normal saline, lactated ringers (LR), and plasmalyte. With so many options to choose from, does one rule over the others?

Well folks, today we’re going to answer all questions related to fluid resuscitation in septic shock. By the end, we’re going to figure out which fluid is king above all. And on the way, we’re going to debunk several myths regarding fluids and sepsis. So strap in and enjoy the ride.

P.S. Here’s a sneak peek of our roadmap for everything that we’re going to cover today:

• Which is better: crystalloids or colloids?

• Battle of the crystalloids: balanced crystalloids vs. normal saline

• Does lactated ringers solution increase serum lactate?

Also one more thing. We’re not going to cover other aspects of sepsis in this post. We’re just focusing on fluid resuscitation. But lucky for you, take a look here if you need a refresher on everything you need to know about sepsis and septic shock. And if you want even more in-depth material, check out our sepsis cheat-sheet and antibiotic pocket guide :).

What is the Difference between Crystalloids and Colloids?

Great question. If you want an in-depth review of fluids, give this post a read. But if you want a quick summary, then keep on reading.

Long story short, colloids and crystalloids differ in their composition and volume expansion. Colloids are composed of large molecules that remain in the intravascular space due to high oncotic pressure. On the other hand, crystalloids are composed of small dissolved electrolytes or molecules that freely cross capillary membranes. As a result, only 10-25% of crystalloids remain intravascularly compared to ~100% of colloids. Let’s go over the numbers.

How much of the fluid stays in the intravascular space?

• Crystalloids

  • Dextrose: ~10%

  • Normal Saline: ~20-30%

  • Lactated Ringers: ~20-30%

  • Plasmalyte: ~20-30%

• Colloids

  • Albumin: ~100%

  • Dextran: ~100%

  • Starch: ~100%

  • Fresh Frozen Plasma: ~100%

Let’s put these numbers into perspective. If we give a patient 1 liter of normal saline, approximately ~250 mL will stay in the vascular space while the rest leaks out into the extravascular space. On the other hand, if we give a patient 1 liter of albumin, then almost the entire liter will stay in the intravascular space. Considering septic patients are volume depleted, we generally want to maintain as much fluid in the intravascular space to improve blood pressure. (Image)

So technically, colloids sound like they would be a better option, right? Keep on reading.

Colloids or Crystalloids for Septic Shock?

When it comes to medical debates, primary literature rules all. To avoid any bias, we’re going to review the guideline recommendations and the studies. The most popular studies comparing crystalloids versus colloids in sepsis include the SAFE trial, ALBIOS trial, CRISTAL trial, and the 6S and CHEST trials. Let’s go over them one by one. I don’t want to bore you to death so I will give a very quick and simplified summary of each study. However, I will link each study in case you’re a nerd like me and want to read more.

The SAFE Trial (Saline vs Albumin Fluid Evaluation, 2004)

This landmark trial randomized 6,997 critically ill adults to receive either 4% albumin or 0.9% saline for fluid resuscitation. Overall mortality was similar between groups (20.7% for albumin vs 20.8% for saline, P=0.87). In the predefined subgroup of 1,218 patients with sepsis, there was a trend toward lower mortality with albumin (30.7% vs 35.3%, P=0.09), though this did NOT reach statistical significance.

The ALBIOS Trial (Albumin Italian Outcome Sepsis, 2014)

This trial enrolled 1,818 patients with sepsis or septic shock and compared 20% albumin plus crystalloids versus crystalloids alone. The trial found no difference in 28-day mortality (RR 1.0, 95% CI 0.87-1.14) or 90-day mortality (RR 0.94, 95% CI 0.85-1.05). A post hoc analysis suggested potential benefit in the septic shock subgroup (RR 0.88, 95% CI 0.77-0.99), though the interaction test was not significant (P=0.19). Albumin resulted in higher blood pressure, higher static filling pressures, and lower net fluid balance.

The CRISTAL Trial (Colloids vs Crystalloids for the Resuscitation of the Critically Ill, 2013)

This multicenter trial randomized 2,857 adults in hypovolemic shock (including sepsis) across 57 ICUs to colloids (albumin, gelatin, or hydroxyethyl starch) versus crystalloids. The trial found no difference in 28-day mortality or renal outcomes between groups, with consistent treatment effects across diagnostic subgroups including sepsis, trauma, and other causes of shock.

The 6S Trial (Scandinavian Starch for Severe Sepsis/Septic Shock, 2012)

This trial of 804 patients with severe sepsis compared 6% hydroxyethyl starch (HES) 130/0.42 versus Ringer’s acetate and found increased 90-day mortality with HES (51% vs 43%, P=0.03). HES also increased the incidence of acute kidney injury (34.9% vs 22.8%, P=0.002).

The CHEST Trial (Crystalloid vs Hydroxyethyl Starch, 2012)

This trial of 7,000 ICU patients compared 6% HES 130/0.4 versus saline and found increased need for renal replacement therapy with HES (7.0% vs 5,8%, P=0.04). In the subgroup of 1,921 patients with sepsis, mortality was not significantly different but trended higher with HES (25.4% vs 23.7%, RR 1.07, 95% CI 0.92-1.25).

Alright, that's a lot of studies. What are the key takeaways, tl;dr style?

• Mortality was similar in patients that received crystalloids versus albumin.

• While there was no statistical significance in hemodynamics, patients that received albumin trended to better blood pressure, static filling pressure, and lower net fluid balance.

• Hydroxyethyl starch (HES) is a horrible colloid and had higher mortality and need for renal replacement therapy compared to crystalloids. (Image)

Now let’s review the guidelines. The Society of Critical Care Medicine (SCCM) and Infectious Diseases Society of American (IDSA) recommend the following:

• For adults with sepsis or septic shock, we “recommend” using crystalloids as first-line fluid for resuscitation

• For adults with sepsis or septic shock, we “suggest” using crystalloids alone over crystalloids with supplemental albumin for fluid resuscitation

• For adults with sepsis or septic shock, we ‘recommend against” using starches for resuscitation

• For adults with sepsis and septic shock, we “suggest against” using gelatin for resuscitation

Their rationale? Crystalloids are preferred based on the absence of clear benefit from colloids compared to crystalloid solutions, combined with crystalloids being inexpensive and widely available.

Final Take: Crystalloids are recommended over colloids because they’re equally efficacious, have lower side effects, are much cheaper, and are more readily available.

Battle of the Crystalloids: Balanced Crystalloids vs. Normal Saline

Okay we now know to use crystalloids over colloids. On to the next step. Which crystalloid? Our options include dextrose, normal saline, and balanced crystalloids such as lactated ringers and plasmalyte. In case you need a refresher on what’s in each crystalloid, take a peek below.

Let’s start with dextrose. Unlike the other crystalloids, only ~10% of dextrose stays intravascularly. So if we give 1 L of D5W, only ~100 mL will stay intravascularly while the rest leaks out. Obviously that’s not a favorable outcome considering we want as much fluid to stay intravascularly as possible to bring up that blood pressure.

In addition, dextrose contains no electrolytes and is therefore a hypotonic fluid. Large volumes of dextrose are going to plummet patients’ serum electrolytes and cause more harm than good (in addition to skyrocketing their blood sugar). So given all these points, dextrose should NOT be used for fluid resuscitation in septic patients.

On to normal saline versus balanced crystalloids. This is where the debate is. Just like we did before, we’re going to review the literature that shaped guideline recommendations.

The SMART Trial (2018)

This single-center, cluster-randomized, multiple-crossover trial enrolled 15,802 critically ill adults, including 1,641 patients with sepsis. The overall trial showed that balanced crystalloids reduced the composite outcome of death, new renal replacement therapy (RRT), or persistent renal dysfunction (14.3% vs 15,4%, P=0.04). In the sepsis subgroup specifically, 30-day in-hospital mortality was significantly lower with balanced crystalloids (26.3% vs 31.2%, P=0.01). The sepsis subgroup also showed reduced major adverse kidney events and increased vasopressor- and RRT-free days.

The BASICS Trial (2021)

This Brazilian trial enrolled 10,520 critically ill adults and found no difference in 90-day mortality between balanced crystalloids and saline overall (26.4% vs 27.2%, adjusted HR 0.97, 95% CI 0.90-1.05). Among patients with sepsis, 90-day mortality was 46.7% with balanced crystalloids versus 49% with saline, which is not statistically significant.

The PLUS Trial (2022)

This trial of 5,037 critically ill adults found no difference in 90-day mortality between balanced crystalloids and saline (21.8% vs 22.0%). Among patients with sepsis, mortality at 90 days was not significantly different between groups.

The CLOVERS Secondary Analysis (2025)

This recent analysis of 1,563 patients with sepsis-induced hypotension found that initial fluid resuscitation with lactated ringers solution compared to normal saline was associated with lower mortality (12.2% vs 15.9%, adjusted HR 0.71, 95% CI 0.51-0.99, P=0.043) and more hospital-free days. Patients receiving saline had higher chloride and lower bicarbonate levels.

The SALT-ED Trial (2018)

While this trial enrolled 13,347 noncritically ill adults in the emergency department, it showed that balanced crystalloids resulted in lower major adverse kidney events (4.7% vs 5.6%, P=0.01) but no difference in hospital-free days. A secondary analysis suggested that early balanced crystalloid use in the ED may be particularly important for sepsis outcomes. A meta-analysis of 6,574 patients with sepsis from 5 RCTs showed no significant difference in mortality between balanced crystalloids and saline (31.3% vs 33.9%, RR 0.93, 95% CI 0.86-1.01), though Bayesian analysis suggested an 89.5% probability that balanced crystalloids decrease mortality.

Based on all this, the Surviving Sepsis Campaign 2026 guideline updates issued the following recommendation:

• For adults with sepsis or septic shock undergoing initial resuscitation, we “suggest” using balanced crystalloids over 0.9% saline (normal saline)

Final Take: Balanced crystalloids are recommended over normal saline for fluid resuscitation in sepsis.

Does Lactated Ringer’s Solution Increase Serum Lactate?

The first step in our one-hour sepsis bundle is to collect a serum lactate to assess the severity of septic shock. In case you need a refresher, lactic acid (lactate) is a byproduct that is released when our tissues undergo anaerobic metabolism. If lactate is elevated, then it’s clear that we are not oxygenating our tissues appropriately (aka shock). Hence, we are forcing our organs to undergo anaerobic metabolism leading to increased serum lactate.

To reduce our serum lactate, we need to oxygenate our tissues appropriately so that our organs can go back to aerobic metabolism. How do we do that? Fluids, pressors, and stress-dose steroids.

So far we’ve come to the conclusion that balanced crystalloids (LR and plasmalyte) are the recommended fluids in sepsis. But LR stands for LACTATED Ringer’s. So could it worsen our serum lactate levels and make sepsis look worse than it actually is?

No. Lactated ringer’s has sodium lactate, NOT lactic acid. This is a completely different product and has absolutely no effect on our serum lactate levels. So please don’t avoid using LR in septic patients because you’re worried about increasing serum lactate. It’s just a myth folks. (Image)

P.S. If you want to read about other myths we debunk, check out our two posts here and here.

The tl;dr of Fluid Resuscitation in Sepsis

We’re going to keep it very very brief here. That’s the point of tl;dr anyway, isn’t it? So here you go:

• Colloids are composed of large molecules that remain intravascularly due to high oncotic pressure.

  • ~100% of colloids remain intravascularly.

• Crystalloids are composed of small dissolved electrolytes or molecules that freely cross capillary membranes.

  • Only ~10-30% of crystalloid fluids remain intravascularly.

• Crystalloids are recommended over colloids for fluid resuscitation in sepsis given equal efficacy, lower side effect profile, cheaper cost, and availability.

• Hydroxyethyl starch should be avoided in sepsis due to increased mortality and need for renal replacement therapy when compared to crystalloids.

• Balanced crystalloids (LR and plasmalyte) are recommended over normal saline for fluid resuscitation in sepsis given trends of better mortality, hospital-free days, and fewer adverse events.

• LR has sodium lactate, NOT lactic acid. Therefore, use of LR is recommended in sepsis and has no direct correlation with increasing serum lactate.

Today I am here to tackle something more…clincal. And something that impacts a lot of our patients: Type 2 diabetes. Most of my career has been spent tackling Type 2, and it has even inspired me to cohost a podcast on the subject of Type 2 diabetes remission (in case you wanted a non-tl;dr source from Apple, Spotify, or Youtube). Given my non-clinical posts in the past, you could say I look at pharmacy a little differently. Today we are putting a new lens on Type 2 physiology, treatment, and expectations. Let’s dive in.

Type 2 diabetes is a…problem. A big problem. And, in this pharmacist’s humble opinion, a reversible problem. But before we get there, a quick reality check on the scope of the problem:

• Of the 40 million Americans with diabetes, it is estimated that 90-95% have Type 2 diabetes, specifically. 

• Over 50% of American adults have Type 2 diabetes or prediabetes (and for some sad context, about 1/3 of American kids have prediabetes).

Depressed yet? Great! Let’s cheer you up with some “good” news. Way back when I graduated pharmacy school in 2011, there weren’t cool medication tools like “SGLT-2 inhibitors” or “GLP-1 agonists that were only once a week and celebrities endorsed on Tik Tok.” 

Of course, I am old, and back then Tik-Tok didn’t exist. (Image) We basically had insulin and a bunch of other oral options that have already been covered on tl;dr.

Oh, the “good” news: pharmacists now have more medication tools that actually help improve diabetes outcomes and prevent serious heart and kidney complications instead of just making your A1c look good so the doctor is happy.

Back to the bad news: even with all these fancy tools at our disposal, diabetes is still a massive problem. And it’s time to get a little uncomfortable, perhaps even a little awkward, and ask the question that gave my pharmacy career direction back in 2016:

Are we treating the symptoms of Type 2 diabetes… or the underlying pathophysiology driving the disease?

Don’t get me wrong, I don’t want a world of people with blood sugars in the 300s in whom we avoid medications because “welp, no point, it’s just the symptoms not the root cause!” I think there is room for medications as well as a discussion and PLAN to address the underlying problem to actually put Type 2 diabetes into remission. But to get there, there is, I know, yet another question to ask:

What if Type 2 diabetes is fundamentally a disease of total energy overload rather than simply high blood sugar?

That, my friends, is what is called a teaser. Because first, I want to dive into what Type 2 diabetes remission actually means. To do so, we’ll hit up our friends at the American Diabetes Association, whose definition of remission is:

“HbA1c below 6.5% for at least 3 months without glucose-lowering medications.”

Remission does not mean the disease has disappeared permanently. It means the underlying metabolic dysfunction has improved enough that blood sugar remains normal without pharmacologic support. In other words: the physiology has improved enough that medication is no longer required for blood sugar to be controlled.

Cool cool cool. We have defined the growing prevalence, acknowledged we have some better med tools to fight it, asked some tough questions, and defined Type 2 diabetes remission. Now, I’d like you to take what you have thought Type 2 diabetes is and throw it out the window. And if you could do me a favor, really break that window good, because it’s time to…totally reframe how we look at Type 2.

See what I did there? Window…reframe…window frame. Hehe.

Traditionally, Type 2 diabetes has been thought of as a glucose disorder. You know, check an A1c, see the glucose readings from fingersticks, maybe get lucky enough to have a continuous glucose monitor to track glucose trends. 

In fairness, some of you intrepid readers may actually see Type 2 diabetes as a problem of insulin resistance that develops over years in people. Simply put, the insulin the pancreas produces no longer works as well as the body develops resistance to it, and blood sugar rises as a result. (Image)

The insulin resistance angle is not entirely wrong. But I want to reframe Type 2…even more.

My bold hypothesis is that Type 2 diabetes is primarily a muscle disease that manifests as a chronic energy storage problem. Let me build my case, then talk about how us pharmacists can help our patients get on the road to remission. 

I want you to start thinking in terms of energy storage “tanks” in the body. Some store glucose in the form of glycogen, some store body fat. When humans consume energy in the form of carbohydrates (don’t worry, not gonna carb bash…too much) and there is an excess, it is first stored in the liver as glycogen, which capacity is 80-120 grams. Once our liver glycogen tank is full, the next place for any excess energy to go is the muscle. Here there is much more room for glucose to be stored as glycogen, as in 300-500 grams depending on muscle mass and training by the person. In our storage tank analogy, muscle is…much bigger.

And here’s another important distinction: the glycogen in the liver can be mobilized for the entire body. Muscle glycogen? It’s selfish and can only be used for the muscle itself. 

If the glycogen “tanks” in the liver and muscle get full, but there is still extra energy floating around, the next stop for storage is subcutaneous fat once excess energy is converted into triglycerides. There is good news and bad news about storage in subcutaneous fat. The good news? It’s a “safe” place for excess energy to be. Unlike liver and visceral fat (we’ll tackle these in a moment), there is less danger in energy being stored here. The bad news? Excess weight in any place is not good for the overall health of the body.

The final storage tank for excess energy, and the one the body tries desperately to avoid filling, is ectopic fat. Here is where we can see fatty liver, as well as fat around the pancreas. All this leads to issues with insulin release as well as hepatic insulin resistance and excess glucose production. 

An interesting, or more likely, frustrating aside. There is a concept known as the “personal fat threshold,” which basically says a person is genetically limited to how much subcutaneous fat they can store before it starts accumulating ectopically. While Type 2 diabetes is typically associated with being overweight or obese, that is not always the case. If you have ever had a patient frustrated with a Type 2 diagnosis or high blood sugar because they are “not overweight,” this could partly explain why. It can also explain why there are people who are morbidly obese with very normal blood sugars who can store excess energy more effectively in their subcutaneous fat tissue.

Returning back from our aside, if I had to summarize what Type 2 diabetes is in a single sentence, it would be: Type 2 diabetes develops when the body runs out of safe places to store energy.

Once all of the safe “storage tanks (hepatic glycogen, muscle glycogen, and subcutaneous fat)” fill up, then the “unsafe” ones fill up (ectopic fat). And at that point, we have full blown insulin resistance and energy (glucose and often, triglycerides) with no where else to go but the blood.

Ok, once we hit “energy storage overload,” insulin resistance develops, and blood sugar is high, things look pretty grim. But what if there were a secret weapon in the body that could help reverse all of this energy excess nonsense? An underused, underdeveloped, and underappreciated diabetes “drug”?

Good news, there is. And I have already mentioned it.

Are you ready for me to pump you up…with strong blood sugar lowering advice? (Image)

Good, because I see Type 2 diabetes as a muscle disease. Why exactly? Because muscle is the largest storage “tank” in the body, accounting for 70-80% of post prandial glucose disposal. That means more muscle, more effective removal of glucose from the blood.

Think of our muscle system as a metabolic “sink” for blood sugar to drain. It is why, in this humble pharmacist’s opinion, that one of the risk factors for developing diabetes is age. Because as we age, we tend to lose muscle mass and thus, a major source of glucose regulation in the body.

Of course, this hypothesis runs contrary to the opinion that age-related diabetes risk is directly correlated to grandparents eating the leftover sugary sweets they give their grandkids. 

While the volume of muscle affects glucose regulation, skeletal muscle has another trick up its bulging bicep-y sleeve. Because while we were all taught insulin needs to be around to open the “gate” for glucose to enter our bodies’ cells, muscle has a secret side door.

GLUT-4.

Cool name. Even cooler effect. Because GLUT-4 allows for glucose to leave the blood and enter muscle cells independent of insulin secretion…provided the muscle contracts. 

That means lowering blood glucose even in a setting of insulin resistance or impaired beta cell function. Indeed, muscle is one of the only tissues that can clear glucose from the blood without insulin.

Is your mind blown?

With that knowledge in your back pocket, let’s start constructing that roadmap to Type 2 diabetes remission.

I like the simple things: 90’s alternative rock, adding guacamole to my Chipotle order, and keeping lists in groups of three. Which is why I am going to give you the three simple levers for diabetes remission. (Image)

Diabetes Remission Lever #1: Muscle

You just got the reasons why muscle is so important for blood glucose regulation as it is our bodies’ largest glucose storage tank. It can even remove glucose from the blood without needing insulin. Why’s are great, but how can we encourage the people we care for to actually implement muscle building. The simple answer is resistance training, but the more complicated answer is “how much, which kind, where, and do I need to spend lots of hours in the gym?”

The internet, your local gym, and your Uncle Rico (no, not the one who could throw a pigskin a mile) all have lots of opinions on resistance training protocols. (Image) I lean towards a simple protocol that is just 15 minutes twice a week.

That’s right, 15 minutes twice a week. It sounds like a scam, but the evidence backs it up (actually, this study showed how going to muscle failure once a week worked too). If you’d like a book on the subject, 15 Minutes to Fitness by Dr. Ben Bocchicchio is the place to nerd out. I typically just send my patients to one of the many videos where the 7-8 movements are described. The trick to getting these done in such short order is that each rep is done sloooooowly so that if you pick the right resistance, you get to muscle failure in 60-90 seconds. 

I’ll admit my bias, but I like this protocol as a “minimum effective dose” of strength training to put it in pharmacist language. Personally, I follow this protocol due to the time constraints of three very young, needy, and often loud children and have been very upset by it. Only because I spent years doing hours of exercise but didn’t get the same strength gains as this workout. 

This workout will build muscle to help lower sugar, not take a ton of time, and can be done at home with resistance bands. It’s basically a perfect workout for anyone who says, "I don't have time to workout." And the low reps and slow movements are great for minimizing injury risk. 

But if you think 15 minutes twice a week is ALL you have to do to reverse Type 2 diabetes, let me introduce you to Lever 2.

Diabetes Remission Lever #2: Smart Movement

Let me preface this by saying any kind of movement someone with diabetes can do is better than none. But we are tl;dr for a reason: work smarter, not harder. While volume of movement is good, what if we could time things in a targeted way to get the most blood sugar lowering bang for the buck. Because many patients have exercise framed in a way that is doomed to failure, like “exercise 30-45 minutes a day.”

I don’t know about you, but life is chaotic. To get a chunk of time even as small as that EVERY day would be a challenge for many. But if we can encourage smaller bouts of exercise with better timing, we can help people incorporate movement into their lives that is doable, sustainable, and actually helpful for lowering blood glucose.

To that end, we want to focus on a couple of action items:

• Move when glucose is **typically** highest

• Move throughout the day periodically (aka exercise snacks)

First, timing of movement around elevated glucose. This could mean going for a walk after meals for just 5-10 minutes. This can help with post meal glucose spikes. And if after a meal doesn’t work, going before can be useful in glucose lowering too.

The other is small amounts of movement throughout the day, also known as exercise snacks. This can mean those walks around meals, but it can also mean fitting in 10 bodyweight squats every hour, or taking 2 minutes an hour to go up and down the stairs. Anything to break up sitting and sedentary behavior throughout the day can help lower glucose and improve insulin sensitivity. In fact, one study found that doing those intermittent squats throughout the day lowered glucose better than one continuous 30 minute walk.

So we grow some muscle and contract it regularly throughout the day, and blood sugar will improve. But we can’t ignore that diabetes may still stick around if energy intake is still too high. Which brings us to…

Diabetes Remission Lever #3: Satiety-Driven Nutrition

“Too many calories and not enough nutrition.”

This is the line I have given to countless patients. And I’ll explain what I mean in a second. But before I do, I’d like to make an (another) aside. 

If you have ever given diet advice, read about diet advice, or turned on the TV or internet to learn more about nutrition, you have probably seen some form of The Diet Wars. And like Star Wars, there seems to be a sequel every week. 

• Paleo

• Plant Based

• Keto

• Low Fat

• Mediterranean

I am going to plant my flag in the “no more diet wars” camp and provide a framework that is diet camp agnostic. Because it works for any approach to eating that…works for better blood sugar. And all of those approaches, like the ones I listed, reduce overall energy intake.

The approach I recommend for Type 2 reversal is a satiety-based approach that helps people naturally regulate food intake and can be adapted to nearly any dietary preference. That is, other than the “Standard American Diet” which…is not conducive to controlled blood sugars.

The framework is a “Nutrient to Energy” ratio. The leap I am taking here is that our bodies regulate appetite primarily through protein and nutrient intake, not calorie intake. As I said earlier, I often tell people suffering with high blood sugar that they eat too much energy (calories) and not enough food (nutrition).

Modern processed foods are:

• High energy (lots of fats and carbohydrates)

• Low satiety (don’t make you feel full)

• Easy to overeat (hello my friend, the old bottom of a bag of chips)

It would not be beyond someone, like myself, to eat 1000 calories of tortilla chips and still feel hungry. But a 1000 calories of broccoli…good luck. 

The goal is to consume more “nutrient dense” foods that are less “energy dense". For example:

• Higher protein foods

• Meat

• Fish

• Eggs

• Greek yogurt

• Lower energy density foods

  • Vegetables

  • Fruits

  • Some whole food carbohydrates

When people increase protein and nutrient density, total energy intake (calories) from fats and carbohydrates often falls naturally. And the good news is that we can all join hands and sing kumbaya because this “maximum nutrition with minimal energy” approach works for all sorts of different dietary approaches.

No fights about diet required. 

So now you, intrepid pharmacist, are armed with the three pronged approach to help your patients with Type 2 diabetes reverse course and set sail onto the Sea of Remission.

And because you see these patients so often: in your clinics, at your counters, and at the family barbecue while Uncle Frank won’t stop asking why his copay went up 3 dollars, you have the power to help them.

You can educate on the importance of muscle, smart movement, and a fight free approach to eating that will help them build a better capacity for handling glucose, utilize it more effectively, and stop overfilling their bodies with energy.

Lest we forget, you are, in fact, a pharmacist with vast medication knowledge. So remember that on the road to Type 2 diabetes remission, there are certain classes of medications that can be used as supportive tools. 

• GLP-1s can improve satiety to reduce energy intake.

• SGLT-2 inhibitors can help rid the body of excess glucose.

• Metformin can improve insulin sensitivity.

• Sulfonylureas can burn out their pancreas and cause dangerous hypoglycemia. (Can you tell I am no fan of sulfonylureas?)

Remember that medications treat the symptoms, but fixing the underlying physiology treats the root cause of Type 2 diabetes. And lifestyle will determine if patients continue accumulating excess energy or begin reversing the problem.

I hope you now realize that Type 2 diabetes doesn’t have to be a lifelong progressive disease. When we treat muscle as medicine and prioritize satiety, remission becomes a realistic outcome for many patients.

Steph’s Note: Every once in a while, you run across a news article that makes you go, huh, that’s cool…why didn’t I think of that? Or at least that was my thought when I saw the articles about the approval of 2 novel diuretic formulations for use at home. (Could’ve been rich…sigh. I guess I’ll keep working lol).

So that we can all learn more about how old drugs can learn new tricks, Jenny Hoang grabbed hold of this topic baton and fleshed out what you need to know about these cool new drug delivery systems. (If you haven’t read anything by Jenny yet, you should - herbals, CAR-T, and PISCES.) Thanks again, Jenny, take it away!

Just about any pharmacist has seen a good ol’ case of edema, or fluid retention, in their career. You may recall that it is common in patients who have heart failure or chronic kidney disease. And you (hopefully) remember that we often use diuretics to alleviate this swelling. This is because these medications work in the kidneys to adjust the balance of ions and water so that the body doesn’t hold onto all the excess water causing the edema. 

Specifically, we tend to see loop diuretics. They are the first line of treatment for congestion in heart failure patients. Loop diuretics work when the kidney is filtering the blood and is sorting out how much water and salt to keep. If we look at the nephrons that are inside the kidney, loop diuretics act at the Loop of Henle.

Normally at the Loop of Henle, a lot of salt is absorbed. And remember that water follows salt. So if the Loop of Henle reabsorbs a lot of salt, then it makes sense that a lot of water is also reabsorbed. (Image)

But in the case of edema, we do not want more water to be absorbed, so we need to stop this. Loop diuretics come to the rescue by blocking salt absorption at the Loop of Henle. By doing this, salt stays in the urine, drawing water out with it.

The result? Less edema as less fluid is retained.

Pharmacokinetics of Loop Diuretics

Now let’s think about some real life application of loop diuretics. They are available in both IV and PO forms. The most common loop diuretic is furosemide.

Oral furosemide takes anywhere from 30 minutes to an hour to start working, and its action lasts about 6 hours (hence why the brand name is Lasix…get it, LaSIX). Oral tablets are highly effective for maintenance diuretic treatment. Patients can be monitored through routine check ups and can also watch their weight to have a good idea of how much fluid they are retaining, which allows them to adjust their dosing at home.

On the other hand, the IV version takes only minutes to start working, but more is excreted via urine compared to the oral tablet. So it only lasts about 2 hours. 

We should also consider the dosing differences between IV and PO furosemide. Furosemide’s bioavailability is about 50%. This means that, when given orally, about 50% of the dose is lost to metabolism. This means only the other 50% that is absorbed is actively blocking salt retention.

So let’s look at a quick example. You have a patient who was hospitalized and stabilized on a dose of furosemide 20 mg IV daily, and he is now ready for discharge. What should his outpatient furosemide dose be? His IV dose should be doubled to 40 mg when converting to oral tablets for discharge.

One of the biggest problems however with the oral tablet is that if a patient has severe edema, they may have a lot of fluid stuck in their gut. This can cause highly variable absorption of the oral tablet, which can cause it to be not as effective. Due to this, despite the accessibility of oral tablets, patients may find themselves having to come to the hospital for IV loop diuretics.

Intravenous diuretics come in handy for situations such as acute pulmonary edema, heart failure, impaired gut absorption, intubation, or severe nausea and vomiting. The IV formulation is also a lot more predictable since it goes directly into the bloodstream. And another big plus about IV diuretics is that they allow for a quick, high plasma concentration that passes the threshold to be effective.

Many patients who chronically use loop diuretics may find that they have blunted responses due to the kidneys compensating through different mechanisms. (Because of this, some patients have to take another type of diuretic such as a thiazide diuretic). Some patients have blunted diuretic responses because they are so overloaded with fluids that they are not effectively absorbing higher levels of diuretics. (These patients have to keep taking higher and more frequent doses to get the same effect).

While IV administration helps eliminate those issues, the drawback to IV diuretics is that they require hospitalization, which is costly and time consuming - not to mention increases the burden on the healthcare system. There are also those patients who simply don’t recognize the severity of their condition soon enough and fail to get to the hospital in time for help.

If only there were solutions at home…

A New Subcutaneous Loop Diuretic Formulation 

Home is where my bathroom is. This is the proud slogan of SQ Innovation INC’s new drug Lasix ONYU. It is a wearable (ONYU, “on you,” wink wink) drug delivery device that releases 80 mg of furosemide in 2.67ml prefilled syringes subcutaneously through an infuser. Each infusion lasts about 5 hours and can be used once or twice a day, with typical treatment lengths from 3-10 days. Patients can expect to go to the bathroom a lot during that time.

The infuser consists of a rechargeable, reusable unit that attaches to a disposable unit that is attached to the skin (stomach area, rotating sites each use). It releases the prefilled syringe with the medication dose. Each reusable unit can be used for 48 treatments. And best of all, patients can easily use it at home without needing to go to the doctor or hospital! (Image)

In the 2023 SQIN-Furosemide PK/PD trial, they tested 80 mg intravenous (IV) furosemide head to head with the 80 mg subcutaneous (SC) injectable furosemide in ~2.7ml with the primary outcome of absolute bioavailability of the SC furosemide. The resulting bioavailability was found to be 112% for SC compared to IV. The urine volume percent in 8 hours was 116% with 118% sodium excretion, and 115% urine volume in 24 hours for SC vs. IV. (Image)

This tells us that the SC formulation performed just as well as, if not slightly better than, the IV formulation, especially with increasing time from dose. Few patients reported transient skin irritation with the SC injection and most patients found the application very usable and acceptable for their use. Overall, this study demonstrated that the SC formulation was very promising.

However, it should be noted that this first study was conducted in a small group of 18 participants and all were in stable heart failure using oral diuretics. So, what about clinical outcomes instead of PK/PD? And what about in decompensated patients rather than stable?

Enter the 2024 AT HOME-HF study, conducted by scPharmaceuticals on their subcutaneous furosemide on-body device FUROSCIX. In this study, 51 outpatients with chronic HF and increasing fluid congestion were randomized 2:1 to either SC furosemide or usual care. The primary outcome was a win ratio of a 30 day composite of cardiovascular death, HF events, and changes in N-terminal pro-BNP levels (a marker of fluid overload). Secondary endpoints were related to patient functionality and quality of life.

Side bar - what’s a win ratio? Glad you asked because I had to look it up too!

A win ratio is a statistical representation of wins versus losses (aka good outcomes in the treatment group vs bad outcomes in the control group). A win ratio of greater than 1 means the treatment helped. It’s different than other outcome statistics in that it accounts for the order in which patients and outcomes are compared, allowing for some prioritization of outcomes. That is, patients may be compared according to hierarchal levels. First may be death rates (as that is the most important consequence!), but if that’s equal between groups, then the comparison moves on to the next component of the endpoint (e.g., HF events in the case of the AT HOME-HF study). Pretty interesting representation of outcomes when we’re so used to seeing time-to-event hazard ratios in most studies.

Alright, now that we’ve had our little statistics side bar, back to the study results for SC furosemide. The SC furosemide to usual care win ratio was 1.11 (95% CI 0.48-2.50, p=0.806). Bit difficult to interpret with that wide confidence interval and nonsignificant p-value…not super great there. Of course, there were only 51 people in the study total, so perhaps a missed significance due to insufficient sample? IDK, TBD. The positive news was that the SC furosemide group did experience a significantly greater reduction in weight at day 3 than the usual care group, as well as improved dyspnea and functionality scores. So perhaps there’s something there…further studies needed!

A New Intranasal Loop Diuretic Formulation

Let’s take a look into a new nasal spray form of bumetanide, which is another loop diuretic. As we’ve already discussed, IV is often needed for quick and effective diuresis in emergency situations, but it can prove to be inconvenient and costly. The new Bumetanide Nasal Spray (BNS, brand name Enbumyst) is designed to provide an intranasal solution that is both quick and highly bioavailable. (Image)

As we discussed earlier, oftentimes those characteristics are difficult to achieve at home with oral diuretics, which is why people require IV diuresis. Additionally, if patients have excess fluid retention, they may have gut edema that will hinder absorption of their oral maintenance doses. So this is where the nasal spray can be a great solution as it bypasses those absorption issues.

The BNS is designed to be highly absorbed through the nasal mucosa. In this randomized PK/PD open label crossover trial of the BNS, they looked at the primary outcomes of Cmax and AUC for BNS versus oral and IV bumetanide. They found that BNS was bioequivalent to oral bumetanide, and there were no differences in Cmax and AUC between the two as well. However, the BNS did reach max concentrations (Tmax) more quickly than the oral tablet (1 hour versus 1.5 hours, respectively). There were also no differences in urine output at 2 and 24 hours or in sodium excretion.

The researchers also noted that both the BNS and IV formulations only had 27% variability in absorption instead of the over 40% for the oral formulation. Patients found the formulation comparatively tolerable to other formulations, and no overt nasal irritation occured. But again, they recruited healthy individuals, who may not be representative of those needing diuresis the most.

While both the new SC formulation and this BNS provide excellent diuretic options at home, the BNS is less invasive and simpler to use. Another consideration is that, if a patient has nasal congestion, they may not experience the same absorption observed in the studies, so the SC option may be preferred in that instance. 

The tl;dr of New Loop Diuretic Formulations 

All in all, loop diuretics are very effective at reducing fluid retention. In many disease states, such as heart failure or chronic kidney disease, they are often used orally for fluid maintenance. Oral formulations, however, can be finicky when it comes to gut absorption, especially in patients with lots of edema. Increasingly higher doses may be required to achieve the same effect.

In emergency situations, such as acutely decompensated heart failure, patients may need to be hospitalized to receive IV loop diuretics for better bioavailability and quicker, more effective fluid reduction. This is time consuming and costly, so drug manufacturers are creating alternatives to at-home oral doses to provide the efficacy of IV formulations without the need to be hospitalized.

There are a lot of promising data for both a new SC and nasal formulation of loop diuretics. In small, preliminary studies, these new formulations were found to be similar to IV in kinetics and effects. As more studies are conducted, especially in patients who more severely decompensated, we will find out if these new formulations actually live up to their promise of IV efficacy in the comfort of home. 

Suddenly, those febrile seizures topic discussions you had a few years back start flowing through your head. You get nervous. (Image) Google and/or some form of AI become your best friend as you search:

• “What is febrile seizure?”

• “What temp should I be concerned about for febrile seizures?”

• “How do I treat febrile seizures?”

• “Should we go to the ED?”

• “Is my infant at risk for febrile seizures?”

• “Can I prevent a febrile seizure?”

Okay maybe that’s not your story, but it is mine. So, to spare you the anxiety that I had to go through, I decided it would be good to write about febrile seizures and prepare all the new parents out there. If you want the answers to those questions above, keep on reading!

What is a Febrile Seizure?

As the name suggests, febrile seizures are generalized seizures that occur in febrile (fevering) pediatric patients. They are typically seen in children between the ages of 6 months to 5 years and occur with a fever ≥ 100.4℉. And in case you need a refresher on normal infant temperature ranges, take a look below.

Oh and one more thing. Rectal measurement is the gold standard for accuracy in children under 3 years old since it provides the most reliable core body temperature.

• Normal Temperature Range (rectal): 97.7℉ to 99.5℉ (36.5℃ to 37.5℃)

• Low-Grade Fever (rectal): 100.4℉ to 102℉ (38℃ to 39℃)

• Moderate Fever (rectal): 102℉ to 104℉ (39℃ to 40℃)

• High-Grade Fever (rectal): 103℉ to 104℉ (39℃ to 40℃)

• Very High/Dangerous Fever: >104℉ (>40℃)

Now it’s also a little tricky because age plays into urgency as well. For example, a temperature of 101℉ in a 4 year old may not make you blink more than to say, “Oh hun, you’re probably coming down with something.” (And then you feel dread wash over you because you know you’re next on the list of whatever plague your dear sweet Petri dish has brought home…) But in a newborn, that same temperature is actually a medical emergency that warrants getting to a doctor ASAP. Check out this chart to see how not all ages are created equally when it comes to fever:

What Causes a Febrile Seizure?

Not to beat a dead horse but the straightforward answer is fevers ≥ 100.4℉ (38℃). And yes, even low-grade fevers can induce seizures in kiddos. (Comforting, right?) That being said, I think it’s important to talk about what DOESN’T cause febrile seizures.

This type of seizure is generally not neurogenic in nature. Meaning that it’s not associated with a central nervous system infection or any other known seizure-provoking etiology, such as electrolyte imbalance, hypoglycemia, or substance abuse.

Risk factors for febrile seizures include existing neurologic impairment, the presence of a viral infection, a family history of seizure, developmental delay, decreased serum zinc and iron levels, and maternal smoking and stress. Essentially, this seizure is caused by febrile illness NOT related to the CNS and does not meet criteria for other acute symptomatic seizures.

Got it? Great, moving on.

Febrile seizures are divided into 2 main categories: simple febrile seizures and complex febrile seizures. Let’s compare:

In general, simple febrile seizures are significantly more common than complex febrile seizures (phew). In fact, simple febrile seizures account for roughly 65-90% of all cases. That being said, simple febrile seizures should not be taken lightly. If not appropriately treated, they manifest into complex and even febrile status epilepticus. We’ll get more into treatment in a little bit. But for now, let’s talk about the pathophysiology of febrile seizures.

Patient-Friendly Pathophysiology of Febrile Seizures

Seizures are so complex, and I’m definitely not smart enough to get into the nitty gritty details of generalized seizures. So to spare you the medical jargon, I decided it would be best to give a very basic patient-friendly explanation of what happens during febrile seizures.

It typically all starts with some form of viral infection. To fight the infection, our immune system releases a bunch of cytokines (interleukins, interferons, TNF, etc), which results in a fever. Why does our body purposely increase our internal temperature?

Because inducing a fever creates an inhospitable, high temperature environment for pathogens, while simultaneously accelerating the immune system’s response. Fevers boost the production and efficiency of white blood cells, enhance the release of heat-shock proteins to aid immune cell trafficking, and speeds up metabolism for faster tissue repair. Pretty neat right?

In a mature fully developed brain, low-grade fevers are great and dandy since they can help fight infection and boost repair. But the young brain of infants and toddlers is not fully developed. These kiddos have more excitatory signals and less mature inhibitory control. And while fevers may help fight the infection, they also make neurons fire faster, leading to increased metabolic demand in brain cells.

Think of it as a car with a strong gas pedal but weak brakes. Or an overly sensitive smoke alarm that goes off with any heat rise, even though there isn’t a dangerous fire. (Image)

So yes, while fevers may fight infection, they also can cause neuronal excitement leading to unwanted seizures in young patients.

How to Treat Febrile Seizures?

Yay, we’re at the fun part now :). Before we get into the treatment, I want to give a very important disclaimer. The majority of febrile seizures are self-limiting and treatment mostly focuses on managing fever and preventing injury/recurrence. Most febrile seizures resolve spontaneously and return to baseline is quickly achieved without the need for acute intervention.

That being said, that’s not the case for every single patient. If a febrile seizure persists for longer than 5 minutes, emergency rescue therapy is needed. Luckily, treatment is the same as for status epilepticus. We’re not going to go super in-depth on the treatment of status epilepticus since we have a whole article about it here. But, to prevent you from having to click back and forth between the two articles, here is a step-wise approach I made for the treatment of acute status epilepticus:

The Role of Preventative Therapy - Anticonvulsants

I know. Logically speaking, if someone (especially a pediatric patient) experiences a febrile seizure, you’d assume that chronic antiepileptic medication would be needed to help prevent recurrence. While it sounds like a genius plan, literature would recommend otherwise.

Why? Great question.

Let’s take a step back and go back to the basics. When we treat any disease state, it’s vital to weigh the risks versus benefits of starting therapy. All meds come with unwanted side effects/adverse events. It’s impossible to avoid this. And when the benefits of treating a disease outweigh the risks, treatment is appropriate. But when the risks outweigh the benefits, then treatment is generally NOT recommended.

Now let’s take this concept and apply it to febrile seizures. Like we talked about earlier, febrile seizures have an excellent long-term prognosis with no evidence of causing structural brain damage, cognitive impairment, learning problems, or increased mortality. I’ll let the numbers speak for themselves.

The negatives first. Approximately 3-6% of children with febrile seizures will develop epilepsy later in life. That’s fairly significant tbh.

But many trials have been conducted to see if chronic antiepileptic therapy after a febrile seizure helps prevent the development of epilepsy. And the overwhelming answer is no, they don’t.

Now let’s look at the other side. Not only do antiepileptics NOT prevent the development of epilepsy in patients with a febrile seizure, but they also come with a handful of unwanted side effects. Specifically, it is estimated that phenobarbital and valproic acid cause adverse events in up to 30% of children, including behavioral problems and lower comprehension scores. Phenobarb and valproic acid are some of the more toxic antiepileptics, but the point remains true for all anticonvulsants.

As you can see, the risks of chronic antiepileptic therapy outweigh the benefits of preventing the development of epilepsy in patients that experience a febrile seizure. So please, do NOT start chronic seizure meds for these little kiddos.

The Role of Preventative Therapy - Antipyretics

Alright, on to our next med class. This one's a little more iffy in my opinion. For starters, the main antipyretics we’re talking about here are acetaminophen (most common) or ibuprofen (if >6 months old). On paper, it makes perfect sense. Viral infection causes fever, and fever causes seizure. So why not give an antipyretic to reduce/prevent that fever to avoid a seizure?

Because evidence shows that routine antipyretic use does NOT prevent febrile seizures during fever episodes.

A 2021 systematic review found no evidence supporting antipyretic prophylaxis for preventing seizures in distant fever episodes (odds ratio 0.92; 95% CI 0.57-1.48). Similarly, randomized controlled trials of ibuprofen showed no difference in recurrence rates compared to placebo, with 2-year recurrence probabilities of 32% versus 38% respectively. One recent randomized controlled trial suggested that rectal acetaminophen may reduce seizure recurrence within the same fever episode (9.1% recurrence with acetaminophen versus 23.5% in controls). However, this represents very limited evidence, and the systematic review examining this question concluded there is insufficient support for routine use even during the same illness.

Because of this overwhelming data, The American Heart Association and American Red Cross guidelines explicitly state that fever treatment can help children feel better but will not prevent subsequent seizures. The American Academy of Pediatrics similarly concluded that the risks and potential side effects of prophylactic antipyretic therapy do not justify their use for seizure prevention, as they don’t demonstrably improve long-term outcomes.

So what’s the overall consensus for use of antipyretics?

In general, antipyretics should be used on standard indications for comfort, NOT for seizure prophylaxis. Having a viral infection sucks, and these kiddos feel poopy. While acetaminophen or ibuprofen won’t necessarily reduce the risk for seizures, they definitely can help the child feel more comfortable.

So, What Can We Do for Febrile Seizures?

Truthfully, not much. Obviously if the febrile seizure escalates into status epilepticus, then rescue therapy is needed. But for the majority of cases, these seizures will resolve on their own, and supportive therapy remains the mainstay of management.

What you can do is provide parental education. It is important to emphasize the excellent prognosis, low risk of epilepsy brain injury, and practical guidance on home seizure management. Families should be provided with emergency contact information and reassurance about the benign nature of febrile seizures.

Oh and one more thing. Don’t forget to treat the underlying cause. Why is the patient febrile to begin with? Is it an infection, is it a recent immunization, are they dehydrated, etc? If we treat the underlying cause, we treat the fever and prevent the seizure. Pretty cool, right?

Tl;dr of Febrile Seizures

We went over a lot of information today. Incase you skipped all my beautifully written paragraphs above and want a quick tl;dr version, then please see below:

• Febrile seizures are generalized seizures that occur in febrile (fevering) pediatric patients. They are typically seen in children between the ages of 6 months to 5 years and occur with a fever ≥ 100.4℉.

• Febrile seizures are either simple or complex depending on duration, persistence, and recurrence.

• The young undeveloped brains of infants and toddlers have more excitatory signals and less mature inhibitory control, leading to increased seizure risk.

• The majority of febrile seizures are self-limiting, and treatment mostly focuses on managing fever and preventing injury/recurrence. If a febrile seizure persists for longer than 5 minutes, emergency rescue therapy is needed (please see picture above regarding the treatment of complex febrile seizures).

• Febrile seizures have an excellent long-term prognosis with no evidence of causing structural brain damage, cognitive impairment, learning problems, or increased mortality.

• Chronic (long-term daily) anticonvulsants are NOT recommended to prevent febrile seizures because the risks outweigh the benefits.

• The American Academy of Pediatrics states that antipyretics should be used on standard indications for comfort, NOT for seizure prophylaxis.

• Parental education, supportive care, and treatment of the underlying cause is the cornerstone for prevention and management of febrile seizures.

Steph’s Note: It’s back! We haven’t don’t a journal club in (*cough*) quite a while, so we figured it was a good time to revisit our old friend. Who doesn’t love a good fireside chat about studies and statistics? We know we do!

This journal club is brought to you by our own Jenny Hoang, who previously taught us about Aucatzyl and CAR-T as well as herbals. Thanks, Jenny!

Happy New Year to all! While it may be Aquarius season, today we will be diving into the depths of hemodialysis and cardiovascular disease with the PISCES trial, which was published in NEJM in November 2025. In this journal club, we will learn whether fish oil supplementation has the potential to improve the heart health of hemodialysis patients.

But first, let’s look at how cardiovascular disease affects hemodialysis patients, specifically. 

Hemodialysis (HD) is used in patients with end stage renal disease (ESRD). These patients’ kidneys no longer work properly to filter waste in the body, so a machine is used for this job instead. Blood is pumped out of a patient into a dialysis machine, where it encounters dialysate fluid. This fluid draws out the waste through a combination of diffusion and convection, and the “scrubbed” blood is then reinfused back into the patient.

For a more thorough discussion of hemodialysis mechanics, check out this post.

Pretty neat, right? However, there are MANY risks associated with performing hemodialysis, including infection, high or low blood pressure, fluid overload, anemia, and electrolyte imbalances - just to name a few. To make things worse, these issues can also lead to secondary cardiovascular changes that can cause unwanted cardiovascular disease (CVD). In fact, more than half of ESRD patients die from CVD. Yet despite their mortality being nearly 20 times higher than the average population, there are few proven medication interventions to prevent CVD events.

With such high risks and few interventions, the purpose of the PISCES trial was to see if fish oil supplementation could lower the rates of CVD in HD patients. Fish oils and the fatty acids they contain have been studied in research for many years, with significant findings in their ability to help reduce risk of CVD in the general population. In the PISCES trial, the authors highlight that many HD patients tend to have a lower amount of fatty acids in their blood. So they decided to see if giving some extra would produce protective heart benefits.

Methods of the PISCES Trial

Now let’s move on to how this trial was set up. It was a double-blind, randomized, placebo-controlled trial conducted at 26 sites in Canada and Australia. Patients on maintenance HD were to take either daily fish oil or a corn oil placebo.

Corn oil, you say? Is that really an inert placebo, or would that be bad for the heart (making any other intervention look good by default)??

Glad you asked. Because so did the American Heart Association. In this 2023 study that compared potential atherogenic effects of various oils, including corn and mineral oils, corn oil did not appear to contribute to LDL oxidation (and subsequent atherogenesis). This means it doesn’t appear to be a harmful oil and should be an appropriate placebo. (Image)

In PISCES, the fish oil dose was 4 g of n−3 polyunsaturated fatty acids, which is equivalent to 1.6 g of EPA and 0.8 g of DHA. Simply put, the body needs omega fatty acids to help the cells function properly in the body. EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) are fatty acids commonly found in fish. According to studies from the American Heart Association, consuming about 3 g of omega 3s in a day can help lower blood pressure, thereby helping to prevent CVD. So it makes sense that the researchers in the PISCES trial picked 4 g of fish oil as their intervention since it is just around the previously studied dose found to have CVD benefit. It’s just a tad more to account for what we mentioned earlier - that HD patients tend to be a little deficient at baseline. 

Breaking down the double blinded and randomized part, it means that both the patients and the researchers were unaware of who was given fish oil or placebo. The randomization was done by an independent, web-based system, meaning a computer generator helped assign the groups to eliminate human error or accidental bias. The benefit of this is that both parties are less prone to any bias that may occur if they believe the patient is or is not receiving the fish oil. Randomization helps to give the study the best chance at capturing a realistic distribution of variables.

The placebo control allows the researchers to ensure that any treatment effect observed is due to the intervention rather than other factors. The researchers tried their best to control how similar the patients were in the experimental and control groups at baseline, and patients in both groups were measured and studied in the same ways over the follow up period to prevent any biases or errors that could skew their results. All of these things are very reassuring for the accuracy of the study.

The patients were assigned 1:1 for fish oil or corn oil placebo. Both were deodorized and citrus flavored to taste and perform similarly when taken by the participants. (Image) The participants signed written consent to be followed and have data collected for a year, and then they checked in after an additional 2.5 years.

Inclusion/Exclusion Criteria of the PISCES Trial

Eligible participants were at least 18 years old and had ESRD managed with HD 3 to 4 times a week. They also had to be considered clinically stable before enrollment, so no active bleeds, blood pressures over 180/120, or life expectancy less than 6 months (palliative dialysis patients).

Any patients who were already taking any fatty acid or omega supplements prior to randomization or had any allergies to fish, soy, corn, or any other materials in the study were excluded. This tells us that the researchers were trying to isolate any effect from the study intervention rather than muddying the waters with confounding previous treatments.

PISCES Study End Points

For their primary end points, they looked at a composite of all serious cardiovascular events, including cardiovascular related deaths (e.g., sudden/non sudden cardiac death, fatal myocardial infarctions/heart attacks, and fatal strokes) as well as non fatal cardiovascular events (including non fatal myocardial infarctions/heart attacks, non fatal strokes, or peripheral vascular diseases that led to amputations).

They chose not to include heart failure as an endpoint. This makes sense because HD patients have many other non cardiac related factors that contribute to and cause fluid overload.

Overall, this seems like a very reasonable primary end point because they were hoping to see if there is a connection between the patients taking the fish oils and any and all cardiovascular disease. 

For the secondary endpoints, they chose to elaborate on the primary ones:

1. Non cardiac causes of death,

2. Individual components of the primary end point (meaning that while the primary end point tallied up all the events, in the secondary endpoints, they decided to separately tally them up so we could see how many of each event happened), and

3. First cardiovascular event or death from any cause (meaning they measured the time it took for any patient to have a cardiovascular event, regardless of what caused it).

So overall, these secondary end points make a lot of sense because they wanted to dive a little deeper into whether the fish oils affected mortality. These endpoints also are a window into whether there were any patterns of what type of cardiac events happened in connection with fish oil. And they help to illuminate time to benefit (IF it was effective at all).

Analytic Strategies in the PISCES Trial

A little bit on how these end points were analyzed. The intention to treat principle was used. As a reminder, this means that the results of the trial were computed based on the patients’ original treatment assignments and study protocol, not what actually happened. So even if a patient didn’t go through with the entire protocol as designed (e.g., drop out), they would still be included in the data analysis.

The Cox proportional hazard model was used. This statistical model is used to assess how different variables affect the risk of an event happening over a period of time. This makes sense for this study’s endpoints because they were looking to see what factors influenced the occurrence of cardiovascular events during the trial. The standard Cox model does not reset time to zero after each event, meaning the risk is assumed to be constant over time.

On top of that, the Prentice-Williams-Peterson (PWP) gap time model was used. This is an extension of the Cox model. It looks at the same subjects but also assesses whether they experience events more than once and in what order. The gap time part means that they reset the time to event clock to the very beginning after each event (unlike the standard Cox model), allowing for a new assessment of risk after each new event.

The calculations were done from a sample of 1100 participants followed over at least 3.5 years. They provided the trial with a 82% power at an alpha level of 0.05. These values are pretty standard in the research world - for a more detailed look at power and alpha levels, check out our biostatistics series here.

The study designers targeted a hazard ratio of 0.825, meaning that they expected a 17.5% risk reduction in patients who took the fish oils. (1-0.825=0.175) They also assumed baseline event rates as follows:

• recurrent cardiovascular event 0.74 times per 1000 patient days,

• 0.12 cardiovascular deaths per 1000 patient days, and

• 0.27 non cardiovascular deaths per 1000 patient days.

They also assumed 10% of the participants would be lost to follow up and 3% would drop out. 

These numbers are important to assess because these baseline assumptions shape the remaining study design, including how many participants they think they’ll need to reveal a difference between groups. If these calculations are off because the baseline assumptions aren’t real world, then it’s possible a treatment’s impact can be missed. Which would be a shame after all the time, effort, and money that go into running a study!

Results of the PISCES Trial

And on to our favorite part of a journal club…the results! 

Here’s a little bit on the baseline characteristics of the bunch. The mean age was 64.3 +/- 13.7 years old. They were on HD for a mean duration of 3.7 +/- 4.1 years, and 35.3% of the participants had a history of cardiovascular disease. 

Moving on to the primary endpoint, the rate of all serious cardiovascular events was lower in the fish oil group (0.31 per 1000 patient days) than the placebo group (0.61 per 1000 patient days) with a hazard ratio of 0.57 (95% confidence interval 0.47 to 0.70, p<0.001). So that means there was an estimated 43% reduction in risk of cardiovascular events in the fish oil group compared to the placebo. That’s pretty good! (And much better than their target 17.5% reduction!)

Additionally, the percent of patients with at least one cardiovascular event was lower in the fish oil group (20.8%) vs the placebo group (33.7%).

The researchers also noted that these lower rates of cardiovascular events with the fish oil group were similar between those with or without a history of cardiovascular events. That really highlights how the fish oil intervention was helpful to anyone on hemodialysis.

16.6% of patients in the fish oil group vs 23.1% of patients in the placebo group had only one serious cardiovascular event, while 4.3% of fish oil patients and 10.5% of placebo patients had recurrent events. As you can see, the fish oil won in preventing the first and only serious event, but it pretty much halved the number of patients experiencing recurring ones. Pretty impressive if you ask me. (Image)

Now it’s time for the secondary endpoints. When they accounted for the primary endpoint and non cardiac causes of death, the hazard ratio was 0.77 (95% confidence interval 0.65 to 0.90). This means there was a 23% reduction in risk of death (cardiac or otherwise) if taking fish oil! The occurrence of at least one component of the primary end point was found to be lower in the fish oil group (35.2%) than the placebo group (43.7%). The percent of patients with heart failure was 1.6% for the fish oil group and 2.3% for the placebo group with 8.5% and 9.9% needing cardiovascular intervention, respectively.

All of these numbers sure do paint fish oil in a pretty positive light.

And when we flip the coin and look at safety, serious bleeding occurred in 4.8% of fish oil patients vs 7.6% in the placebo group. So it’s not like there was even a trade off there. Usually you can’t have your cake and eat it too, but…maybe we can in the case of fish oil.

A Few Additional Thoughts on the PISCES Trial

In this study, it looked like fish oils really did help in lowering the rate of serious cardiovascular events in HD patients, both with or without a history of cardiovascular disease. The researchers measured the patients’ phospholipid concentrations before and after the trial and found increased concentrations afterwards.

These may have contributed to antithrombotic, antiinflammatory, antilipid, antiarrhythmic, and remodeling effects in the cardiovascular system…all good things that the patients could benefit from. While this trial was only able to enroll patients on maintenance HD, it shows promise for future research and development into cardiovascular interventions in this patient population. 

The tl;dr of the PISCES Trial

Patients on HD have lower levels of fatty acids. There are few interventions for CVD prevention in patients on HD even though these patients are at high risk of CVD. Fish oil supplementation may lower HD patients’ risk of cardiovascular events and death. The increase in phospholipid concentration may be the key to the reduction in cardiovascular risks. More research can and will be done to develop cardiovascular interventions for HD patients.

Steph’s Note: This week, I’m psyched. I have the pleasure of introducing you to my friend, Dr. Hannah Morris. Hannah and I worked together at UVA for several years, where we bonded over our mutual love of baking, sports, and the outdoors, and then she went off to make the world a better place whereas I started increasing its population. She is legitimately one of the kindest and best people I know, not to mention one of the coolest, smartest, jet setting pharmacists. (Honestly, when I text her, it’s a bit like Where in the World is Carmen Sandiego?, the service edition.) How did she make the leap from transplant to global pharmacy? How is she using her pharmacy knowledge now? Pull up a chair and settle in because here’s her fascinating story.

Have you ever seen your friends go on a missions trip or work with a humanitarian organization and thought how cool it would be do it too? If yes, this post is for you. Not only can you do international work as a pharmacist, there’s a definite need for pharmacists around the world. And guess what - you don’t have to go back to school or get licensed in a foreign country to do it!

I’m Hannah, a residency-trained clinical pharmacist who transitioned to working in humanitarian aid in 2021. For over 4 years, I worked full-time in humanitarian aid and have completed multiple deployments overseas, both in development health programs and short-term missions/disaster relief. I’m currently working part-time in an institution and part-time with a medical missions agency.

While I am by no means an expert in the field, I have learned a lot and hope the information I share is helpful for anyone who has an interest in international pharmacy work. If you want to know more, I’m always happy to answer questions or connect you to people who can help get you more information. I’ll also happily regale you with stories from my time overseas. For example, waking up to a hoard of baboons surrounding you and barking is quite a start to your 30th birthday!

The first thing people ask me is why I decided to leave a job as a solid organ transplant clinical pharmacist at an academic medical center to live in insecure areas of the world. I am not an adrenaline junky, and I very much enjoy the comfort of home. I had worked into a specialist job I loved, and I enjoyed where I lived. So why did I leave it all behind?

Everyone has a different reason, but for me it was my faith and a passion I’ve had since I was a young child. I grew up in a Christian family and was fascinated by the stories of medical missionaries reaching people all over the world. It was something that stuck with me, and when I decided to pursue healthcare in college, I had in the back of my head that I would at least be active in short-term medical mission work.

When I graduated and began working, I still had the desire to do medical mission work, but I found it nearly impossible to get the time off. Any pharmacist can tell you that vacation requests usually have to be submitted multiple months ahead and that there’s usually heavy competition for specific times of the year.

Over the next 5 years of working, the desire to do medical missions only increased, and I began looking for international healthcare jobs. The amount of times I heard, “We appreciate the interest, but we don’t take pharmacists” were too numerous to count. (Image) So I began looking for opportunities adjacent to healthcare and found a position that sounded amazing…but they were looking for a public health degree in addition to a healthcare degree.

After a lot of prayer, I went back to school and completed a master’s degree in public health with a concentration in global health (yay for down time during CoVID). I was able to do my intern hours in El Salvador with a medical missions organization, and while standing on the hostel balcony in a remote town in the mountains of El Salvador, I received a call offering me a post-graduate fellowship with an international disaster relief organization. That was Easter of 2021. I resigned my position at the hospital, packed all my possessions into my parent’s garage, and started my international humanitarian career on June 1st. 

I recognize my story is a bit of an oddity. Not many people have the ability to leave a full-time job that provides income, health insurance, and a retirement plan to work with international people who have limited or no access to healthcare. But if international work sparks your interest, I hope this post gives you some information to help you on your way to reaching people all over the world with your skills and knowledge. 

Pharmacy in the International Short-Term/Disaster Relief Setting

Short-term relief is one of the most common ways people get involved in international work because let’s be honest, most people don’t have the ability to move to another country on a permanent basis. Short-term relief can range from weeklong medical mission trips to month long disaster relief deployments. You can even do missions in the United States! For the sake of this post, we’re going to focus on international work, but domestic service is definitely an option.

Disaster Relief

There are so many options to get connected to short-term relief work. Humanitarian organizations (aka non-governmental organizations or NGOs) often have disaster relief rosters that are in need of medical professionals, including pharmacists. You can generally find postings for these positions on the career or volunteer pages for NGOs that do relief work. These include organizations such as MEDAIR, Project Hope, International Medical Corps, Americares, etc. Some of these organizations may provide compensation or cover the costs for the trip if you deploy in an emergency response. You’ll go through either a volunteer or job application process to get on the emergency response roster, and then if approved, you usually go to onsite training. 

Every organization provides different types of services in disaster relief, so the type of pharmacy you may be doing could vary from an emergency field hospital (EFH) with a full pharmacy to mobile medical clinics with small backpacks of medicine. If you’re working in an EFH, there are tiers to the level of services that are provided:

• outpatient and urgent care only,

• basic inpatient services,

• operating rooms with inpatient services, and

• intensive care.

The level of services provided dictates your formulary, although your access to opioids for pain management will likely be limited. You generally have oral antibiotics from nearly every class and injectable antibiotics for treatment of sexually transmitted infections (STI). There are also chronic disease medications, but these are more limited than you’re used to. For example, you may have an ACEi, selective beta-blocker, and a calcium channel blocker, but it’s unlikely there’s more than one agent or more than one strength. At the higher levels of care, there are refrigerated medicines such as succinylcholine, but because of cold chain challenges, it’s a very limited supply of a very few agents that need to be refrigerated. Regardless, you’ll stretch yourself as a practitioner working in a limited resource setting, especially since you may or may not have access to the internet for drug information resources. (Image)

One of the most creative pharmacy challenges I’ve been a part of is making peritoneal dialysis (PD) fluid with IV fluids and 50% dextrose. We were in Turkey running an EFH made of inflatable tents in the week after the 2023 earthquake that hit southern Turkey and northern Syria. Shortly after we got up and running, a second 6+ magnitude earthquake hit, and we received multiple patients that night and in the days following. One was a middle aged lady who had crush injuries and had been turned away from several other hospitals. By the time she arrived at our EFH, she was in renal failure, and without dialysis, it was unlikely she would survive.  We were fortunate enough to have a surgeon on staff who had run a dialysis program in a rural part of Africa and had a formula to make PD fluid. You would not believe how well PD worked with the fluid we made! She began improving within a few days of starting PD and was safely discharged with return of renal function not long after.

Then there was the night we ran a mass casualty event, and I was cracking tranexamic acid ampules like a crazy person. We got so busy that I ended up working under the medical director to prescribe pain meds and antibiotics for stable people going to wards so the physicians could focus on the urgent cases in the ER and ICU. In those moments, I knew I was exactly where I was supposed to be and that I brought tremendous value to the team as a pharmacist.

Disaster relief is unlike anything else you can do in pharmacy. Word of warning, it will not be the most comfortable environment. I’ve spent more days sleeping on a canvas bunk cot, eating MREs (Meals, Ready to Eat), and using a bathroom trailer than I can count. Usually you’re living and working in tents or out of hotel rooms converted into offices. If you go on the front end to get things started, resources are sparse while your logistics team gets things set up, such as bathrooms, showers, food, and laundry. Once the logistics are established, life gets a bit more comfortable.

You still may not have hot water, and odds are at least some of your laundry will disappear or end up in someone else’s bag. If you have food allergies you’re definitely going to have to bring your own supply because food allergies are not something that can be accommodated in a disaster type setting. But you’ll never forget the people you work with.

If you’re someone who enjoys disaster relief work, odds are you don’t know many people who share that passion. However, when you go on disaster relief deployments, you’re surrounded by people who love it just as much as you. You find your people, and it’s really special. Plus you’ll have the best stories to share when you get back. For example, one of my friends was stuck in the bathroom trailer during a 6+ magnitude earthquake, and she says the only thing she could think of in the moment was how gross it would be if the trailer tipped over!! You’re there to serve, but you’re also going to make memories and friendships that last for a lifetime.  

Medical Missions

For those who do not find the idea of more austere and risky environments appealing, medical mission trips are a great way to serve around the world with a bit more comfort. Usually for a medical missions trip, you’re staying in a hotel or hostel that provides all the basic necessities, such as beds, showers, toilets (type may vary), and a secure space. Your access to comforts such as air conditioning and hot water may or may not be available, but odds are you’ll have more comforts overall.

Usually lunch is provided at the clinic, which will often be a local dish, but you’ll want to be cautious about what you eat. Some basic rules are essential to not end up with a GI issue during the trip:

1. Don’t drink the local water or brush your teeth with it,

2. Only eat raw fruits/vegetables if you can peel them, and

3. All meats should be cooked to well done.

Trust me when I say that you do not want to break those rules. The consequences can be in a word…violent. 

You’ll see many interesting cases and refresh your primary care knowledge on a medical mission trip. The population you’re serving really determines what kind of diseases you treat. For example, if you’re working in a low-income community with limited access to clean water, you’re going to likely treat more communicable diseases and dermatologic conditions. In places where people are unable to regularly wash their clothes and their bedding, you’ll find more incidences of scabies, lice, bedbugs, etc. If prostitution or trafficking is common in the community, you’ll also find that you’re treating many cases of STIs and pelvic inflammatory disease (PID). Sometimes you get to see things you’d never come across in the states, such as parasites or things even more exotic.

For example, the bubonic plague is still endemic in Madagascar. Ebola is endemic in subsaharan African countries, such as the Democratic Republic of Congo. And malaria is rampant across much of Africa, South America, and Asia.

One of the craziest moments for me was during a clinic in Madagascar. A small child was being seen by a provider for a suspected GI parasite. The next thing we know, the kid leans over his mom’s arm and vomits up a 6 inch long roundworm! We had been debating whether to give him a long course of albendazole to treat an active tapeworm or a short-course for a roundworm, so that event definitely helped clinical decision making (made lunch sound unappetizing though). (Image)

I cannot recommend enough that everyone does a medical mission trip at least once in their life. Experiencing another culture and not just being a tourist will have a profound impact on you and give you a more rounded perspective of the world to which you belong. You’ll challenge your preconceived ideas and realize that countries are not monolithic, nor do they usually match how they are portrayed in the media. For example, I went to Nigeria in 2024 and worked with some of the most lovely Nigerian healthcare workers. They were professional, well-educated, passionate about serving their people, and incredibly generous. While the country indeed has problems and we had limited travel because of the security concerns, the staff I worked with left a mark on me, and I’m still friends with several of them today.

Using Pharmacy Skills in International Settings

Regardless of whether you’re doing disaster relief or medical missions, there are limitations that you have to work within, which is where your pharmacy knowledge gets a chance to shine. While it would be nice to have access to all the medications we can get in the United States, unfortunately that’s unlikely to be the case in relief work. Whether you’re working with medicines shipped in or purchased locally, there’s probably a limited formulary of only essential medicines. There may be some medicines you need depending on the scenario or community needs. (For example, if you’re going into Madagascar you may want to make sure you have ciprofloxacin to treat the plague.)

Rarely - if ever - will there be controlled substances, such as opioids or benzodiazepines, on a medical mission trip. And for people like me, who are clinical institutional pharmacists, a refresher on some basics, like how to dose amoxicillin for tonsillitis, is essential. I always have to refresh on H. pylori and STI treatment regimens because I don’t see those often in my practice. Also, just try coming up with an H. pylori treatment regimen when you don’t have bismuth or clarithromycin! It can be tough, even more so now that the guideline’s first-line regimens use vonaprazan, which is not available in most countries and cost-prohibitive.

The other aspect of being a pharmacist in relief work is managing your formulary supply. On a medical mission trip, odds are you won’t be able to restock the majority of your meds, so what you have at the beginning of the trip is all you will have. For a disaster response that lasts several weeks, you may get a resupply… But it takes time to make that happen, and you need to monitor usage rates to avoid a stock out. This requires significant communication with the providers so they are aware of stock levels and can adjust their prescribing habits to reduce or increase use of a specific drug.

For example, because of the bulk and weight of creams, we usually take a limited amount of permethrin cream to treat scabies. However, there’s always a plentiful supply of ivermectin since tablets are so much lighter and easier to pack. I’m constantly running to providers to talk through the change I want to make to their prescriptions in order to best utilize the stock I have. At times, I’ll go look at the patient with the doctor, and we decide on a treatment regimen together that best meets the patient’s needs - but also works for our stock.

There are multiple reasons pharmacists are crucial for relief work. First, pharmacists have unique expertise in designing treatment regimens with limited resources. We have the ability to be creative and problem solve because of our deep knowledge of the medicines that other healthcare professionals do not have. Antimicrobial stewardship is another huge reason for pharmacists to be involved in relief work. Over prescribing of antibiotics is a significant problem that we are able to address. Whether it’s getting the antibiotics deprescribed because the patient likely has a viral respiratory illness or switching to an alternative, more narrow spectrum agent, we can reduce the harm that is done by international teams overprescribing antibiotics.

(Side note, there’s a book called “When Helping Hurts” that I’d recommend to anyone interested in international work.)

Another unique benefit of a pharmacist working on an international relief team is our willingness to intervene on the patient’s behalf. I had a situation recently on a trip where a relatively new nurse practitioner was seeing a patient with what they suspected was an acute heart failure exacerbation. We didn’t have furosemide so she prescribed hydrochlorothiazide, assuming that because it’s also a diuretic, it would be better than nothing for helping with the lower extremity edema. I had the opportunity to discuss with her why hydrochlorothiazide would not be helpful and that we really needed to send this patient to the ER for evaluation. Because I could explain to her the difference in the mechanisms of action of furosemide and hydrochlorothiazide, she understood that her treatment would not work and agreed to send the patient to the ER.

There are few things more rewarding and exhausting than international relief work, and I can guarantee you will not regret it. If you have an interest in bringing medical help to people in need around the world through pharmacy, we need you. Check out medical NGOs and medical mission organizations to see if any of it is feasible for you!

Disclaimer: this is NOT a post listing what medications are or are not safe for lactation. That’s what drug references are for. This is for understanding the physiologic processes that shape how medications enter and exit milk. Now that we have that out of the way, let’s learn.

Badass Breastmilk

Mother’s milk. Call me biased (given I’m currently nursing my third nugget), but the human body is just so freaking cool. Not only does mom’s milk turn skinny premature legs into adorable chunky trees, but it literally transforms to be exactly what baby needs at each stage of life. On top of this, it transforms across the course of a day. And it’s not just food… It’s protection, both now and in the future. It’s developmental aids. It’s communication and bonding between mom and baby. It’s literal magic, like a mom’s hidden superpower.

Some evidence-based benefits of breastfeeding include decreased risks of:

• Infections (especially GI and ear infections)

• Necrotizing enterocolitis (NEC)

• Lymphoblastic and myeloid leukemias

• Types 1 and 2 diabetes

• Asthma

• Sudden Infant Death Syndrome (SIDS)

(Not necessarily due to the milk itself, but breastfeeding is also thought to promote better speech development because of all the facial muscles needed for nursing. And it has multiple health benefits for mom too! Win win!)

So what’s in this magic drink?

This pretty famous infographic from the Human Milk Foundation illustrates just how wonderfully comprehensive and complex this ambrosia is:

When I say it has everything…I mean it has everything. Which is why the World Health Organization recommends exclusive breastfeeding for the first 6 months of life and complementary breastfeeding (along with solids and other foods) through at least 2 years.

Time for a summary reality check. Breastmilk is 100% magic. But just FYI, breastfeeding is also hard. Sure, it’s been done for how many tens of thousands of years, so you would think it’s this primitive, easy thing to accomplish. (I know that’s what I thought before I had my first.) But it’s actually really really hard, which truly surprised me.

It’s hard to find the right position, get the right latch, find time to pump to get the supply going (and keep it going as needed), get up every 1-2 hours at night for months on end, not end up with milk everywhere…and I could go on. And yes, for the record, it hurts (no matter what every lactation consultant tells you in the hospital).

But helloooo, check out those benefits!!!

So now that we got a grip on what’s in breastmilk and how awesome (albeit often hard) it is to achieve successful breastfeeding, let’s take a look at the physiology.

How is Breastmilk Made?

Just like every other part of the body, breasts are comprised of specialized tissues to fulfill their purpose of feeding a baby. Let’s take a look at the anatomy of a female breast:

Squished in with the supporting tissues and surrounding fat are the alveoli, which (just like the alveoli you think of in the lungs) are sacs. Except instead of being filled with air (as in the lungs), these alveoli fill with milk made by the milk-secreting cells. Each alveoli is encased by myoepithelial cells, aka muscle cells, that squeeze the milk from the alveolar lumen into the milk ducts during lactation.

The milk ducts carry milk from the alveoli to the nipple and then outside to a hungry, nursing baby. Each nipple has about 9 ducts that feed it, along with muscles and nerves. The areola (the pigmented circle around the nipple) has Montgomery’s glands, which (fun fact) produce a unique “mommy scent” to help baby know where to latch right after birth.

Breast tissue is supplied with blood by several main arteries as shown in the figure below.

That’s the anatomy. Now let’s talk physiology. Breastmilk is made and released by a system of 3 main substances:

• Prolactin

• Oxytocin

• Feedback inhibitor of lactation (FIL)

Check out the figure to see how these substances play together in the sandbox.

Basically, prolactin stimulates milk production. Oxytocin stimulates milk release (or letdown) via ductal smooth muscle contraction. And FIL is the negative feedback loop to prevent overproduction if milk is not removed from the breast (because clogs are no fun).

Another fun fact is that each breast operates independently of the other. Leftie may be the “hero boob,” producing enough fatty milk for your infant along with 3 others, while Righty is lucky to make 30ml of skim milk. Don’t give up on Righty though… production may be ramped up by continuing to let baby nurse there because production is triggered by suckling and removal of milk!

That is, you can try this if baby doesn’t get too frustrated about the slow tap. #hangrybaby

Lactation and milk production are broken down into the 3 stages of lactogenesis as noted below. Although some moms can and do begin pumping colostrum before delivery, appreciable milk production is inhibited by mom’s own placental progesterone. It isn’t until delivery of the placenta (the so called 3rd stage of labor!) that the progesterone blockade drops and full manufacturing can begin.

Alright. Now that we’ve talked about how and where milk is made, it’s time to move into the pharmacy part of this post…

How Medications Interact with Breastmilk

Research is ongoing, but to date, there have been 4 identified modes of transport for drugs to get from mom’s bloodstream into her milk:

• Passive diffusion

• Active transport

• Lipid co-transport

• Transcytosis

Let’s take a closer look at each one of these.

Passive Diffusion of Medications into Breastmilk

Passive diffusion is the most common way for drugs to enter the breastmilk from the blood. As you may remember from chemistry class, diffusion is the movement of a substance down a gradient - from higher concentrations to lower concentrations. So it makes sense that medications the mom takes are absorbed into her bloodstream and then travel passively into the breastmilk, where that medication is not initially present.

However, the story isn’t quite so simple as this. Of course, there are other factors that influence how well a drug is able to passively diffuse into milk. They include…

• Molecular weight

  • Medications with lower molecular weights passively diffuse more easily. (Makes sense, right? Larger molecules have a harder time getting through the myoepithelial and glandular cell layers than small molecules.)

• Plasma protein binding

  • Medications that are highly protein bound to mom’s plasma proteins do not diffuse as easily into milk. They’re kinda “stuck” in mom’s serum.

• Milk protein binding

  • While this isn’t thought to be a major factor, it does still seem to play into the equation of creating a gradient. Some medications may bind to proteins in the milk, changing the gradient for passive diffusion.

• Drug ionization

  • Remember, it’s easier for non-charged particles to cross cell membranes than charged ones. Milk’s pH is ~7.1-7.2, which is slightly more acidic than mom’s serum (pH 7.4). So nonionized, weakly basic drugs may cross mammary epithelial cell membranes relatively easily but then become “trapped” after ionizing in the more acidic milk environment. On the other hand, ionized, weakly acidic drugs may not diffuse easily from mom’s serum. These trapping scenarios can alter the gradient for passive diffusion.

• Lipid solubility

  • Medications with higher lipid solubility more easily cross mammary epithelial cell membranes.

So you can see that even though passive diffusion seems like a simple high concentration to low concentration transport method, exactly what that gradient looks like is influenced by a number of factors. On to the next method.

Active Transport of Medications into Breastmilk

When the milk to plasma ratio of drug concentrations is higher than that predicted by (not-so-simple) passive diffusion, it seems to suggest there is another mode of drug transport at play, which leads us to active transport. This is when substances are transported across a membrane using energy and/or protein carriers. Basically, transport proteins in the membranes of the mammary epithelial cells give medications an assist in crossing from blood to milk.

You might think these carrier proteins are special to the mammary cells, but interestingly, I bet you’ll recognize quite a few of these! Some of the mammary epithelial cell transporters thought to influence drug concentrations in the milk include…

• P-gp (yep, that same efflux pump protein)

• OATPs (organic anion transporters)

• OCTPs (organic cation transporters)

• BCRP (breast cancer resistance protein)

Now, what’s really intriguing is that expression of these transport proteins changes during lactation! For example, BCRP is upregulated during lactation, which can alter transport of medications like nifedipine and lamivudine. To complicate matters further, expression is not only altered during lactation in general but changes throughout the period of lactation. For example, expression at 2 months post partum is different than at 5 months post partum.

Talk about tricky!

Lipid Co-Transport of Medications into Breastmilk

To understand this method of transport, it’s important to first understand that the fat content of breastmilk is not consistent. And I'm not just referring to being consistent from one breast to the other as previously mentioned. I’m saying fat content changes from the beginning of a nursing session to the end.

The milk at the beginning of a feed is called the foremilk, and it is equivalent of skim milk from mom. Still full of good stuff, just not as fatty. This is in contrast to the hindmilk, which is the milk released towards the end of a feeding session. It can have up to 5 times more fat than the foremilk! Why does this matter when it comes to medications?

Well, it’s thought that when the mammary epithelial cells are making and secreting milk into the lumen of the alveoli, fat is added by a budding process. Yep, much like we talk about viruses budding off and taking bits of the host cell with them, these fat globules may bud from the mammary cell membrane, taking bits of the cytoplasmic contents with them.

What might be in that cytoplasm? You guessed it. Drugs.

So when fat globules bud off from the mammary cell into the lumen to become part of the milk, they may very well take medication particles with them. Another thought is that medications may cross from mom’s blood into the milk through previously discussed methods only to dissolve into the fat of the milk stored in the alveolar lumen.

Either way, medications may be transported into the milk via fat. And this is where the foremilk versus hindmilk matters. Because some medications have a higher affinity for fat, the amount of medication transferred from mom to baby can vary depending on whether baby consumes foremilk or hindmilk during a feed!

For example, one study found that duloxetine had a 1.4-2 fold higher concentration in hindmilk compared to foremilk. So consider the potential implications for transfer to baby if mom pumps before nursing to encourage a milk letdown, if baby falls asleep before finishing a feed, etc.

Transcytosis of Medications into Breastmilk

Finally, there’s transcytosis, which is the transfer of large molecules across a membrane. These large molecules are endocytosed from the blood into the mammary epithelial cell, transported across the cell, and then exocytosed on the other side into the lumen.

This mode of transport is largely for immunoglobulins, and it is thought to be mediated by the neonatal Fc receptor (FcR). While this method has been studied with regards to transfer of mom’s endogenous immunoglobulins (e.g., SARS-CoV-2 antibody transfer to breastmilk), it’s also been observed with exogenous IVIG therapy. So what does that mean for all the new monoclonal antibody therapies being developed? How will they transfer to breastmilk?

Medications and Breastfeeding

Armed with this background knowledge about how medications pass into breastmilk and what factors may influence that passage, now let’s get practical. You’re at work, you get an order for a medication, and you see that the patient is newly post partum. You think, mmm, is she breastfeeding, and if so, is this medication ok?

This is where your drug references come in handy, especially information from Brigg’s Drugs in Pregnancy and Lactation. And your clinical judgment.

When you look up the drug, it reports an RID, or relative infant dose. This is a calculation based on breastmilk sampling that is supposed to impart information about drug exposure to the infant. The classic formula for RID is in the image here.

Most texts consider RIDs less than 10% to be compatible with breastfeeding, and medications with RIDs greater than 25% should be avoided due to significant potential risk to the baby. However, some countries/organizations are pushing for lower thresholds (e.g., <5% for compatibility) and/or greater breakdowns to assist with decision making. For example, one scheme advocates for classifying RID as follows:

• <2%: minimal exposure

• 2-5%: small exposure

• 5-10%: moderate exposure

• >10%: high exposure

But really, please remember that (like our other big calculations, CrCl, etc) RID is not a black and white tool! It is one piece of a puzzle that should include your clinical judgment. Hypersensitivity can occur in a nursing infant regardless of RID. Breastfeeding should be avoided when moms need cytotoxic therapy, regardless of RID.

Additionally, consider that RIDs are calculated from moms taking standard doses of medications. If your patient is taking a high dose, the RID may be higher than that reported. If your patient is on a normal dose but has genetic factors, drug interactions, or organ dysfunction that impact drug clearance, the RID may not be as reported either.

Baby’s weight, age, and gestational age/maturity should also be taken into account when making determinations. Younger infants tend to be more sensitive to the effects of medications (as you would expect). The liver and those kidneys just aren’t fully mature at birth, not to mention newborns weigh less!

For babies who are not exclusively breastfed, meaning they receive supplemental formula in addition to breastmilk, it’s possible their RID is lower than reported.

So please do use the RID as one tool in your arsenal for making recommendations during breastfeeding. But please do not fall into the trap of forgetting to think critically about each individual patient.

The tl;dr of Medications and Breastmilk

To review, moms make magic milk (ah, you like that alliteration?!). But really, breastmilk is the most complete and individualized functional food there is. With benefits for both baby and mom, it nourishes development efficiently and completely. The breast is anatomically formed to be a micro dairy farm, adding all the necessary components to the milk and then delivering it on demand.

As milk is made, substances from mom (including medications) can be added to the mix by passive diffusion, active transport, lipid co-transport, or transcytosis. How much makes it into the milk from her bloodstream and then into baby’s stomach depends on a wide variety of factors, including drug molecular weight, lipid solubility, ionization, protein binding, transporter protein expression, milk fat content, and nursing practices.

The relative infant dose (RID) is a calculation intended to assist with making decisions about medication use during breastfeeding. Although it is generally considered acceptable to breastfeed if the RID is <10%, additional factors should be taken into consideration, including baby’s gestational age, current age, weight, mom’s dose and drug clearance, and whether baby is exclusively breastfed. Discussions with providers and patients are useful when weighing risk and benefit so that a fully informed decision can be made.

There you have it - the long and short of the wonders of breastmilk. Hopefully this post helps you to better understand the mechanisms by which medications can pass from mom to baby post partum so that you can help your patients make informed decisions about their pharmacotherapies.

What is Influenza?

When you think of the flu, you may envision what Hollywood tells us: splayed out on a couch, violent vomiting into a bowl, freezing under a blanket while simultaneously sporting pink fever cheeks, and draining snot like a faucet. (Image)

While some of this portrayal is accurate, once again (just like with its horribly off-base depictions of CPR) Hollywood can be a bit misleading…

Generally speaking, having the “flu” means contracting a strain of the influenza virus, which is a respiratory pathogen. GI symptoms are not usually part of the picture. (Now, if someone says they have the “stomach flu,” that usually does refer to violent emesis and/or diarrhea but is associated with norovirus, which is totally separate from the seasonal flu.)

Let’s take a little trip down influenza lane to make sure we’re all on the same page.

Influenza is caused by the influenza virus. It is an enveloped virus with a lipid bilayer that it steals from its host. (Image) The lipid bilayer is dotted with surface glycoproteins known as hemagluttinins (HA) and neuraminidases (NA), as well as the transmembrane protein M2. Hemagluttinins facilitate viral binding and fusion with the host cell. Neuraminidases aid with viral release from the host. Inside the lipid bilayer is the M1 matrix protein, which contains the viral genetic material and also helps with viral budding.

In the case of influenza, the genetic material is segmented, single stranded, negative sense RNA (ssRNA). Like other viruses (including HIV), this ssRNA must be “read backwards” by viral RNA-dependent RNA polymerase to create messenger RNA (mRNA) that can then be translated into proteins. The segments of RNA can be rearranged…this fun mix and match is the major antigenic shift that causes pandemics. (This is opposed to more minor antigenic drift that drives vaccine makers crazy trying to predict and occurs from smaller mutations in the glycosylation of HA and NA.)

The influenza virus life cycle follows a usual viral hijacking process:

1. Attachment via hemagluttinins to siliac acid receptors in human bronchial and upper respiratory tissues

2. Entry into the host cell by endocytosis

3. Fusion and uncoating of virus particle after pH-dependent opening of the M2 transmembrane protein

4. Invasion of the host cell nucleus by viral genetic material, where transcription and replication transform viral RNA into viral proteins

5. Assembly of newly-made viral parts

6. Budding of new viruses through the host membrane

7. Release of new viruses after siliac acid residue cleavage by neuraminidase

Although the exact receptors and proteins are different, the general scheme is similar to viruses such as HIV: attach, enter, use the host to make more viral stuff, assemble new viral stuff, new viral stuff peaces out to infect other cells. Viruses - such users (and abusers). But it does make it easier to remember since it’s a similar mooching scheme. (Image)

Influenza viruses are classified into 4 flavors based on differences in their proteins: A, B, C, and D. For us humans, types A and B are clinically relevant. Type C usually causes mild symptoms only, and type D infects cattle, sheep, and pigs, not humans.

The subtypes are defined according to variations in their HA and NA glycoproteins. To give some frame of reference, for influenza A, there are currently 18 known subtypes of HA and 11 subtypes of NA. So when you see a designation like H1N1, that’s referring to the H1 hemagluttinin subtype and the N1 neuraminidase subtype. And when you see A/H1N1 or A/H3N2, that refers to influenza A with those subtypes of HA and NA.

It’s not actually gibberish…like it may sometimes seem.

Influenza Season 2025

While it’s not a novel COVID pandemic, the seasonal flu remains a major public health concern every year. For last year’s flu season (Oct 2024 through May 2025), this wily virus is estimated to have caused…

• Up to 82 million flu cases

• Up to 37 million medical visits

• Up to 1.3 million hospitalizations

• As many as 130,000 deaths

Looking at CDC estimates for this year’s flu season (through December 13, 2025), so far influenza is thought to have caused…

• Up to 8.2 million flu cases

• Up to 3.7 million medical visits

• Up to 97,000 hospitalizations

• As many as 9600 deaths

And we’re only about halfway through the season with the peak numbers usually occurring between December and February! Actually, in the last 40 years, the peak month for flu cases has been February. So TBD on how we’ll fare after making it through the whole season.

What we do know so far is that there may be a mismatch between the influenza strains covered by this year’s vaccine and what is actually circulating. Since the strains to be covered are picked in advance (how else would they be produced for administration ahead of flu season!?), there is a bit of a gamble involved.

It appears that there’s a surprise H3N2 subclade K causing some hubbub since the vaccine was targeted towards the H3N2 subclade J2 based on the end of the 2024-2025 flu season. Apparently, summer vacation allowed the flu virus to do some unexpected changing (much like the kids who come back to school a foot taller than when they left!). (Image)

That being said, experts are still recommending flu vaccination since it is the best way to protect against severe disease. For children especially, the flu vaccine is effectively preventing hospital attendance up to 75% (while adult efficacy is 30-40%). I mean, sure, it’s not as high as we’d maybe like to see, but I’d certainly take a shot in the arm for that reduction in possible hospitalization!

Oseltamivir for Influenza

Now that we know a little more about the lay of the land when it comes to the flu and what’s going on this year, let’s move on to the star drug of the season: oseltamivir. Although there are some other medications that may be used for influenza management (amantadine, zanamivir, baloxivir, etc), this post focuses on oseltamivir as it is by and large the most commonly encountered.

Oseltamivir (Tamiflu) is a prodrug, which when hydrolyzed to its active oseltamivir carboxylate form, inhibits viral neuraminidase. This prevents cleavage of new viral buds from host cells, preventing release and proliferation of the virus.

Dosing for adults is straight-forward. Treatment of influenza calls for 75mg by mouth twice daily for (at least) 5 days, although longer durations up to 10 days may be considered for more severe cases or those who are immunocompromised. Post-exposure prophylaxis dosing is 75mg by mouth daily for 10 days. It is conveniently available as both capsules and a suspension for those unable to swallow pills. Renal adjustments are recommended for CrCl < 60 mL/min and for those on hemo- or peritoneal dialysis.

While not non-existent, the drugs that interact with oseltamivir aren’t exactly numerous or your every day, run of the mill meds. (When was the last time you had someone on probenecid?). But because interactions do exist, albeit with less common (but still used) meds like teriflunomide and leflunomide, it’s always a good idea to cross check.

Oseltamivir is generally well-tolerated with the most commonly reported adverse events being nausea/vomiting (up to 16%) and headache (up to 17%). For the GI adverse effects, these usually occur within the first 2 days of the course and are usually short-lived. Higher doses are also implicated. As for the headache, if you have the flu, what are the odds you also have a headache… Hard to tease out the chicken and the egg there.

One oddity to be aware of is the possibility of psychiatric side effects. Although causation has not been established (and influenza with subsequent encephalitis or encephalopathy could also be responsible), there have been a handful of reports of confusion, delirium, and/or hallucination within the first couple of days of using oseltamivir, especially in children and teenagers. Counseling of patients and/or their caregivers is important so that monitoring is in place.

Evidence for Use of Oseltamivir

As we move into discussing efficacy, we need to take a trip down memory lane. Let’s take a quick look at the study that started it all.

Published in JAMA in 2000, efficacy and safety of oseltamivir was assessed in this randomized, placebo-controlled, double-blind study. It included 629 febrile but previously healthy adults from 60 American health centers who were symptomatic for no more than 36 hours. Of note, these were unvaccinated patients meaning no receipt of the flu vaccine in the previous 12 months. They were followed for 21 days, and the primary outcome was time to resolution of illness after starting study drug. The majority of patients who ended up having the flu had influenza A and were symptomatic for about 24 hours before starting therapy. Oseltamivir 75mg PO BID reduced duration of illness by about 30 hours compared with placebo, and severity was reduced by 38%. Oseltamivir patients returned to their regular activities 2-3 days sooner than placebo patients.

And voila, the oseltamivir era was born.

But has this benefit been seen in the real world? And does it matter that this original study was only in unvaccinated patients? Is the external validity there in a vaccinated (or at least partially vaccinated) population?

Well, good thing we have more info. A new 2024 meta analysis published in The Lancet sought to answer this question using 8 published trials of 1424 eligible patients who received an antiviral against seasonal flu (including oseltamivir, but also peramivir, zanamivir, rimantidine, and baloxivir). For the 4 trials that evaluated mortality, there was very low certainty evidence of antiviral effect with anywhere from 18 fewer to 4 more deaths per 1000 cases of seasonal flu. For the 2 trials that assessed ICU admissions, there was a similar issue of very low certainty: anywhere between 29 fewer to 43 more ICU admissions per 1000 patients. In 1 included trial, oseltamivir decreased duration of hospitalization by 1.63 days compared with standard of care/placebo. In 3 included trials, oseltamivir’s time to alleviation of symptoms was actually longer (albeit by 0.34 days).

Soooo, a bit of a different story than the original 2000 study in terms of efficacy. While current IDSA guidelines do recommend initiation of antivirals for seasonal influenza, those guidelines are also from 2018… It will be interesting to see what changes (if any) are made in future guidelines based on the most recent data.

We’ve talked about the potential benefits of oseltamivir, but does that benefit vary based on time of medication initiation? Let’s look at some details.

If you look at those same 2018 IDSA guidelines, they recommend starting antiviral treatment for outpatient adults and kids with severe flu regardless of illness duration OR those within 2 days of documented or suspected flu onset who are not high risk. But how much does that timing really matter?

In this 2024 study from Clinical Infectious Diseases, over 26,000 adults with lab-confirmed flu were assessed for association between delayed antiviral initiation and 30 day mortality. Mean patient age was 71, and over 90% had at least 1 other health condition. Thirty-day mortality rates were as follows: 7.5%, 8.5%, and 10.2% in those who started treatment on day 0, day 1, and days 2-5 (median 2 days), respectively. Based on adjusted odds ratios, there was a 14% increased risk of death in those who started on day 1 and 40% increased risk in day 2-5 starters compared with those who started on day 0.

Basically, this study said don’t delay antiviral initiation. (Image)

This 2024 study of 840 hospitalized flu patients also encourages early use of oseltamivir on the day of admission, noting lower peak pulmonary disease severity, as well as lower risks of ICU admission, kidney replacement therapy, vasopressor use, and in-hospital death. So again, don’t delay initiation.

BUT then the question becomes whether it’s still worth starting oseltamivir if it’s been more than 2 days since symptom onset.

Resoundingly, the general consensus is yes. Even if the medication appears to have its greatest benefits when started within 2 days of symptoms, this 2025 study of over 6000 flu patients demonstrated a 30 day mortality benefit of oseltamivir even when started after the 2 day mark (weighted HR, 0.66 [95% CI, .49-.90]). Also of interest, they found that oseltamivir’s benefit was present with influenza A but not B, and vaccination status did not influence this benefit.

The tl;dr of Oseltamivir for Influenza

Flu season is upon us, and we’re heading into peak months now. So bolster your oseltamivir supply because the patients are coming.

So to summarize (we are tl;dr after all!), oseltamivir’s efficacy and benefits are still somewhat uncertain, although evidence seems to point to mortality benefits as well as amelioration of disease severity, especially in hospitalized patients. If the decision is to initiate treatment, earlier is better, whether a person is vaccinated or not.

A professor of mine used to say that evolution hasn't caught up to our current lifestyles. 

What he meant was that our blood evolved in a setting where it needed to clot. At any moment, we could be hit with a spear or mauled by some pre historic beast such as a Mega-Tiger.

Our blood needed to react to trauma.

In order to keep us alive, it had to clot (and clot well).

In today's world, we're much less likely to get mauled by a Mega-Tiger. In fact, in the latest reports by the WHO, I can't find any reported incidents of death by Mega-Tiger (it looks like our vigilance has paid off...for now). But now we're seeing a shift to the opposite end of the spectrum. Now our blood clots so well that it can clot when we don't need it to. 

This is problematic because it cuts off the flow of blood (read: oxygen) to some of our important inside parts like the brain, heart, lungs, and other internal organs. 

In order to keep us alive when this happens (and to prevent it from happening in the first place), we've come up with some nifty drugs called anticoagulants. These all inhibit some part of blood clot formation, and keep our blood thin and flowing. 

Anticoagulation is an area of high impact for pharmacists.

And so that means we've gotta spend some time learning about it. 

By the time you account for renal function, pharmacokinetics, and drug interactions, you realize that anticoagulants are kind of a double-edged sword.

They save lives by preventing and treating strokes, pulmonary embolisms, and DVTs…

But if they're not dosed correctly, anticoagulants can cause the minor inconvenience of massive internal hemorrhaging. Go just a little too far with the dosing and anticoagulants can kill. It turns out that blood pooling around the brain can cut off the oxygen supply just as well as a blood clot can. 

In this guide, I'll break down the pharmacology of all things anticoagulation. I'll also give you clinical pearls (i.e. test questions) that will help you pass the NAPLEX and your next therapeutics exam. For the most part, I'm going to avoid getting into the specifics of dosing. There are so many subtle dosing differences depending on the indication that this article will get unwieldy in a hurry if I try to include them all. 

However, for your convenience, we have created an incredibly handy cheat sheet that covers the common doses (and a whole lot more) for anticoagulants and antiplatelets. If you've grabbed any of our cheat sheets before, you already know how much info we cram into them. Our anticoagulant cheat sheet is easily the most detailed one yet. 

Also, as action packed as this article is…you won’t find any mention of warfarin. That’s because warfarin is such an important drug it deserves it’s own post. Check out our magnum opus on warfarin (and how to dose it) - Warfarin: The Definitive Guide.

It’s a lot to take in. If you’d like a downloadable (and printer friendly!) PDF of this article, you can get that right here.

And, just for fun, in case you’d like a PDF of our Definitive Guide to Warfarin, you can get that here.

Oh and one more thing. We do also have a post about the use of DOACs in special populations that can be found here.

Anyway, moving on...let's get started with our “road map” for the lesson…

Not confusing at all, right? I'll be referring back to this behemoth throughout the guide. So get good and comfy with it. Be friends with it. Get to know it. See if you two have anything in common. 

You can plug in visually where each anticoagulant fits in the clotting cascade. That covers most of the pharmacology right there (Welp...my job here is done...).  

Background and Terminology

Normally, your blood flows all loosey-goosey through your veins and arteries. It goes from the heart, to the lungs, back to the heart, and then it's pumped all over the body before returning to the heart to start the whole trip over again. 

But sometimes a clot can happen and muck everything up.

In medicine, a clot is called a "thrombus." And the resulting block in blood flow is called a "thrombosis." 

Sometimes a stationary clot can break free and travel through the circulatory system. At this point, it's called an "embolus" (and it results in an "embolism."). Usually, an embolism travels until it gets stuck in a smaller blood vessel where it proceeds to take up permanent residence. 

The result of a thrombus or an embolus is bad:

• Stroke

• Myocardial infarction (MI) (i.e. heart attack)

• Pulmonary embolism (PE)

• Deep vein thrombosis (DVT)

• And still others...

Collectively, these disorders are the most common cause of death in most developed countries. 

So what actually makes up a clot?

If you refer to that monstrosity of a diagram we've made above, you'll see that a clot is made up of a lot of things in your blood. But there are two things that are the most important in terms of clot stability and structural integrity:

1. Fibrin

2. Platelets

Fibrin and platelets basically stop a clot from falling apart once it has formed (and they have a role in actually forming the clot in the first place).

Platelets notice a hole in the blood vessel, and they plug it up. They first adhere to the surface (adhesion), and then they send off a chemical signal flare to tell all their friends to join them (activation). Once their friends arrive, they all join hands in an impressive showing of unity (aggregation). All of these platelets joined together effectively form a nice plug that stops the bleeding.

At some point during the platelet aggregation process, Fibrin is created via the clotting cascade (again, see the above diagram). Fibrin lays a cross-layered sheath over the clot which basically stops it from falling apart and keeps it structurally safe and sound. 

There is, of course, some overlap between the processes of platelet aggregation and the creation of the fibrin sheath. And both processes are important whether the clot is being made in an artery or a vein. 

But...

You could make an argument that fibrin is more important to clots formed in a vein (red clots). These are the DVTs and PEs that you know and love. Likewise, you might say that platelets are more important to clots formed in an artery (white clots). These are the strokes and MIs of the clotting world. 

Again, I'm not saying they are singularly important. Fibrin and platelets are both important whether a clot is arterial or venous. But the medical management of clots is different depending on where the clot formed. We tend to use antiplatelet medications for strokes and MIs, but we use anticoagulants for DVTs and PEs. That's because strokes and MIs are usually arterial clots, while DVTs and PEs are usually venous clots. 

Alright, now that we're good and comfy with how clots form, let's move on to fixing those clots. To do this, we'll use anticoagulants and antiplatelet medications. 

This article will focus on anticoagulants. We'll cover antiplatelet medications in a future article. 

A Quick Note on Anticoagulants versus Thrombolytics

There's an important bit of trivia that I need to mention before we dig in any further.

None of the anticoagulants we're about to review actually break up clots. 

This seems counter intuitive, doesn't it? Why are we giving heparin or rivaroxaban to a patient with a DVT if it doesn't actually break up the clot?

Look again at that monster clotting diagram above. Notice that it's only moving in one direction. Every step of it proceeds to the final process of cross-linking fibrin. There is no reverse. 

All of the anticoagulants that we'll cover in this article stop one or more steps of the above diagram. So they stop the clotting process from moving forward, but they don't do anything to reverse it. Instead, they stop an existing clot from growing or spreading. And they stop new clots from forming (having an existing clot is a major risk factor for developing a secondary clot). 

So how do you get rid of a clot?

With thrombolytics.

Your body makes something called plasmin. This is your own natural clot buster (aka: thrombolytic). While anticoagulants prevent new clots and stabilize existing ones, your body converts plasminogen into plasmin (via an enzyme named plasminogen activator [PA]) and gets to work actually destroying the clot. 

Do we have a drug that does that too?

Absolutely. We've got several thrombolytics, in fact. Historically, the most commonly used is recombinant tissue plasminogen activator (tPA). This is also known as alteplase or by it's brand name, Activase. Just like the name implies, it's a synthetic version of the enzyme that activates your body's own plasminogen into plasmin. So if you give tPA, your body will make more plasmin, and existing clots will go bye-bye.

More recently, there has a been surge in tenecteplase (TNKase) use all over the nation de to its cheaper cost, ease of administration, and longer half-life. Chances are, your hospital already switched over from alteplase to tenecteplase for the treatment of ischemic strokes. If you haven’t, you probably will soon. Speaking of strokes, here is a nice refresher you should read before you get called to help out with a stroke alert.

Some other versions (besides alteplase and tenecteplase) of tPA that you may come across are reteplase, streptokinase, and urokinase. Reteplase and streptokinase are no longer available in the U.S. so there’s no need to review those. Urokinase is available in the U.S. but it’s only FDA-approved for the treatment of submassive and massive pulmonary embolisms.

Incase you need a quick summary of our three main thronbolytics, take a peek below:

• Alteplase [Activase] - Indicated for Acute Ischemic Stroke, Acute Myocardial Infarction (AMI), and the lysis of Acute Massive Pulmonary Embolism

• Tenecteplase [TNKase] - Indicated for Acute Ischemic Stroke and Acute Myocardial Infarction

• Urokinase [no bran name available in the U.S.] - Indicated for the lysis of Acute Massive Pulmonary Embolism

So, where else can we use thrombolytics?

Most commonly, they are used in tiny doses to clear clogged up IV lines and ports. There's a handy brand of alteplase called [Cathflo] that comes in a 2 mg vial and is quite useful at clearing up clogged lines. Occasionally, you may also see alteplase used during vascular procedures or as an (off label) adjunctive treatment for frost bite in cold parts of the world. 

Risk Factors for Developing a Blood Clot

We're almost ready to get into the drug part, I promise! But first, we should briefly mention what sort of patients develop clots in the first place. That way we can be on the lookout ahead of time. In some high risk cases (which we'll discuss below), we may elect to prophylactically give an anticoagulant.

Anyway, the following is not an exhaustive list. But here are some common risk factors associated with developing a thrombosis:

• Inherited disorders such as Antiphospholipid Syndrome (APS) or Factor V Leiden

• Certain cardiac arrhythmias such as atrial fibrillation

• Presence of a mechanical heart valve

• Prolonged bed rest/immobility or paralysis

• Pregnancy

• Oral contraceptive pills

• Cancer

• Traumatic blood vessel injury or surgery

• Smoking

• Obesity

• Having an existing clot (or a history of clotting)

It should be noted, also, that these risk factors can be synergistic. If your patient is an overweight female who smokes and takes an oral contraceptive, the relative risk of developing a DVT is higher. 

Prophylaxis versus Treatment

I hinted above that we occasionally give anticoagulants preemptively to high risk patients to prevent a clot from developing in the first place. What sort of patients do we do that with? Who actually needs prophylactic anticoagulation? 

It's pretty much impossible for me to give you a clear answer. Like most other things in medicine, it's a gray area with wiggle room for clinical judgement.

There's also room for common sense here. If you have a cancer patient with a history of DVTs that presents to the ER with a GI bleed, prophylactic anticoagulation probably shouldn't be on your immediate "to do" list. 

In some areas, it's common to perform a thromboprophylaxis risk assessment to help guide the decision on prophylaxis or not. Here's a helpful sample calculator to give you an idea of what criteria goes into the decision. 

Another point to mention is that the doses we use for prophylaxis are usually (but not always) much lower than the doses we use for treatment. This changes the need for monitoring (we almost never monitor prophylactic dosing).

In some of the cases above, patients will get full therapeutic dosing of anticoagulants as prophylaxis. Often times, this is used as secondary prevention after a clot has developed. But not always. 

As an example, cancer patients with any history of DVT or PE usually require lifelong prophylaxis with therapeutic enoxaparin. Another example is any patient on warfarin therapy (there isn't really a "prophylactic" dose of warfarin). So here you'll see patients with a-fib, APS, mechanical heart valves, and the like. 

So just think of prophylaxis on a case by case basis. Assess the risk factors for clotting, as well as the bleed risk for the patient. 

Also a fun fact because I’m a nerd. Have you ever heard of sequential compression devices (SCDs)? You know, the little inflatable things that we put around our patient’s legs? And every so often they inflate and deflate? Well, believe it or not, SCDs are commonly used in the inpatient setting to prevent a DVT. How you ask? When the SCDs inflate, they squeeze the legs to mimic muscle pumps which in turn leads to the natural release of tPA from endothelial cells. This literally helps prevent and breakdown miniature clots. Pretty cool, right?

Anticoagulant Drugs (Finally)

As a quick disclaimer, before moving on to the reason you're reading this article. All of the following medications have a potential side effect of bleeding. I’m not going to repeat that each and every time.

They're anticoagulants. It's just what they do. They don't wanna hurt nobody but a bee has got to sting. 

I'm going to cover the most important pharmacology and therapeutic info below. But again, I'll stop just shy of providing dosing (which in some cases is going to be institution-specific anyway). 

If you find yourself wanting some guidance on dosing info, check out our Anticoagulant/Antiplatelet Cheat Sheet. It's loaded with common doses, dosing adjustments, clinical pearls, and a whole lot more. 

Unfractionated Heparin

Unfractionated Heparin (UFH) is one of the oldest (and most widely used) anticoagulants. It binds to and activates antithrombin III.

So what is antithrombin III? It’s one of your body’s natural anticoagulants. It floats around your blood and inhibits thrombin (Factor IIa) and Factor Xa from propagating the coagulation cascade. That's pretty easy to remember, right? Antithrombin inhibits thrombin.

So in essence, heparin binds to antithrombin III (AT-III) and makes it work more efficiently. It's like a task master that pushes AT-III productivity to new heights.

I sort of envision it like this:

Heparin primarily impacts Factors IIa and Xa (via AT-III). And in a nutshell, that’s its mechanism of action.

So here's the thing with heparin. Its kinetics are horribly unpredictable. It seems to affect everyone a little differently, and the only way for us to get around this is by monitoring.

In my experience, most institutions monitor the activated Partial Thromboplastin Time (aPTT). But you may come across some that monitor the anti-Xa level. Whether aPTT or anti-Xa is more accurate is actually the subject of ongoing debate. It seems like you can safely use either.

However, at least at the time of this writing, aPTT is used more commonly. So use that as your launching point for test questions while you're in pharmacy school.

Moving on...

When used for treatment (usually dosed IV), heparin is very closely monitored. It is usually given as a continuous infusion and the aPTT (or anti-Xa) levels are monitored every 6 hours.

If it’s being used for prophylaxis (dosed subcutaneously), it doesn’t require monitoring. I should point out here that heparin does have a subcutaneous treatment dose listed in it's labeling (250 units/kg q12h). I have never seen this in practice, and I strongly suspect you won't run into either. But at least you know there's labeling for it now. 

Practicing Pharmacists: If you have used the subcutaneous treatment dosing of heparin in your practice, please email me at mail@tldrpharmacy.com with any wisdom on patient population, clinical scenario, etc... I'll update this article with the knowledge you drop my way. Thanks!

Despite the erratic kinetic profile, heparin is still a drug of choice in a lot of situations (for treatment or prophylaxis). It has a very short half life, and heparin can be used in any stage of renal failure (including dialysis).

That's an important fact, because many of our other anticoagulants cannot be used in the later stages of renal failure. 

Another benefit of heparin is that it has an antidote; protamine sulfate. 1 mg of protamine will neutralize 100 units of heparin (I'd remember that for the NAPLEX if I were you). Protamine has a max dose of 50 mg. It's also derived from fish, so it should be used with caution or avoided altogether in patients with a fish allergy. 

Adverse Effects of Heparin

Heparin has a number of "weird" side effects that you wouldn't necessarily think about for an anticoagulant.

For starters, it can actually block the synthesis of aldosterone, which basically makes it an aldosterone antagonist. As you might suspect, this can lead to hyperkalemia. 

Through an unknown mechanism, heparin also seems to increase osteoclast activity, and decrease osteoblast activity. So you can end up with osteoporosis after prolonged use. 

Heparin is porcine in origin. So if your patient has a pork allergy (or even if they prefer to avoid pork products for cultural or religious reasons) then you need to look elsewhere. In the case of pork allergy, administering heparin can lead to anaphylaxis. 

The final clinical pearl I’ll offer on heparin is a potential (but rare) side effect. It’s called Heparin Induced Thrombocytopenia (HIT).

As the name implies, HIT is a situation where your platelet count drops in response to heparin therapy. There are two types of HIT (Type I and Type II).

HIT Type I, for all intents and purposes, is the "better" one to have if you're the patient. It's also known as heparin "associated" thrombocytopenia. It's a transient, usually mild drop in platelet count that happens within the first couple of days of initiating heparin. Platelets rarely drop below 100k, and the effect is reversed (within 3 or 4 days) after stopping heparin. There's actually a group of clinicians proposing to change the name from HIT Type I to "non-immune heparin associated thrombocytopenia" to reduce the confusion between Type I and Type II. 

HIT Type II is a much worse clinical picture. This time, there's an immune response associated with the drop in platelets. Effectively, heparin binds to your platelet and undergoes a conformational change that makes it immunogenic. Your immune system doesn't like this, so it goes to the scene to bust up the offending platelet like a bouncer at a night club. Your platelet counts will drop accordingly. But in a weird twist, your immune system actually activates the platelets before it clears them out. So, ironically, even though platelet counts are dropping, patients with HIT Type II are at risk for developing clots (pretty much any and everywhere in the body).

To diagnose HIT, we often use a test informally called the 4 Ts of HIT. One of the primary things to look at are platelet count (specifically, a 50% reduction from baseline). This reduction in count should also coincide with heparin administration. So if the patients platelets were 300k on Monday, then heparin was started and the patients platelets were 150k on Wednesday, that's the beginning of a HIT diagnosis.

It's not the full HIT diagnosis of course. You also want to evaluate if there are any thromboses or any other reason for thrombocytopenia (maybe the patient just received chemotherapy?). Since HIT Type II is immune mediated, we would also run an antigen test to confirm the presence of heparin antibodies.

Obviously, you don't wait around for the results of HIT antigen testing to intervene clinically here. The patient needs anticoagulation (and is at additional risk now due to the platelet activation caused by HIT Type II). LMWH also has an association with HIT (albeit, much lower than unfractionated heparin), so you cannot transition the patient to LMWH.

In the acute setting, you'll usually transition the patient to either bivalirudin or argatroban. Once you're gearing up for a transition to the outpatient world, you can use pretty much any oral anticoagulant on the market. Warfarin, or any of the NOACs are a fine choice here (though it is recommended to wait until the platelet count recovers before initiating).

If the HIT antigen test comes back negative, you could consider rechallenging with heparin (depending on your institution's protocol and everyone's comfort level with re-challenging). If the HIT antigen is positive, you can pretty much remove heparin and LMWH as possible anticoagulants for this patient in the future.

Low Molecular Weight Heparin (LMWH)

Next up, we have heparin’s little brother, LMWH. These all end in the suffix "-parin." Far and away, the most common LMWH heparin is enoxaparin [Lovenox]. But for the sake of completeness, there is also dalteparin and tinzaparin.

As the name implies, these are low molecular weight versions of heparin. They're literally a heparin molecule that’s been cut down to a fraction of the original size.

LMWH still binds to AT-III like heparin. But something weird happens with the smaller size of LMWH. Antithrombin III preferentially starts inhibiting only Factor Xa (and stops inhibiting Factor IIa).

To be clear, LMWH still slightly inhibits IIa. But it inhibits Xa a lot more.

So, Xa >>> IIa.

What does that mean clinically?

For starters, the kinetics are much more predictable. Unlike heparin, LMWH is pretty consistent with its anticoagulation effect. The upshot of this is that we don't routinely need to monitor levels (even with therapeutic dosing).

I italicized "routinely" above...that should clue you in that there are some exceptions to the "You don't need to monitor LMWH" rule. Namely, we might monitor in renal disease (like heparin, LMWH is renally cleared), extremes of body weight (because it's not extensively studied in very under or overweight patients), and pregnancy (because you just have to be careful in pregnancy). If someone experienced a treatment failure or a bleed while on therapeutic LMWH, you'd probably also want to monitor levels going forward. 

To recap that (in bullet form!), here are some patient populations where you would consider monitoring LMWH levels:

• Renal disease

• Extremely under or overweight

• Pregnancy

• Prior bleeds or treatment failures

As for what to monitor with LMWH, you usually will monitor anti-Xa levels. This makes sense because remember that LMWH is much more specific to Xa than to IIa. I'd consider that the 'gold standard' of monitoring that should be your starting point on any test question.

That being said, you may come across literature or an occasional institution that uses the aPTT for LMWH. You may even have some institutions with a special LMWH assay. Just be aware that these exist, so you're not completely thrown off if you see them in practice. 

And remember, for most patients, we can give therapeutic doses LMWH without monitoring. Those therapeutic doses are given as subcutaneous injections twice daily (and in some cases only once daily). Compare that to the IV drip of heparin with monitoring every 6 hours and LMWH looks pretty attractive in the right patient population.

Even better, enoxaparin syringes are pre-filled in a variety of strengths. Patients can self-administer therapeutic doses at home and don't need to stay in the hospital, providing another benefit of LMWH to heparin. 

Adverse Effects of LMWH

We run into an issue with LMWH in renal disease. Remember from above that we can give heparin no matter what your kidney function is. Even in dialysis.

That's not true with LWMH.

In general, we start getting cautious (and monitoring) when LMWH is used in patients with CrCl < 30. And it’s absolutely contraindicated in dialysis patients. Unlike heparin, LWMH has a pretty long half life (that's why we can get away with dosing it once or twice a day). It will accumulate in renal disease (and predispose the patient to bleeding).

So, if your patient has bad (or even just unstable) renal function, I'd recommend heparin.

As for other side effects, remember that LMWH is like a little cousin to heparin. The potential side effects are similar, but the likelihood of those side effects is less frequent with LMWH. 

LMWH does have a risk of hyperkalemia. According to this small trial with n=60, it's got the same risk as heparin. However, this older (and smaller) trial says there's no risk at all. When you run into contradictory situations like this, my recommendation is to go with a "guilty until proven innocent" policy. I'm not saying you should empirically put a LMWH patient on kayexalate or anything. Just that you should be mindful of potassium levels and watch out for synergistic drug interactions. 

As for Osteoporosis...it's also debated whether there is an association with LMWH. Some think we're chasing a red herring just because LMWH is similar to heparin. The jury is still out, but again I'd consider it a possibility worthy of monitoring until proven otherwise. 

LMWH is also associated with HIT, but to a much lesser degree than heparin. So it's much less likely. That being said, if you have a patient with confirmed HIT, you will not be switching them to LMWH. 

LMWH is also contraindicated in patients with neuraxial anesthesia (i.e. an epidural). It can cause a spinal hematoma which can lead to paralysis. So, umm. Don't do that.  

As for a reversal agent, protamine sulfate can be used. However, unlike when used to reverse unfractionated heparin, protamine sulfate does NOT fully reverse the effects of LMWH. In fact, it’s estimated that protamine can neutralize a maximum of 60% of LMWH.

The protamine dose is dependent on the time of enoxaparin administration. If you have a severe bleed and enoxaprain was last administered ≤8 hours, then 1 mg of protamine will neutralize 1 mg of enoxaparin. If enoxaparin was administered >8 hours, then 0.5 mg of protamine will neutralize 1 mg of enoxaprain.

Fondaparinux [Arixtra]

Last in the AT-III family of anticoagulants we have fondaparinux. You will often (incorrectly) see fondaparinux grouped with the direct factor Xa inhibitors (we'll cover these in a bit). That's because fondaparinux only inhibits factor Xa. But, fondaparinux works via AT-III...it doesn't bind to Xa at all (so it's not "direct"). So it belongs in a list with the other AT-III inhibitors. 

I mentioned above that LMWH is just a trimmed up version of heparin. Think of fondaparinux as being trimmed up even further. It is literally the precise 5 pentasaccharide sequence that binds to AT-III (so you could say that it's binding is pretty specific).

Clinically, this means that it only inhibits factor Xa. There is no significant IIa inhibition here. I think this is why it often gets grouped with the direct factor Xa inhibitors.

In general, monitoring is not required for fondaparinux. The special patient populations in which you would monitor are less clearly defined than they are with LMWH. However, what you should monitor is pretty clear: anti-Xa. 

Personally, I'd monitor fondaparinux in the same situations that I would for LMWH. So that's renal disease, extremes of body weight, pregnancy, and history of bleeds or treatment failures. The package insert even goes so far as to recommend monitoring in patients who are less than 50kg, as fondaparinux is associated with a higher risk of bleeding in these patients. 

Adverse Effects of Fondaparinux

The neat thing with fondaparinux is that it's not really associated with those "weird" side effects from above like osteoporisis and hyperkalmia.

Additionally, (and this is important), it has no association with HIT.

In fact, fondaparinux can actually be used to treat HIT in the acute setting.

In my experience, that's been the most frequent reason for using fondaparinux. So why don't we use it more?

Like most decisions in modern medicine, cost is certainly a factor. Fondaparinux is considerably more expensive than LMWH, and even more so than heparin. 

Its other big strike is in renal failure. Fondaparinux has a solid 17 - 21 hour half life (even longer than LMWH). So its risk of accumulating (and causing a subsequent bleed) in renal failure is even more probable. In fact, fondaparinux is contraindicated with a CrCl of < 30ml/min. 

So here's a quick summary our AT-III anticoagulants in renal failure:

• Heparin – Can use in HD

• LMWH – Contraindicated in HD…consider monitoring if CrCl < 30

• Fondaparinux – Contraindicated CrCl < 30

Making matters worse for renal accumulation, there is no specific reversal agent for fondaparinux. Protamine is not recommended. So you really have to use caution when selecting patients for fondaparinux. 

That pretty much wraps up our AT-III anticoagulants. Let’s move on to some other agents.

Argatroban

Argatroban is a direct thrombin inhibitor (DTI). Refer back to the clotting cascade earlier from this post (there's also one included in our anticoagulant cheat sheet). You'll see that Thrombin (Factor IIa) is the thing that activates fibrinogen to fibrin (which is then the material that cross-links the clot). So you inhibit thrombin, you inhibit fibrin (and cross-linking). Make sense?

The earlier DTIs (hirudin, lepirudin, and bivalirudin) are used so rarely anymore that I'm not going cover them in this article. You can read a neat timeline on the history of DTIs here if you're interested.

You can probably surmise this from the name "Direct Thrombin Inhibitor," but argatroban directly binds to thrombin (Factor IIa) and inhibits it. Clever, no?

It is not used very often, but it does have its niche in therapy.

As previously mentioned, it is the second of the two "go to" drugs for patients that develop HIT.  Far and away, this is the most common reason that argatroban is used. 

Should you use argatroban or fondaparinux for HIT? It depends on why the patient was on heparin in the first place. Argatroban has a super short half life (about 45 min) compared to the 17 - 21 hour ordeal for fondaparinux. So if the patient is getting surgical procedures or has renal failure, you'd lean towards argatroban. 

Obviously, a drug with a 45 minute half life is going to have the need for an IV infusion, and it's usually going to be titrated to therapeutic effect (which means monitoring). There are two options for monitoring argatroban: aPTT and the Activated Clotting Time (ACT). 

Argatroban and bivalirudin are the only two drugs in somewhat regular use that are monitored with ACT that I'm aware of...so I'd at least be aware of that fact as a possible test question. 

Outside of HIT, you'll usually see argatroban used during invasive surgical procedures, such as PCI. Again, that glorious 45 minute half life makes argatroban pretty useful for short-term anticoagulation during a procedure. 

There is no reversal agent for argatroban, but this usually doesn't matter. Its half life is so small that it’s effect will wear off quickly on its own by just stopping the infusion.

It should also be noted that argatroban has to be used carefully (if at all) in patients with liver failure. Everything we've talked about up to this point has been renally cleared, so this is an exception worth remembering.

As a final clinical pearl, I offer you a common test (and NAPLEX) question. Argatroban interferes with the assay we use to monitor warfarin therapy (the INR). Specifically, it falsely elevates the INR by several points.

So if you were transitioning a patient from argatroban to warfarin (which is exactly what you’d do in a patient with HIT who needed long-term anticoagulation), you'd actually shoot for an initial target INR of > 4.0 before stopping the argatroban.

That seems like crazy talk, but remember, it's a falsely elevated INR. Argatroban's effect will wear off fairly soon after stopping the infusion, at which point you'd adjust the INR to the "normal" range for the patient's indication. 

Direct Oral Anticoagulants (DOACs)

Next up, we've got a new classification of drugs called Direct Oral Anticoagulants (DOACs). You may also see these referred to as New Oral Anticoagulants or Novel Oral Anticoagulants (NOACs). However, the ISMP has issued statements preferring the term DOACs because there were reported incidents of confusion where the acronym "NOAC" was mistaking for "No Oral Anticoagulation." So, we'll be using DOACs in this article. 

DOACs are not tied to a specific mechanism. They are just “newer” than warfarin (which is the original oral anticoagulant...in fact, warfarin was the only oral anticoagulant for about 60 years).

Currently, our DOACS are either Direct Thrombin Inhibitors (dabigatran) or Direct Factor Xa Inhibitors (rivaroxaban, apixaban, edoxaban). 

I'm going to discuss the DOACs all as one group (even though they have different mechanisms of action). The reason I'm doing this is because they're pretty much all approved for the same indications (with some minor variances). It'll be easier to talk about the pros and cons of using one over another in a single section instead of making you scroll back and forth.

You're welcome, by the way. 

I'll also make sure to highlight some relevant clinical pearls for each of the DOACs individually. 

The big "draw" of the DOACs is that none of them require the cumbersome monitoring that warfarin requires (although that does keep pharmacists employed). And although all of them have drug interactions via the P-gp pathway (and some have interactions with CYP as well), DOACs have considerably less drug interactions than warfarin. And they have basically no interactions with food. 

On the down side, in many ways the frequent monitoring associated with warfarin can be considered a plus in many cases. Monitoring is the only way to be sure you're not over or under anticoagulating your patient. Additionally, in the case of a bleed, warfarin can be reversed with Vitamin K, fresh frozen plasma (FFP), or 4PCC (which is just a concentrated version of FFP that goes by the brand name Kcentra).

We can use Praxbind to reverse dabigatran and Andexxa to reverse the Xa inhibitors (although Andexxa use to reverse edoxaban is “off-label”). But we’ve got much more clinical experience with warfarin reversal.

All of that is to say that while DOACs have a definite place in therapy, they do not yet spell the end of warfarin. Warfarin is cheaper, has a longer history of use, and is still the only oral anticoagulant approved for some indications (such as mechanical heart valves).

If you want more info, here is an excellent read that gives a more detailed comparison of the NOACs. If you're happy taking my word for it, I'm going to do my "tl;dr thing" with the DOACs. 

Alright, so let's get into the nitty gritty of this. Again, when I say "DOAC" I'm referring to the following:

• Dabigatran [Pradaxa] - DTI

• Rivaroxaban [Xarelto] - Xa Inhibitor

• Apixaban [Eliquis] - Xa Inhibitor

• Edoxaban [Savaysa] - Xa Inhibitor

Notice how all of the Xa Inhibitors end in "-xaban." Think of this as "Xa Ban," and it'll make it easy for you to remember their pharmacology. 

In general, DOACs are approved for the following:

• Stroke prevention in non-valvular afib

• DVT/PE treatment

I said "in general" because the above is a pretty big generalization. You may see a couple of them used for DVT prophylaxis in patients who just had hip or knee surgery. You can also see them used as a sort of secondary prophylaxis in patients who've had recurrent DVT/PEs. Rivaroxaban, for example, is approved for both of those indications.

Also notice that DOACs are specifically approved for non-valvular afib. If the patient has valvular disease and/or a mechanical or bioprosthetic heart valve, warfarin is your only PO choice. 

How do you know which DOAC to use? 

I'll assume you've already determined that the DOAC(s) you're considering can be used for the indication you're treating (again, it's usually DVT/PE or non-valvular afib). 

From there, a good place to start is renal function. Check to see if the DOAC has a dose adjustment or contraindication based on your patient's renal function. The dose recommendations change by indication and renal function, so I won't list them out comprehensively here. Instead, I'll give you some general cutoffs:

• Dabigatran - Dose adjustment for afib at CrCl < 30 ml/min. Contraindicated for DVT/PE at CrCl < 30 ml/min. If patient is taking a strong P-gp inhibitor, the dose adjustments start at CrCl < 50 ml/min.

• Rivaroxaban - No renal dose adjustment necessary for VTE if CrCl ≥30 mL/min (avoid use if CrCl <30 mL/min). For Afib, dose adjustments start at CrCl < 50 ml/min

• Apixaban - No renal dose adjustment necessary for VTE. However, dose adjustment is needed for Afib if your patient meets two out of these three criteria: age ≥80 years, weight ≤60 kg, serum creatinine ≥1.5 mg/dL (I can almost guarantee you that will show up on a test question sometime in your life)

• Edoxaban - Dose adjustments start at CrCl < 50 ml/min. Amazingly, there is actually an upper CrCl limit for afib. You must avoid edoxaban in patients with non-valvular afib and a CrCl > 95 ml/min. (I can almost guarantee you that will show up on a test question sometime in your life)

Alright, we've got renal function accounted for. I also want to point out that there are also potential dose adjustments for hepatic function with the DOACs, but they are much less clear cut (so I'm going to take the easy way out and just not talk about it :))

Let's move on to dosing schedule and enteral status (there's some weird restrictions with feeding tubes).

• Dabigatran - Dosed twice daily. Capsule CANNOT be opened and administered via tube.

• Rivaroxaban - Dosed once daily. Tablet CAN be opened and administered via tube. However, rivaroxaban must go through the stomach to be properly absorbed. So if it is given via tube, that tube must end in the stomach. NG, OG, PEG, or G tubes are all ok for rivaroxaban. You CANNOT use tubes that bypass the stomach such as NJ, J, or GJ.

• Apixaban - Dosed twice daily. Tablet CAN be crushed and administered via tube.

• Edoxaban - Dose once daily. Tablet CANNOT be crushed and administered via tube.

Moving on, what about drug interactions? 

• Dabigatran - P-gp interactions

• Rivaroxaban - P-gp and CYP 3A4 interactions

• Apixaban - P-gp and CYP 3A4 interactions

• Edoxaban - P-gp interactions

The recommendation for how to handle the drug interaction varies depending on the indication and on how strong of an inhibitor/inducer you're working with. In general, it's recommended to avoid any DOAC with a strong P-gp inhibitor. There's enough of an overlap between P-gp inhibitors and CYP 3A4 inhibitors that you'll run into a lot of problems here. If your patient has HIV and is on a protease inhibitor, you're on a one-way trip to warfarin land. 

What about if the patient develops a life-threatening bleed? Is there a reversal agent available?

• Dabigatran - Reverse with idarucizumab [Praxbind]

• Rivaroxaban - Technically Andexxa* but realistically 3-factor PCC or 4-factor PCC

• Apixaban - Technically Andexxa* but realistically 3-factor PCC or 4-factor PCC

• Edoxaban - Technically Andexxa* but realistically 3-factor PCC or 4-factor PCC

*Not that your hospital even had Andexxa to begin with since it costs an arm and a leg. But as of December 22, 2025 the FDA put out a statement that Andexxa will no longer be manufactured or sold in the U.S. Long story short, the FDA was concerned about post marketing data that revealed an increased risk of serious and fatal thromboembolic events that outweigh the drug’s benefit. AstraZeneca (Andexxa’s manufacturer) refused to partake in further randomized control trials and decided it was best to just drop it in the U.S. That being said, Andexxa remains available outside the U.S under the brand name Ondexxya. So for all of our international readers, you may still deal with Andexxa/Ondexxya.

Now, let's talk about efficacy...

Like everything else on this site, the following are my opinions. So please take them with a grain of salt.  

I'll start with DVT/PE treatment, because that's an easy starting point.

In my mind, all DOACs are equally effective for DVT/PE treatment. You can select which one fits your patient best based on the above differences (renal function, dosing schedule, etc...) and on insurance coverage, formulary choices, and patient preference.

The only thing to keep in mind with DOACs and DVT/PE treatment is that they must be "bridged." I don't mean in exactly the same way that you bridge someone to warfarin, but the concept is sort of the same. With all DOACs, you either start with a parenteral anticoagulant (such as heparin or LMWH), or you start with a higher dose of the DOAC itself for a set period. Here are the specifics:

• Dabigatran - Start with 5 - 10 days of a parenteral anticoagulant. Then begin normal dosing of dabigatran (150 mg BID)

• Rivaroxaban - Start with 15 mg BID x 21 days. Afterwards, the dose is 20 mg Daily

• Apixaban - Start with 10 mg BID x 7 days. Afterwards, the dose is 5 mg BID

• Edoxaban - Start with 5 - 10 days of a parenteral anticoagulant. Then begin normal dosing of edoxaban (60 mg Daily)

That pretty much covers DVT/PE treatment. And again, you may also see some of the DOACs used for prophylaxis following hip or knee surgeries or in the setting of recurrent DVT/PE. Edoxaban is the only DOAC that does not have an FDA approval for this indication. 

Let's move on now to non-valvular afib. 

All of the DOACs were compared to the standard of care (warfarin) in their phase III trials. And all of the trials were non-inferiority trials (meaning they were just trying to prove that the DOAC was equal in effect to warfarin, not "better").

Because anticoagulation is such a high impact area for pharmacists, it's probably a good idea to look more closely at the individual trials. I'll give you my tl;dr take home points here, but I encourage you to read more closely into the studies for more detail. This post is already over 7000 words long, so if I were to try to add a journal club to it I might break the internet. 

Here are the phase III trials for each of the DOACs:

• Dabigatran - RELY

• Rivaroxaban - ROCKET

• Apixaban - ARISTOTLE

• Edoxaban - ENGAGE-AF

And again, this article does a pretty great job at comparing and contrasting the DOACs (and their phase III trials). For some context, when we talk about stroke prevention in afib, we often calculate a CHADS2 score (or CHADS2VASC, or any of several other variations).

All these scores are doing is looking at patient risk factors to calculate their risk of having a stroke sometime within the next 10 years (it's kind of like the ASCVD score, but specifically for strokes). A higher CHADS2 score means a greater risk for a stroke.

Here is my "off the cuff" way of how I think about DOACs non-valvular afib for stroke prevention (at least in terms of the results of the above trials).

• Dabigatran - Non-inferior to warfarin, but higher risk of GI bleed. Patients in the trial had an average CHADS2 score of >/= 1

• Rivaroxaban - Non-inferior to warfarin. Patients had a higher average CHADS2 score (>/= 2)

• Apixaban - Superior to warfarin. Less risk of bleeding compared to warfarin. Patients had an average CHADS2 score of >/= 1

• Edoxaban - Non-inferior to warfarin. Average CHADS2 score was >/= 2

So what does all of that mean? 

If your patient has a higher CHADS2 score, you could consider leaning towards rivaroxaban or edoxaban (because the patients in those trials had a higher CHADS2 score). But remember, edoxaban has that silly upper CrCl limit of 95 ml/min, so make sure your patient doesn't fit that profile.

All things being equal, apixaban is probably my favorite DOAC. It can be used in renal failure (again, with a caveat for dialysis patients), and I like the safety profile. Plus it can be crushed and administered via tube easily in the inpatient setting. 

I don't like that dabigatran has an increased risk of bleeds. And unless the patient uses the blister packs (and doesn't open them), the drug has a ridiculously short shelf life. If a bottle of dabigatran is opened, it's only considered stable for 4 months. After that, you have to discard the medication. 

So again, those are only my opinions. But that's how I think about the DOACs in afib. 

What about Warfarin?!

I don't want to leave you hanging, but there's so much to say about warfarin that it really needs it's own article. I've written some short blurbs on it here and here, but warfarin deserves its own definitive guide. With that said: check out our definitive guide on warfarin.

Get Your Anticoagulant/Antiplatelet Cheat Sheet

We've covered a lot in this article (get a printable/savable PDF of it here!). If this is new for you, you might be a little overwhelmed. Or, maybe you want information on dosing (which we've included in our cheat sheet). Either way, the anticoagulant cheat sheet is the cure for what ails you. 

This is easily our most comprehensive cheat sheet to date. It covers basically everything you need to know about anticoagulants and antiplatelet medications. You'll get common dosing (by indication), dosage adjustments for renal and hepatic failure, drug interactions, reversal agents, hold times for procedures, pregnancy category, basic pharmacology, relevant clinical pearls, and a whole lot more. 

Honestly, you'll be amazed at how much information fits onto 3 sheets of paper when designed properly. 

Use this sheet to ace your next exam. Or hang it up on the wall at your practice site as a quick and handy reference. You can even add it to your peripheral brain. Trust us, this cheat sheet is exactly what you've been looking for if you're someone who works with anticoagulants and antiplatelet medications. 

And (like all of our other products), if you buy this cheat sheet, every revision or update we make to it is yours free for life. We are wayyyy to Type-A not to update this thing if a new anticoagulant gets approved by the FDA in 2 years. For literally $9, you can have your anticoagulant bases covered for the rest of your practice career. 

We were mixing up some Deep Eddy’s Ruby Red with lemonade for our guests (IYKYK), when one of our friends said, “Mmm, I’m on atorvastatin, and I’m supposed to avoid grapefruit juice. Will it be ok?” And of course, everyone stared at me, the pharmacist, for an answer.

Which got me to thinking… how much do we really understand this grapefruit-drug interaction deal? Sure, we all memorize which drugs carry the major warnings to avoid the combination, but as with anything in medicine, there’s always more to the story. So how much do you know about this, and is it truly an absolute contraindication?

This is what we’re here for today! Let’s learn together!

What is CYP3A4?

“CYP3A4” is a smushed moniker meaning cytochrome P 450 enzyme, family 3, subfamily A, and protein 4. The CYP3A superfamily of enzymes is largely comprised of CYP3A4. And when I say largely…I mean it takes the cake. On mass spectrometry, CYP3A4 is ~85% of the total CYP3A protein in the body with families 3A5, 3A7, and 3A43 accounting for only 3-5% each. Like all of the CYP450 enzymes, CYP3A4 is an oxidizer, and it is vital for metabolism of both endogenous and exogenous substances, including medications.

For the record, CYP3A enzymes aren’t exactly picky. Due to their substrate non-specificity, it’s estimated that up to 60% of pharmacotherapeutic agents on the market today undergo metabolism by CYP3A enzymes. And since CYP3A4 is the mega member of this family, that’s why we need to know more about this protein. It literally affects over half of the meds we manage. (Image)

CYP3A4 is found in the liver and intestines of humans. Although the liver is certainly a powerhouse of metabolism, let’s not downplay the role of intestinal metabolism. With a convenient location right at the site of medication absorption, intestinal CYP3A4 is heavily involved in the biotransformation and first pass metabolism of many, MANY agents. (Image) As such, it’s an important gatekeeper for bioavailability and therapeutic effect.

Consider this… If CYP3A4 isn’t at the intestinal wall as usual - or isn’t functioning normally (ahem, ahem) - then medications that are usually metabolized at the intestinal wall won’t be. Which means more of the medication is absorbed into the bloodstream, leading to potentially increased effects - and adverse effects.

So why might intestinal CYP3A4 not be present or functioning appropriately… Good question and precisely why we’re here today!

What’s the big deal about grapefruit?

You might be wondering, “What’s the deal with grapefruit? Are all citrus fruits a problem, or just this one?”

Well, it really is mostly just grapefruit that’s the issue, although Seville (sour) oranges, pomelos, limes, and tangelos can also be implicated in this food-drug interaction. While the acidity from lemons and sweet oranges may wreak havoc on someone’s GERD, those fruits don’t have any foul play with CYP3A4. So what is it about grapefruit (and friends) that makes it a problem child, and how was this curiosity uncovered?

It was actually totally coincidental. (Image) In the late 1980s, there was a study conducted to evaluate the effects of ethanol on felodipine concentrations, and grapefruit was used to mask flavors. Incidentally, the investigators noticed that felodipine patients who were exposed to grapefruit had about 5 times higher felodipine levels. And voila! The interaction was discovered. Happy accident, right?

So now as far as grapefruit itself… This citrus fruit has been touted for its positive health effects, due to its antioxidants, vitamin C, fiber, and phytochemicals. Phytochemical is just a fancy word for a substance found in plants that’s supposed to have beneficial health effects in humans. (Think polyphenols from tea or anthocyanins from berries as common examples. Not necessarily useful for nutrition but thought to be helpful in preventing diseases.) Phytochemicals found in grapefruit include flavonoids and coumarins.

Yes, you read that right. “Coumarins.” Your brain may have just gone down a pharmacy rabbit hole, where you’re now trying to figure out if grapefruit contains natural anticoagulants. BUT this is not the case. While Coumadin (aka warfarin) is a potent anticoagulant and coumarin derivative, coumarins themselves have no blood thinning properties and are actually often used for their vanilla-like fragrance in the cosmetic and food industries. (Image)

Now that we’ve dug ourselves out of that rabbit hole, check out the info below noting the theorized health benefits of grapefruit’s phytochemicals:

• Flavonoid: naringin

  • In addition to giving grapefruit its bitter taste, this component is thought to be antioxidant, anti-inflammatory, anti-apoptotic, anti-ulcer, anti-osteoporotic, and anti-carcinogenic. A bit of everything, eh?

• Furanocoumarins: bergamottin and 6,7-dihydroxybergamottin (DHB)

  • In addition to helping grapefruit plants ward off pests and diseases, these phytochemicals are thought to have antioxidant, anti-inflammatory, and anti-cancer properties. More wonder substances!

These 3 phytochemicals - naringin, bergamottin, and DHB - are found in varying levels in all 3 grapefruit varieties (white, pink, and ruby red). In general, white grapefruit has more of all 3 phytochemicals than pink or red. The seeds and pulp of the red grapefruit have the least of them. However, other factors such as where the fruit are grown, fruit maturity, storage, and processing have all been associated with variations in phytochemical levels, so it’s hard to even make generalizations about phytochemical distribution.

All this to say that not all grapefruits are created equally when it comes to these substances…and not even all parts of the grapefruit are consistent. Eating grapefruit flesh delivers different quantities of these substances than drinking commercial grapefruit juice (or even home squeezed grapefruit juice). Why do we care? Well, these 3 phytochemicals are suspected to be the main culprits responsible for interactions between grapefruit and medications. Let’s talk about how.

Naringin weakly inhibits intestinal CYP3A4. So while it’s a player in the game, it’s second string. The furanocoumarins are the stars of the drug interaction show. They inhibit intestinal CYP3A4 in 3 ways:

1. Competitive inhibition (most common)

   1. Reversible

   2. Occurs after the first dose of grapefruit

2. Permanent inactivation

   1. Irreversible

   2. Must regenerate new CYP3A4 to restore activity

   3. Occurs within 30 minutes after grapefruit ingestion and lasts 2-3 days after last grapefruit

3. Complete loss of enzyme

Of note, the grapefruit furanocoumarins do not inhibit CYP3A4 in the liver - only the intestine. Studies have also demonstrated no impact from grapefruit’s CYP3A4 inhibition when medications are administered intravenously, further supporting that this interaction occurs at the intestinal wall.

So then the next question is this: what factors affect the degree of grapefruit’s CYP3A4 inhibition?

Grapefruit Quantity

Simply put, the amount of grapefruit and/or juice consumed matters. The more grapefruit products ingested, the more impact on intestinal CYP3A4. (Image) Along the same lines, frequency of ingestion also influences the impact on medication levels. Elevations in felodipine went from 3 times higher to 5 times higher when consumption increased from 250mL (about one grapefruit) once to 250mL of juice 3 times daily for 6 days.

Timing of Grapefruit Ingestion

Again, simply put, how much time passes between grapefruit and medication ingestion matters. The more time between grapefruit products and medication, the less effect there is from intestinal CYP3A4 inhibition.

For reference to give some idea, in that same felodipine - grapefruit juice study, the greatest interaction (aka the most inhibition) occurred when there were 4 hours between ingestion of the 2 substances. That interaction dropped by 50% with a 10 hour gap and to 25% with a 24 hour interval. So the time gap matters.

Medication and Dose

Obviously, some medications depend on CYP3A4 metabolism more than others. I could never make a 100% inclusive list of medications that rely on CYP3A4, (ain’t nobody got time for that), that’s what LexiComp is for. But here’s a decent overview of classes with sample drugs to refresh your memory (Image):

FYI, don’t forget to consider the compounding effect of a person taking multiple medications that influence CYP3A4 activity! While grapefruit inhibits intestinal CYP3A4 enzymes, other medications could do this as well AND may inhibit liver CYP3A4 too. So be sure to account for drug interactions on top of food interactions.

We told you being a pharmacist is complicated, didn’t we? Have we said that? If we haven’t in all these years…being a pharmacist is complicated. There you have it. (Image)

Oral Bioavailability

Medications with innately low oral bioavailability stand the highest chance of causing issues in the presence of grapefruit. Again consider felodipine.

This drug normally has an oral bioavailability of about 15% after being metabolized by CYP3A4 in the intestine and then the liver (before even reaching systemic circulation!). However, this bioavailability significantly increases in the presence of grapefruit’s enzymatic inhibition, which is why the potential clinical effect is markedly increased.

If a drug isn’t so reliant on CYP3A4 in the first place, the presence of grapefruit won’t really be that big of a deal. That’s why medications with low oral bioavailability carry the potential for higher risk in the presence of grapefruit.

Individual Patient

Somewhat unfortunately for us pharmacists, there’s not exactly an easily available assay for our patients to use to evaluate variations in intestinal CYP3A4 expression and distribution… But we do know there are differences between patients. Not only are there allelic variants which affect individual enzyme function, but there are also differences in protein expression throughout the enteric tissue. In studies, the largest increases in drug concentrations under the influence of grapefruit juice were in patients who had the highest amounts of CYP3A4 in their intestines.

Makes sense, right? More enzymes to inhibit, bigger effects on dependent drugs. But how does a person with normal CYP3A4 in their gut compare with a person who has low amounts of high metabolizer CYP3A4? Or high amounts of slow metabolizer CYP3A4?

So while a patient could theoretically undergo pharmacogenomic testing to determine if they have a wild-type CYP3A4, there’s no way as yet to figure out if the expression through the intestinal tissue is normal, high, or low, or even distributed geographically in a common pattern. (Try convincing a doctor or your patient they need to have an intestinal biopsy to take that statin. Yeah, not happening…)

Also, don’t forget that each medication is absorbed (and metabolized) across different sections of the GI tract, so enzyme LOCATION in addition to function and amount could also compound the variability of this medication-food interaction!

You can see how trying to predict which patients are more susceptible to the impact of grapefruit juice’s inhibitory properties at baseline is kind of a…crapshoot. Potentially you could theorize that patients who require higher doses of a CYP3A4 medication for desired clinical effect may have higher amounts of intestinal enzyme, but that’s even a stretch.

In terms of patient characteristics, we should also suspect older adults (especially those over 70) of being at higher risk for grapefruit-drug interactions. First, they’re the ones who eat the most grapefruit. It’s not just a stereotype! Consumer data shows that people 45 years and older buy the most grapefruit. (Although you could argue that this flavor is making a comeback in seltzers, sodas, and alcoholic beverages that younger generations also like, it’s pretty rare to run into young folk straight up eating grapefruit everyday).

Second, older adults take the highest number of medications, thereby creating the most potential to have some sort of interacting drug. Third, they are likely more susceptible to the adverse clinical consequences of the interaction due to lack of physical compensation or tolerance. For example, those baroreceptors just don’t signal hypotension quite so quickly at 75 years old as they do at 25, so get ready for the orthostatic fallout.

As pharmacists, it’s important to consider our patients as individuals and assess their risk outside of general statements. This is just one more example of that.

The tl;dr of Grapefruit Interactions with Medications

Grapefruit contains flavonoid and furanocoumarin phytochemicals that inhibit the activity of intestinal CYP3A4. There can be significant variability in the degree of this inhibition depending on grapefruit type, source, processing and product, storage, as well as individual patient factors.

While this makes it tricky (to say the least) to determine what scenarios might produce clinically significant drug elevations and adverse effects, the factors we can account for include asking patients about how much grapefruit they’re ingesting, when do they consume it in relation to their susceptible medications, and are they experiencing any possible adverse effects. We can review medication lists to assess for potential additive inhibition or clinical effects, and we can inquire about their medical history to see if they’re at elevated risk from consequences of the interaction. From there, it’s clinical judgment.

As for my scenario that started this whole shebang, it turned out our friend forgot to take his dose of atorvastatin the day before. The time gap was over 24 hours from his last dose, and he had at least 10 hours until resuming his statin. He was on the lowest dose of atorvastatin with no other medical history or medications. And the drink, while advertised as being “infused” with real grapefruit juice, was mixed conservatively with a much larger quantity of lemonade (we were certainly nowhere near the 200-250mL of a whole grapefruit referenced in the above studies!). So grapefruit quantity was very restricted. All in all, in this particular scenario, I told him he should enjoy his beverage and have some pie! But this is definitely to be taken on a case by case basis.

Let’s contrast this with the example of my then 69 year old dad, who at one point was taking nilotinib, atorvastatin, amlodipine, and apixaban (to name just a few of his meds). Did I advise that he avoid any grapefruit juice at all? YES.

Consider your own clinical judgment. What would you have done?

For today’s topic, I figured it’d be good to talk about beta-blocker toxicity considering how commonly used they are. Heart failure, atrial fibrillation/flutter, hypertension, akathisia, migraine prevention, performance anxiety, thyroid storm, essential tremor, and portal vein hypertension…just to name a few indications. And let’s be real, it’s all fun and games until you’re asked to verify an insulin infusion running at 100 units/hour for a beta blocker overdose. (Image)

So, to avoid this scare, let’s get right into it.

How Do Beta Blockers Work?

To understand the toxicity of a drug, it’s important we first review how a drug actually works. Once we understand the mechanism of action, the toxicity portion will make more sense. Now, we’re not going to focus on the nitty gritty details of beta blockers in this post, but luckily for you, we have a previous post that goes over everything you need to know about beta blockers. This includes how they work, when they’re used, different clinical pearls, indications, and much more. For now, I’ll give you a quick refresher.

Remember our autonomic nervous system? And how our autonomic nervous system is further broken down into the sympathetic (“fight or flight”) and the parasympathetic (“rest and digest”) nervous systems? Oh, and remember those alpha and beta receptors? No?

Okay fine. Let’s review.

• Alpha-1 (A1)

  • Location: blood vessels

  • Agonist Effect: vasoconstriction

• Beta-1 (B1)

  • Location: heart

  • Agonist Effect: increase in heart rate (chronotropy) and heart contractility force (inotropy)

• Beta-2 (B2)

  • Location: Primarily lungs

  • Agonist Effect: bronchodilation

So now moving on to beta blockers. As the name suggests, they primarily block beta receptors (duh). Some are cardioselective while others are non-selective. The cardioselective ones only block B1 receptors (found in the heart), while the non-selective ones can block B1, B2, and even A1. And in case you need a quick refresher on which ones block what:

Signs & Symptoms of Beta Blocker Toxicity

The clinical features of beta blocker toxicity are pretty straightforward now that we understand how beta blockers work. If we antagonize B1, we get reduced heart rate and decreased cardiac output. If we antagonize B2, we get bronchoconstriction. If we antagonize A1, we get vasodilation. So, how do overdose patients present?

• Cardiovascular (most common): bradycardia, hypotension, heart block, cardiogenic shock

• Central nervous system (if severe toxicity): altered mental status, seizures, coma

• Respiratory: bronchospasm, respiratory depression

• Metabolic & Endocrine: hypoglycemia (due to inhibited glycogenolysis and gluconeogenesis), metabolic acidosis, hyperkalemia

• Other: cold, clammy skin, hypothermia

Treatment Algorithm for Beta Blocker Toxicity

A lot of meds can be used to treat beta blocker toxicity. Sometimes it can feel overwhelming with how many options we have. I promise we’ll review each treatment one by one. But before I throw all these meds at you, I figured it might be nice to give you a visual of the treatment algorithm first. Hopefully this will help simplify the treatment:

What’s the Role of Activated Charcoal in Beta Blocker Toxicity?

Activated charcoal is hit or miss. Different studies tell you different things. It’s not a specific antidote for just beta blockers. It can really be used for the intoxication of any oral medication. How?

It adsorbs toxic substances and inhibits GI absorption to prevent or limit systemic toxicity. (Image) The sooner you give it the better the outcome. The longer you wait, the more a drug gets absorbed, and the less effective the activated charcoal is.

In fact, there’s this 2005 study that tested the mean reduction in drug absorption following a single dose of ≥50 g activated charcoal. Here are the results:

• If given within 30 minutes after ingestion: 47.3% reduction

• If given at 60 minutes after ingestion: 40.07% reduction

• If given at 120 minutes after ingestion: 16.5% reduction

So, if your patient presents within ~2 hours of a beta blocker ingestion, you can potentially administer 25 to 100 g of activated charcoal. Also don’t forget that you have a longer administration window with extended release (ER) formulations (like metoprolol succinate). In that scenario, you may still administer activated charcoal even 4-6 hours after ingestion.

Atropine for Beta Blocker Toxicity

Atropine is one of those drugs that’s usually not very effective…but also doesn't have much risk. Kinda one of those “eh, let’s give it a try” drugs. I mean if you go to LexiComp, it literally says, “Note: atropine may not be effective for type II second-degree or third-degree heart blocks.”

I am not making this up. You can go and check for yourself. But either way, it’s still going to be a drug that we give for beta blocker toxicity.

If you don’t remember, atropine is an anticholinergic agent. It blocks the action of acetylcholine at the parasympathetic (rest & digest) nervous system. So what effects do you get? The opposite of rest and digest. I.e., increased heart rate, cardiac output, dryness, constipation, decreased urination, etc. The main effect we’re aiming for in the scenario of beta blocker toxicity is the increase in heart rate. Everything else is an unwanted side effect (but can be dealt with later).

Atropine can be given IV, IM, or IO. IV is always going to be preferred as long we have intravenous access. Regarding dosing, give 1 mg of IV atropine every 3 to 5 minutes as needed until symptoms resolve or heart rate is stabilized. Don’t forget, there is a max of 3 doses (max total dose: 3 mg). After that, we move on to other agents.

Glucagon for Beta Blocker Toxicity

This one always confused me. Glucagon is a hormone produced by the pancreas that plays a crucial role in regulating blood sugar levels. When serum glucose drops too low, glucagon is released, which then stimulates the liver to release stored glucose into the bloodstream. It pretty much is the perfect counter for insulin.

But its use in this setting is slightly confusing. How does increasing serum glucose have anything to do with beta blocker toxicity?

Yes, glucagon increases glucose release from the liver. But there are also specific glucagon receptors on the heart (surprise, surprise!). (Image) When glucagon binds to these receptors, it stimulates the production and release of cAMP. Increased cAMP levels lead to increased calcium influx into myocardial cells, which in turn enhances myocardial contractility, heart rate (positive chronotropy), and atrioventricular (AV) conduction. This directly reverses the effects of beta blocker toxicity.

Pretty neat, right?

Glucagon should only be given intravenously when used to treat a beta blocker overdose. Dosing generally ranges from 2 to 10 mg as a bolus with a potential to repeat after 10 to 15 minutes. If clinical response is achieved with the bolus, start a continuous infusion at 2 to 5 mg/hr, and titrate the rate to achieve adequate hemodynamic response.

Calcium for Beta Blocker Toxicity

Calcium administration is usually more integral for a calcium channel blocker overdose; however, it may help with beta blocker toxicity as well. How? Great question.

Like we talked about earlier, beta blockers inhibit B1 receptors in the heart → lead to decreased cAMP → reduced intracellular calcium influx → leads to bradycardia, hypotension, negative inotropy, and cardiogenic shock.

So if we give intravenous calcium, this should hypothetically increase intracellular calcium influx, which would counteract the negative cardiac effects caused by beta blockers (particularly the negative inotropy). Calcium does not directly reverse receptor blockade. Instead, it overrides the downstream effects by flooding the myocardium with calcium, helping restore vascular tone and cardiac output.

In terms of calcium products, you can either use calcium chloride or calcium gluconate. Remember, calcium chloride is approximately three times more concentrated in elemental calcium than calcium gluconate (1 g of calcium chloride = 270 mg elemental calcium; 1 g of calcium gluconate = 90 mg of elemental calcium).

Therefore, calcium chloride generally needs to be pushed slower and through a central line if able. How do you choose a calcium product? Simple. Give calcium chloride for severe beta blocker toxicity with major hemodynamic instability and calcium gluconate for more mild/moderate beta blocker toxicities. In terms of dosing:

• Calcium chloride: 1 to 2 g over 5-10 minutes; may repeat every 10-20 minutes for 3 to 4 additional doses or initiate a continuous infusion of 20 to 40 mg/kg/hour titrated to improve hemodynamic response

• Calcium gluconate: 3 to 6 g over 5-10 minutes; may repeat every 10-20 minutes for 3 to 4 additional doses or initiate a continuous infusion of 50-120 mg/kg/hour titrated to improve hemodynamic response

Vasopressors for Beta Blocker Toxicity

If you’ve given IV fluids, atropine, glucagon, and calcium but your patient remains hemodynamically unstable, then it’s time to add a vasopressor. This one is pretty self explanatory in my opinion. Beta blockers inhibit B1, B2, and maybe even A1 receptors (depending on the agent). Vasopressors agonize those same receptors and therefore counteract the toxic effects of beta blockers.

Now we’re not going to go super in-depth on how vasopressors work and all that. We have an entire post on vasopressors. Choosing a vasopressor to reverse beta blocker toxicity is generally institution specific as there is no clear guidance on which pressor to utilize first. That being said, we should still use our clinical judgment when determining which vasopressor to start for our patients.

Like we’ve talked about, not every beta blocker works the same. For example, metoprolol is cardioselective and only inhibits B1 receptors. However, carvedilol is not as selective and usually inhibits B1, B2, and
A1 receptors. When picking a vasopressor, try to use an agent with a mechanism of action that would counteract the effects of whatever beta blocker toxicity we’re treating.

For example, epinephrine agonizes B1, B2, and A1. So if we have a carvedilol overdose, then epinephrine might be our best agent. On the other hand, phenylephrine only agonizes A1 and has no effect on beta receptors. So in this situation, phenylephrine would NOT be the best choice for treating beta blocker toxicity.

High-Dose Insulin Euglycemia Therapy (HIET) for Beta Blocker Toxicity

If you’ve given all the above agents and nothing seems to be helping then you move on this super scary high-dose insulin therapy. High-dose insulin euglycemia therapy (HIET) is very confusing and startling at the same time. I mean, you usually start this infusion at 1 unit/kg/hour but can go up to >10 units/kg/hour.

Let’s just take a moment to talk about how crazy that is. That means if you have a 100 kg patient, there is a possibility that you could crank that infusion to >1000 units/hour. That’s legit madness, folks. (Image)

Before we go into the crazy dosing, let’s talk about how high dose insulin helps with beta blocker toxicity. I’m going to preface this by acknowledging that the mechanism is not completely understood. But there are multiple theories on how high-dose insulin with dextrose may help with beta blocker toxicity. These include:

• Shifts myocardial fuel preference: in a stressed state, the heart’s preferred energy source shifts from free fatty acids to glucose. Beta-blocker toxicity impairs the heart’s ability to use available glucose and fatty acids. So....

  • Give high dose insulin with dextrose → increase the uptake and utilization of glucose by the heart cells → allows the heart to function more effectively

• Positive inotropic effects:

  • Stimulates the phosphatidylinositol-3-kinase (PI3-K) pathway → leads to increased intracellular calcium availability

  • Increases the activity of calcium-dependent ATPase in the sarcoplasmic reticulum → improves calcium inflow into mitochondria → allows for stronger contractions

Long story short, HIET with dextrose provides the heart with more glucose and calcium leading to more “food” and “power” for the heart to pump more effectively. This in turn leads to positive inotropy and reversal of beta blocker toxicity.

Before we go into the dosing of HIET, let’s review some really important points since this is a very high risk medication. For starters, you need to get baseline labs before starting HIET. Baseline labs should include:

• Venous blood gas (VBG)

• Blood glucose

• Serum potassium

• Serum magnesium

• Serum phosphorus

Speaking of labs, remember that IV insulin pushes potassium back into the cells and can cause severe hypokalemia if not treated appropriately. This is very dangerous and can be life-threatening if not accounted for. So remember to always correct hypokalemia prior to initiation of insulin therapy. And in terms of glucose, a dextrose infusion will always be co-administered with HIET. Your goal is to keep the blood glucose between 150-250 mg/dL.

Okay now onto dosing. Each institution has slightly differing protocols regarding HIET. So make sure you review your hospital’s protocol and get familiar with it. But to avoid any bias, I will use the recommended dosing found on LexiComp.

• IV (U-100): 1 unit/kg bolus, followed by a continuous infusion at 0.5 to 1 unit/kg/hour titrated to clinical response.

  • Higher doses (e.g., boluses of up to 10 units/kg and continuous infusions of >10 units/kg/hour) have been administered with good outcomes and minimal adverse effects.

  • Once hemodynamic parameters have stabilized, gradually decrease insulin infusion.

Generally speaking, the benefits of HIET are seen pretty quickly with most cases improving within 30-60 minutes of initiation. So if the insulin infusion has been running for a long time with no benefit, it might be time to move onto our next agent.

I told you there were a lot of treatment options, didn’t I?

Lipid Emulsion Therapy for Beta Blocker Toxicity

On to our last-line agent. This is when everything isn’t working and your patient has failed IV fluids, activated charcoal. atropine, glucagon, calcium, multiple vasopressors, and HIET. Very few patients ever reach this point. But if they do, you have one last option: lipid emulsion therapy.

However, there is a caveat here. Intravenous lipid emulsion (ILE) can’t be used to treat all beta blocker overdoses. ILE is only beneficial in treating lipophilic beta blocker toxicities such as propranolol, metoprolol, and labetalol. It is unlikely to be effective when treating non-lipophilic beta blockers such as atenolol. Why is that?

Because when you give intravenous lipid emulsion, it creates an expanded, lipid-rich phase within the bloodstream. Highly lipophilic drugs preferentially partition or are “sequestered” into these circulating lipid droplets. This decreases the concentration of the free drug available to bind to target tissues. In addition, the emulsion then acts as a “lipid shuttle” and transports the bound drugs from the heart to sites of metabolism and excretion such as the liver.

So, if the beta blocker of concern is hydrophilic, then none of this would occur, and there would be no benefit. Bah.

In terms of dosing, most protocols recommend giving an IV bolus of 1.5 mL/kg of a 20% lipid emulsion solution over one minute. If there is no response, the same dose can be repeated every 3 to 5 minutes for a total of three bolus doses.

The tl;dr of Beta Blocker Overdose

We covered quite a lot of information today. Kudos to you if you made it all the way to the end. In case you didn’t, here’s a quick tl;dr version of everything we talked about…

Beta-blockers primarily block B1 and B2 receptors. Certain beta blockers (e.g., carvedilol, labetalol) antagonize A1 receptors in addition to B1 and B2.

Patients with beta blocker toxicity commonly present with bradycardia, hypotension, cardiogenic shock, altered mental status, bronchospasm, hypoglycemia, and hypothermia.

A step-wise approach to treating beta-blocker toxicity would be IV crystalloid fluid (if hypotensive) → activated charcoal (if appropriate) → atropine → glucagon → calcium → vasopressors → high-dose insulin euglycemic therapy → lipid emulsion.

Activated charcoal may be administered to patients that present within ~2 hours of beta blocker ingestion. Atropine is an anticholinergic agent that is known to increase heart rate by blocking the parasympathetic nervous system (“rest & digest”). A maximum of 3 total doses of atropine may be administered when treating beta blocker toxicity.

IV glucagon treats beta blocker toxicity by stimulating the production and release of cAMP leading to increased calcium influx into myocardial cells. Increase in intracellular calcium enhances myocardial contractility, heart rate, and AV conduction.

Either calcium chloride or calcium gluconate may be administered to treat beta blocker toxicity. Calcium chloride has 3x more elemental calcium than calcium gluconate and generally requires a central line. Calcium gluconate can be administered peripherally but generally requires higher dosing than calcium chloride.

There is no one preferred vasopressor for treating beta blocker toxicity. However, it is always recommended to administer a vasopressor with good B1, B2, and A1 activity, such as epinephrine.

High-dose insulin euglycemia therapy (HIET) may be beneficial in treating beta blocker toxicity as it provides the heart with more glucose and calcium, which in turn leads to positive inotropy and chronotropy. Before starting HIET, it is recommended that baseline labs be collected, including VBG, blood glucose, serum potassium, magnesium, and phosphorus. HIET must always be administered with a dextrose infusion to ensure blood glucose remains between 150-250 mg/dL.

Lipid emulsion therapy may be used as a last-line agent for treating beta blocker toxicity, but it is only beneficial when treating lipophilic beta blocker overdoses, such as propranolol, metoprolol, and labetalol. It is unlikely to be effective when treating non-lipophilic beta blockers, such as atenolol.

But…is that really all you should do? Do you actually know what you’re checking?

Sure, those little boxes of eye drops are quick, easy scripts to check to boost your quota numbers, but do you actually stop to think about these meds beyond them being the right product with the right patient?

Mmmhmm. I hear you.

That’s why today, we’re here to give you the quick rundown on what you need to know about the most commonly encountered eye drops. So you can give those scripts a little more TLC.

Pearls about Medicated Eye Drops

Before we get into the different types of eye drops, let’s talk about these meds in general. There are a couple pearls you should log away (NAPLEX question alert!).

First, as a general rule of thumb, many eye drops can be used in the ears as well. Eye drops are formulated to be gentle and non-irritating to ophthalmic tissues, and they are sometimes used in the ears due to cost or availability. BUT the reverse isn’t true. When ear drops are accidentally instilled in the eyes, they can cause significant burning and pain! (Image)

So be sure to pay close attention to a prescription’s sig, especially whether it says “optic” vs “otic.” And gasp! Sometimes you still get scripts with abbreviations like “OD,” “OS,” and “OU.” As much as you may want to avoid learning those shorthands (because they really shouldn’t be in use anymore with computerized order entry), they are still used. Frequently. I can’t tell you how many times I receive an electronic script with these abbreviations…smh.

As tempting as it may be to think that the “O” stands for “otic,” throw that out the window now. That “O” actually stands for the Latin “oculus,” meaning…you guessed it…eye. Here’s the list for you visual folks:

• OU = oculus uterque = both eyes

• OD = oculus dexter = right eye

• OS = oculus sinister = left eye

Ok, so eye drops in the ears may be a yes. Ear drops in the eyes are a NO.

Now that we have that straight, let’s move on to the next pearl. When you receive a script for eye drops, it’s up to you to determine the days supply of the product you’re dispensing. Normally, this calculation is super easy (e.g., 14 tabs of amox/clav given twice a day = a 7 days supply). However, when the sig is written in drops and the product is dispensed in milliliters, you gotta know one more crucial bit of info.

While there is some variance depending on the medication’s viscosity and the size of the dropper, it is generally accepted that there are 20 drops to 1 milliliter. Another way of looking at this (if you do the math) is that 1 drop is about 0.05 milliliter. Whichever way is easier for you to remember is dandy, just log that away.

Armed with this tidbit, calculating the days supply of an eye drop product becomes much easier. Let’s say you have a script for prednisolone ophthalmic suspension with directions to instill 1 drop in both eyes 4 times a day. It’s a 5 milliliter bottle. That means the patient will use 8 drops/day, which is approximately 0.4mL/day. So the 5mL bottle should last 12.5 days. Voila, you have your days supply (and you can also make sure the patient will have enough for the intended treatment duration!).

Moving on, this is a common question from patients picking up eye drops. “Can I use this with my contacts?”(Image)

Overwhelmingly, the answer is, “No.”

Unless a product is specifically labeled for use while wearing contact lenses (usually a rewetting product), contacts should be removed before using medicated eye drops because they can be damaged by the eye drops. Patients should wait at least 15 minutes after their last eye drop before putting contacts back in.

Let’s get to the drugs now.

Antibiotic Eye Drops

Ophthalmic antibiotics encompass a variety of drug classes and may be single or combination products. As you can imagine, they are used to treat bacterial infections of the eye and eyelid. The ones we see the most include the following:

Key points to remember with antibiotic eye drops will likely sound very familiar to you. Finish the full course of therapy to prevent half-treated infections and bacterial resistance. Discard any remaining product (rather than hanging on to it to self-treat later). (Image)

This is especially important when it comes to eye drops since the product can become contaminated if a patient accidentally touches their eye with the dropper…and then when they pull it out of the cabinet or fridge to use it again 6 months later, badness. Just badness.

Moving on…

Steroid Eye Drops

Next, we have the corticosteroids. Just like with their systemic counterparts, ophthalmic steroids are used to reduce inflammation. This may manifest as eye swelling, redness, and/or irritation, and it could be caused by anything from wearing contact lenses too many days - and nights - in a row (ahem, my younger self wouldn’t know aaaaaanything about this…) to post-surgical to allergies to uveitis to chemical injuries.

Also like their systemic cousins, ophthalmic steroids come with a slew of possible issues. These include cataracts, glaucoma (secondary open-angle), secondary infections, and delayed healing. So choosing an appropriate potency product, using for enough time to quiet down the inflammation, and tapering off are all important tenets of therapy.

Intraocular pressure (IOP) can also be monitored if a patient requires prolonged topical steroids, especially high potency medications. Interestingly, the risk of increased IOP with ophthalmic steroids is significantly increased (5% vs 90%) in patients with a family history of glaucoma, so inquiring about family history is a useful risk stratification tool for devising monitoring strategies.

The Glaucoma Team

Contrary to the plethora of memes that make glaucoma seem easy breezy (Image), it’s actually a very scary - and scarily common - umbrella of diseases. There are 2 types of glaucoma: open-angle (the most common type) and closed-angle (or angle-closure) glaucoma. Regardless of type, the main issue in glaucoma is increased intraocular pressure (IOP) due to an imbalance in aqueous humor production vs drainage. High IOP damages the precious optic nerve. Optic nerve damage, if left unchecked, eventually leads to blindness.

As one of the leading causes of blindness in people over the age of 60, glaucoma sounds like a great space for pharmacists to learn more and improve patient care, right?

That’s why we’re here! On to the medications!

Topical (ophthalmic) therapies for glaucoma focus on decreasing IOP. They do this in 2 ways:

1. Decrease fluid production in the eye, or

2. Improve fluid drainage out of the eye.

Let’s take a closer look at these 2 mechanisms and the drugs that produce these effects.

When it comes to how these medications are used, typically patients are started on a single agent (often a prostaglandin given their relatively low risk of systemic adverse effects). If IOP lowering is insufficient, agents from different classes may be added on for increased effect.

How much do these agents lower IOP? Good question!

In addition to cost and number of times per day they must be used, medications are selected for individual patients based on their local and systemic effects. We’ve already mentioned that the prostaglandins are highly utilized early in therapy due to their tolerability and low risk of systemic effects, but let’s take a moment to compare local and systemic effects of these agents:

They can all cause local burning and stinging, surprise surprise. But yes, you read that earlier sentence correctly. There absolutely can be systemic absorption and effects from eye drops! So just because it’s being applied to the eye doesn’t mean that it’s benign for the rest of the body, especially the beta blockers.

I’m not sure why it’s tempting to think of the eye as isolated from the other organ systems (or maybe that’s just my brain’s way of thinking), but don’t fall into this trap. The eye can be a systemic medication portal too.

Many of these medications are also available in combination products to improve adherence. Speaking of adherence, you wouldn’t think it would be too bad to do an eye drop in both eyes once or twice a day, would you? So why do we worry about adherence so much with these glaucoma regimens?

Well, think about it like this. Patients are supposed to wait at least 5 minutes between eye medications. Consider the patient who is on 2-3 of these eye drops. That’s waiting 5-10 minutes several times a day to do multiple doses. Consider how long it takes you to pop that multivitamin just once a day and how often you miss a dose…and that’s just a quick down the tube! Even an albuterol inhaler only requires waiting a minute between puffs, and people don’t even like to do that!! So how often do you think people actually wait the 5 minutes between eye drops…

Mmmhmm. We’re not exactly a patient society. (Image) So the more combination products patients can use, the fewer the rounds of eye drops, and the less waiting.

Voila, there you have it! The members of the glaucoma eye drop team, lowering IOP and (ideally) glaucoma diagnoses one drop at a time.

The tl;dr of Eye Drop Medications

This post is certainly far from all-inclusive, but hopefully you’ve taken away some ophthalmic knowledge that you didn’t have previously. Now when you encounter those little labeled pharmacy Christmas present boxes at the pharmacy - or when you’re reviewing a patient’s home medication list in the hospital - you will be better informed to do more than just check that NDC number.

A few key takeaways about eye drops:

• Beware abbreviated sigs and be sure that the product chosen makes sense for use in the eyes. Remember, eye drops may be used in the ears, but the reverse is not true!

• Patients should remove contact lenses for eye drop administration and wait 15 minutes before putting contacts back in after instilling drops. Wait 5 minutes between eye drop medication applications.

• For conversions, 20 drops = 1 milliliter.

• Antibiotic eye drops come in a variety of mechanisms, and counseling points are similar to their oral counterparts. Finish the full course, and know that systemic exposure is possible.

• Steroid eye drops are also reminiscent of their systemic cousins, especially as pertains to their plethora of adverse effects. Choose wisely when it comes to potency and duration of therapy to avoid undesirable consequences.

• Topical glaucoma medications either increase fluid outflow or decrease fluid production with the goal of decreasing intraocular pressure (IOP) and preserving the optic nerve. Systemic adverse effects, cost, and frequency of use may dictate the order in which these medications are used.

Being of Southeastern Asian descent, I’ve always had an interest in complementary alternative medicine. Looking through all the herbs and spices inside traditional medicine shops always made me feel like I was in some sort of candy store, where each selection had its own health superpower. But it wasn’t until pharmacy school that I began to truly understand the role that these supplements play in conventional medication therapy. 

In fact, one of my favorite rotations was when I got to participate in a school of integrative medicine, where the students were learning traditional Chinese medicine and acupuncture. Upon first glance, this seemed like an odd elective rotation for a P4 student. After all, weren’t we supposed to reinforce the endless lectures on the pharmacotherapy of conventional medicine?

But in reality, I quickly found that my knowledge of conventional medicine came in handy given the patients seeking complementary treatments were also taking multiple prescription drugs. Knowing how to find, interpret, and educate patients on drug interactions was extremely valuable!

The students and professors at the school also spoke of their deep desire for conventional clinicians (including pharmacists) to have a better understanding of supplements. This is because patients tend to trust us and our advice, and our influence could bring complementary medicine more to the forefront of treatment. The FDA estimates that around 75% of Americans use supplements, so as pharmacists, it is essential for us to understand how prescription and complementary medications work and interact.

What are Supplements?

First, we must dive into a better understanding of what complementary alternative medicine is. Usually this term encompasses many holistic approaches such as acupuncture, herbal supplements, yoga, meditation, and more.

The term “natural medicine” is generally used to describe anything from plant-derived (or “herbal”) products to vitamins and minerals. Additionally, the FDA considers many products to be “dietary supplements,” which can be obtained via prescription or bought over the counter. Given how broad these definitions are, you can see how almost every one of your patients may be using some form of supplementation.  

On the positive side, this means a large majority of Americans have access to and are taking supplements that can help them stay happier and healthier, even if they have little to no access to other healthcare services. But the downside of this is that it is extremely hard for healthcare providers to monitor utilization and advise patients on whether the supplements they are taking are safe and efficacious.

A Quick History of Supplements

This is where a quick understanding of the law comes into play. We know that the FDA regulates conventional prescription drugs for safety and efficacy. Supplements, however, are not regulated in the same manner. They are regulated by the Dietary Supplement Health and Education Act (DSHEA) of 1994, which requires manufacturers to ensure products are safe.

IMPORTANT TAKEAWAY HERE! Read that DSHEA bit again, and notice how this requirement differs from prescription drugs, which have to have proven safety and efficacy through rigorous clinical trials. Another effect of DSHEA-only regulation is that dietary supplement companies can release new products to the market whenever they like since FDA approval is not necessary.

It is also important to understand that companies cannot claim that their supplement can treat or cure a condition (whereas prescription drugs may obtain an FDA-approved indication for specific disease states). However, companies can make claims about the supplement’s relationship to health. A seemingly subtle difference, but this is what that looks like.

For example, a company selling calcium supplements can claim that it helps build strong bones, but it cannot state that their product treats osteoporosis. Like I said, subtle…but a necessary distinction as there have been no studies of that calcium supplement on osteoporosis prevention and progression. So to claim that would be false information!

Even though supplements are not approved by the FDA, that doesn’t mean the FDA isn’t involved at all with them. Here’s what the FDA can do:

• The FDA can periodically inspect the factories that produce the supplements to verify they are meeting manufacturing and labeling requirements.

• The FDA also has the MedWatch service. This is a program that healthcare providers and patients alike can use to report adverse events in response to taking both prescription drugs and supplements. If MedWatch receives any pertinent information, they can issue safety alerts, such as recalls. 

In addition to input from DSHEA and the FDA, the United States Pharmacopeia (USP) sets the standards for supplements by verifying strength, quality, and purity of the ingredients. Supplements can receive a USP-verified mark, which means the following:

• The ingredients listed on the label are actually contained in the product in the amount and potency declared.

• The supplement does not contain harmful contaminants like lead, mercury, or bacteria.

• The supplement was tested against performance standards to guarantee that it will actually break down and release into the body for its intended effect.

• The product was made according to the FDA’s current Good Manufacturing Practices (cGMP), which assures safe, sanitary, well-controlled, and well-documented manufacturing and monitoring processes.

As you can see, all of these processes help regulate purity of the supplement’s contents…but there’s no oversight or guarantee of efficacy or safety for a specific individual. This is where pharmacists come in handy with the knowledge and ability to help patients find the highest quality supplements that also suit their needs.

What’s in a Supplement’s Label

Similar to food items you find at a grocery store, supplement bottles must contain an information label on the back stating its ingredients, the quantity of ingredients per serving, serving size, calories, number of supplements per container, and so forth. Let’s check this one out below:

One of the first things that we as pharmacists should look at is the serving size or recommended daily intake at the very top. That is like the “sig,” and we can use it to help educate patients on how to take the product. Risks with supplements are often dose dependent, so this is especially important (along with drug interactions that we will talk about later).

Next, the suggested use section tells us how and when to take the supplement. This is where patients learn if the supplement should be taken with or without food.

Turning the bottle over to read the label is one of the easiest first things we can do as a pharmacist when helping a patient decide if they should take a supplement and, if so, how and when to do it. Other things to note on the bottle include the health claim or functional description of what the supplement is intended to do. This is where we can use our clinical judgement to decide if the claims make sense.

Moving along, there is a section for precautions, such as avoiding use in heart disease. These are super useful talking points when discussing use with a patient.

Finally, there are storage instructions to keep the supplement in the best form for consumption.

Questions to Ask When Assessing Supplements

As pharmacists, one of our main jobs related to supplements is helping decide if they are safe for patients to use alongside their other medications and disease states. Our ability to ask the right questions should lead us to the most beneficial supplement for a patient.

Because of this, it is important to have a few questions in mind to ask yourself as you help the patient decide if its best to take a supplement or not. 

Does the supplement work? 

Many companies make grandiose claims about ingredients, so it’s important to do some research to see if there have been any studies on efficacy. I’ve found that the National Center for Complementary and Integrative Health is a good place to start. 

Natural Medicine Comprehensive Database and PubMed are also helpful resources. 

What is the mechanism of action?

This is usually a good question to consider when you are trying to determine if the supplement works. Sometimes the supplement’s main active ingredient mimics the mechanism of action of standard prescription drugs used for the same disease state. If they do, this is a good clue that the supplement may be effective.

A great example of a supplement that is used for its similar mechanism of action is berberine in diabetes. Berberine has been shown to have many properties such as activating AMP-activated protein kinase and inhibiting gluconeogenesis, along with its anti-inflammatory and antioxidant effects. We know that metformin, a frequently used prescription drug for diabetes, also activates AMP-activated protein kinase and inhibits liver gluconeogenesis.

What this means is that both metformin and berberine act on similar metabolic pathways to inhibit the process of making more glucose (gluconeogenesis), which if left unmanaged causes sugar spikes in diabetes. So you can see how there would be some folks who think that they can just take berberine instead of metformin, assuming it will have the same therapeutic effects. Or they might even take both berberine and metformin for additive effects.

Either of these scenarios could have undesirable consequences, including uncontrolled diabetes due to lack of berberine efficacy, increased risk of adverse effects from increased levels of metformin in the presence of berberine, and/or increased risk of hypoglycemia from the combination.

Is the supplement safe to use?

Just as mechanism of action can help us decide if it’s an effective supplement, it can also help us understand if it is safe to use. Adding on a supplement with the same mechanism and/or adverse effect profile as the patient’s current prescriptions can lead to serious drug interactions.

A great example of a supplement that should be carefully monitored is kava. Kava is known for its anxiolytic benefits. However, kava has been found to inhibit enzymes needed for the metabolism of many drugs, leading to higher systemic concentrations. Kava also depletes glutathione, an essential antioxidant for metabolizing alcohol.

If kava use is unregulated or unmonitored in a patient with preexisting liver disease or alcohol use disorder, they could be at a significantly higher risk of alcohol/drug overdose. As a result, it is extremely important to ask patients about preexisting conditions to get a better picture of whether a supplement is right for them.

What is a safe dose?

Like prescription drugs, supplements must be taken correctly. This is especially important if we want to prevent overdoses. The NIH has a useful nutrient recommendation database with recommended dietary intakes based on things like age and gender. Some vitamins are water soluble, meaning there’s a little more leeway when it comes to taking too much at one time as excess product is flushed out of the system through urine. But this is not the case with fat soluble vitamins, which include vitamins A, D, E, and K. Being fat soluble, they get stored in the body’s tissues, and overdoses may lead to adverse effects ranging from diarrhea, vomiting, and hairloss to more severe symptoms like kidney stones and hemorrhaging.

So the next time a patient asks about supplements, be sure to help them decide on an appropriate dose. 

What medications and/or other supplements are they currently taking?

Just like we must watch for drug-drug interactions, it is important to also consider any additive adverse effects when combined with the patient’s current medication/supplement list. NatMed Pro has a drug-supplement interaction checker, which can come in handy. 

You may recall that many drugs are metabolized through common enzyme pathways, such as the CYP450 enzymes. It’s essential to know if a supplement inhibits or accelerates these metabolic pathways. For example, the notorious St. John’s Wort supplement used for depression is well known to strongly induce CYP3A4, CYP2C9, and CYP1A2. So it can interfere with the efficacy and safety of many drugs that are also metabolized through these common pathways.

Just for a few examples… St. John’s Wort can decrease the efficacy of many birth controls and lead to increased risk of pregnancy. It is also serotonergic, so it should be completely avoided with MAO inhibitors. There’s also danger at high doses with SSRIs and SNRIs. It can lower the seizure threshold and increase risk of seizures, so it should be avoided with medications like bupropion. St. John’s Wort can also cause photosensitivity, so pharmacists should counsel patients on sun protection and increased caution with other photosensitive medications, like retinoids or sulfa drugs. 

Yep, believe it or not, St. John’s Wort is available OTC. Even with all of those potential effects. The takeaway here? Always remember to treat supplements like prescription drugs and check for interactions!!

The tl;dr of Supplements and Herbals

As you can see, there are numerous supplements that can benefit patients. However, it is important to remember that they have adverse effects and drug interactions that we need to be aware of. Because of this, pharmacists play a key role in assisting patients with discerning if a supplement is right for them given their unique disease states and prescription medications. We can help them find supplements that are not only safe but also effective.  

So the next time you are helping a patient look at some supplements remember to ask yourself:

• Does this supplement work?

• What is the mechanism of action?

• Is it safe to use?

• What is a safe dose?

• What other medications or supplements are they currently taking?

Useful resources include the supplement’s label, NIH, FDA/Medwatch, NatMedPro (aka Natural Medicines Comprehensive Database), and your favorite clinical resources, such as Clinical Pharmacology and UptoDate/Lexicomp.

Supplements are very accessible, but so are pharmacists. So next time a patient comes by to ask about them, be sure to help guide them through the process of getting the appropriate ones that will help - not harm - them.

Here at tl;dr pharmacy we try to touch on the subjects that are commonly requested by our pharmacy peeps. Things like how to study for multiple choice tests, PCOA, MPJE, and even the CPJE. We’ve even written on how to memorize drug side effects (and on developing a study system).

So it’s only right we talk about the most important test that every single pharmacy student has to pass in order to practice. The test that your pharmacy school is training you for (because your performance is crucial to keeping your school's accreditation in good standing).

The NAPLEX. The North American Pharmacist Licensure Exam.

Let's dig in.

By the way, if you’d like a downloadable (and printer friendly!) PDF of this article, you can get one of those here. Also, if you need help preparing for the NAPLEX, check out the NAPLEX resources we currently provide. More on those resources later.

NAPLEX Background 

Similar to my other test reviews, I'm not going to dig too deep in the background. It's all available online (from the people that make the test), and it's better to get that info straight from the horse's mouth.

Plus, I suspect that's not what you're reading this for anyway.

That said, it is worth mentioning a few highlights given the new NABP updates that took place in 2025.

For starters, let me point you to the NAPLEX page on NABP. This is where you're going to get the most up to date information about registration, cost, and availability. 

Of note, I'd recommend checking out the NAPLEX Registration Bulletin on that page. I'd link it here, but NABP updates it pretty regularly so you're better off clicking the link above and getting the most up to date version. 

Anyway, the registration bulletin is super handy. It's around 50 pages and you should read through all of it. It gives you a complete breakdown of the competencies (i.e. what is tested) as well as some sample questions (you know I love me some sample questions!). Speaking of competencies, let’s review these quickly.

I am not going to dive super deep into this because it can be found in the bulletin linked above. But I did want to touch base on the most recent NAPLEX updates. As of May, 2025, the NABP revised and reorganized the competency statements to better align with current pharmacy practice. The structure and length of the exam did not change but the blueprint was updated. What exactly does this mean for us test takers?

Really, these “updates” are just a fancy way of saying “the NAPLEX is now a lot more case-based and clinical than it ever was before”.

Here’s a side-by-side table I made to compare the “old” and “new” NAPLEX.

Other important things the registration bulletin covers include what to bring to the test center and what types of IDs are acceptable.

Actually, on that note.

This personally bit me in the behind, and I had to reschedule my NAPLEX.

Why?

Because I registered for the test as "Brandon Dyson" and my ID reads "Brandon Michael Dyson." 

It turns out that I am not a very smart man. So, learn from my foolishness. Read the registration bulletin and make sure you have acceptable forms of ID that match your registration name. 

Types of Questions on the NAPLEX

The NAPLEX is a whopping 225 questions long. Of these, 200 questions are scored ("real") and 25 are unscored ("experimental").

The experimental questions are test questions that are evaluated for use in future NAPLEXs. They don't affect your score. They are mixed in throughout the test, and there is no way to know if the question you're looking at is real or experimental. 

So, before you ask, the only way to truly approach the NAPLEX is to assume that all 225 questions are real. There's no way to game the system out of taking the experimental questions. 

Let's talk about the types of questions that are on the NAPLEX...

First, some good news. They've phased out the K-type questions that are the bane of pharmacy students everywhere! 

But...

They've replaced these K types with questions that are (in my opinion) even harder. Multiple response questions.

Here's a quick breakdown of the types of questions you'll be pitted against (and how to prepare for them) on the NAPLEX.

Multiple Choice

The classic question you're familiar with. You select only the most appropriate answer. This means that only one answer can be right.

The best way to approach these questions is to narrow your options by eliminating answer choices. Use contradicting answers and polarity words (such as "except," "not," "always," and "never") to weed out answer choices. 

We cover a whole bunch of ways to do this in Pharmacy School: The Missing Manual, but the general gist is to whittle your potential answers down to 1 or 2. 

Multiple Response

These are the little devils that have replaced K-type questions. In other words, they have usurped the Iron Throne and have become the most hated type of question in all of The Seven Kingdoms. 

They are the dreaded "Select ALL that apply" questions...and they're annoying AF. 

The only real way to handle these types of questions is to treat each answer choice as a true or false statement. Ignore everything else, and just evaluate each choice individually.

This helps to reduce the "overwhelm" the multiple response questions can bring.

It's true or false, yes or no, black or white. There is no room for "maybe" (at least not if you want to get the question right). 

Constructed Response

These sound hard on the surface, but they are really not that bad. With a constructed response question, you are filling in the blank (by actually typing in your answer).

In practice, the NAPLEX tends to use these for your calculation questions. So you'll have to actually calculate an answer and type it in (instead of picking from one of the multiple choice options).

The (obvious) thing to watch out for is to make sure you enter your answer in the correct format. If the question calls for 2 decimal places, make sure your answer has 2 decimal places. It'd be a real shame to have the right answer but miss the question because you didn't follow directions. 

With that in mind, make sure you brush up on your rounding. If the NAPLEX asks for your answer to be rounded to the nearest whole number, make sure you're doing that correctly. 

Also, double check yourself for typos. Typos are really bad here.

Ordered Response

As the name sort of implies, here you're given a list of options and your job will be to rank them. 

You might be asked to rank corticosteroids from greatest to least potency. Or the strength of a few types of statistical studies. Or the potency of statins. 

There's not really a NAPLEX study hack for these. You just have to know the information. 

Hot Spot

Yay! There's pictures! With Hot Spot questions, you are given a diagram and you are asked to select the correct portion of said diagram that pertains to the question.

These are mostly used with mechanism of action questions. You might get asked where in the clotting cascade rivaroxaban works. Or what part of the HIV life cycle is inhibited by abacavir. Or how to dose vancomycin to ensure CNS penetration. 

Again, there isn't really a "trick" to these questions. But it's usually basic pharmacology (mechanism of action) being tested. Just know the info, and answer accordingly. 

How "Clinical" is the NAPLEX?

You've probably heard that the NAPLEX has been getting more "clinical" over the years. This is now more true than ever. There are more scenario based questions where you are given a clinical case and asked to interpret questions about it. 

That said, the NAPLEX is still a minimum competency exam. 

I hate the phrase "minimum competency exam." It implies that the NAPLEX is easy. Or that you are somehow inadequate if you don't pass it. Neither of these is true. The NAPLEX is NOT easy, and a lot of really great pharmacists have failed it a time or two.

Don't let your ego convince you that you don't need to study that much. You need to prep for this exam like it's the most important one you'll take in your life (because quite possibly, it is).

The real meaning of "minimum competency" is that the exam is more focused on safety. This means you need to give extra weight to studying contraindications and black box warnings.

The goal of the NAPLEX is to make sure you can practice pharmacy without killing someone. You are more likely to get asked about a rare (but potentially fatal) side effect than you are to get asked about the 4th line of therapy in a patient with refractory hypertension and Stage 4 CKD.

Prioritize your studying accordingly.

Minimum competency also means that the NAPLEX won't ask many questions that are ambiguous or in a clinically gray area. The questions asked won't be open for judgement. They should be black and white, "yes or no" type situations.

Remember that, and remember it well. Especially if you're someone who is prone to talking yourself out of the answers you've picked.

Given enough time, you can make an argument for just about anything on a test. Resist your temptation to do that on the NAPLEX. 

How Long Do You Need to Study for the NAPLEX?

This is, of course, a tough question to answer. And my "politician" answer will be...

"It depends."

That said, you're here because you want answers. So let me see what I can do. 

A quick google search says the average recommendation is 6-8 weeks of focused prep with 2 to 3 hours per day on weekdays and 4 to 6 hours on weekends. However, different students have different needs. In my personal experience, my recommendation is as follows:

• Fast-track/Strong Student:

  • 3 to 4 weeks of review, focusing on calculations and high-yield disease states (more on this shortly)

• Average Student (most candidates):

  • 6 to 8 weeks with structured daily blocks (therapy + calculations + practice)

• Need more support:

  • 10 to 12 weeks with gradual content review before ramping up questions

Depending on how intensely you study, I think you can prep for the NAPLEX in 3 - 8 weeks on average. Can you do it in less (or more) time? Yes, but it really just depends on your study style.

Some people (fueled by gallons of coffee) can continue retaining information after 8 solid hours of studying. Others can't. It really requires you to self-evaluate and see where you are.

In my continued research, Google led me to a surprising number of forums where people claimed to not have studied at all. Many just practiced calculations, passed the NAPLEX, saved the princess, and lived happily ever after. 

In my opinion, that's a hell of a risky proposition. If you have to err on the side of being over or under prepared, which would you rather be?

Outside of the $575 you're spending to take the exam, the NAPLEX is also one of the only things standing between you and a decent income. Waiting 45 days for a second attempt is only costing you money.

Plus if you're doing a residency, most programs require that you pass the NAPLEX so you can complete the "distribution" requirement of their program. Fail the NAPLEX more than once, and you may have a difficult conversation with your residency program director. 

So, my best advice is to study for the NAPLEX for as long as it takes you to feel over-prepared. Best to leave nothing to chance with so much at stake. For most people, this should be achievable in 3 - 8 weeks.

Sample NAPLEX Study Calendars

Although not really my style, many students like the structured format of a study schedule to help guide their NAPLEX studying. There are a few nifty ones floating around online (links below).

I was going to create a tl;dr NAPLEX study calendar for this article, but honestly it seemed like I was re-creating the wheel. There are already so many posts and sample calendars that can be found online. I'm not sure what value I'd be adding to the world if I created another one.

So, without further ado, here is a sample calendar that you can imitate to help you prepare for the NAPLEX.

I would use that as your baseline, and personalize it to your own studying. For myself, I think I would start forgetting material with a 7-month study plan, so I'd condense that calendar into 1 or 2 months if I was taking the NAPLEX again. 

NAPLEX Review Guides

So, now that we've got a calendar laid out for us...what should we actually use to study for the NAPLEX?

Should you go for the live review? The book only? The question bank plus the book? Should you use different programs to capitalize on the strengths and weaknesses of each?

You can really stress yourself out wrapping your brain around questions like that.

And if you're not careful, the decision paralysis you feel trying to sort through all of that information can really set you back.

The old adage "Don't let the perfect be the enemy of the good" applies here.

Don't bog yourself down with the (somewhat meaningless) decision on what is the perfect NAPLEX studying program. Just pick one, and move on.

Then, study the shit out of that one resource. 

Truthfully, most available NAPLEX study guides are good enough to get you to pass the NAPLEX. So pick the one that best fits your learning style and go from there.

Tl;dr Pharmacy NAPLEX Resources

Not to be biased, but I personally think that our NAPLEX resources are some of the best products out there. Is it because we created them? Yes. Just kidding. No.

The reason I think our products provide value is because they were made in compliance with the new NABP guidance. We imitated the real NAPLEX test to the tee. Here’s the highlights:

• The exam has 225 questions and is timed for 6 hours (just like the real exam)

• You can leave and re-enter the exam tot ake breaks at the two and four hour marks (just like the real exam)

• The questions and answer choices are randomized (just like the real exam)

• The exam will automatically fail if you are gone for more than the half hour break you are given (You guessed it. Just like the real exam)

• The results include rationale and references for each answer choice

• The purchase gives you access to the exam for up to three (3) attempts

• The purchase is good for twelve (12) months

If the practice exam is not good enough, we also offer private, 1-on-1 online tutoring sessions with out very own Josef Hadib Nissan, PharmD, BCPS, BCCCP. Each session includes a pretest in a specific content area followed by an hour long tutoring session focused on your specific needs. Some of the highlights include:

• Each pretest comes with questions designed like the NAPLEX

• Ability to choose the time for the one-on-one session that works best for you

• Ability to buy as few or as many sessions as you need to prepare for the exam

Other NAPLEX Review Programs

UWorld RxPrep and Kaplan are two other very popular programs that we can recommend. Personally, I used the UWorld RxPrep book to study for the NAPLEX. I still have it. That 500-page monster still sits in the corner of my room. Gives me PTSD every time I look at it.

If you have used some other NAPLEX prep service and are willing to give me feedback on it, email me at brandon@tldrpharmacy.com. I'll update this article to make it more comprehensive for readers. Thanks in advance!

How to Study for the NAPLEX

And so here we are, finally. After all of that background and study calendars and review guides talk, we get to talk about how to actually study for the friggin NAPLEX. 

What follows are my best general NAPLEX studying tips, as well as the "target areas" that I recommend you spend a little extra time studying.

General NAPLEX Tips 

Take the Break

I know you just wanna get the hell out of the exam room, but when you are given the option for a break (there are potentially a couple offered), do yourself a favor and take it. 

You have up to 6 hours to take the NAPLEX (the optional breaks don't count against your time). Imagine how intensely focused you are during an exam. Imagine doing that to your body for 6 hours. Trust me, you WILL burn out, and you will get sloppy on the second half of your exam.

Better instead to take your break. Walk around, stretch, maybe get a light snack. Take some deep breaths and just try to put your mind literally anywhere else for a few minutes. It'll be worth it.

Be (Potentially) Prepared to Travel

You'd be amazed how fast the exam sites near you can fill up (especially if you're in an area with several pharmacy/nursing/med schools nearby). Try to register as early as you can, but if sites are full, be prepared to travel a little further to the next site. Luckily, COVID times are over now so there should be more availability. But back in COVID times (not that long ago tbh), recent grads had to travel to other states just to take the NAPLEX.

Be Prepared for the Exam Room

You, unfortunately, do not have control of the thermostat in the exam room. Make sure to bring a jacket if you get cold easily. Keep in mind that you are NOT allowed to remove anything that goes over your head (like a hoodie) in the exam room, so make sure it's an easily removable jacket. 

Have a Few Marathon Study Sessions

So, you have 6 hours to answer 225 questions (that's about 90 seconds per question, for those keeping track at home). How much time do you usually spend studying?

If you max out at 1 or 2 hour chunks, you need to practice sitting down and giving laser focus to something for 6 hours (and no, I don't mean binge watching This is Us).

In the age of smart phones and tik tok, our collective attention spans are dwindling. As it gets closer to exam time, schedule yourself a few "marathon" study sessions where you ONLY study for at least 6 hours.

Really own these practice sessions. Turn off your phone, use a browser blocker to block Facebook, Youtube, or whatever else might draw your attention away.

I even recommend taking our practice NAPLEX test to help mimic the real exam.

Only 2 or 3 sessions should be enough. You just want to make sure that you know what it feels like to be in a pressure cooker for 6 hours. 

Use the Scratch Paper Provided

The exam center will offer you some scratch paper before going into the exam room. USE THIS. Even if you don't normally use scratch paper during exams.

You may need to sketch out an odds ratio table, or figure out the number needed to treat. Maybe you just need to sort out your thoughts and a quick diagram will help. Maybe you just want to compulsively doodle. 

This is a scenario where it is better to have and not need than to need and not have. If you come across a question where you'd benefit from being able to draw it out, you'll regret not taking the paper. 

Answer Every Question

Unanswered questions are the bane to your NAPLEX score. Unfortunately, you can't skip around during the exam, and once you've submitted your answer it's lost and gone forever. 

You have to keep yourself on pace to finish the entire exam. Of course, blindly guessing on 30 questions in the last 10 minutes isn't going to help your score much more than leaving the answer blank. 

So the take home message here is not to spend too much time on any one question. If you truly don't know the answer to a question when you first look at it, it's unlikely that you're going to have a magical epiphany after staring at it for 4 minutes.

Try your best to narrow down the answer choices and move on. 

Be Prepared for a Ton of Patient Cases

One of the ways the NAPLEX has gotten more "clinical" in the last couple of years is by incorporating more patient cases. Make sure you can (quickly) figure out what the question is asking and answer the question.

The only real way to do this for speed is to practice. But here's a big "pro tip" to help you out.

Do not read the entire case (at first). Instead, just skip to the part at the bottom that has the actual question (hint: it's usually followed by a question mark). 

Many (many) patient case questions will give you a full background of HPI with social history, family history, a set of labs, a list of medications, and so on. Then the question at the bottom will be "Which of the following drugs could be increasing the patient's potassium?"

You don't need an entire patient case to look at a list of drugs and pick one that causes hyperkalemia. You can save yourself a bunch of time (and mental bandwidth) by skipping ahead to the question, seeing what information is needed, and then going back and scanning through the case to find it.

As another bonus, the same clinical scenario is often used for several questions in a row, so don't feel compelled to re-read the entire thing every time. Remember, you're on a strict timer. 

Do Every Practice Question You Can Get Your Grubby Little Mitts On

As I've said (dozens of times on this site), practice questions are a huge part of my prep strategy. They are the only "brass tacks" way to identify what you know (and what you don't).

The key is to go through each question and to know why each answer choice is correct or incorrect. This way, each question actually prepares you for multiple questions that might test the same subject. 

I know times are tight as a student, but these questions will force you to start remembering what facts are often tested. Plus, you need a lot more mental focus on a practice exam than you do going through your notes.

Reading your notes or a chapter in RxPrep still allows you the mental space to daydream. Your mind can and will wander. That's much less likely on an actual exam, because of the intense concentration needed.

Since the NAPLEX is just a big ole collection of test questions, the best way to prepare is by...you know...doing test questions. 

We made a practice NAPLEX test that is as close to the real thing as you can get. It’s the best way to prepare yourself for actual exam. You can check out our Practice NAPLEX here.

You Will Never Feel 100% Prepared

Don't push back your test date (outside of family emergencies or other pressing issues). Just take the plunge and knock the exam out. 

Also, it's normal to feel like you failed after taking the exam. Almost everyone does. Just relax and wait. Have a glass of wine and re-watch Pitch Perfect. 

Scores are usually posted on NABP within 2 - 3 business days. You are NOT emailed about when they post, so you'll just have to keep obsessively checking every so often. Fun, right?

Specific Areas to Study for the NAPLEX

The NAPLEX is no longer an adaptive test, which is kind of a good thing. The adaptive model basically had a tendency to highlight what you DON'T know, because when you missed a question on a given area (say, HIV), the test would "adapt" by giving you more HIV questions. 

So when you've heard people say that they felt like their entire NAPLEX was HIV or oncology questions, that's why. 

And, that shouldn't happen so much anymore with the new format.

But, there are probably some areas you still need to brush up on. The obvious place to start would be any therapeutic area where you don't feel comfortable. You'll have to self-reflect and assess that for yourself. 

Beyond that, there are some key areas that most students tend to struggle with.

Or, even if you don't struggle with them, they are emphasized so much on the NAPLEX that you need to brush up on them. 

I'd recommend making sure you are set in all of the following areas.

Brand/Generic

NAPLEX questions usually only include the brand name. If you don't know what the generic is, how are you ever going to answer the question?

You can know every single clinical fact about ticagrelor. But if you don't know that it's Brilinta, you'll miss the NAPLEX question anyway. 

There are a dozen resources on Amazon for the Top 200 (or even Top 500) drugs. Just pick one of those and get to memorizing.

Calculations

Look, pharmacy math isn't hard. If you can cross-multiply, you can be a pharmacist. 

But on the NAPLEX, you have to be able to do those calculations with speed. Remember, you get less than 90 seconds per question. And calculations are "over emphasized" on the NAPLEX (because they're that important).

You need to practice calculations until your brain is numb. 

NAPLEX math questions are often not "one step" problems. You may have to make several calculations to figure out what the question is actually asking for. And the steps are not spelled out for you. You have to figure it out for yourself.

It's already a high-stress environment. Don't make it worse by fumbling through calculations that (should be) easy points. Practice calculations, and practice them often. Practice them by the hundreds.

Remember, the NAPLEX is a minimum competency exam. If you cannot demonstrate basic math skills (used to calculate doses, drip rates, and all sorts of stuff) in the time allowed, you will not pass the test. 

Statistics

Another side effect of the NAPLEX getting more "clinical" is an increased emphasis on biostats and literature evaluation.

Guidelines change. Practice changes. And the only real way for you to keep up (and continue to be a competent pharmacist) is to be able to read and interpret clinical literature.  On top of that, stats is a subject where most students want to burn their notes after they've passed the module. 

Luckily, tl;dr pharmacy has your back. 

Here is our guide on biostats and literature evaluation. This guide has a total of four parts so be sure to read them all.

My recommendation would be to take the amount of time you think you need to spend on stats preparation, and double it. Yes, stats are THAT emphasized on the NAPLEX. 

At a minimum, make sure you're comfortable with ARR, NNT, OR, RR, and every other fun acronym from your stats class. Also, be able to recognize what kind of statistical test is appropriate for a given type of data.

Again, check out our post above for some help. 

Sterile Compounding and Hazardous Drugs

Didn't think this would show up here, did you?

But guess what, this is now tested on the NAPLEX (as of the recent updated). If USP 797 (sterile compounding) and USP 800 (hazardous drugs) are as foreign to you as they were to me when I was a student, you will be missing out on the NAPLEX. 

Don't do that. 

Spend some time learning about beyond use dates, low vs. medium vs. high risk compounding, and how to properly sterilize a hood.

Drugs with a Narrow Therapeutic Index

The logic here is simple. These drugs have a narrow therapeutic index, and therefore are prone to causing toxicity.

I like to call these "drugs that keep pharmacists employed." 

You need to at a minimum be familiar with preventing, identifying, and treating associated toxicities with these drugs. Also, it wouldn't hurt to be rudimentarily familiar with the basics of dosing (at least be able to recognize that 6 grams BID is a bat-shit crazy dose for vancomycin).

Here are some articles that you might find helpful:

• Vancomycin

• Phenytoin

• Aminoglycosides

• Warfarin

Other Clinical Areas You May Be Rusty On

Like I mentioned above, it pays to spend some time focusing on areas where you're uncomfortable (or that are highly emphasized). 

Most students (and most pharmacists for that matter) could use an occasional brush up in the following areas.

• Antibiotics - At a minimum, know what drugs treat the resistant pathogens (MRSA, Pseudomonas, C. diff, and all of the ESKAPE bugs).

• Antifungals - What agent treats what fungus? What relevant drug interactions exist (especially for voriconazole and the other azoles)? I'd also recommend knowing the many formulations (and which are equivalent) for itraconazole and posaconazole.

• HIV - Especially the brand names of the combo products and what makes a complete regimen. Also drug interactions with protease inhibitors etc...

• Oncology - Know the dose limiting toxicities and adverse effects of common chemotherapies. This post should more than cover what you need to know for the NAPLEX.

• Anticoagulation - Every drug here has a narrow therapeutic index and it's a high-impact area for pharmacists.

• Vaccines

Final Thoughts on How to Study for the NAPLEX

The NAPLEX can be stressful. I’ve been there before. It can feel like your entire pharmacy career depends on this one exam. But with the right preparation, you’ll ace it! Remember, the NAPLEX is a minimum competency exam and the national pass rate average is about 80%. And if you continue to feel unprepared and need some further guidance, book a private NAPLEX tutoring session with us!

Good luck! 

Let’s talk about osteomyelitis, which is the infection that says, “I could’ve just been a skin abscess, but I’m feeling extra today.” This is what happens when bacteria get ambitious and decide to colonize your skeleton like it’s the Oregon Trail. Only, instead of settlers, it’s Staph aureus, and instead of wagons, it’s biofilm. So buckle up, if you like long courses of antibiotics, MRSA, and radiology reports that might as well be in Latin, you’re in the right place.

What the Heck Is Osteomyelitis?

• Bone infection. Not cute.

• Most common culprit? Staph aureus. Bonus points if it’s MRSA, because of course it is.

• Can be acute (new mischief) or chronic (lingering nightmare).

• Requires weeks of IV antibiotics, maybe surgery, definitely drama.

• You’ll need labs, imaging, cultures, and a good therapist (for you, not the patient).

How Does This Happen?

Osteomyelitis is basically just a bacterial field trip gone wrong. Here’s how they get there:

1. Hematogenous Spread – Bacteria catch a ride in the bloodstream like it’s an Uber to the femur. Common in kids and the elderly.

2. Contiguous Spread – That diabetic foot ulcer that’s been ignored for 8 months? Yeah, it finally RSVP’d to the bone.

3. Direct Inoculation – Trauma, orthopedic surgery, open fractures, or that one time someone thought “cleaning the wound with motor oil” was a good idea.

Once inside, the bacteria throw a biofilm rave, shut down the bone’s defenses, and make themselves at home. Ever tried evicting a tenant with squatters’ rights? It’s like that. But in your spine.

Who’s on the VIP List?

• Diabetics (especially with zero foot sensation and questionable shoe choices)

• Patients with hardware (prosthetic joints, rods, you name it)

• People with crap circulation (PVD, dialysis patients, the eternally cold, individuals with sickle cell disease)

• IV drug users (because bones apparently looked like a fun place to inject by proxy)

Clinical Clues: Red, Swollen, Angry Bone Vibes

• 🔴 Localized pain – Think “hurts when I move it, hurts when I don’t.”


• 🔥 Fever – Optional, because bacteria love to keep things unpredictable.


• 🌋 Redness/swelling – Cellulitis’ evil twin.


• 🚿 Drainage – Especially in chronic osteo. Might look like pus. Might smell like regret.

Labs and diagnostics you'll pretend aren’t as bad as they are:

• ↑ WBC – Classic.

• ↑ ESR/CRP – Because inflammation is a lifestyle.

•  💉 Positive blood cultures – Sometimes! Don’t get too excited.

• 🧲 MRI – The gold standard because X-rays are like “I’ll show something… in a few weeks maybe.” There is typically a lag of about 10-14 days. Don’t wait by the phone.

Bugs and Drugs: AKA “Which IV Do We Hang Today?”

The Greatest Hits:

• Staph aureus (the Beyoncé of bone bugs)

• MRSA (because life isn’t hard enough)

• Strep species

• Pseudomonas (in IV drug users or diabetic feet that have been marinating)

• Enteric Gram-negatives

• Salmonella (look out for this in your sickle cell patients!)

• Anaerobes (you’ll smell them before you see them)

Empiric Antibiotic Regimen:

• Vancomycin (because it’s not osteo without it)

++PLUS++

• Something Gram-negative friendly like cefepime, ceftriaxone, or piperacillin-tazobactam (Zosyn) (for when you really want to cover the whole periodic table)

• Feeling extra polymicrobial? Add metronidazole or just go all in with Zosyn and question your life choices later.

Key Principles

• Start empiric antibiotic(s) after cultures unless the patient is already septic.


• Target high bone penetration and biofilm activity when hardware is involved.


Duration?

• 4-6 weeks minimum, and that’s if you’re lucky.

• Chronic cases? Sit tight—you're looking at 6+ weeks, maybe lifelong suppression if that metal’s staying in there.

And yes, oral step-down might be on the table, but only if:

• The bug is pansensitive,

• The patient is reliable,

• And ID gives it a reluctant nod.

Pathogen-Directed Therapy

Oral Step-Down Therapy Evidence

As an Antimicrobial Stewardship Specialist, it would be borderline sacrilegious not to talk about the OVIVA trial since it basically rewrote the gospel on bone and joint infections.

The Oral versus Intravenous Antibiotics for Bone and Joint Infection (OVIVA) trial, published by Ho-Kwong Li et al (NEJM, 2019) tackled a long-standing dogma in infectious disease: that bone and joint infections need 6+ weeks of IV antibiotics. Researchers randomized over 1,000 patients with confirmed bone or joint infections to receive either standard IV antibiotics for 6 weeks or switch to oral therapy within 7 days. The result? Oral therapy was non-inferior to IV in terms of treatment failure at 1 year (13.2% oral vs. 14.6% IV), meaning patients did just as well without the PICC lines and infusion pumps.

Why it matters: This is a big deal, especially for antimicrobial stewardship and outpatient care. Oral regimens were easier, cheaper, and came with fewer line-related complications (like bloodstream infections and thrombosis). The study included a wide range of infections (including prosthetic joint infections), and the oral regimens were selected based on susceptibility and good oral bioavailability (think fluoroquinolones, rifampin, linezolid, etc.). Bottom line: in stable patients with bone or joint infections and good oral options, early switch to oral antibiotics is not just safe — it’s smart, like you!

Oral Step-Down Therapy Options

• Linezolid → reliable MRSA oral option, but monitor for myelosuppression and serotonin syndrome.
Super conveniently, a 1:1 IV:PO conversion.

• Fluoroquinolones (cipro, levo) → excellent bone penetration; resistance and QT prolongation risks.


• Clindamycin → good for susceptible MSSA/MRSA; beware GI upset and C. diff.
Remember, just one dose of clindamycin puts your patient at risk for C. diff! Be mindful of your local antibiogram because it may suck at covering some common Gram-positive bugs.

• TMP/SMX → decent bone penetration; often combined with rifampin for biofilm-related Staph.

Biofilm Considerations

• Rifampin = MVP when hardware is present and Staph is cultured.

  • Start after source control and after bloodstream clearance.


  • Check for CYP interactions (warfarin, antiepileptics, DOACs).

Choose Your Own Nightmare: Special Cases Edition

Diabetic Foot Osteomyelitis

• Polymicrobial dumpster fire.

• Start with broad-spectrum everything. Narrow once you tame the chaos.

• Usually needs debridement, wound care, and probably new shoes.

Vertebral Osteomyelitis

• Patient says: “My back hurts.” You say: “That’s normal.”

• MRI says: “Surprise, it’s osteo.”

• Can be Staph, but don’t forget TB if they’ve traveled, coughed, or just have bad luck.

Hardware-Associated

• Because bacteria LOVE prosthetics.

• Surgery + long-term antibiotics is your only hope.

• Rifampin may help nuke biofilms, but only when used with other agents. Never solo, unless you’re trying to breed resistance in a petri dish.

PharmD Pro Tips 💊

• 🧠 Vanc kinetics = Your moment to shine. Get that AUC/MIC on point or forever hold your peace.


• 🧪 Culture the bone. Not the drainage. Not the toe jam. The bone.


• 📆 Track antibiotic start dates. Because a “4-week course” that lasts 87 days isn’t cute.


• 📉 Monitor CRP/ESR weekly. Not diagnostic, but if it’s trending down, your patient might be too.

• And yes, always call ID. Osteo is not a DIY infection. Unless your idea of DIY includes necrosis and malpractice.

TL;DR of the TL;DR (for your pre-rounding brain)

Osteomyelitis = infected bone. Usually caused by Staph, treated with IV antibiotics for 4-6 weeks, and best managed with ID on speed dial. MRI is your bestie, oral step-down is a maybe, and CRP is your mood ring for progress.

Final TL;DR Summary

Treating osteomyelitis is like babysitting a gremlin. It looks like you’ve got it under control, but blink once and suddenly it’s wearing hardware, leaking pus, and asking for a PICC line.

So take a deep breath, hang your vancomycin, and remember: bones may be hard, but osteo is harder.