USMLE1 For Dummies

USMLE1 Pharmacodynamics - Antagonists

2011-09-23T12:23:00.000-07:00

Antagonist : Drugs that interact with receptors to interfere with their activation by agonists.

Can be classified as:

· Competitive

· Non competitive

Can be classified as:

· Pharmacologic : same receptors

· Physiologic : diff receptors

· Chemical

· Competitive antagonists cause a parallel shift to the right and can be reversed completely by increasing the dose of agonist drug.

In effect ,such antagonists appear to decrease the potency of the agonist drug.

Most receptor antagonists used in medicine are competitive.

Examples include atropine blocksà acetylcholine at M receptors and propranolol blocksànor epinephrine at beta receptors.

· Noncompetitive/Irreversible antagonists cause a nonparallel shift to the right and can be reversed only partially by increasing the dose of agonist drug.

Such antagonists appear to decrease both the potency and efficacy of agonists.

One example is phenoxybenzamine , which irreversibly blocks the effects of nor epinephrine at alpha receptors by the formation of covalent bond. Phenoxybenzamine makes a co-valent bond with alpha receptor in the vasculatures.

Diazoxide binds with alpha receptors.

Pharmacologic antagonism (same receptor)

· An agonist and antagonist compete for a single receptor type.

Ach + M receptor= effects

Atropine + M receptor= blocks the effect of ACH on M receptor

Physiologic antagonism (Different Receptors).

· Occurs when an agonist response mediated through one receptor is antagonized by an opposing agonist action at different receptor.

· E.g. acetylcholine causes àbradycardia through M receptor activation, which may be antagonized by NE via beta receptor activation.

Histamine H1 receptorà bronchospasm

Epinephrine beta 2 receptorà bronchodilatation

Chemical antagonism:

· Occurs when drug effect is antagonized by the formation of a complex between the effector drug and another compound.

E.g. protamine binds to heparin to reverse its actions.

Dimercaprol, a chelator of lead poisoning

· In this case, a given quantal effect (a condition that can be expressed only as occurring or not occurring) is chosen , and the concentration of the drug is plotted against the percentage of a specific population in which the drug produces the effect.

· These curves plot the percentage of a population responding to a specified drug effect versus dose.

Use to estimate ED50, TD50, LD50

· ED50 (median effective dose) : The amount of a drug required to produce a response in 50% of the subjects to whom the drug is given.

· TD50 (median toxic dose): the dose that produces a toxic effect in 50 per cent of the population.

·

LLD50 (median lethal dose) the quantity of an agent/drug that will kill 50 per cent of the test subjects/population

Toxicity and the Therapeutic Index:

· Comparisons between ED 50 and TD 50 values permit evaluation of the relative safety of a drug (the therapeutic index)

· TI = TD50/ED50

· Also comparison between ED50 and LD50 if the latter is known.

· TI = LD50/ED50

USMLE1 Pharmacodynamics-1

2011-09-19T21:06:00.000-07:00

Pharmacodynamics described as what a drug does to the body, involves….

• receptor binding

• postreceptor effects

• chemical interactions

Receptor: is the component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug's observed effects.

Drug + Receptor à Drug-receptor complex-àResponse

The magnitude of drug effect depends on its concentration at the receptor site, which in turn is determined by the dose of drug administered and by factors characteristic of the drug such as

▪Rate of absorption

▪Distribution and

▪Metabolism.

Pharmacodynamic characteristics of drug:

Agonist: Is defined as an agent that can bind to a receptor and elicit a response.

2 types:

· Full agonist

· Partial agonist

Full agonists: produce a maximal response, they have maximal efficacy.Partial agonists are incapable of eliciting a maximal response and are less effective than full agonists.

Antagonist: they interfere with the ability of an agonist to activate the receptor and blocking their biologic actions.

Efficacy: Is the maximum response produced by the drug.It depends on the number of drug-receptor. Efficacy is a Measure of how well a Drug produces a response (Effectiveness), shown by the Maximum Height reached by the Curve on X Axis.complexes formed.

Potency: potency is measured of how much drug is required to elicit a given response.The lower the dose is required for a given response, the more potent the drug.

The primary determinant of potency is the affinity of the drug for the receptor.

Dose-response relationship:

Dose: the amount of drug required to elicit a biologic response.

Dose-response relationship: the intensity of the response elicited by a drug is proportional to the dose administered.

Two types :

Graded dose-response curve : for maximum response.

Quantal dose-response curve : for specific responses, e.g.ED50, LD50, TD50

Affinity: Ability of the drug to bind to the receptor, shown by the proximity of the curve to

the y axis; the nearer the y axis, the greater the affinity.

When two drugs interact with the same receptor, the D-R curves will have parallel slopes.

Affinity (ability of the drug to bind to the receptor) can be compared only when two drugs bind to the same receptor.

Duality of Partial Agonists:

In the presence of full agonist , partial agonist will act as antagonist. As the partial agonist displaces the full agonist from the receptor,the response is reduced-the partial agonist is acting as an Antagonist.

USMLE1 Systemic Lupus Erythematosus (SLE)

2011-09-14T19:16:00.001-07:00

Systemic lupus erythematosus (SLE):

· SLE is a chronic autoimmune connective tissue disease that can affect any part of the body.

· In SLE the immune system attacks the body’s cells and tissue, resulting in inflammation and tissue damage.

· SLE affects the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system.

The course of the disease is unpredictable, with periods of illness (called flares) alternating with remissions.
The disease occurs nine times more often in women than in men, especially between the ages of 15 and 50, and is more common in those of non-European descent
Survival for patients with SLE in the United States, Canada, and Europe is approximately 95% at five years, 90% at 10 years, and 78% at 20 years.

Causes:

· There is no one specific cause of SLE. There are however a number of environmental triggers and a number of genetic susceptibilities.

Genetics

· SLE may have a genetic link. SLE does run in families.

· The most important genes are located in the HLA region on chromosome 6, where mutations may occur randomly or may be inherited.

Environmental triggers

· They include extreme stress, exposure to sunlight, hormones, and infections. UV radiation has been shown to trigger the photosensitive lupus rash and some evidence suggests that UV light might be capable of altering the structure of the DNA, leading to the creation of autoantibodies. Sex hormones such as estrogen play an important role in the occurrence of SLE and it is observed that during reproductive years, the frequency of SLE is 10 times greater in females than in males.

Drug reactions

· Symptoms of drug-induced lupus generally disappear once the medication that triggered the episode is stopped.

· There are about 400 medications that can cause this condition, the most common of which are INH, procainamide, hydralazine, quinidine, d-penicillamine and phenytoin

· These drugs are known to stimulate the immune system (by drugs with slow acetylation reactions) and cause SLE.

Signs and Symptoms:

Common initial and chronic complaints include :fever, malaise, joint pains, myalgias, fatigue.

· Dermatological manifestations : Most common is the skin rash: malar rash (or butterfly rash)

· Some may exhibit thick, red scaly patches on the skin (referred to as discoid lupus)

· Anemia

· mouth, nasal, and vaginal ulcers

· Cardiac manifestation: pericarditis, myocarditis, and endocarditis. The endocarditis of SLE is characteristically noninfective (Libman-Sacks endocarditis) and involves either the mitral valve or the tricuspid valve.

· Pulmonary manifestations: Lung and pleura inflammation can cause pleuritis, pleural effusion, chronic diffuse interstitial lung disease, pulmonary hypertension, pulmonary emboli, pulmonary hemorrhage.

· Renal involvement : Painless hematuria or proteinuria

· A histological hallmark of SLE is membranous glomerulonephritis with "wire loop" abnormalities. This finding is due to immune complex deposition along the glomerular basement membrane, leading to a typical granular appearance in immunofluorescence testing.

· CNS manifestations of SLE include: headache, cognitive dysfunction, mood disorder, cerebrovascular disease, seizures, polyneuropathy, anxiety disorder, and psychosis.

· Patients with SLE may have an association with antiphospholipid antibody syndrome (a thrombotic disorder), wherein autoantibodies to phospholipids are present in their serum.

· Abnormalities associated with antiphospholipid antibody syndrome include a paradoxical prolonged PTT and a positive test for antiphospholipid antibodies.

· Another autoantibody finding in SLE is the anticardiolipin antibody, which can cause a false positive test for syphilis.

How is lupus diagnosed?

CBC: anaemia, sedimentation rate and C-reactive protein

For autoimmune SLE:

· anti-dsDNA antibodies

· anti-Sm [Smith] antibody

· antinuclear antibody

For drug induced SLE:

· Anti-histone antibody

· Low level of C3, C4 and high level of anti-dsDNA

· antibody associated with relapse(flare up) and poor prognosis.

Treatment:

· There is no cure for SLE. Treatment is aimed at controlling symptoms

· NSAIDs (Nonsteroidal anti-inflammatory medications) are used to treat arthritis and pleurisy.

· An anti-malaria drug (hydroxychloroquine) and low dose corticosteroids are sometimes used for skin and arthritis symptoms

· Immunosuppressive : azathioprine and cyclophosphamide for renal and cerebral involvement

· For drug induced SLE: withdrawal of medication

· Patients should wear protective clothing, sunglasses, and sunscreen when in the sun

USMLE1 Smooth Muscle Contraction

2011-09-14T19:10:00.001-07:00

How does smooth muscle contraction occur?
Smooth muscle contractile mechanism is slightly different form the cardiac and skeletal muscle. They all need the interaction between myosin and actin but one important difference is, smooth muscle does not have troponin and tropomyosin. So in smooth muscle for myosin to interact with actin, myosin must be phosphorylated.
who phosphorylate the myosin?
We all know phosphorylation is done by an enzyme called kinase, so here the enzyme is called myosin light chain kinase. That means if the myosin light chain kinase is inhibited then it won’t be able to phosphorylate myosin and then there is no interaction between the myosin and actin, hence we have relaxation of smooth muscle.
How do we inhibit myosin light chain kinase?
As we all know, phosphorylation of an enzyme will either activated or inhibit the enzyme, so here phosphorylation of myosin light chain kinase will result in inactivation.
How do we phosphorylate myosin light chain kinase?
There are several mechanisms. Increasing cAMP will result in increased level of Protein kinase A. the kinase will phosphorylate the myosin light chain kinase. This is how beta-2 adrenergic causes relaxation of bronchial smooth muscle and blood vessels.
How does nitric oxide dilate blood vessels?
Nitric oxide dilate blood vessels by binding to intra cytoplasmic Guanylate cyclase, which will convert GTP to cGMP and it in turn activates Protein Kinase G. the PKG will phosphorylate the Myosine light chain kinase and inactivate it.
How does milrinone cause blood vessels to dilate?
Milrinone is phosphodiestrase inhibitor. Phosphodiesterase inhibit cAMP. so if you inhibit Phosphodiesterase then cAMP is free to activate PKA. PKA will phosphorylate myosine light chain kinase and inactivate it. If myosin is not phosphorylated it cannot interact with actin, which means relaxation of smooth muscle.

USMLE1 Cytochrome P450 Isozymes (CYP)

2011-09-02T07:32:00.000-07:00

Cytochrome P450 Isozymes (CYP)

These are major enzyme systems involved in Phase I reactions. Localized in the smooth endoplasmic reticulum (microsomal fraction) of cells ( especially liver , but including GI tract, lungs ,and kidney)

· P450s have an absolute requirement for molecular oxygen and NADPH.

· Reactions include hydroxylation’s, oxidation, and dealkylations.

· Multiple CYP families differing by amino acid(AA) composition , by substrate specificity, and by sensitivity to inhibitors and to inducing agents.

Cytochrome P450 Isozymes: 3 types

CYP1A
CYP2D6

· CYP3A4

CYP1A

· Main substrate is theophylline; inhibited by fluoroquinolones and macrolides; induced by aromatic hydrocarbons.

CYP2D6

· Genotypic variations in hydroxylation(fast and slow);substrates include codeine,and metaprolol; inhibited by haloperidol and quinidine; not inducible.

CYP3A4

· Most abundant isoform; wide substrate range ; inhibited by cimetidine, macrolides, azoles, and ethanol(acute); induced by general P450 inducers such as carbamazepine, phenobarbital(Barbiturates), phenytoin, and rifampin and by ethanol(chronic).

Cytochrome P450 Isozymes:

· These are major enzyme systems involved in Phase I reactions. Localized in the smooth endoplasmic reticulum (microsomal fraction) of cells (especially liver , but including GI tract, lungs ,and kidney)

· Inhibited by : Cimitidine, Macrolides, Azoles (Miconazole, Ketoconazole), Alcohol (acute), grapefruit juice

· Induced By : Carbamazepine, Barbiturate, Phenytoin, Rifampin, Alcohol (Chronic intake)

USMLE1 General Pharmacology-3

2011-09-02T07:21:00.000-07:00

General Pharmacology

Elimination of drugs:

Concerns the processes involved in the elimination of drugs from the body (and/or plasma) and their kinetic characteristics. The major modes of drug elimination are:

· Bio-transformation to inactive metabolites

· Excretion via the kidney.

· Excretion via other modes including the bile duct (HBS), lungs and sweat.

2 types of elimination

Zero Order elimination Rate
First-Order elimination Rate

Zero Order elimination Rate

· Rate of elimination is independent of plasma concentration (or the amount in the body).

· A constant amount of drug is eliminated per unit time

· for example, if 80 mg is administered and 10 mg is eliminated every 4 hrs, the time course of drug elimination is: 80 mgà 70 mgà60 mgà50mgà40mg(each 10 mg in 4 hrs.)

Drugs with zero order elimination have no fixed half-life. Graphically , zero order elimination follows a straight-line decay versus time.

Drugs with zero order elimination include

· Ethanol (except for low doses),

· Phenytoin (high therapeutic dose),

· Salicylates (toxic doses).

ELIMINATION KINETIC

· Zero order is due to saturation of elimination mechanisms; e.g, drug-metabolizing reactions have reached Vmax.

Most drugs follow first order kinetic

First-Order Elimination Rate

· Rate of elimination is directly proportional to plasma level. The higher the amount, the more rapid the elimination.

· A constant fraction of the drug is eliminated per unit time. Graphically , first order elimination follows an exponential decay versus time.

For example, if 80 mg of a drug is administered and its elimination half-life = 4 hrs, the time course of its elimination is:80 mg à40 mgà20mgà10 mgà5 mg(each step 4 hrs)

Clearance is defined as the volume of blood cleared of the drug in unit time.

Volume of plasma from which all drugs are removed in a given time.

· Drug clearance is concerned with the rate at which drug is removed from the body; and for most drugs at steady state, clearance remains constant so that drug input equals drug output.

· It represents the relation-ship between the rate of drug elimination and its plasma level.

For drugs with first-order elimination, clearance is constant because the rate of elimination is directly proportional to the plasma level.

· Total body clearance may involve several processes, depending on different routes of drug elimination.

· CL= CLr + CLnr

Where CLr = renal clearance and CLnr = non renal clearance.

· With no active secretion or reabsorption, the renal clearance is same as glomerular filtration rate(CLr =GFR)

Half life of drug : Time to eliminate 50% of a given amount (or to decrease plasma level to 50% of a former level) is called the elimination half-life (t ½).

T ½ = 0.7 x Vd/CL

Steady state(Css):

· Css is the desired plasma concentration of drug required for optimal activity.

· Steady rate is reached either when rate in (Rate of infusion) = rate out (Rate of elimination) or when values associated with a dosing interval are same as those in succeeding interval.

Css is achieved in which plasma conc of drug remains constant.

The time to reach steady state is dependant on the elimination half-life of a drug

· Although it takes > 7 t ½ to reach mathematical steady state , by convention clinical steady state is accepted to be reached at 4 t ½.

Css = Ro/CLt

Ro- infusion rate, CLt - total body clearance e.g Css of plasma conc is directly proportional to infusion rate. If infusion is doubled the plasma conc ultimately achieved at the Css is doubled.

· Css inversely proportional to clearance of the drug. In CRF decreases CL, so increase Css of an infused drug.

· If the rate of infusion is doubled, then the plasma level of the drug at steady state is doubled.

· Irrespective of the rate of infusion, it takes the same amount of time to reach steady state.

· A similar relationship can exist for the other forms of drug administration (e.g, per oral)- doubling oral doses can double the average plasma levels of a drug.

Maintenance Dose:

In most clinical situations, drugs are administered in such way as to maintain a steady state of drug in the body, ie, just enough drug is given in each dose to replace the drug eliminated .

· At steady state, the dosing rate ("rate in") must equal the rate of elimination ("rate out").

IN Css,

Dosing rate (rate of infusion) = Rate of elimination

= CL x target plasma conc

If intermittent doses are given, the maintenance dose is calculated from:

Maintenance dose (MD) = Dosing rate(rate of infusion) x Dosing interval

Loading Dose: A single dose of drug injected to achieve the desired plasma level rapidly

· Loading dose (LD): LD =Vd x Css , where Css = plasma at steady state , the desired plasma concentration of drug required for optimal activity.

· Adjustment may be needed in calculations with bioavailability < f =1 ; for example, if f = 0.5 , the LD must be doubled.

USMLE1 General Pharmacology-2

2011-08-30T13:17:00.000-07:00

Pharmacokinetics is the study of what the body does to a drug.

· Absorption

· Bioavailability

· Distribution

· Metabolism

· Excretion.

Drug pharmacokinetics determines the onset, duration, and intensity of a drug's effect.

Absortion:

· Concerns the processes of entry of a drug into the systemic circulation from the site of its administration.

· The determinants of absorption are those described for drug permeation (Solubility, Concentration gradient, Surface area and vascularity)

Intravascular administration (e.g. IV) does not involve absorption, and there is no loss of drug.

For drug absorption:

· Acidic drugs absorb in Acidic media

· Basic drugs absorb in basic media

Bioavailability:

Is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route

Bioequivalence:

For Bioequivalence to occur between two formulations of the same compound, they must have the same bioavailability and the same rate of absorption.

Bioequivalence is a term used when comparing brand name and generic drugs

With oral administration, drugs are absorbed into the portal circulation and initially distributed to the liver. Drugs administered I.V enters directly into the Systemic circulation. But drugs administered PO are 1^st exposed to liver through portal circulation and may be extensively metabolized before reaching the rest of the body (syst. circulation).

For some drugs , their rapid hepatic metabolism decreases bio-availability – the “First-Pass” effect. Example: Propranolol, Lidocaine.

· The processes of distribution of a drug from the systemic circulation to organs and tissues involve its permeation through membrane barriers and are dependant on its

· Solubility

· the rate of blood flow to the tissues

· binding of drug molecules to plasma proteins.

Plasma Protein binding

· Many drugs bind to plasma proteins, including albumin, with an equilibrium between bound and free molecules

· recall that only unbound drugs cross bio-membranes

· Drug + Protein = Drug-Protein complex

· Competition between drugs for plasma protein binding sites may increase the “free fraction”, possibly enhancing the effects of the drug displaced (NSAID, OHA, Warfarin, Sulfonamide)

Special barriers to distribution

· Placental : most small molecular weight drugs cross the placental barrier, although fetal blood levels are usually lower than maternal.

· Blood-Brain: permeable only to lipid-soluble drugs or those of very low molecular weight.

Volume of distribution : Is a volume of fluid into which the drug is disseminated. Two types:
Physical VD (plasma, ECF, interstitial space)
Apparent VD: A kinetic parameter of a drug that correlates dose with resultant plasma levels.

· Vd = D/C = Total amount of drug in the body

plasma conc of drug

· The higher the volume of distribution, the lower the plasma concentration and vice versa.

· Vd is low when a high percentage of a drug bound to plasma proteins.

Redistribution

· In addition to crossing the blood-brain barrier(BBB), lipid-soluble drugs redistribute into fat tissues prior to elimination.

· In the case of CNS drugs, the duration of action of an initial dose may depend on the redistribution rate than on the half-life.

· With repeated doses, fat and other tissue depots become saturated ,resulting in longer durations of action than the first dose.

The general principle of biotransformation is the metabolic conversion of drug molecules to more water-soluble metabolites that are more readily excreted.
In many cases, metabolism of a drug results in its conversion to compounds that have little or no pharmacologic activity.
In such cases, biotransformation rate can be a primary factor in determining the duration of drug action.

A few compounds (pro-drugs) have no activity until they undergo metabolic activation.

Phase I : modification of the drug molecule via oxidation, reduction and hydrolytic reactions. Involves cytochrome p450 enzyme system.

Phase II : conjugation with endogenous compounds via the activity of transferases – a prerequisite is the presence of a reactive group (-OH,-NH2, acetate) on the molecule.

Phase I: Hydrolysis

· Phase I reactions involving addition of a water molecule with subsequent bond breakage.

· Include esterases and amidases.

Oxidations:

Non-microsomal Oxidations

Microsomal oxidation: Most common, requires CYP

· Non-microsomal Oxidations

Include monoamine oxidases that metabolize both endogenous amines (e.g. dopamine, seratonin) and exogenous compounds(e.g. tyramine).

Alcohols are metabolized by alcohol dehydrogenase(ADH) to aldehydes, which are then substrates for aldehyde dehydrogenase, which can be inhibited by disulfuram.

Phase II:

Conjugation

· Conjugated drugs are usually inactive but occasionally activate some drugs (morphine, minoxidil).

· If metabolite from phase 1 is sufficiently polar/ionized it can be excreted by kidney. But many metablolites are too lipophilic to be retained by kidney tubules.

So subsequent conjugation reaction with endogenous substrate e.g. Glucoronic acid, Sulfuric Acid, Amino Acid, Glutathione, Acetate results in polar/more water soluble compounds that are therapeutically inactive

Types of conjugation

· Glucuronidation : addition of glucoronide group

· Inducible

· Conjugates may undergo enterohepatic cycling.

· Reduced activity in neonates (Grey Baby Syndrome)

· Acetylation: addition of acetate group

· Genotypic variations present

· Some people are fast acetylators but some are slow.

· hydralazine, procainamide, isonicotinic acid hydrazide (INH) (treatment for TB and need to take for 6 months)

· Sulfation : addition of sulphate group

E.g. minoxidil, steroids

Glutathione( GSH)conjugation: depletion of GSH in the liver is associated with acetaminophen (Tylenol) toxicity.

USMLE1 General Pharmacology-1

2011-08-30T13:11:00.000-07:00

A drug is any substance that, when absorbed into the body of a living organism, alters normal bodily function.

Routes of Drug Administration:

1. Enteral route:

Oral

Sublingual

Rectal

2. Parenteral :

Intravascular (I.V)

Intramuscular (I.M)

Subcutaneous (S.C)

3. Other:

Inhalation

Intranasal

Intrathecal (injection into the spinal canal )

intradermal

Topical

Most drugs gain entry to cells by passive diffusion with 1^st order kinetics

The passive flux of molecules down a concentration gradient is given by Fick’s Law:

Flux(molecules per unit time)=

(C1-C2)x area x permeability coefficient

thickness

Where:

C1 is the higher concentration, C2 is the lower concentration

area is the area across which diffusion is occurring,

permeability coefficient is a measure of mobility of the drug molecules in the medium of the diffusion path, and thickness is thickness of diffusion path.

Ionization

Many drugs are weak acids or weak bases and can exist in either non ionized or ionized forms in an equilibrium depending on the p H of the environment and their p Ka (the p H at which the molecule is 50 % ionized and 50% nonionized ).

Only the non ionized (uncharged) form of a drug crosses biomembranes.

· Ionized = water soluble

· Non ionized=lipid soluble

· acidic media: p H < p Ka

· basic media p H >p Ka

Weak acid =

R.COOH ßà R.COO- + H+

(cross membranes)

Weak base =

R.NH3+ ßà R.NH2 + H+

(protonated weak base) (cross membranes)

Weak acids:

· Aspirin

· Salicylic acid

· Ibuprofen

· Phenobarbital

· Acetazolamide

Weak bases :

· Atropine

· Cocaine

· Codeine

· Morphine

Only nonionized forms of drug undergo active secretion and active or passive reabsorption

Change of urinary pH:

· Acidification of urine à increases ionization of weak bases àincreases renal elimination.

· Alkalization of urineàincreases the ionization of weak acids àincreases renal elimination.

TO CHANGE URINARY pH

· Acidify :NH4Cl, vitamin C, Cranberry juice

· Alkalinize: NaHCO3

USMLE1 Antiherpetics

2011-08-16T18:48:00.000-07:00

Antiherpetics :

(HSV1, HSV2, CMV, chickenpox, shingles)

Rx of HSV and CMV, VZV :

Acyclovir, Valcyclovir
Famciclovir, Penciclovir
Ganciclovir, Valganciclovir
Foscarnet
Fomivirsen
Trifluridine, Idoxuridine
Vidarabine
Docosanol
Cidofovir

USMLE1 Antifungal Drugs

2011-08-16T10:55:00.000-07:00

Antifungal Agents

General information:

Mycosis (plural: mycoses): an inflammatory condition caused by a fungus

Dermatophytes: are a common label for a group of three types of fungus that commonly causes skin/nail/hair diseases. These are: Microsporum, Epidermophyton and Trichophyton.

Classification: mycoses are classified according to the tissue levels initially colonized:

· Superficial fungal infections

· Deep seated or disseminated fungal infections

Superficial fungal infections involve:

· Cutaneous surfaces : such as the skin, nails, and hair.

· Mucous membrane surfaces : such as the oropharynx and vagina.

· Deepseated or disseminated fungal infections caused by

· Dimorphic fungi (fungi which can exist as mold/hyphal or as yeast.

Example include: Coccidioides, Paracoccidioides , Candida)

Yeasts Cryptococcus neoforman various Candida spp.

Clinical fungal infections are generally divided into four types:

1. superficial, including tinea versicolor, piedra, and tinea nigra

2.cutaneous, including onychomycosis, tinea capitis, tinea corporis, tinea barbae, tinea pedis, and candidiasis of skin, mucosa, and nails

3. subcutaneous, including mycetoma, sporotrichosis and

4. systemic, including blastomycosis and cryptococcosis.

· Superficial fungal infections are defined as infections in which a pathogen is restricted to the stratum corneum, with little or no tissue reaction.

· Superficial and cutaneous infections are both sometimes regarded as superficial.

Types of Dermatophyte Infections:

· Tinea Infections , AKA-Ringworm

· Athlete's foot or tinea pedis: affects the webs between the toes

· Jock itch or tinea cruris : groin to the perianal skin and gluteal cleft

· Tinea corpora : Ringworm of the body

· Tinea capitis : Scalp ringworm

· Onychomycosis ( tinea unguium) : Ringworm of the nail

· Tinea barbae : is a superficial dermatophyte infection that is limited to the bearded areas of the face and neck and occurs almost exclusively in older adolescent and adult males

Tinea versicolor AKA Pityriasis versicolor and Tinea flava

· is a condition characterized by a rash on the trunk and proximal extremities.

· Recent research has shown that the majority of pityriasis versicolor is caused by Malassezia globosa, although M. furfur is responsible for a small number of cases.

· These yeasts are normally found on the human skin and only become troublesome under certain circumstances, such as a warm and humid environment.

Symptoms: include:

· Generally oval or irregularly-shaped spots (0.6 to 2.5 cm), often merging together to form a larger patch

· Occasional fine scaling of the skin producing a very superficial ash-like scale

· Sometimes itching in the affected areas

· These spots commonly affect the back, underarm, upper arm, chest, lower legs, and neck. Occasionally in the face.

· In people with dark skin, hypopigmentation are common, while in those with lighter skin color hyperpigmentation. These discolorations have led to the term "sun fungus“

Antifungal agents:

The antifungal drugs presently available fall into several categories:

· systemic drugs (oral or parenteral) for systemic infections, topical drugs for mucocutaneous infections.

Systemic agents:

Polyenes: Amphotericin B

Flucytosine

The newer azoles, including

Ketoconazole

Fluconazole

Itraconazole

Voriconazole

Capsofungin-à inhibits synthesis of beta-D- glucon in fungal CW.

Topical :

POLYENES : Nystatin

Miconazole

Clotrimazole

Terbinafine

ketokonazole

Polyenes:

· Amphotericin B (Amp B)

· Nystatin: (too toxic for Systemic use) is used topically for Localized Infections (Eg;Candidiasis)

Mechanisms:

· Amphoteric compounds with both polar and non polar structural components interact with ergosterol in fungal membranes to form Artificial “pores”, which disrupt membrane permeability.

· Resistant Fungal strains appear to have low ergosterol content in their cell membranes.

Clinical Uses:

· Amphotericin B has a wide Fungicidal spectrum and remains the DOC for severe infections caused by……

· Aspergillus

· Candida

· Cryptococcus

· Histoplasma

· Mucor and Sporothrix.

Amp B is Synergistic with Flucytocine in Candidiasis and Cryptococcoses.

Infusion Related:

· Fever, Chills (premedication with steroid or antipyretic helps prevent this S/E)

· Muscle Rigor

· Hypotension (Histamine release) occur during IV infusion (a test dose is advisable)

This S/E can be alleviated partly by pretreatment with NSAIDs, Antihistamines, Meperidine and Adrenal steroids.

Dose Dependent:

· Nephrotoxicity includes decreased GFR, tubular acidosis, decreased K+ and Mg2+.

Nephrotoxicity is potentiated if given with aminoglycosides, cyclosporine, pentamidine

· Anaemia through decreased Erythropoietin

· Neurologic effect : intrathecal administration

· Thrombophlebitis

Flucytosine(5-FC):

· Activated by Fungal cytosine deaminase toà5-Fluorouracil(5-FU), which after triphosphorylation is incorporated into Fungal RNA to disrupt NA and protein synthesis.

· 5-FU also forms 5-Fluorodeoxyuridine monophosphate (5-Fd-UMP),which inhibits Thymidylate synthaseàwhich decreases thymineàinhibits DNA synthesisà death of fungal cells

Resistance emerges rapidly if Flucytosine is used alone.

Used in Combination with Amphotericin B in Severe Candidal and Cryptococcal infections

Enters CSF

5-Fluorouracil (5-FU)is used as an Anti neoplastic(Anti cancer) drug.

Adverse Effects: Flucytosine and 5-FU

· Bone marrow suppression: pancytopenia

· Hepatic dysfunction

· GI distress

· Alopecia.

Azoles-

· Ketoconazole

· Fluconazole

· Itraconazole

· Voriconazole

· Clotrimazole

Mechanism of action:

· Azoles are fungicidal and interfere with the synthesis of ergosterol by inhibiting the P450 dependent 14 alpha methylation of its precursor molecule, Lanosterol.

Resistance occurs via decreased intracellular accumulation of Azoles.

Clinical Uses:

Ketoconazole:

· Co-DOC for Paracoccidioides and back up for Blastomyces and Histoplasma.

· Oral use in Mucocutaneous candidiasis or dermatophytoses.

Itraconazole:

· DOC in Blastomycoses and Sporotrichoses

· back up drug for several other mycoses and Candidiasis

Fluconazole:

DOC for Esophageal and Invasive Candidiasis and Coccidioidomycosis.
Prophylaxis and suppression in Cryptococcal Meningitis.

Voriconazole: Newest Triazole (azole)

· Well absorbed orally

· Low propensity for inhibition of CyP450

· Excellent for candida specis, more effective in Rx of invasive aspergillosis

Clotrimazole and Miconazole:

· Used topically for Candida and Dermatophytic infections.

Biodisposition of Azoles:

· Effective orally

· Absorption of Ketoconazole is decreased by Antacids.

· Absorption of Itraconazole is increased by Food.

· Itraconazole requires an acidic gastric environment for absorption; any drug reducing gastric acid production (H2 blockers, proton pump inhibitors) or neutralizing gastric acid (antacids) will significantly reduce itraconazole absorption.

· Only Fluconazole penetrates into the CSF and can be used in Meningeal Infection.

· Ketoconazole and Itraconazole are eliminated by Liver

· Fluconazole eliminated by kidney

Adverse Effects:

· Decreased synthesis of steroids, including cortisol and androgens--àdecreased libido, gynecomastia, menstrual irregularities.

· Rash

· Fluid retention--àincreased BP

· Abnormal LFTs and hepatotoxicity

· Inhibition of Hepatic P450s---àdecrease metabolism of cyclosporine, vincristine , phenytoin, warfarin etc.

· Disulfiram like reactions with Ethanol

· Transient visual disturbance (Voriconazole)

Other antifungal drugs:

Griseofulvin:

· Active only against Dermatophytes by disrupting Microtubule structure.

· It accumulates in the infected, keratin-containing tissues, making them unsuitable for the growth of the fungi.

· Active only against Dermatophytes (fungi that cause superficial skin inf) : Trichophyton, Microsproum, Epidermophyton

· Absorption is promoted if ingested with a high fat diet

· Distributes mainly to infected keratinized tissue where it becomes bound.

Adverse Effects:

· Headache, nausea

· Peripheral neuritis

· hepatotoxicity

· Potentiates Ethanol toxicity

· Avoid with History of Porphyria

· Teratogenic

· Induces CyP450 (Azoles inhibit cyP450)

Terbinafine:

· Active only against Dermatophytes by inhibiting Squalene epoxidase , inhibits ergosterol synthesis

· Possibly superior to Griseofulvin in Onychomycoses (fungal infection of the nail)

Adverse Effects:

· GI distress

· Rash

· Headache

· Alters LFTs----possible Hepatotoxicity.

Rx: Topical antifungal medications:

2.5% selenium sulfide: applied to dry skin and washed off after 10 minutes, repeated daily for 2 weeks.
Ketoconazole
Clotrimazole, miconazole or terbinafine are less widely recommended

USMLE1 Anti-Malarial Drugs

2011-08-12T08:18:00.000-07:00

Malaria is caused by – Plasmodium

• Plasmodium vivax

• Plasmodium falciparum

• Plasmodium malariae

• Plasmodium ovale

• Plasmodium knowlesi : Is a zoonosis that causes malaria in macaques but can also infect humans

Clinical note:

• Cerebral malaria is only caused by Plasmodium falciparum. Falciparum malaria can also cause hepatitis, gastrointestinal symptoms(diarrhoea), glomerulonephritis/acute tubular necrosis and blackwater fever.

• Plasmodium ovale is the rarest of the four species and is apparently more restricted in distribution. common in the West African countries of Ghana, Liberia, and Nigeria.

• Plasmodium vivax and ovale are the only ones which have liver parasite dormancy.

• Plasmodium vivax and ovale only infect reticulocytes whilst falciparum infects erythrocytes of all stages and malariae infects mature erythrocytes. The Duffy blood group is essential for vivax spread as the merozoites of these attach to the Duffy receptor on red blood cells.

• Plasmodium malariae causes quartan fever (every 72 hours or fourth day) whereas the other species cause tertian fever (every 48 hours or third day).

Anti-malarial drugs:

• Chloroquine – most common

• Quinine – if chloroquine resistant

• Pyrimethamine (or in combination with Sulfonamides)

• Primaquine – Radical cure

• Mefloquine

• Artemisinin (Artemether, Arteether, Artesunate)

• Halofantrine – New drugs

1. Drugs for the Exo-erythrocytic phase (liver) and gametocytes :

• Primaquine

2. Drugs to suppress erythrocytic phase / Schizontocides /

Clinical cure :

• Chloroquine

• Quinine

• Pyrimethamine

• Mefloquine

• Artemisinin: Artemether, Arteether, Artesunate

3. Radical cure : Exoerythrocytic phase (hypnozoites) with the clinical cure thus achieve total eradication of parasite

• Primaquine + Chloroquine

Chloroquine :

• It is rapidly acting erythrocytic schizontocide against all species of plasmodium

• No effect on exo-erythrocytic phase

• It is concentrated by intraerythrocytic plasmodium

• Chloroquine prevents the formation of hemozoin, which in turn leaves heme in an uncrystallised form.

• The drug can also decrease DNA synthesis in the parasite by disrupting the tertiary structure of NA.

Chloroquine: spectrum of activity:

• Chloroquine is active against entameoba histolytica and giardia lamblia

• It has anti-inflammatory actions and use for rheumatoid arthritis and SLE (discoid lupus)

• It is used for the treatment of malaria in pregnancy

Pharmacokinetics : Chloroquine

• Oral absorption is excellent

• It has high affinity for melanin (retina) and concentrated in liver, spleen, kidney

• Metabolized by liver and excreted in urine

• Half life ~ 3-10 days

Uses : Chloroquine

• Clinical cure and prophylaxis in malaria

• Extra-intestinal ameobiasis

• Rheumatoid arthritis, SLE

• Lepra reactions

Adverse effects : Chloroquine

• Nausea , vomiting and epigastric pain

• Parenteral administration -àhypotension and cardiac arrhythmia, convulsions

• Prolonged treatment ( as in RA) retinal damage, decrease vision

• Loss of hearing, mental disturbances, rashes

C/I:

• Psoriasis

• Porphyria

Quinine :

• It is a levo-rotatory alkaloid from cinchona bark ( dextro isomer – Quinidine)

• It is an erythrocytic schizontocide

• The action of quinine has not been fully resolved.

Mechanism Of Action:

• involves the inhibition of hemozoin biocrystallization, which facilitates the aggregation of cytotoxic heme.

• Toxic heme accumulates in the parasites, leading to their death

• It is orally well absorbed

• It has local irritant action and has antipyretic action, affects hearing and vision at high dose

• High intravenous dose can cause hypotension and cardiac depression

Adverse effects

• Cinchonism (S/A: Quinidine) – ringing in ears, nausea , difficulty in hearing, visual defects

• Hypersensitivity reactions

• Hemolysis – can result in hemoglobinuria

• Embryotoxic

Hypoglycaemia is an important side effect of quinine therapy (causes insulin release) and Pl. glucose should be checked every 2 hours.

Primaquine :

• Primary indication is radical cure of malaria.

• It is more active against exo-erythrocytic phase of Pl. falciparum and vivax

• It is highly active against gametocytes and hypnozoites.

Mechanism Of Action:

• It attacks the sexual forms of the parasite, rendering them incapable of maturation in the mosquito and making it valuable in preventing the spread of malarial infection.

Side Effects:

• Dose limiting side effect is hemolysis, methemoglobinemia and cyanosis (dose > 60 mg/day)

• Other adverse effects - abdominal pain and neutropenia

• Avoided in pregnancy & G6PD deficiency.

Mefloquine

• It is rapidly acting erythrocytic schizontocide

• Effective against even chloroquine resistant strains of plasmodium.

Mechanism Of Action:

• It appears to damage the plasmodia membranes

• Oral absorption is good

• Concentrated in liver, lungs and intestine

• Metabolized in liver and excreted in bile

• QT interval prolongation (arrhythmia) when given with halofantrine or quinine

• Mefloquine is C/I in mental illness e.g schizophrenia

Artemisinin derivatives :

Artemether

Arteether

Artesunate

• It is a potent and rapidly acting blood schizontocide (and produce peroxide – responsible for its action)

• Obtained from Chinese herb Artemisia annua

• No resistance to Pl .falciparum

Adverse effects :

• ST segment and QT prolongation –conduction defects

Halofantrine/Lumefantrine :

• halofantrine is never used to prevent malaria and its mode of action is unknown.

• A crystallographic study have shown that halofantrine binds to hematin, suggesting a possible mechanism of action .

• It is highly active against Pl. falciparum resistant to chloroquine

Adverse effects:

• abdominal pain, diarrhoea, vomiting, rash, headache, itching and elevated liver enzymes.

• It can be associated with cardiotoxicity

• Cardiac arrhythmias: causes significant QT prolongation

Uses : Halofantrine/Lumefantrine

• is only used to treat malaria. It is not used to prevent malaria (prophylaxis) because of the risk of toxicity and unreliable absorption.

USMLE1 Anti-Protozoal drugs-2

2011-08-11T13:27:00.000-07:00

Anti-Ameobic Drugs

Asymptomatic cysts carriers: Iodoquinol or Paromomycin or Diloxanide furoate

Diarrhea / Dysentery: Metronidazole + Iodoquinol or Paromomycin or Diloxanide

Amebic liver abcess: Metronidazole + Chloroquine

Protozoal Infections:

Giardiasis :

• is a diarrheal infection of the small intestine by Giardia lamblia

Transmission

• Giardiasis is caused by the ingestion of infective cysts.

• Person-to-person transmission accounts for a majority of Giardia infections and is usually associated with poor hygiene and sanitation.

• Water-borne transmission is common in United States Giardia epidemics, which are often associated with the ingestion of unfiltered water (contaminated).

• Venereal transmission happens through fecal-oral contamination.

Symptoms

• Fever, abdominal cramps

• explosive, watery diarrhea, vomiting

• loss of appetite, malaise, and fatigue.

Rx: Metronidazole

Trichomoniasis:

• is a common cause of vaginitis (STD).

• is caused protozoa Trichomonas vaginalis

• Trichomoniasis is primarily an infection of the urogenital tract; the most common site of infection is the urethra and the vagina.

Symptoms

• inflammation of the cervix (cervicitis), urethra (urethritis), and vagina (vaginitis) which produce an itching or burning sensation.

• Discomfort increases during intercourse and urination.

• Yellow-green, itchy, frothy foul-smelling vaginal discharge

• Lower abdominal pain

Symptoms usually appear in women within 5 to 28 days of exposure.

Rx: Metronidazole 2000mg( 2gms) single dose.

Trypanosomiasis refers to two chronic diseases caused by Trypanosoma:

• African sleeping sickness, and

• American sleeping sickness

African trypanosomiasis: the disease is transmitted in the following ways:

• bite of the tsetse fly.

• Mother to child infection

• through the handling of blood of an infected person and organ transplantation

• Blood transfusion

• Sexual contact (might be possible, but happens rarely)

Symptoms and clinical features

• Symptoms begin with fever, headaches, and joint pains, lymph node swelling

( Winterbottom's sign, the tell-tale swollen lymph nodes along the back of the neck)

If untreated

• anemia, endocrine, cardiac, and kidney diseases . The disease then enters a neurological phase when the parasite passes through the blood-brain barrier

• sleep cycle is disturbed with bouts of fatigue punctuated with manic periods progressing to daytime slumber and night-time insomnia.

• Without treatment, the disease is invariably fatal, with progressive mental deterioration leading to coma and death.

The diagnosis rests upon demonstrating trypanosomes by microscopic examination of body fluid, lymph node aspirates, blood, bone marrow, or, cerebrospinal fluid.

Chagas' disease (American sleeping sickness)

• is a tropical parasitic disease caused by Trypanosoma cruzi. T. cruzi is commonly transmitted to humans and other mammals by an insect vector

The disease may also be spread through

• blood transfusion and organ transplantation

• ingestion of food contaminated with parasites, and

• from a mother to her fetus

Signs and symptoms: 2 stages

Acute stage: Sign and symptoms

• fever, fatigue, body aches, headache, rash, loss of appetite, diarrhea, and vomiting.

• The signs on physical examination can include mild enlargement of the liver or spleen, swollen glands, and local swelling (a chagoma) where the parasite entered the body.

The most recognized marker of acute Chagas disease is called Romaña's sign, which includes swelling of the eyelids on the side of the face near the bite wound.

Chronic : occurs several years after initial infection:

• The symptomatic chronic stage affects the nervous system, digestive system and heart

• About two thirds of people with chronic symptoms have cardiac damage, including cardiomyopathy which causes arrythmias and may result in sudden death.

• About one third of patients go on to develop digestive system damage, resulting in dilation of the digestive tract (megacolon and megaesophagus), accompanied by severe weight loss.

Swallowing difficulties may be the first symptom of digestive disturbances and may lead to malnutrition. Secondary achalasia may arise from Chagas disease.

Drugs used for Trypanosomiasis:

• Melarsoprol

• Pentamidine isethionate

• Nifurtimox

• Suramin

• Benznidazole

Melarsoprol :

• Trivalent arsenical compound

• Mainly used to treat trypanosoma infections with CNS involvement

Mechanism of Action:

• The drug acts by reacting with sulfhydryl groups of various enzymes in both parasite and host – more sensitive to parasite enzymes.

• Well absorbed orally

• Well distributed to CNS

• Short half life and excreted in urine

Adverse effects:

• Encephalopathy

• Hemolytic anemia in G-6-PD deficiency

Pentamidine : Active against

• protozoa – trypanosoma and leshmaniasis and

• fungus - blastomyces

Mechanism of Action:

• T. brucei concentrates the pentamidine by active uptake system and interfere with synthesis of RNA, DNA and proteins.

• Administered IV or aerosol

• Does not penetrate CNS

• Excreted by the kidney

Adverse effects:

• Nephrotoxicity

• It can cause histamine release

• Mental confusion , liver and kidney damage

• Lysis of pancreatic beta cells

Nifurtimox

• Used in the treatment of Trypanosoma cruzi.

• It acts by generating super oxide and hydrogen peroxide radicals – toxic to t.cruzi as they lack catalase.

• Orally well absorbed

Adverse effects:

• Anaphylaxis and peripheral neuropathy are common.

Suramin

• Used in the early treatment and prophylaxis of African trypanosomiasis.

MOA:

• It acts by inhibiting many enzymes of energy metabolism including glycerol phosphate dehydrogenase – for trypanocidal activity.

• Used intravenously

• Accumulated in liver and kidney

Adverse effects:

• Photophobia, palpebral edema, paresthesias.

Leishmaniasis

Leishmaniasis is a disease caused by Leishmania and is transmitted by the bite of certain species of sand fly (subfamily Phlebotominae).

Classification : divided into the following types:

• Cutaneous leishmaniasis : most common form

• Mucocutaneous leishmaniasis

• Visceral leishmaniasis: severe form in which the parasites have migrated to the vital organs

• Post-kala-azar dermal leishmaniasis

• Viscerotropic leishmaniasis

Cutaneous leishmaniasis of the Old World heals in 4-18 months leaving a scar. No serious sequelae occur. It may be left alone but is usually treated with intra-lesional sodium stibogluconate therapy.

New World cutaneous leishmaniasis should be treated due to the risk of mucocutaneous disease and sodium stibogluconate is given intravenously

Visceral leishmaniasis is most commonly caused by Leishmania donovani. Fever, malaise, anaemia, weakness and weight loss are common Hepatosplenomegaly develops gradually and the skin may become grey.

Treatments

• Pentavalent antimonials, such as sodium stibogluconate, are the conventional therapy used in the treatment of leishmaniasis, with pentamidine and amphotericin B as backup agents.

• Allopurinol has also been reported to be effective (it is converted to a toxic metabolite by the amastigote form of the organism).

Sodium stibogluconate:

• The exact mechanism of action has not been determined.

• Evidence for inhibition of glycolysis in the parasite at the phosphofructokinase reaction has been found.

• Because it is not absorbed on oral administration, sodium stibogluconate must be administered parenterally, and it is distributed in the extravascular compartment.

• Metabolism is minimal, and the drug is excreted in the urine

Adverse effects include

• pain at the injection site

• gastrointestinal upsets, and

• cardiac arrhythmias

Renal and hepatic function should be monitored periodically.

USMLE1 Anti-Protozoal drugs-1

2011-08-11T08:41:00.000-07:00

Protozoal diseases

• Amebiasis and Balantidial Dysentery

• Trichomoniasis and Giardiasis

• Leishmaniasis and Trypanosomiasis

1. Amebiasis (E. histolytica)

Diseases caused by E. histolytica:

• Asymptomatic cysts carriers

• Diarrhea / Dysentery

• Amebic liver abscess

Route of transmission:

• E. histolytica is a water-borne pathogen transmitted by the fecal-oral route.

E. histolytica exists in two forms

Cysts – that can survive outside the body

Trophozoites – do not persists outside the body but invasive.

Anti - Ameobic Drugs

Luminal amebicidal drugs:

• Diloxanide furoate

• Iodoquinol

• Tetracycline/Doxycycline/Azythromycin

• Paromomycin (aminoglycoside)

Systemic amebicidal drugs :

• Chloroquine

• Emetine

• Dihydroemetin

Mixed: Luminal / Systemic amebicidal drugs :

• Metronidazole

• Tinidazole

• Secnidazole

• Ornidazole

Clinical uses of Mixed Drugs:

• Broad spectrum cidal activity against = Protozoa – E.histolytica, T.vaginalis, G.lamblia

• Anaerobic bacteria – B.fragilis, C.perfringes, H.pylori, C. Difficile.

Metronidazole:

MOA: Metronidazole, a nitroimidazole, is the mixed amebicide of choice for treating amoebic infections. The nitro group of metronidazole is able to serve as electron acceptor, forming reduced cytotoxic compounds that bind to proteins and DNA to result in cell death.

• Widely distributed in the body secretions – semen, saliva and CSF

• Metabolized by oxidation and glucuronide conjugation and excreted in urine.

Clinical uses:

1. Antiprotozoal: Metronidazole is DOC for most infections caused by E. histolytica, Giardia species, and Trichomonas vaginalis.

2. Antibacterial: DOC for most anaerobic infections including those caused by B.fragilis, C.difficile and Gardnerella vaginalis.

3. Used in regimens for H.pylori-associated GI ulcers. (MOC-Omeprazole, Metronidazole, Clarithromycin)

Adverse Effects:

• Nausea, vomiting, epigastric distress, abdominal cramp

• Unpleasant metallic taste are most common

• Neurotoxicity : dizziness, vertigo, numbness or paresthesias in the PNS

• If taken with alcohol, a disulfiram-like effect

• Seizures at high dose

Contra-indications:

• First trimester of pregnancy

• Chronic alcoholism.

Tinidazole:

• It was approved by the U.S. Food and Drug Administration in 2004 for treatment of amebiasis, amebic liver abcess, giardiasis, and trichomoniasis but was used outside the United States for decades prior to approval.

Diloxanide furoate :

• Effective luminal amebicidal – kills trophozoites – responsible for the cyst production

• No anti-bacterial activity

• Diloxanide is weaker ameobicidal than furoate ester.

• High cure rates in mild intestinal amoebiasis and asymptomatic cyst passers

Iodoquinol :

• Amebicidal against luminal trophozoites and cysts

• Adverse effects includes – peripheral neuropathy and optic neuritis.

Paromomycin :

• Aminoglycosides which is not absorbed from GIT.

• Effective against luminal forms of E. Histolytica – directly

• It acts indirectly by reducing the intestinal flora also.

Emetine :

• Inhibit protein synthesis by blocking chain elongation.

• It is concentrated in the liver

• administered by i.m injection.

• Adverse effects includes cardiotoxicity and neuromuscular weakness.

USMLE1 -AntiBacterial- Cephalosporins

2011-08-06T11:09:00.000-07:00

Cephalosporins:

Mechanism Of Action and Resistance:

Bind to Penicillin Binding Proteins on cytoplasmic membrane.
Are Bactericidal and require the intact Beta Lactam ring structure for activity.
Resistance occurs mainly via production of Beta –lactamases, but changed PBPs and changes in porin structure may also be involved.

Cephalosporins are classified into 4 generations:
First generation:
• Acts as Pc G substitutes
• activity includes Gram positive cocci(not MRSA), E.coli, Klebsiella pneumoniae and some proteus species .
• Common use in Surgical prophylaxis
• Does not enter CNS
Drug list:
• Cefazolin is the DOC for surgical prophylaxis, good penetration into bones.
• Cephalexin
• Cephradineis the DOC oral preparation (Gram +ve + E.coli, Klebsiella pneumoniae)
Second Generation are effective against:
• Gram-negative organisms (Haemophilus, Enterobacter aerogenes, Neisserialus)
• Gram positive (less effective than 1st gen) including
• some Anaerobes.
Drug list:
Cefotetan
Cefaclor
Cefoxitin
Cefuroxime
Cefamandole
Cefmetazole
Cefonicid
Third Generation: Wider spectrum that includes Gram positive cocci and Gram negative cocci, plus many Gram negative rods.
Most of the drugs have effect on CNS.
3rd generation Cephalosporins are important in empiric management of Meningitis and Sepsis. Drugs includes:
Ceftriaxone
Cefotaxime
Ceftizoxime
Cefixime
Cefoperazone
Indications:

Ceftriaxone(IM) or Cefixime (PO) used in single dose for Gonorrhea (DOC)
Ceftriaxone and Cefotaxime-active against most bacteria causing Meningitis.
Ceftizoxime is active against B.fragilis.
Fluroquinolone--->Ofloxacin or ciprofloxacin is the treatment of choice for gonorrhea in Pc/Cephalosporin -allergic patients (or) If allergic to Pc (H/O anaphylaxis) or cephalosporin then chlorampehnicol.

Fourth generation:
Even wider spectrum, Resistant to most Beta-lactamases
Drug list:
• Cefepime --only IV
• Cefepime combines the Gram +ve, Gram –ve activities.
Organisms NOT covered by Cephalosporins are:
• Listeria monocytogenes
• Atypicals(Chlamydia,Mycoplasma)
• MRSA(Methicillin Resistant Staphylococcus aureus)
• Enterococci.
Bidisposition of Cephalosporins is through renal clearance with active tubular secretion, Hence dose modification are required in patients with renal dysfunction.
Note: Cefoperazone and Ceftriaxone are largely eliminated in the bile.
Adverse effects:
Hypersensitivity reactions (2% incidence):
• Rashes and drug fever most common.
• Positive coombs test, but rarely haemolysis
• Cefotetan,Cefoperazone,Cefamandole, cause hypoprothrombinemia (anti-vitamin K effect) cause bleeding
• I.V injections-Phlebitis (inflammation of a vein)
• I.M injections-Pain.
Note: Most authorities recommend avoiding cephalosporins in patients allergic to penicillins.
Clinical uses:
• Alternative to penicillins
• Respiratory,urinary and soft tissues injuries
• Staphylococcal infections
• surgical prophylaxis –cefazolin –long half life
• Meningitis-Cefotaxime/Ceftriaxone is DOC/ or I.V PcG
• Gonorrhea: Ceftriaxone(250 mg IM) and Cefixime (400 mg single dose PO) used in single dose .
• Typhoid fever : Ceftriaxone (azythromycin, fluroquinolone..also DOC)
• Acute epiglottitis
Recall: if meningitis caused by Listeria DOC is ampicillin and st. pneumoniae DoC is Pc G
some other Inhibitors of cell wall synthesis include:
• Carbapenams
• Vancomycin
• Monobactam
• Fosfomycin
Carbapenams: include Imipenam , Meropenam , Ertapenem
Mode of Action:
Imipenam,meropenam and ertapenem are carbapenams that are bactericidal and bind to PBPs with the same mechanism of action as penicillins and cephalosporins.However, they are resistant to Beta-Lactamases.
Carbepenams are broad spectrum antibiotics include
• Gram positive cocci
• Gram negative rods(Enterobacter,Pseudomonas species)
• Anaerobes (nocardia and actinomyces)
Mostly used in severe life threatening infections
These group of drugs are administered I.V only and the drugs undergo renal elimination hence drug adjustment is needed in patients with renal dysfunction.
Imipenam is given with Cilastatin (Imipenam +Cilastatin),which inhibits its rapid metabolism by renal dihydropeptidases
Adverse Effects:
Carbapenams:
• GI distress…..nausea, vomiting, diarrhea
• Drug fever(partial cross-allergenicity with penicillins)
• CNS effects,including seizures
• Renal dysfunction.
• Eosinophilia, Neutropenia, Neurotoxicity
Voncomycin:
Mode of Action:
Bactericidal drug that acts at an early stage in cell wall synthesis
Use and Excretion:
One of the DOC in antibiotic associated colitis due to clostridium difficile or staphylococci antibiotic associated colitis/pseudomembranous colitis--ampicillin, Tc, clindamicin, cephalosporin
RX: •Vancomycin…may be 1st choice but it is reserve drug.
•Metronidazole…1st choice)
enters most tissues (eg;bone) but not CNS.
Eliminated by renal filtration(important to decrease dose in Renal dysfunction)
Has a long half life
Adverse Effects:
• Ototoxicity (usually permanent)
• Hypotension/Shock (due to histamine release)
• diffuse hyperemia(“Red man syndrome”/Red neck syndrome) due to histamine release if given too rapidly IV
• nephrotoxicity
• hypersensitivity reactions
Monobactam:Aztreonam:
Mode of Action: Monobactam inhibits of early step in cell wall synthesis.
• It inhibits enterobacteriacea and gram –ve rods, e.g Pseudomonas
• Has no activity against gram +ve and anaerobes.
Use:
• I.V drug mainly used in Hospital acquired infections.
• No cross allergenicity with penicillins or cephalosporins
Fosfomycin:
• Inhibits initial steps in the bacterial wall synthesis
• Active against both gram +ve and gram –ve
• Orally used for UTI
• Safe in pregnancy

USMLE1-AntiBacterial - Pencillins-2

2011-08-06T08:46:00.000-07:00

Beta-lactamase/Penicillinase inhibitors:
Clavulanic acid
Sulbactum
Tazobactum

Beta-lactamases are enzymes produced by gram + ve & gram –ve organisms that inactivate beta lactam antibiotics by opening beta lactam ring.
Beta lactamase inhibitors have--->no antibacterial activity of their own.

beta-lactam antibiotic + beta-lactamase inhibitors combinations
• Ampicillin-Sulbactam
• Ticarcillin-Clavulanic acid
• Piperacillin- Tazobactam
• Amoxicillin–Clavulanic acid

ü Amoxicillin–clavulanic acid is the only combination drug with oral bioavailability.

Beta-lactamase inhibitor :
Clavulanic acid : Naturally occurring beta lactamase inhibitor Inhibits wide variety of beta lactamases
• Amoxicillin + Clavulanic acid
• Ticarcillin + Clavulanic acid
Sulbactum, Tazobactum: Semi synthetic beta-lactamase inhibitor Oral bioavailability poor

Combinations given parenterally
• Ampicillin + Sulbactum
• Piperacillin + Tazobactum
The addition of the beta- lactamase inhibitor significantly broadens the spectrum of antibacterial activity against beta-lactamase-producing organisms
Elimination of the combination drugs occur primarily by renal excretion. Therefore, all of the beta-lactamase inhibitor combinations require dose adjustments in patients with renal insufficiency

clinical uses: in treating infections with known or suspected mixed bacterial flora, such as biliary infections, diabetic foot ulcers, endomyometritis, and peritonitis

Penicillins safe in Pregnancy:
• Ampicillin
• Penicillin G
• penicillin V
Adverse Effects of Pencillins:
Penicillins are among the safest drugs , although adverse reactions do occur.
• Hypersensitivity:
The major antigenic determinent of Pc hypersensitivity is its metabolite. penicilloic acid which reacts with proteins and serve as a hapten to cause an immune reaction.Incidence 5% to 7% with wide range of reactions (types 1 to 4).
• Urticarial skin rash common, but severe reactions, including anaphylaxis are possible.
• Interstitial nephritis occurs with Methicillin.
• cross-allergenicity between individual Pc.
• GI distress(NVD),especially Ampicillin
• Diarrhea by disruption of normal balance of intestinal microorganisms
• Superinfections leading to Candidiasis or Colitis
• Neurotoxicity : Pcs are irritating to neural tissues and can provoke seizures
• Jarisch Herxheimer Reaction in the treatment of Syphilis, Penicillin injected in a secondary syphilitic patient produce fever, exacerbation of lesions and vascular collapse
• Maculopapular Rash common with Ampicillin. Although rashes can develop with all the Pc, maculopapular rashes are most common with ampicillin.

USMLE1-AntiBacterial-Pencillins-1

2011-08-06T07:44:00.000-07:00

PENICILLINS-1

The structure common to all penicillins is a beta-lactam ring fused with a thiazolidine nucleus.

Mechanism of Action:

Bactericidal, require intact beta-lactam ring structure for activity.
Bind to Penicillin-binding proteins(PBPs) on cytoplasmic membrane, then decrease transpeptidation reactions involved in “cross-linking” of peptidoglycan chains
Activation of autolytic enzymes.

Mechanisms of Resistance:

Penicillinases(beta-lactamases) break Lactam ring structure (eg;Staphylococci).
Structural change in PBPs (eg;Methicillin Resistant Staphylococcus aureus [MRSA], penicillin resistant pnemococci)
Change in Porin structure (eg;Pseudomonas)
Reduced permeability - gram –ve organism.

Penicillins may be classified into four groups:

Natural penicillins (G and V)
Antistaphylococcal (penicillinase resistant) penicillins
Aminopenicillins
Antipseudomonal penicillins.

Note: Natural penicillins have therapeutic effects limited to streptococci and a few gram-negative organisms.

Natural penicillins:

Penicillin G
Penicillin V

Antistaphylococcal penicillins (penicillinase resistant Pc):

Nafcillin , Oxacillin,Cloxacillin, Flucloxacillin, Dicloxacillin

Aminopenicillins:

Ampicillin ,Amoxicillin

Antipseudomonal penicillins:

Carbenicillin, Mezlocillin, Piperacillin, Ticarcillin.

Clinical uses of penicillin G:

Endocarditis caused by S. viridans (or Streptococcus bovis)
Pharyngitis (group A –beta hemolytic streptococci)
Cat bite cellulitis (Pasteurella multocida)
Syphilis (Treponema pallidum)--->Pc G DOC
Intravenous penicillin G---->DOC for meningitis caused by S. pneumoniae.
Benzathine penicillin G(IM route)---> DOC for rheumatic fever prophylaxis

Clinical uses of penicillin V:

Penicillin V is used to treat streptococcal infections when oral therapy is appropriate and desirable.
Penicillin V (oral route) DOC--->for rheumatic heart disease/carditis prophylaxis may be casued by ARF/RF

Antistaphylococcal (penicillinase resistant) Pc:

Nafcillin, oxacillin, cloxacillin, and dicloxacillin are more resistant to bacterial beta-lactamases than is penicillin G.
Nafcillin : Primariliy eliminated through the biliary route.

Indications of Antistaphylococcal (penicillinase resistant) Pc:
severe staphylococcal infections like:

Cellulitis (but….Group A streptococci is the causative agent for rapidly spreading cellulitis and necrotizing fasciitis in most healthy young patients).
Erysipelas: a specific form of cellulitis
Empyema (collection of pus within a naturally existing anatomical cavity, such as the lung pleura)
Endocarditis, Osteomyelitis, Pneumonia, Septic arthritis, Toxic shock syndrome.

Aminopenicillins: Ampicillin, Amoxicillin
good oral bioavailability

ampicillin is effective treatment for meningitis caused by Listeria monocytogenes.

Indications for ampicillin include:

meningitis caused by Listeria monocytogenes--->DOC
serious infections like enterococcal endocarditis
pneumonia caused by beta-lactamase-negative H. influenzae.

Amoxicillin oral therapy is appropriate for

Clinically acute nonserious bacterial infections like otitis media and sinusitis.

Amoxicillin also has use in multidrug regimens for the eradication of Helicobacter pylori in duodenal and gastric ulcers.

Aminopenicillins uses:

Infections caused by the following organisms:

Haemophilius influenzae
E.coli
Listeria monocytogenes
Proteous mirabilis
Salmonella typhi

Ampicillin

Active against gram +ve and gram - ve organisams
Diarrhea is a side effect

Aminopenicillins

Active against gram +ve (mainly) and gram -ve organisams.

Antipseudomonal Penicillins: Carbenicillin, Ticarcillin, Mezlocillin, Piperacillin

The antipseudomonal penicillins have comparable spectra of activity against many gram-positive and gram-negative pathogens, including most anaerobes.

Antipseudomonal penicillins are used to treat

Pneumonias associated with cystic fibrosis--->DOC (Fluroquinolone e.g. Ciprofloxacin also DOC)
Mechanical ventilation---For prophylaxis of pseudomonal infection--->DOC
UTI (if…..caused by E.coli, Pseudomonas, proteus, Kebsiella)
It has good activity against Pseudomonas aeruginosa
►High dose cause bleeding by interfering with platelet function.

USMLE1-Anti Bacterial Pharmacology

2011-08-03T02:31:00.000-07:00

Antibacterial agents: substance that destroy bacteria or prevent their growth or replication.

Antibiotics: the general class of medications that are used against bacteria and also some parasites.

Anti microbial drugs can be either:

Bactericidal: kill infecting organisms
Bacteriostatic: slow their growth

Bactericidal drugs: Penicillin, Cephalosporins, Aminoglycosides, Quinolones/Fluoroquinolones
Bacteriostatic drugs: Sulfonamides, Tetracyclines, Erythromycin

Mechanism of Action of antimicrobial agents:

Inhibition of Bacterial Cell wall synthesis: Penicillins,Cephalosporins,Imipenem,Vancomycin

Inhibition of Bacterial protein synthesis: Aminoglycosides,chloramphenicol,macrolides,tetracyclines3.Inhibition of 3.Nucleic acid synthesis: Fluoroquinolones,Rifampicin

Inhibition of Folic acid synthesis: Sulfonamides,Trimethoprim,Pyrimethamine
Disruption of cell membrane function: Azoles and Polyene Anti fungal agents.

Bacterial Cell Wall - Basics:
Gram positive:

Presence of Teichoic and lipoteichoic acids
Have thick peptidoglycan layer, embeded in them is teichoic acid and lipoteichoic acid, most of the Antibiotics works on the peptidoglycans.

Gram negative:

Thin peptidoglycan layer
Outer membrane containing lipopolysaccharide (LPS), phospholipids and protiens
It has periplasmic space which is btw cytoplasmic membrane and outer membrane.
Gram -ve bacteria is resistance to antibiotic due to enzymes in periplasmic space.

Microbial Resistance to drugs

Mutation: A stable and heritable genetic change that occurs spontaneously and randomly among microorganism e.g., Rifampicin resistant mycobacterium tuberculosis.

Resistance due to Gene transfer by:

Conjugation: R factor transferred
Transduction : transfer of resistance gene by bacteriophage (virus that infect bacteria)
Transformation: by release of the resistance carrying DNA into the medium.

Due to alteration of expression of proteins in drug resistant organism:

Lack or alteration of binding site: Penicillin (PBP)
Lowered penetration/permeability:Beta lactams
Increased efflux:Tetracycline, Fluoroquinolones
Antibiotic inactivating enzyme: Beta lactams

Anti Bacterial Agents:

Beta-Lactam Antibiotics : Pc, Cephalosporine

Three other classes of beta-lactam antibiotics are available
These are:

Carbapenems/Imipenem
Carbacephems
Monobactams.

All beta-lactam antibiotics have the same bactericidal mechanism of action.- bacterial cell wall synthesis

USMLE1-Muscle cells of Cardiac physiology

2011-08-02T20:17:00.000-07:00

The muscle cells of the heart can be divided into 2 parts

Muscle cells specialized in the conducting system: The conducting system includes:

Inoatrial (SA) node
Atrioventricular (AV) node
Conducting cells

Atrial conducting cells are found in internodal pathways
Ventricular conducting cells consist of the AV bundle, bundle branches, and Purkinje fibers

Contractile cells: Contraction is what muscles do, and in the heart, the contraction is what makes the heart beat. When it beats, it is actually moving in an organized pattern that pumps (squeezes) the blood in a certain direction. I will refer to this as the heart's mechanical ability.