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Atropine's anti muscarinic effects- jimson Weed (Datura stramonium) poisoning - USMLE 1

2011-12-31T14:53:00.000-06:00

Atropine's anti muscarinic effects:

Anticholinergic properties jimson weed and Atropine poisoning similarities:

jimson Weed (Datura stramonium) poisoning -This condition is also called as "Gardener's mydriasis" jimson Weed produce toxins (belladonna alkaloids) that possess strong anticholinergic properties jimson weed and atropine poisoning are strikingly similar. Blockade of visceral muscarinic receptors produces the following effects

1 Heart -diminished vagal tone at the SA node causes relative tachycardia

2 Blood vessels- vasoconstriction via muscarinic receptor blockade in endothelial cells results in decreased nitric oxide synthesis In spite of this effect, atropine poisoning is associated with cutaneous flushing: the pathogenesis of this effect is unknown

3 GI- delayed gastric emptying, decreased intestinal motility, and secretion 4 Respiratory bronchodilatation

5 GU- urinary retention vi a detrusor relaxation and contraction of the external urethral sphincter

6 Secretions decreased lacrimation (dry eyes), salivation (dry mouth) and sweating (dry and hot skin) Atropine decreases one's ability to sweat, contributing to hyperthermia

7 Eye- mydriasis (dilated pupils) and cycloplegia (inability to focus on the near objects, blurry vision)

8 CNS -hallucinations, agitation and delirium

Atropine's anti muscarinic effects can be counteracted by increasing the concentration of acetylcholine in the synaptic cleft increased acetylcholine concentrations are produced by cholinesterase inhibitors that suppress acetylcholine degradation Physostigmine, a cholinesterase inhibitor, can be used for treatment of atropine overdose

The renin-angiotensin-aldosterone system (RAAS)- USMLE 1

2011-12-29T22:46:00.000-06:00

The renin-angiotensin-aldosterone system (RAAS) is one of the most important neurohormonal systems that regulate arterial blood pressure and sodium and fluid content in the body In response to decreased sodium, fluid volume, or arterial blood pressure, renin is released from the kidneys converting angiotensinogen to angiotensin I Subsequently, angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II Angiotensin II then increases aldosterone secretion from the adrenal cortex leading to increased sodium and fluid retention in the collecting tubules of the kidneys Angiotensin II is also a potent vasoconstrictor that ultimately increases systemic vascular resistance and arterial pressure

Angiotensin II itself is involved in two negative feedback mechanisms that help regulate the RAAS In short loop negative feedback, elevated angiotensin II stimulates the angiotensin receptors on juxtaglomerular cells to inhibit renin release In long loop negative feedback, elevated blood pressure and sodium levels secondary to angiotensin II eventually decrease renin release via intrarenal baroreceptor and maculadensa pathways, respectively

Pharmacodynamics-2 Antagonists: USMLE1

2011-10-31T10:34:00.000-05:00

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

Pharmacodynamics-1 : USMLE1

2011-10-31T10:30:00.002-05:00

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.

Tricyclic antidipressents (TCA): Adverse effects(high yield)

2011-10-30T15:13:00.000-05:00

Tricyclic antidipressents (TCA): side effects
TCA'S:
Thrombocytopenia
Cardiac (arrhymia, MI, stroke)
Anticholinergic (tachycardia, urinary retention, etc)
Seizures

Systemic lupus erythematosus (SLE)- USMLE1

2011-10-25T13:01:00.000-05:00

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

Cytochrome P450 Isozymes (CYP)- USMLE1

2011-10-25T12:47:00.000-05:00

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)

Artery Defects and Ophthalmologic deficits( Highyield Concept)

2011-10-20T10:00:00.000-05:00

Artery Defects and Ophthalmologic deficits

Anterior communicating artery - Bitemporal hemianopia

Internal carotid artery - Binasal hemianopia

Ophthalmic artery - Monocular blindness

Posterior cerebral artery - Homonymous hemianopia with macular sparing

Posterior communicating artery - Cranial nerve III palsy

Cranial Nerve Reflexes; Afferent and Efferent (High Yield concept)

2011-10-19T21:35:00.003-05:00

Cranial Nerve Reflexes; Afferent and Efferent (High Yield concept)

CORNEAL REFLEX
Afferent: Trigeminal nerve (Ophthalmic division)
Efferent: Facial nerve (bilateral)

GAG REFLEX
Afferent: Glossopharyngeal
Efferent: Vagus (bilateral)

LIGHT REFLEX
Afferent: Option nerve
Efferent: Occulomotor nerve

JAW REFLEX
Afferent and efferent served by Trigeminal (only reflex that can check both the sensory and motor parts of the Trigeminal).

General Pharmacology-3 for USMLE1

2011-10-18T22:26:00.002-05:00

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.

General Pharmacology-2 for USMLE1

2011-10-18T22:23:00.002-05:00

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.

General Pharmacology-1 for USMLE1

2011-10-18T22:20:00.001-05:00

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

Smooth Muscle Contraction

2011-10-17T12:54:00.002-05:00

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.

Pharmacology Quick review

2011-10-16T18:10:00.002-05:00

Pharmacology: General principles

1. The most important factor influencing drug absorption rate following intramuscular injection is:

a. needle diameter

b. rate of administration

c. injection site blood flow

d. injection volume

2. Mechanism(s) of drug permeation

a. lipid diffusion

b. aqueous diffusion

c. use of carrier molecules

d. endocytosis and exocytosis

e. all of the above

3. Pharmacological antagonists:

a. cause receptor down regulation

b. prevent binding of other molecules to the receptor by their binding to the receptor

c. atropine (blocks ACh action on the heart

d. A & B

e. B & C

4. Dramatic decrease in systemic availability of a drug following oral administration is most likely due to:

a. extreme drug instability at stomach pH

b. hepatic "first-pass" effect

c. drug metabolized by gut flora

d. tablet does not dissolve

e. patient non-compliance

5. Drug delivery method LEAST suitable for long term (days to weeks) slow release

a. pellet implant under the skin (subcutaneous)

b. time release capsule

c. i.m. injection of a drug-oil suspension

d. transdermal patch

6. Factors that influence the rate of passive movement to molecules down the concentration gradient (Fick's Law)

a. concentration difference across the barrier

b. area across which diffusion occurs

c. drug mobility in the diffusion panel

d. thickness -- length of the diffusion pass

e. all the above

7. Definition: Therapeutic Index

a. ED50/LD50

b. potency/selectivity

c. EC50/LD50

d. TD50/ED50

e. ED50

8. Primary site for drug metabolism:

a. stomach

b. small intestine

c. kidney

d. muscle

e. liver

9. Drug mixed-function oxidase (p450) mainly localized:

a. mitochondrial fraction

b. cell membranes

c. golgi bodies

d. microsomal fraction

e. nucleolus

10. Cytochrome-P450 INDEPENDENT oxidation:

a. amine oxidase

b. epoxidation

c. N-oxidation

d. S-oxidation

e. deamination

Answers: 1. C, 2. E, 3. E, 4.B, 5. B, 6. E, 7. D, 8. E, 9. D, 10. A

USMLE1- Practice questions Cranial Nerves

2011-09-24T18:49:00.001-05:00

Cranial Nerves:Which of the following cranial nerves is necessary for horizontal conjugate movements of the eyes?

a. III

b. IV

c. VI

d. Both A and B

e. Both A and C –Occulomotor & Abducens

2. Which of the following cranial nerves is necessary for elevation of the eyeball?

a. III- Occulomotor

b. IV

c. VI

d. V

e. None of the above

3. Which of the following combinations of extraocular muscle and cranial nerve of supply are involved in mediating depression or downward movements of the eyeball?

a. superior oblique - Nerve III

b. inferior oblique - Nerve IV

c. inferior rectus - Nerve VI

d. inferior oblique - Nerve IV

e. superior oblique - Nerve IV-Trochlear

4. Which of the following is NOT a function of cranial nerve III?

a. elevation of eyes

b. adduction of eyes

c. constriction of pupil

d. dilatation of pupil

e. changing the shape of the lens

5. Which of the following ganglia is involved in mediating pupillary light reflex?

a. ciliary ganglion

b. celiac ganglion

c. trigeminal ganglion

d. pterygopalatine ganglion

e. none of the above

6. Which of the following in NOT a sign/symptom of dysfunction of cranial nerve III?

a. constricted pupil (miosis)

b. downward and outward deviation of the eye ball

c. loss of pupillary light reflex

d. ptosis (drooping of the upper lid)

e. none of the above

7. Which of the following cranial nerves innervate smooth muscles?

a. IX

b. V

c. VII

d. Both A and C

e. III-occulomotor

8. Which of the following muscles remain functional after a complete interruption of cranial nerve III?

a. ciliary muscle

b. lateral rectus

c. superior oblique

d. superior rectus

e. Both B and C

9. Which of the following cranial nerves has the longest intracranial course (between points of attachment to the brain stem and exit through its cranial foramen)?

a. III

b. V

c. VI -abducens

d. VII

e. IX

10. Which of the following is a TRUE statement?

a. all cranial nerves carry motor, sensory and parasympathetic fibers

b. all cranial nerves have sensory ganglia attached to them

c. cranial nerves carry sympathetic preganglionic fibers

d. all spinal nerves carry sensory and motor fibers

e. all spinal nerves carry parasympathetic fibers

11. Trigeminal nerve:

a. is a mixed cranial nerve with both motor and sensory functions

b. has a sensory ganglion

c. innervates the muscles of mastication

d. does not carry preganglionic parasympathetic fibers

e. all of the above are true

12. Which of the following cranial nerves is/are closely related to the cavernous sinus?

a. III -occulo

b. VI -abducent

c. IV -trochlear

d. ophthalmic and maxillary divisions of V-trigeminal

e. all of the above

13. The ophthalmic nerve:

a. gives rise to branches which supply the cornea

b. innervates the muscles of mastication

c. is necessary for the motor response of the corneal reflex

d. innervates the buccinator muscle

e. provides sensory innervation to the skin of the cheek

14. The maxillary division of trigeminal nerve:

a. passes through the pterygopalatine fossa

b. becomes the infraorbital nerve

c. supplies the skin of the cheek, lower eyelid and upper lip

d. supplies the lining of the maxillary air sinus

e. all of the above are true

15. Damage to the motor fibers in the trigeminal nerve may cause:

a. flattening of the side of the jaw due to atrophy of the masseter muscle

b. difficulty in closing the eyes

c. slight deviation of the jaw toward the affected side when the mouth is opened

d. Both A and B

e. Both A and C

16. Mandibular division of the trigeminal nerve conveys cutaneous sensory information from:

a. the upper lip

b. the lower lip

c. the bony part of the cheek

d. Both A and C

e. Both B and C

17. Which of the following is NOT supplied by branches of the mandibular division of V:

a. gums and teeth of the lower jaw

b. anterior two-thirds of the tongue

c. muscles of mastication

d. skin over the angle of the mandible

e. e. mucous membrane lining the cheek

18. Facial nerve:

a. enters the internal auditory meatus

b. courses in the facial canal in the petrous temporal bone in relation to the middle ear cavity

c. exits from the skull through the stylomastoid foramen

d. enters the substance of the parotid salivary gland

e. all of the above are true

19. Which of the following cranial nerves is likely to be damaged during surgery on middle ear and mastoid antrum?

a. V

b. VI

c. VII -facial

d. X

e. None of the above

20. Which of the following is NOT supplied by the vagus, along with the cranial accessory?

a. constrictor muscles of the pharynx

b. muscles of the soft palate

c. muscles of the larynx

d. mucous membrane of the larynx

e. mucous membrane of the nasal cavity

21. The recurrent laryngeal branch of the vagus:

a. arises in the thorax on the left side

b. is found in the groove between the trachea and the esophagus in the neck

c. supplies all muscles of the larynx except the cricothyroid

d. only A and C are correct

e. A, B and C are correct

22. The cranial division of the accessory nerve:

a. arises from the spinal cord

b. contains parasympathetic fibers which innervate the heart and other viscera

c. joins the vagus and is distributed through it to the skeletal muscles of the larynx, soft palate and pharynx

d. is found in the roof of the posterior triangle

e. supplies the sternocleidomastoid muscle

23. A normal gag reflex is dependent on the intactness of the following nerves:

a. V

b. IX

c. X and cranial XI

d. Both A and B

e. Both B and C

24. You are testing palatal movements in a patient. When the patient is asked to say "Ah", the right side of the palate is found to be at a lower level than the left and the uvula is deviated toward the left. This patient is likely to have a lesion of the:

a. right vagus and cranial accessory

b. left vagus and cranial accessory

c. right glossopharyngeal nerve

d. left glossopharyngeal nerve

e. none of the above

25. Which of the following cranial nerves carry parasympathetic preganglionic fibers?

a. III -occulo

b. VII -facial

c. IX -glossopharyngeal

d. X -vagus

e. all of the above

26. Which of the following muscles is innervated by parasympathetic postganglionic fibers?

a. ciliary muscle

b. superior rectus

c. sphincter pupillae

d. dilator pupillae

e. both A and C

27. A complete interruption of the right cranial nerve VI will result in:

a. paralysis of the left lateral rectus

b. inability to abduct the right eye

c. diplopia in looking to the left

d. inability to adduct the right eye

e. all of the above

28. Which of the following can produce ptosis (drooping of upper eyelid)?

a. loss of innervation of the levator palpebrae superioris

b. loss of function of cranial nerve III

c. loss of sympathetic innervation of the eye

d. paralysis of orbicularis oculi muscle

e. all of the above except D

29. Pupillary dilation results from:

a. contraction of dilator pupillae

b. activation of sympathetic preganglionic neurons in the spinal cord

c. activation of sympathetic postganglionic fibers arising from the superior cervical ganglion

d. release of norepinephrine from nerves which innervate the dilator pupillae

e. all of the above

30. Which of the following cranial nerves carry motor fibers to skeletal muscles?

a. facial

b. hypoglossal

c. vagus

d. mandibular branch of trigeminal

e. all of the above

31. Which of the following cranial nerves travel through the superior orbital fissure?

a. III –occulo

b. IV -troch

c. ophthalmic division of V

d. maxillary division of V

e. all of the above except D

32. Ophthalmic division of V:

a. passes through the optic foramen

b. enters the orbit through the inferior orbital fissure

c. supplies skeletal muscles in the orbit

d. is the major sensory nerve to the eye by way of its nasociliary branch

e. all of the above

33. The frontal nerve:

a. divides into supraorbital and supratrochlear branches

b. supplies the skin of the forehead

c. supplies the frontal air sinus

d. is a sensory nerve

e. all of the above

34. Cutaneous distribution of the maxillary nerve includes:

a. upper eyelid

b. lower eyelid

c. lower lip

d. bridge of the nose

e. all of the above

35. Branches of the trigeminal nerve supply:

a. Meninges

b. mucous lining of nasal cavities and paranasal air sinuses

c. cornea

d. mucosa of the anterior two-thirds of the tongue

e. all of the above

36. Branches of the mandibular division of the trigeminal nerve supply:

a. masseter

b. buccinator

c. medial and lateral pterygoids

d. orbicularis oculi

e. A and C

37. The corneal reflex is a test for the integrity of:

a. ophthalmic division of V

b. cranial nerve III

c. cranial nerve VII

d. both (a) and (b)

e. both (a) and (c)

38. The mandibular nerve:

a. passes through the foramen spinosum

b. is a purely sensory nerve, with no motor components

c. provides sensory innervation to the posterior third of the tongue

d. passes through the pterygopalatine fossa

e. its lingual branch carries the chorda tympani branch of nerve VII

39. Which of the following types of fibers is/are NOTcontained in the facial nerve?

a. motor

b. parasympathetic preganglionic

c. special sensory from taste buds

d. general sensory from the facial skin

e. general sensory from the mucous membranes

40. Parasympathetic fibers contained in the facial nerve are responsible for the innervation of:

a. submandibular salivary gland

b. lacrimal gland

c. sublingual salivary gland

d. parotid salivary gland

e. all of the above except D

41. Inflammatory reaction confined to an area around the stylomastoid foramen is one of the conditions that leads to a clinical entity referred to as "Bell's palsy". This is likely to manifest as:

a. difficulty in opening the eyes

b. absence of wrinkling of the forehead

c. complete lack of secretion of saliva

d. inability to perceive taste sensation from the anterior two-thirds of the tongue

e. all of the above

42. Loss of taste sensation at the tip of the tongue indicates an involvement of:

a. branches of the facial nerve in the parotid gland

b. chorda tympani branch of facial nerve

c. the facial nerve at the level of the stylomastoid foramen

d. the facial nerve in the cranial cavity before it enters the facial canal

e. Both B and D

43. Glossopharyngeal nerve innervates:

a. taste buds in the posterior third of the tongue

b. general sensory receptors in the posterior third of the tongue

c. stylopharyngeus muscle

d. baroreceptors in the carotid sinus

e. e. all of the above

44. Sensory innervation of the mucous membrane of the larynx is provided by:

a. the glossopharyngeal nerve

b. trigeminal nerve

c. the spinal accessory nerve

d. the vagus

e. all of the above

45. On asking a patient to protrude her tongue, you observe that the tongue deviates to the right side. This patient is likely to have:

a. a paralysis of the right genioglossus muscle

b. a complete interruption of the right hypoglossal nerve

c. wasting (atrophy) of the right half of the tongue

d. a normal left hypoglossal nerve

e. all of the above

46. Which of the following is correct regarding the larynx?

a. mucous membrane below the vocal cords is supplied by the internal laryngeal branch of vagus

b. external laryngeal branch supplies the cricothyroid muscle

c. all muscles other than the cricothyroid are supplied by the internal laryngeal branch

d. one muscle is supplied by the glossopharyngeal nerve

e. sensory innervation is in part provided by the glossopharyngeal nerve

47. Which of the following combinations of skeletal muscle and its nerve of supply is/are NOT correct?

a. buccinator - facial nerve

b. lateral cricoarytenoid - vagus

c. genioglossus - hypoglossal nerve

d. mylohyoid- cervical spinal nerve

e. infrahyoid muscles- hypoglossal nerve

48. Which of the following cranial nerves is/are responsible for initiating reflexes resulting from the stimulation of receptors in the carotid body and sinus?

a. IX –the carotid sinus is thickening of wall of internal carotid artery, near common carotid. Baroreceptors fire when pressure in sinus is changed.

b. V

c. XI

d. VII

e. all of the above

49. Which of the following branches of cranial nerves contains preganglionic parasympathetic fibers?

a. chorda tympani

b. greater superficial petrosal

c. lacrimal

d. both a and b

e. All of the above

50. Which of the following cranial nerves carry taste sensation?

a. VII -facial

b. IX -glosso

c. X -vagus

d. XI -accessory

e. all of the above except D

1. A&C, 2. E, 3. E, 4. D, 5. A, 6.A, 7.E, 8.E, 9.C, 10. D, 11.E, 12. E, 13.A, 14. E, 15.E, 16. B, 17. D, 18. E, 19. C, 20. E, 21. E, 22. C, 23. E, 24. A, 25. E, 26. E, 27. B, 28. E, 29. E, 30. E, 31.E, 32. D, 33. E, 34. B, 35.E, 36. E, 37. E, 38. E, 39. D, 40. E, 41. B, 42. E, 43. E, 44. D, 45. E, 46. B, 47. D, 48. A, 49. E, 50. E.