USMLE Pharmacology

What are the pharmacokinetics of pharmacology?

ADME

Absorption

Distribution

Metabolism

Excretion... What the body does to a drug

What are the pharmacodynamics of pharacology?

What the drug does to the body, mostly via receptor interactions including side effects

Which form of a drug is water soluble?

The Ionized from (better excreted renally

Which form of a drug is lipid soluble?

The non-ionized form

What is the pKa of a drug?

The pH at which the molecule is 50% ionized and 50% unionized

Give a small list of Weak acid drugs...

Aspirin

Penicillins

Cephalosporins

Loop and Thiazide Diuretics

Give a small list of weak bases!

Morphine

Local anesthetics

Amphetamines

PCP

What is true about Weak acids and Weak bases WRT a low pH environment?

Increased H+ concentration will lead to attachment of H+ to the drugs...

In the case of Weak acids this forms the R-CooH form, which is lipid soluble and crosses membranes

In the case of Weak Bases, this forms the R-NH3+ form, which is ionized and is better cleared as it is water soluble

General rule for drugs and pH values if you want to ABSORB a drug?!

Put them in the same type of environment!

Weak acids will be lipid soluble in acid pH where lots of H+ ions are attached and the drug is predominantly in the COOH form...lipid soluble

General rule for drugs and pH values if you want to EXCRETE a drug?

Put it in its opposite environment! Put weak acids in a basic environment to eliminate them as this causes dissociation of the H from COOH leading to COO-.... Water (URINE) soluble.

Normal body pH of the urine?

5-8

Important to remember about filtration of drugs at the glomerulus?

Only FREE UNBOUND drugs are filtered but BOTH ionized and nonionized forms are filtered...

Only the nonionized forms undergo active secretion or reabsorption since only they can cross membranes

Common compound used to acidify urine in cases of weak base overdose?

NH4Cl

or

Cranberry juice

Common compound used to alkalinize the urine in cases of weak acid overdose?

NaHCO3

or

Acetazolamide (inhibits carbonic anhydrase, which leads to decreased reabsorption of bicarb in the kidney, leading to alkaline urine

Why is lactulose administration in hepatic encephalopathy usedful in treating the problem?

Lactulose gets converted to lactic acid in the gut, leading to H+ production. This binds to the NH3 ammonia that is causing the encephalopathy, converting it to NH4+ and trapping it in the lumen for excretion

Which two transport mechanism in the kidney can be saturated?

Facilitated diffusion and active transport, because they require carriers!

What is the fastest route of absorption of a drug?

Inhalation! NOT IV administration, because those drugs do not need to be absorbed.

What is the "LAG" time of a drug?

The time between administration of a drug and the start of the first molecule being absorbed by the body...Doesn't mean the drug is working yet tho.

What is the minimum effective concentration of a drug?

The concentration at which we first see a pharmacological effect of the drug

What is the 'onset of activity' of a drug?

The time between administration of the drug and the point that it reaches its minimum effective concentration

What is the 'duration of action' of a drug?

The time between the drug rising above the minimum effective concentration and the the decline back down below the MEC due to elimination

What are two examples of things that are highly protein bound in the blood that can easily be displaced by Sulfonamides and lead to bad thingees?

Sulfonamides displacing biliruben in neonates, causing kernicterus

or

Sulfonamides displacing warfarin, which is 98% protein bound, leading to excessive bleeding.

What is true about drugs if they can cross the BBB?

They are highly lipid soluble, or have a low molecular weight and will EASILY CROSS THE PLACENTA AS WELL

What are three characteristics of a drug that would decrease its ability to cross the placenta and make for a safer pregnancy drug?

Water soluble

Large molecular wt

Highly protein bound

What is one of the safer anticonvulsants that can be used in pregnancy and why?

Phenobarbitol! It is highly protein bound...

Most anticonvulsants are highly lipid soluble and can easily cross placenta

What is a likely equation that will be asked on the USMLE regarding Volume of distribution?

Vd= Dose/Co where plasma concentration at time 0= Co..

Most likely calculate the dose needed.

What is the typical plasma volume of a 70kg man?

3L

What is the typical blood volume of a 70 kg Man?

5L

What is the typical Extracellular fluid volume of a 70 kg Man?

14L

What is the typical total body water of a 70 KG man?

42L....

What is redistribution of a drug?

When after administration of a drug and reaching the active site, it is redistributed to body tissues...so although it is not being eliminated the effect of the drug is gone. Think Thiopental.

Clinical consequences of repeated doses of drugs that are redistributed?

Saturation of the fat can occur after the first few doses, so subsequent doses will not undergo redistribution as much and more of the dose will hit the target, usually the brain

Important fact to remember about the BIOTRANSFORMATION of benzodiazepines?

The drug is often converted from an active drug to an ACTIVE metabolite, often times with a half life longer than that of the original drug

What are the three main reactions that occur in P450 phase 1 reactions?

Oxidation, Reduction and Hydrolysis

Where are benzopyrines classically found?

Cigarette smoke... These are actually inducers of P450 1A2s in addition to cruciferous vegetables.

What are classic inhibitors of P450 1A2?

Quinolones and Macrolides..

Classic example is of a pt on Theophylline to bronchodilate because they have chronic bronchitis... Then they get an URI, so are prescribed a Macrolide! It will cause theophylline toxicity

What macrolide antibiotic has virtually no inhibitor effect on P450 enzymes?

Azithromycin

What is a classic USMLE scenario involving grapefruit juice as an inhibitor of P450?

A pt who is placed on a statin drug to lower cholesterol... They also decide to workout and change their DIET...GRAPEFRUIT JUICE! This inhibits metabolism of the statin, leading to toxicity and liver damage

What types of reactions are seen in Phase II reactions?

Glucuronidation (reduced activity in neonates... can lead to Grey Baby syndrome in Chlorophenicol use.... Can also lead to Gilbert of Crigler Najjar)

and

Acetylation--- Fast and slow acetylater... Slow acetylaters lead to accumulation, leading to drug induced SLE, esp in HIPP

What is characteristic of a Zero order elimination rate of a drug?

A constant AMOUNT of drug is eliminated per unit time...There is NO FIXED HALFLIFE! Caused by saturation of elimination enzymes

Zero PEAs for me....

Zero order elimination!

Phenytoin

Ethanol

Aspirin

What is characteristic of First Order elimination Rate?

A constant FRACTION of the drug is eliminated per unit time.... follows constant half lives

How do you determine the Clearance of a protein bound drug?

Cl= the free fraction of the drug times of GFR

(they will have to tell u that the drug is 80% protein bound for example.)

What is true of the clearance when there is no reabsorption or secretion of a drug?

It is equal to the GFR.. normal GFR is 120 ml/min

What is the calculation for a Loading Dose of drug?

Concentration in the plasma (target concentration) times Vd

Half life of a drug:

t1/2 =(0.7 x Vd)/Clearance

What is the equation used for Maintenance dosing?

MD= Clearance times Concentration at steady state times tau, the dosing interval all divided by the bioavailability

What is true about antagonists WRT their actions?

They only inhibit an agonist from working, they have no effect themselves

Efficacy is similar to what parameter on a dose response curve?

The Vmax

Affinity of a drug is inversely proportional to...

Kd of the drug, like the Km in biochemistry

Name 5 noncompetitive or irreversible antagonists...

Phenoxybenzamine

Digoxin

Allopurinol

PPIs

Aspirin

Organophosphates

What is potentiation on a Dose response curve?

Shifting the dose response curve to the LEFT!

Can occur rarely, but GABA plus benzodiazepines together are an example of potentiation.

What is classic of pharmacologic antagonism?

2 different drugs trying to work on ONE receptor

What is classic of physiological antagonism!?

Two different drugs acting on two different receptors that have opposing effects

What is classic for chemical antagonism?

Drug-Drug interactions that neutralizes a drug without and receptor activation...Think heparin and protamine or Iron chelators binding to iron

How do you calculate the Therapeutic Index?

TILE! TI=LD 50/ED50

or

TI= TD50/ED50

What are the top 4 drugs to know that have a low therapeutic index?

Digoxin

Warfarin

Lithium

Theophylline

What does the therapeutic index of drug tells you?

You can take the TI times amount of the drug before you seen drug toxicity...

TI of 5, you take 5 times the drug before you see toxicity.

What is the main biochemical effect of cGMP as as signalling molecule?

It facilitates dephosphorylation of myosin light chains, preventing their interaction with actin, thus causing vasodilation.

What are four drugs that work via the cGMP--> NO pathway?

Nitrates

M agonists

Bradykinin

Histamine....all increase NO and vasodilate

The JAK-STAT pathway is essentially a fusion of which two types of signalling pathways?

The TK pathway, as it involves tyrosine kinases, and the steroid hormone pathway, which functions via intracellular messengers.

Epinephrine can work on receptors that Neurotransmitters (NE) cannot, such as B2 receptors...why?

B2 receptors are not innervated, therefore there is no nerve terminal to release NE into a synapse to find the receptor. Epi comes from the adrenal medulla, it is a HORMONE that travels in the blood and has no need for a nerve terminal.

Increased secretions are associated with what type of drugs?

Cholinergic drugs

What are two drugs that can be used to combat the reflex bradycardia caused by drugs that increase TPR?

Ganglionic blockers

or (more realistically)

M2 blockers

What are two ways that drugs can be used to combat the reflex tachycardia caused by drugs that decrease TPR? (Anti hypertensives, for instance..)

Ganglionic blockers

or (more realistically)

B1 blockers, as it is B1 that increase heart rate.

When giving antihypertensive drugs, what are two things you need to take into account?

The fact that the body will cause a reflex tachycardia (use a beta1 blocker) and the fact that the body will increase RAAS when the perfusion pressure of the kidney suffers... (Use ACE inhibitors* or ARBs* or diuretics)

What is the Mean Arterial Pressure?

2/3 diastolic plus 1/3 systolic

What receptors are on the RADIAL muscle of the eye, causing mydriasis?

Alpha 1 receptors, opening the aperture

What receptors are on the sphincter muscle of the eye, leading to miosis?

Muscarinic receptors.....

How can you differentiate between pupillary changes caused by say stimulation of the M receptors or antagonism of the A1 receptor?

Check the accommodation!!

The ciliary muscle of the eye is responsible for accommodation so you can focus for near or distant vision and is only innervated by Muscarinic receptors. Muscarinic drugs will lead to blurred vision***, as you are focused on near objects!

Muscarinic stimulation of the eye will lead to....

Constricted pupils

AND

Blurred distant vision as the patient is accommodating for near vision.

A1 antagonists will not show this

What is cycloplegia?

Paralysis of accommodation for near vision, leading to blurry near vision. Muscarinic antagonists will lead to this, along with pupillary dilation

What is the MOA of Hemicholium?

Blocks reuptake of choline from the nerve terminal, leading to less synthesis of ACh...

Purely theoretical but know it for a diagram

What is the MOA of Botulism Toxin?

Binds synaptobrevein that normally allows for docking of the vesicles containing ACh with the presynaptic nerve terminal for release into the synaptic cleft. Prevents ACh release

What are 4 clinical uses of Bo-tox injections and what receptors does this work on ?

Blepharospasm

Dystonias like spasmic torticollis

Striabismus

Wrinkles....all of these require interaction with the Nm type receptors on the neuromuscular junction

What is a common clinical use of Bo-TOX that requires action at muscarinic receptor subtypes?

Hyperhydrosis...

Decreases secretions from sweat glands by activation of muscarinic receptors not nicotinic...This is because it is working on sweat glands

What receptors are located on the sphincter muscle of the eye?

M3...cause miosis

What receptors are seen on the ciliary muscle of the eye?

M3...cause accommodation for near vision

What type of muscarinic receptors are located on the SA and AV nodes of the heart?

M2 receptors...lead to decreased heartrate (Chronotropy) and decreased conduction velocity, AKA negative dromotrophy. Can potentially increase the PR interval

What portion of the heart does NOT have M2 receptors?

The ventricles! There is no muscarinic effect on the contractility of the heart.

What type of muscarinic receptors are located on the bronchioles and glands of the lungs and what does stimulation lead to?

M3--- Contraction of the SM in bronchioles and increased secretion of mucus....Leads to a COPD like picture and decreased FEV1 to FVC ratio

Peptic ulcer disease patients should not be given...

Muscarinic agonists! It will increase M1 mediated secretion especially of acid production

What does muscarinic stimulation lead to in the gut?

Increased motility, can lead to cramps... Causes increase longitudinal waves and opening of sphincters

What types of muscarinic receptors are on the bladder and what is the function?

M3--- stimulation causes contraction of the detrusor muscle and relaxation of the trigone and sphincter, leading to voiding or urinary incontinence.

Muscarinic M3 receptors in the GI and GU system cause relaxation of all sphincters except for!

The lower esophageal sphincter, which contracts

All glands, except those in the GI that have M1 and which increase secretion, esp of acid, all have what type of receptors and what does stimulation cause?

M3...leads to sweating, salivation and lacrimation.

Useful in treating Sjogrens.

What is important to remember about M3 receptors found on endothelium?

Stimulation causes vasodilation via NO, but they are NOT INNERVATED! Indirect agonists, such as AChE inhibitors will not work

What types of channels are used by Nn and Nm receptors?

Ligand gated channels only, for Ach... Leads to Na+ influx and K+ efflux There are no second messengers.

Nicotinic receptors desensitize VERY QUICKLY...

Leads to decreased muscle tone, flaccid paralysis and can paralyze the diaphragm

What is a primary tested use of Bethanechol on the USMLE?

Treatment of ileus, such as postoperative or neurogenic ileus...as well as urinary retention

What type of drug is Bethanechol?

A direct acting muscarinic agonist

What drug is used to diagnose bronchial hyperreactivity in a patient with potential allergies?

Methacholine

What type of drug is Methacholine?

A direct acting muscarinic agonist

What type of drug is Pilocarpine?

A direct acting muscarinic agonist! PILE on the sweat and tears!

What are two common clinical uses of Pilocarpine?

Topical application for treatment of glaucoma

and

Xerostomia, esp in Sjogren's patients

Bethanachol activates...

Bowel and Bladder! Beth Anne, Call me if you want to move you bowels and bladder!

What type of drug is Carbachol?

A direct acting muscarinic agonist!

What is the drug carbachol commonly used for?

Glaucoma... and release of increased IOP

What drug is commonly used to help facilitate the Chloride Sweat Test in CF patients?

Pilocarpine! Stimulates sweating so enuf can be collected for analysis

What type of drug is edrophonium?

An indirect acting muscarinic agonist.