pharmacology 1

PHARMACOLOGY

USMLE Step 1 Flash cards by Seetal K Dhaliwal H. S

1by Seetal K Dhaliwal H. S

Flash cards by Seetal K. Dhaliwal H. SSection I


Pharmacokinetics:

Vd:

Drugs with low Vd distribute in blood; medium Vd in

extracellular space or body water; high Vd distribute

in tissues.

t1/2:

A drug infused at a constant rate reaches ~94%

steady state after 4 t1/2 (FIRST ORDER ELIMINATION):

by Seetal K Dhaliwal H. S

Competitive

inhibitors

Non-competitive

inhibitors

Resemble substrate YES NO

Overcome by ↑ [S] YES NO

Bind active site YES NO

Effect on Vmax Unchanged ↓

Effect on Km ↑ Unchanged

Pharmacodynamics ↓ potency ↓ efficacy

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# of half-lives 1 2 3 4

concentration 50% 75% 87.5% 93.75%

Pharmacokinetics:

Loading dose:

Cp x Vd/F (F=bioavailability is 1 when given IV)

Maintenance dose:

Cp x CL/F

In patients with renal or hepatic disorder, the loading dose remains unchanged although

the maintenance dose is ↓.

Metabolism of drug:

Phase 1 (reduction, oxidation, hydrolysis) usually yields slight polar, water-soluble metabolites

(often still active). CYP450. Geriatric patients lose phase 1 first.

Phase 2 (acetylation, glucuronidation, sulfation) usually yields very polar, inactive metabolites

(renally excreted). Conjugation phase.

Elimination of drugs:

Zero order constant amount of drug eliminated per unit time. Phenytoin, Ethanol & Aspirin

(high dose).

First order constant fraction of drug eliminated per unit time. Rate of elimination is

proportional to drug concentration. by Seetal K Dhaliwal H. S

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Important Pharmacokinetics calculations:

Single dose equations:

Vd = D/C0

t1/2 = 0.7/k

CL = k x Vd

t1/2 = 0.7 x Vd/CL


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Multiple dose equations:

k0 = CL x Css

LD = Vd x Css

MD = CL x Css x τ

Vd = Volume of distribution

k = elimination constant

D = Dose

C0 = concentration at time 0

t1/2 = half-life

CL = Clearance

Css = steady state concentration

LD = Loading Dose

k0 = infusion rate

MD = Maintenance Dose

τ = dosing interval

Flash cards by Seetal K. Dhaliwal H. SSection II


Central & Peripheral NS:


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ACh receptors:

Nicotinic ACh receptors are ligand-gated Na+/K+ channels; NN (found in autonomic

ganglia) and NM (found in NMJ) subtypes.

Muscarinic ACh receptors are G-protein-coupled receptors that act through 2nd messengers;

5 subtypes: M1, M2, M3, M4 and M5.

G-protein-linked 2nd messengers:


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9G-protein-linked 2nd messengers:

Receptor G protein class Major functions

α1 q ↑ vascular smooth muscle contraction, Mydriasis, ↑ intestinal &

bladder sphincter contraction.

α2 i ↓ sympathetic outflow, ↓ insulin release

β1 s ↑ HR, ↑ contractility, ↑ renin release, ↑ lipolysis

β2 s Vasodilation, bronchodilation, ↑ HR, ↑ contractility, ↑ lipolysis, ↑

insulin release, ↓ uterine tone

M1 q CNS, enteric nervous system

M2 i ↓ HR and contractility of atria

M3 q ↑ exocrine gland secretions (sweat, gastric acid), ↑ gut peristalsis, ↑

bladder contraction, bronchoconstriction, miosis, accomodation.

D1 s Relaxes renal vascular smooth muscle

D2 i Modulates transmitter release (especially in brain)

H1 q ↑ nasal & bronchial mucus production, contraction of

bronchioles, pruritus & pain.

H2 s ↑ gastric acid secretion

V1 q ↑ vascular smooth muscle contraction

V2 s ↑ H2O permeability & reabsorption in CT of kidneys

Sym

pa

thetic

Para

-

sym

pa

thetic

Cholinomimetic agents:

Drug Clinical applications Action

- Direct Agonists

Bethanechol Postoperative & neurogenic

ileus & urinary retention

Activates bowel & bladder

smooth muscle; resistant to

AChE.

Carbachol Glaucoma, pupillary

contraction, & release of IOP

Pilocarpine Potent simulator of sweat, tears,

saliva

Contracts cilliary muscle of

eyes (open angle), pupillary

sphincter (narrow angle);

resistant to AChE.

Methacholine Challenge test for diagnosis of

asthma

Stimulates muscarinic

receptors in airway when

inhaled.


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Cholinomimetic agents:

Drug Clinical applications Action

- Indirect Agonists

(anti-cholinesterases)

Neostigmine Postoperative & neurogenic

ileus & urinary retention,

myasthenia gravis, reversal of

NMJ block (post-operative)

↑ endogenous ACh; no CNS

penetration. NEO CNS =

NO CNS penetration.

Pyridostigmine Myasthenia gravis (long-

acting). Doesn’t cross BBB.

↑ endogenous ACh; ↑

strength.

Edrophonium Diagnosing myasthenia gravis

extremely short acting). If

+MG, symptoms disappear, if ACh

overdose, symptoms get worse.

↑ endogenous ACh.

Physostigmine Glaucoma (crosses BBB) &

atropine overdose

↑ endogenous ACh. PHYS for

EYES.

Echothiophate Glaucoma ↑ endogenous ACh.


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Cholinesterase inhibitor poisoning:

Caused by parathion & other organophosphates. Irreversible inhibitors.

DUMBBELSS symptoms: Diarrhea, Urination, Miosis, Bradycardia, Bronchospasm,

Excitation of skeletal muscle, Lacrimation, Sweating, Salivation (also abdominal

cramps).

Antidote – ATROPINE (muscarinic antagonist) plus PRALIDOXIME (used to

regenerate active cholinesterase).

Atropine (muscarinic antagonist):

↑ pupil dilation (mydriasis), cycloplegia, ↓ airway secretions, ↓ acid secretion, ↓

motility, ↓ urgency & cystitis.

Blocks SLUD: Salivation, Lacrimation, Urination & Diarrhea.

Toxicity: ↑ body temperature, rapid pulse, dry mouth, dry flushed skin, cycloplegia,

constipation, disorientation.

Can cause acute angle-closure glaucoma in elderly, urinary retention in men with

prostatic hyperplasia, & hyperthermia in infants.

HOT as a HARE, DRY as a BONE, RED as a BEET, BLIND as a BAT, MAD as a

HATTER.by Seetal K Dhaliwal H. S

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Muscarinic antagonist:

Atropine, homatropine, tropicamide EYE produces mydriasis & cycloplegia.

Benztropine CNS Used in Parkinson disease (PARK my BENZ).

Scopolamine CNS Anti-motion Sickness.

Ipratropium bromide Respiratory used in Asthma & COPD.

Oxybutynin, glycopyrrolate Genitourinary used to reduce urgency in mild

cystitis & reduce bladder spasms.

Methscopolamine, pirenzepine, propantheline Gastrointestinal peptic ulcer

treatment.

Hexamethonium (Nicotinic antagonist):

Ganglion blocker. Used in experimental models to prevent vagal reflex responses

to changes in blood pressure – e.g., prevents reflex bradycardia caused by NE.

Toxicity: Severe orthostatic hypotension, blurred vision, constipation, sexual

dysfunction.

Put a HEX on smokers (nicotine) to help them quit.


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Direct - Sympatomimetics:

Epinephrine α1,α2,β1,β2; low doses selective

for β1.

Used in anaphylaxis, glaucoma (open-

angle), asthma, hypotension.

NE α1, α2 > β1 Used in hypotension but ↓ renal

perfusion.

Isoproterenol β1 = β2 (isolated to β) Used in AV block (rare)

Dopamine D1 = D2 > β> α, inotropic &

chronotropic

Used in shock (to ↑ renal perfusion),

heart failure.

Dobutamine β1 > β2 , inotropic but NOT

chronotropic

Used in shock, heart failure, cardiac

stress testing (if treadmill cannot use)

Phenylephrine α1 > α2 Used to dilate pupil, as a vasoconstrictor

& nasal decongestant.

Metaproterenol,

albuterol,

salmeterol,

terbutaline.

Selective β2 agonists (β2 > β1) MAST: Metaproterenol & Albuterol for

acute asthma, Salmeterol long-term tx,

Terbutaline to reduce premature uterine

contractions.

Ritodrine β2 Reduces premature uterine contractionsby Seetal K Dhaliwal H. S

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Amphetamine indirect general agonist; releases stored catecholamines

used in Narcolepsy, obesity, attention deficit disorder (ADHD).

Ephedrine indirect general agonist; releases stored catecholamines used

in nasal decongestion, urinary incontinence, hypotension.

Cocaine indirect general agonist; uptake inhibitor causes vasoconstriction

& used as local anesthesia.

Clonidine, α-methyldopa centrally acting α2-agonists, ↓ central adrenergic

outflow.

Used in HTN especially with renal disease (does not ↓ blood flow to kidneys)

Celecoxib, Furosemide, Probenecid, Thiazides, TMP-SMX, Sulfasalazine,

Sulfonylureas, Sumatriptan.

Patients with sulfa allergy may develop fever, pruritic rash, SJS, hemolytic

anemia, thrombocytopenia, agranulocytosis, & urticaria (hives). Symptoms range

from mild to life-threatening.

Drug Application Toxicity

Nonselective

Phenoxybenzamine

(irreversible)

and pentolamine

(reversible)

Pheochromocytoma

(use

phenoxybenzamine

before removing tumor)

Orthostatic hypotension, reflex

tachycardia

α1 selective (-zosin)

Prazosin, terazosin,

doxazosin.

Hypertension, urinary

retention in BPH.

1st-dose orthostatic hypotension,

dizziness, headache

α2 selective

Mirtazepine Depression Sedation, ↑ serum cholesterol, ↑

appetite


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Application Effect

HTN ↓ Cardiac output, ↓ renin secretion (due to β-receptor block on JGA cells)

Angina pectoris ↓ HR & contractility, resulting in ↓ O2 consumption.

MI β-blockers, ↓ mortality

SVT (propanolol,

esmolol)

↓ AV conduction velocity (class II antiarrhythmics)

CHF Slows progression of chronic failure

Glaucoma (timolol) ↓ secretion of aqueous humor


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Toxicity: Impotence, exacerbation of asthma, CVS effects (bradycardia, AV block, CHF),

CNS effects (sedation, sleep alterations); USE WITH CAUTION IN DIABETICS (masks

hyperglycemia)

Selectivity: Nonselective antagonist – Propanolol, Timolol, Nadolol, Pindolol &

Labetolol.

β1-selective antagonists (β1>β2) – Acebutolol (partial), Betaxolol,

Esmolol (short acting), Atenolol, Metoprolol (A BEAM of β1 blockers).

Nonselective α & β antagonists – Carvedilol, Labetolol.

Partial β-Agonist – Pindolol, Acebutolol


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Drug Mechanism Side Effects

α-agonist

Epinephrine ↑ outflow of aqueous humor Mydriasis, stinging, do not use

in closed-angle glaucoma

Brimonidine ↓ aqueous humor synthesis No pupillary or vision changes

β-blockers

Timolol, betaxolol,

carteolol

↓ aqueous humor secretion No pupillary or vision changes

Diuretics

Acetazolamide ↓ aqueous humor secretion due to ↓

HCO3- (via CA inhibition)

No pupillary or vision changes

Cholinomimetics

Pilocarpine,

carbachol,

physostigmine,

echothiophate

↑ outflow of aqueous humor (echothiophate,

physostigmine); contract cilliary muscle &

open trabecular meshwork (pilocarpine,

carbachol); use pilocarpine in emergencies

very effective at opening canal of Schlemm.

Miosis, cyclospasm

Prostaglandin

Latanoprost (PGF2α) ↑ outflow of aqueous humor Darkens color of iris (browning)

pharmacology 1

Documents

releases stored

linked 2nd

neurogenic

aqueous humor

muscarinic

maintenance

cns penetration

endogenous