USMLE Pharmacology Syllabus

Pharmacology syllabus — full chapter and topic list

Expand any chapter to see its topics and sub-topics. This is the whole examinable outline for Pharmacology in USMLE, not a summary of it.

1. 1

   Pharmacokinetics

   3 topics

   • Drug absorption
   • Drug distribution
   • Drug metabolism
2. 2

   Pharmacodynamics

   3 topics

   • Drug-receptor interaction
   • Dose-response relationship
   • Drug toxicity
3. 3

   Autonomic Drugs

   3 topics

   • Sympathomimetics
   • Sympatholytics
   • Parasympathomimetics

Pharmacology flashcards for USMLE

25 of 50 cards from the Pharmacology deck — real questions with worked answers.

1. What is bioavailability (F), and what is its value for an intravenously administered drug?

   Bioavailability is the fraction of an administered dose of unchanged drug that reaches the systemic circulation. $$F = \frac{\text{AUC}_{\text{oral}}}{\text{AUC}_{\text{IV}}}$$ For IV administration $F = 1$ (100%), because the drug bypasses first-pass metabolism and enters the blood directly.

2. State the Henderson-Hasselbalch equation for a weak acid and explain how it predicts drug absorption across membranes.

   $$pH = pK_a + \log\frac{[A^{-}]}{[HA]}$$ Only the non-ionized (uncharged) form crosses lipid membranes. Weak acids are more non-ionized and absorbed in acidic environments; weak bases are more non-ionized and absorbed in basic environments ('acids in acid, bases in base').

3. How does urinary ion trapping enhance elimination of a weak acid such as aspirin, and what agent is used?

   Alkalinizing the urine with sodium bicarbonate raises urine pH, ionizing the weak acid to $A^{-}$. The charged form cannot be reabsorbed across the tubular membrane and is trapped in the urine, increasing renal excretion. For a weak base overdose, acidify the urine instead.

4. What is first-pass metabolism, and which routes of administration avoid it?

   First-pass metabolism is hepatic (and gut-wall) metabolism of an orally absorbed drug via the portal vein before it reaches systemic circulation, reducing bioavailability. It is bypassed by IV, sublingual, rectal (partially), inhalational, and transdermal routes.

5. Contrast zero-order and first-order elimination kinetics, and give drug examples of each.

   Zero-order: a constant amount is eliminated per unit time regardless of concentration (straight line on a linear plot). First-order: a constant fraction is eliminated per unit time, rate proportional to concentration (straight line on a semilog plot). Zero-order: ethanol, high-dose phenytoin, high-dose aspirin. Most drugs are first-order.

6. Define volume of distribution ($V_d$) and give its formula.

   $V_d$ is the theoretical volume needed to contain the total drug in the body at the plasma concentration. $$V_d = \frac{\text{amount of drug in body}}{\text{plasma drug concentration}}$$ Low $V_d$ suggests confinement to plasma (large/charged/protein-bound drugs); high $V_d$ suggests distribution into tissues/fat.

7. How do plasma protein binding and tissue binding affect the volume of distribution?

   High plasma protein binding keeps drug in the vascular compartment, lowering $V_d$. High tissue binding pulls drug out of plasma, raising $V_d$ (often well above total body water). Only free (unbound) drug is pharmacologically active and available for elimination.

8. Which drug property allows a drug to cross the blood-brain barrier and the placenta?

   High lipophilicity (non-ionized, uncharged, low molecular weight) allows passive diffusion across the blood-brain barrier and placenta. Charged/ionized and highly protein-bound drugs cross poorly.

9. Define clearance (CL) and give the equation relating it to elimination rate and plasma concentration.

   Clearance is the volume of plasma cleared of drug per unit time. $$CL = \frac{\text{rate of elimination}}{C_p} = V_d \times k_e$$ where $k_e$ is the elimination rate constant and $C_p$ is plasma concentration.

10. Give the formula for elimination half-life ($t_{1/2}$) in terms of $V_d$ and clearance.

    $$t_{1/2} = \frac{0.693 \times V_d}{CL}$$ In first-order kinetics it takes about $3.3$ half-lives to reach ~90% of steady state, and ~$4$–$5$ half-lives to reach steady state (or to be effectively eliminated).

11. Write the equations for maintenance dose and loading dose.

    Maintenance dose: $$MD = \frac{C_{ss} \times CL \times \tau}{F}$$ Loading dose: $$LD = \frac{C_{ss} \times V_d}{F}$$ where $C_{ss}$ is target steady-state concentration, $\tau$ is the dosing interval, and $F$ is bioavailability. In renal/hepatic failure the loading dose is usually unchanged while the maintenance dose is reduced.

12. What are Phase I versus Phase II drug metabolism reactions, and what is their general purpose?

    Phase I (oxidation, reduction, hydrolysis; mostly cytochrome P450) yields slightly polar, often still-active metabolites. Phase II (conjugation: glucuronidation, acetylation, sulfation, glutathione) yields very polar, usually inactive metabolites for excretion. Purpose: convert lipophilic drugs into water-soluble, excretable forms.

13. Why do geriatric patients often lose Phase I metabolism before Phase II?

    With aging, cytochrome P450-dependent Phase I reactions decline first, while Phase II conjugation reactions are relatively preserved. This is why Phase II-dependent benzodiazepines (lorazepam, oxazepam, temazepam — 'LOT') are preferred in the elderly.

14. Name three important cytochrome P450 inducers and three inhibitors relevant to drug interactions.

    Inducers (decrease drug levels): rifampin, phenytoin, carbamazepine, phenobarbital, griseofulvin, chronic alcohol, St. John's wort. Inhibitors (increase drug levels): cimetidine, ketoconazole, erythromycin/clarithromycin, grapefruit juice, isoniazid, ritonavir, acute alcohol, sulfonamides.

15. Define an affinity constant and how affinity relates to $K_d$ in drug-receptor binding.

    Affinity is the tendency of a drug to bind its receptor. It is inversely related to the dissociation constant $K_d$: $$K_d = \frac{k_{off}}{k_{on}}$$ A lower $K_d$ means higher affinity. At equilibrium, $K_d$ equals the drug concentration that occupies 50% of receptors.

16. Define potency versus efficacy in a dose-response relationship.

    Potency is the amount of drug needed to produce a given effect (reflected by $EC_{50}$/$ED_{50}$; leftward curve = more potent). Efficacy is the maximal effect a drug can produce ($E_{max}$; higher plateau = more efficacious). Potency depends on affinity; efficacy depends on intrinsic activity.

17. Compare a full agonist, partial agonist, and inverse agonist.

    Full agonist: binds and produces the maximal response (intrinsic activity = 1). Partial agonist: binds but produces a submaximal response even at full occupancy (intrinsic activity between 0 and 1); acts as a partial antagonist in the presence of a full agonist. Inverse agonist: binds and produces the opposite effect (intrinsic activity < 0), reducing constitutive activity.

18. How does a competitive antagonist alter an agonist dose-response curve, and how does this differ from a non-competitive antagonist?

    Competitive (reversible) antagonist: shifts the agonist curve rightward, decreasing potency but preserving $E_{max}$; effect is surmountable by more agonist. Non-competitive/irreversible antagonist: decreases $E_{max}$ (unsurmountable), reducing efficacy regardless of agonist concentration.

19. Distinguish a pharmacologic antagonist, a physiologic antagonist, and a chemical antagonist.

    Pharmacologic antagonist binds the same receptor as the agonist and blocks it. Physiologic antagonist produces an opposing effect through a different receptor/pathway (e.g., epinephrine vs. histamine in anaphylaxis). Chemical antagonist inactivates the agonist by binding it directly (e.g., protamine binding heparin).

20. Define the therapeutic index (TI) and write its formula.

    The therapeutic index measures drug safety: $$TI = \frac{TD_{50}}{ED_{50}}$$ (or $LD_{50}/ED_{50}$ in animals), the ratio of the dose toxic to 50% to the dose effective in 50%. A higher TI means a safer drug. Low-TI drugs (warfarin, digoxin, lithium, theophylline) need therapeutic monitoring.

21. What does the $EC_{50}$ represent on a graded dose-response curve?

    The $EC_{50}$ is the concentration of drug that produces 50% of the maximal response ($E_{max}$). It reflects potency: a lower $EC_{50}$ indicates a more potent drug. On a quantal curve, the analogous term is $ED_{50}$, the dose effective in 50% of the population.

22. Explain the concept of spare receptors and its effect on the $EC_{50}$ versus $K_d$.

    Spare receptors exist when a maximal response is achieved with less than full receptor occupancy. In this setting the $EC_{50}$ (50% of maximal effect) occurs at a concentration lower than $K_d$ (50% receptor occupancy), so $EC_{50} < K_d$.

23. What is the mechanism and antidote for acetaminophen toxicity?

    Overdose depletes glutathione, allowing accumulation of the toxic Phase I metabolite NAPQI, which causes centrilobular hepatic necrosis. Antidote: N-acetylcysteine, which regenerates glutathione and provides sulfhydryl groups to detoxify NAPQI.

24. Give the antidotes for: (a) opioid, (b) benzodiazepine, and (c) organophosphate poisoning.

    (a) Opioids: naloxone (or naltrexone). (b) Benzodiazepines: flumazenil (caution: can precipitate seizures). (c) Organophosphates (cholinesterase inhibitors): atropine plus pralidoxime (2-PAM), which regenerates acetylcholinesterase before aging.

25. List the antidotes for warfarin, heparin, and direct thrombin inhibitor (dabigatran) toxicity.

    Warfarin: vitamin K (slow) plus fresh frozen plasma or PCC (rapid). Heparin: protamine sulfate. Dabigatran (direct thrombin inhibitor): idarucizumab. Factor Xa inhibitors (apixaban/rivaroxaban): andexanet alfa.

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