Pharmacology Basics Flashcards

A drug with a volume of distribution (Vd) of 350 L/70 kg is most likely characterized by which of the following pharmacokinetic properties?

Answer: High lipophilicity with extensive tissue sequestration

A Vd of 350 L far exceeds total body water (~42 L) and plasma volume (~3 L), indicating the drug is not confined to the vascular compartment. This large apparent Vd is a hallmark of high lipophilicity and/or strong binding to peripheral tissues (e.g., muscle, adipose). Drugs with extensive plasma protein binding actually have a smaller Vd because binding keeps drug in the plasma. Rapid renal clearance relates to elimination, not distribution.

An inhibitor of CYP3A4 is co-administered with a drug that is a substrate of CYP3A4 AND undergoes extensive first-pass metabolism. Which outcome best describes the net pharmacokinetic effect on the substrate?

Answer: Increased AUC due to reduced presystemic and systemic metabolism

CYP3A4 inhibition impairs both intestinal (presystemic/first-pass) and hepatic metabolism of the substrate. When first-pass metabolism is high, even a small reduction in CYP3A4 activity can dramatically increase bioavailability, leading to a disproportionately large increase in AUC. P-glycoprotein efflux is a separate mechanism and not compensatory for CYP inhibition. Protein displacement and renal clearance are not relevant pathways here.

Which pharmacodynamic phenomenon best explains why a patient on long-term morphine requires escalating doses to achieve the same analgesic effect, yet still experiences significant constipation at the original dose?

Answer: Differential tolerance development across organ systems sharing the same receptor

Opioid tolerance is not uniform across all tissues. Analgesic tolerance (CNS) develops rapidly due to receptor desensitization, internalization, and neuroadaptation in pain pathways. In contrast, the enteric nervous system develops tolerance to opioid-mediated inhibition of GI motility much more slowly, so constipation persists even as higher doses are needed for analgesia. This organ-specific tolerance is a well-recognized clinical phenomenon. CYP2D6 induction is not the primary mechanism, and tachyphylaxis refers to rapid acute tolerance rather than chronic organ-differential tolerance.

A pharmacist reviews a patient's chart and notes they are taking warfarin (a narrow therapeutic index drug, >99% protein-bound) and a new antibiotic is added that is also highly protein-bound. The prescriber is concerned about a clinically significant protein-displacement interaction. What is the pharmacokinetic reality of this interaction?

Answer: Displacement raises free warfarin transiently, but the increased free drug is also subject to increased clearance, so steady-state free drug concentration is minimally affected

Protein-displacement interactions are frequently overstated. When a drug is displaced from plasma proteins, the transient rise in free drug concentration increases both its distribution into tissues and its clearance (hepatic and/or renal). At the new steady state, the total plasma concentration is lower but free concentration returns to near-baseline. For warfarin specifically, the real interaction risk with antibiotics is more often pharmacodynamic (altered vitamin K synthesis by gut flora) or pharmacokinetic via CYP2C9 inhibition—not simple displacement. Displacement does reduce total drug concentration and increases Vd slightly but does not prolong half-life significantly.

A drug follows zero-order kinetics at therapeutic plasma concentrations. Which of the following clinical consequences is MOST directly attributable to this kinetic behavior?

Answer: Small dose increases can cause disproportionately large increases in steady-state plasma concentrations

In zero-order kinetics, a constant amount (not fraction) of drug is eliminated per unit time because the elimination pathway is saturated. As a result, steady-state plasma concentration increases non-linearly with dose — small dose increments can lead to disproportionately large accumulation, making toxicity unpredictable. Phenytoin and ethanol are classic examples. It is NOT true that a constant fraction is eliminated (that describes first-order kinetics). Zero-order drugs do not have a fixed half-life; the apparent half-life increases as dose increases.

Two drugs act on the same receptor system. Drug A produces maximal efficacy equal to the endogenous agonist and has an EC50 of 2 nM. Drug B has an EC50 of 0.5 nM but achieves only 60% of the maximal response even at saturating concentrations. A patient receives both drugs simultaneously at concentrations that saturate their respective binding. What is the most accurate description of Drug B?

Answer: Drug B is a partial agonist with higher potency but lower intrinsic efficacy than Drug A

Drug B has a lower EC50 (0.5 nM vs 2 nM), meaning it is more potent — it achieves half-maximal response at a lower concentration. However, even at saturating concentrations, it only reaches 60% of maximal efficacy, defining it as a partial agonist (lower intrinsic efficacy/Emax). Potency and efficacy are independent properties. A partial agonist, when occupying the receptor, can actually act as a functional antagonist against Drug A in the presence of both, but Drug B itself is not an antagonist — it does produce a response. A superagonist would exceed the endogenous agonist's Emax.