Pharmacokinetics and Pharmacodynamics Flashcards

A patient with severe hepatic cirrhosis (Child-Pugh C) requires analgesia. Compared to a healthy subject, which pharmacokinetic change is MOST likely to affect the free (unbound) plasma concentration of a highly protein-bound opioid such as fentanyl?

Answer: Reduced albumin synthesis increases the free fraction, raising pharmacodynamic effect despite a similar total plasma concentration

In Child-Pugh C cirrhosis, albumin synthesis falls markedly, reducing protein binding for acidic and neutral drugs including fentanyl (normally ~80% protein-bound). A lower bound fraction means a higher free fraction at any given total plasma concentration, amplifying pharmacodynamic effect even when total drug levels appear 'normal'. Hepatic blood flow and extraction ratio changes are secondary considerations; fentanyl's glucuronide metabolites are inactive.

During a prolonged ICU infusion of midazolam, context-sensitive half-time increases dramatically compared to a brief bolus dose. Which mechanism BEST explains why context-sensitive half-time for midazolam diverges so markedly from its elimination half-life in this scenario?

Answer: Extensive redistribution into peripheral fat compartments creates a large tissue reservoir that sustains plasma concentrations after the infusion ends

Context-sensitive half-time is the time for plasma concentration to fall 50% after stopping an infusion of defined duration. Midazolam is highly lipophilic with a large volume of distribution (~3.4 L/kg). During prolonged infusion, peripheral adipose tissue becomes saturated; when the infusion stops, drug redistributes back from fat into plasma, maintaining concentrations and extending the effective half-time far beyond what the elimination half-life alone would predict. CYP3A4 saturation is not a clinically significant mechanism at therapeutic doses.

A 70 kg patient receives rocuronium 1.2 mg/kg for rapid-sequence intubation. Sugammadex 16 mg/kg is given 3 minutes later for immediate reversal. Six hours post-reversal, the patient develops recurarisation. Which pharmacokinetic explanation is MOST plausible?

Answer: Rocuronium redistributes from deep peripheral compartments back into plasma after the initial sugammadex effect, exceeding the encapsulation capacity

After a large rocuronium dose, significant drug resides in peripheral (muscle and fat) compartments. Sugammadex rapidly encapsulates plasma rocuronium and drives redistribution, but rocuronium continues to re-equilibrate from deep compartments back into plasma over hours. If the total rocuronium load in peripheral tissues exceeds the amount of sugammadex available to bind newly released drug, free rocuronium re-accumulates at the neuromuscular junction causing recurarisation. This is a recognised phenomenon particularly after high-dose rocuronium in patients with large volumes of distribution (obesity, oedema).

When comparing the pharmacodynamics of two drugs at the same receptor, Drug A has an Emax of 80% and an EC50 of 10 ng/mL, while Drug B has an Emax of 100% and an EC50 of 50 ng/mL. At a plasma concentration of 10 ng/mL, which statement is CORRECT?

Answer: Drug A produces greater effect than Drug B because its EC50 is lower, indicating higher potency

At 10 ng/mL, Drug A is at its EC50, producing 50% of its Emax = 40% of maximum possible response. Drug B at 10 ng/mL (which is 1/5 of its EC50 of 50 ng/mL) produces approximately 17% of its Emax = 17% of maximum. Therefore Drug A produces a greater effect (40%) than Drug B (17%) at this concentration, because Drug A has lower EC50 (higher potency). Although Drug B is a full agonist (higher Emax and efficacy), at this specific concentration potency dominates the comparison. Intrinsic efficacy determines maximum ceiling, but potency determines effect at any given concentration.

A patient on long-term phenytoin therapy requires fentanyl-based anaesthesia. Intraoperatively, the anaesthetist observes markedly reduced and shortened analgesia from standard fentanyl doses. Which mechanism BEST accounts for this observation?

Answer: Phenytoin induces CYP3A4, markedly increasing fentanyl clearance and reducing its plasma concentration

Phenytoin is a potent inducer of CYP3A4 (and CYP2C9/CYP2C19). Fentanyl is predominantly metabolised by CYP3A4 to norfentanyl. Chronic phenytoin therapy substantially increases CYP3A4 activity, dramatically accelerating fentanyl N-dealkylation, shortening its half-life, and reducing plasma concentrations. This is a well-documented pharmacokinetic drug interaction requiring significantly higher opioid doses in enzyme-induced patients. Phenytoin does not antagonise opioid receptors and actually upregulates (not reduces) P-glycoprotein, which would further limit CNS penetration.

In a two-compartment pharmacokinetic model, a drug exhibits an alpha (distribution) half-life of 5 minutes and a beta (elimination) half-life of 4 hours. A single IV bolus is given and effect-site monitoring shows peak effect at 8 minutes. Which statement about the effect-site equilibration rate constant (ke0) is MOST accurate?

Answer: A large ke0 indicates rapid equilibration between plasma and effect-site, resulting in a short time-to-peak effect

ke0 is the first-order rate constant describing transfer of drug between the central compartment and the hypothetical effect compartment. A large ke0 means rapid equilibration: plasma and effect-site concentrations reach equilibrium quickly, producing a short time-to-peak effect. A small ke0 means slow equilibration with a long hysteresis loop between plasma concentration and observed effect. ke0 is estimated by modelling the temporal relationship between plasma concentration and observed pharmacodynamic effect — it cannot be derived from plasma compartment half-lives alone. It describes kinetics of effect-site transfer, not receptor Emax (which is a pharmacodynamic parameter).