Pharmacokinetics and Pharmacodynamics Flashcards

A patient with severe hepatic cirrhosis (Child-Pugh C) receives a continuous infusion of midazolam. After 72 hours, the patient remains deeply sedated 18 hours after the infusion is stopped. Which pharmacokinetic mechanism BEST explains this prolonged effect beyond simple reduced hepatic clearance?

Answer: Accumulation of the active metabolite 1-hydroxymidazolam glucuronide due to impaired renal clearance secondary to hepatorenal syndrome

In hepatic cirrhosis, particularly with concurrent renal dysfunction (hepatorenal syndrome), the active metabolite 1-hydroxymidazolam glucuronide accumulates. This metabolite is renally cleared and has significant GABA-A agonist activity. While reduced hepatic clearance of the parent drug is the primary mechanism, the prolonged sedation often seen clinically is disproportionate and attributable to this active metabolite accumulation — a phenomenon documented in ICU patients with multi-organ dysfunction.

During target-controlled infusion (TCI) of propofol using the Marsh model, a 70 kg patient's effect-site concentration (Ce) lags behind the plasma target concentration (Cp). The parameter governing the rate of equilibration between plasma and effect site is:

Answer: The ke0 (effect-site rate constant), which determines the t½ke0

The ke0 (keo) is the first-order rate constant describing drug transfer from plasma to the effect site. Its reciprocal relationship defines the t½ke0 (equilibration half-life). A higher ke0 means faster plasma–effect-site equilibration and a shorter lag time to peak effect. This is distinct from redistribution between peripheral compartments. The Marsh model uses a ke0 of approximately 0.26 min⁻¹ for propofol, giving a t½ke0 of ~2.6 minutes, which explains why peak EEG effect occurs several minutes after peak plasma concentration.

A 55-year-old patient on long-term phenytoin therapy requires rocuronium for rapid sequence intubation. The anesthesiologist uses 1.2 mg/kg rocuronium. Compared to a drug-naive patient, which statement MOST accurately describes the expected neuromuscular blockade?

Answer: Both onset and duration are shortened due to upregulation of post-junctional acetylcholine receptors and increased hepatic clearance

Chronic anticonvulsant therapy (phenytoin, carbamazepine) causes resistance to non-depolarizing neuromuscular blocking agents through two mechanisms: (1) pharmacokinetic — induction of hepatic enzymes increases clearance of rocuronium (biliary excretion pathway is also upregulated), and (2) pharmacodynamic — upregulation and proliferation of post-junctional nicotinic acetylcholine receptors increases the number of receptors that must be occupied to produce block. Both mechanisms shorten duration and may impair onset quality. Higher doses or increased infusion rates are often required.

The Hill equation describes the concentration-effect relationship for many anesthetic drugs: E = Emax × C^γ / (EC50^γ + C^γ). When the Hill coefficient (γ) is greater than 1, the concentration-response curve is:

Answer: Sigmoidal, with a steeper slope around the EC50 indicating greater sensitivity to concentration changes near the effective dose

A Hill coefficient (γ) > 1 produces a sigmoidal (S-shaped) concentration-response curve rather than a simple hyperbolic one. The steeper slope around the EC50 has critical clinical implications: small changes in drug concentration near the EC50 produce large changes in effect. This creates a narrower therapeutic window around the inflection point. Propofol has a Hill coefficient of approximately 1.7–2.5 for EEG suppression endpoints, explaining why small concentration increments can shift a patient from sedation to general anesthesia abruptly.

Remifentanil is administered by weight-corrected infusion at 0.25 mcg/kg/min to an obese patient (BMI 48, total body weight 145 kg, lean body weight 75 kg). Compared to dosing on lean body weight, dosing on total body weight is MOST likely to result in:

Answer: Overdose causing respiratory depression because remifentanil's clearance by non-specific plasma esterases does not scale with excess adipose tissue, while dose scales linearly with total body weight

Remifentanil is metabolized by non-specific plasma and tissue esterases. Its clearance correlates with lean body mass, not total body weight, because excess adipose tissue contributes minimal additional esterase activity. Its volume of distribution is also relatively small and does not expand proportionally with obesity. Therefore, dosing on total body weight in obese patients administers proportionally more drug than can be cleared, leading to dose-dependent opioid toxicity. Guidelines recommend using lean body weight (or adjusted body weight) for remifentanil infusion calculations in obese patients.

A patient develops tachyphylaxis to intravenous nitroglycerin after 24 hours of infusion for refractory vasospasm. The mechanism is MOST accurately described as:

Answer: Depletion of intracellular sulfhydryl (thiol) groups required for biotransformation of nitroglycerin to nitric oxide

Nitroglycerin is a prodrug that requires biotransformation to nitric oxide (NO). This conversion depends on mitochondrial aldehyde dehydrogenase (ALDH2) and is critically dependent on intracellular sulfhydryl (thiol) groups as co-factors. Continuous nitroglycerin infusion depletes these thiol groups, impairing NO generation despite adequate drug concentrations. This is a well-characterized pharmacokinetic/pharmacodynamic tolerance mechanism specific to organic nitrates. Administration of N-acetylcysteine (a thiol donor) can partially restore nitroglycerin responsiveness. This differs from tolerance to other vasodilators which may involve receptor-mediated mechanisms.