SPEX Pharmacology Flashcards

A patient with severe hepatic impairment (Child-Pugh Class C) requires analgesia. Which opioid analgesic has the LEAST risk of accumulation due to its reliance on glucuronidation rather than CYP450 hepatic metabolism?

Answer: Hydromorphone

Hydromorphone undergoes primarily glucuronidation to hydromorphone-3-glucuronide, making it less reliant on CYP450 enzymes that are severely impaired in Child-Pugh C cirrhosis. While morphine also undergoes glucuronidation, its active metabolite morphine-6-glucuronide accumulates dangerously in hepatic impairment. Fentanyl and oxycodone are CYP3A4-dependent and pose higher accumulation risk in hepatic failure.

Which mechanism best explains why selective serotonin reuptake inhibitors (SSRIs) cause a paradoxical initial increase in anxiety during the first 1–2 weeks of treatment, before their anxiolytic effect emerges?

Answer: Acute surge in synaptic serotonin activating 5-HT2C receptors before autoreceptor desensitization

When SSRIs acutely block serotonin reuptake, the initial surge of synaptic 5-HT preferentially stimulates anxiogenic 5-HT2C receptors. Over 1–2 weeks, somatodendritic 5-HT1A autoreceptors in the raphe nuclei desensitize, allowing sustained increased 5-HT output that eventually predominates through anxiolytic 5-HT1A postsynaptic signaling. The desensitization of autoreceptors (option A) is what resolves anxiety, not causes it.

A pharmacist counsels a patient on warfarin who has started taking rifampin for latent TB. The patient's INR has dropped from 2.5 to 1.2 over two weeks. If rifampin is discontinued, what is the MOST critical risk in the following 1–2 weeks?

Answer: Supratherapeutic anticoagulation as enzyme induction reverses and warfarin levels rise

Rifampin is a potent inducer of CYP2C9 and CYP3A4, which dramatically increases warfarin clearance, requiring higher doses to maintain therapeutic INR. When rifampin is stopped, the induction reverses over 1–2 weeks, but if the warfarin dose was increased to compensate, the now-uninduced enzymes allow warfarin to accumulate to supratherapeutic — potentially hemorrhagic — levels. Close INR monitoring and proactive dose reduction are essential upon rifampin discontinuation.

Which pharmacokinetic property of digoxin makes renal dosage adjustment uniquely critical compared to most other cardiac glycosides?

Answer: Digoxin is primarily eliminated unchanged by glomerular filtration and tubular secretion

Unlike many drugs, digoxin is eliminated predominantly (60–80%) as unchanged drug via renal excretion — through both glomerular filtration and active tubular secretion by P-glycoprotein. It is NOT significantly metabolized hepatically, undergoes minimal first-pass effect, has a very large volume of distribution (Vd ~7 L/kg), and is only ~25% protein-bound. This means renal impairment directly and proportionally reduces clearance, and dialysis is largely ineffective due to its enormous Vd.

A patient taking phenelzine (an irreversible MAOI) for refractory depression requires treatment for a urinary tract infection. Which antibiotic is MOST likely to precipitate a life-threatening serotonin syndrome in this patient?

Answer: Linezolid

Linezolid is an oxazolidinone antibiotic with clinically significant MAO inhibitory activity. When combined with a serotonergic drug or another MAOI like phenelzine, it can precipitate life-threatening serotonin syndrome. The FDA has issued warnings against combining linezolid with serotonergic agents. Trimethoprim-sulfamethoxazole does not significantly inhibit MAO or increase serotonin. Nitrofurantoin and fosfomycin lack MAO or serotonergic activity. Linezolid's antibiotic classification often masks its MAO-inhibiting risk.

A 68-year-old patient on chronic amiodarone therapy develops symptomatic hypothyroidism. The endocrinologist initiates levothyroxine (LT4). Which mechanism SPECIFICALLY related to amiodarone pharmacology makes LT4 dose titration particularly challenging in this patient?

Answer: Amiodarone inhibits type 1 deiodinase, reducing peripheral T4-to-T3 conversion, altering the expected TSH response to LT4

Amiodarone contains ~37% iodine by weight and inhibits both type 1 and type 2 iodothyronine deiodinases. Inhibition of type 1 deiodinase reduces peripheral conversion of T4 to active T3, causing T3 levels to remain low and reverse T3 to accumulate — even when the patient receives adequate LT4. This uncouples the typical T4→T3 conversion relationship and alters TSH kinetics, making it difficult to predict when TSH will normalize. Clinicians must monitor free T4 and free T3 alongside TSH. CYP3A4 induction is not the primary mechanism, and amiodarone does not displace T4 from TBG.