2 Flashcards
(20 cards)
What is glucuronidation, and which enzyme family catalyzes it?
Glucuronidation is the addition of glucuronic acid to a substrate (e.g., –OH, –COOH, –NH₂, –SH) by UDP-glucuronosyltransferases (UGTs), forming a glucuronide conjugate.
What functional groups on drugs commonly undergo glucuronidation?
Hydroxyl (–OH), carboxyl (–COOH), amino (–NH₂), and thiol (–SH) groups.
Which conjugation reaction uses glutathione, and what enzyme catalyzes it?
Glutathione conjugation uses glutathione (GSH) and is catalyzed by glutathione S-transferases (GST).
Why is the Phase 2 conjugation step critical for excretion?
Conjugation dramatically increases water solubility of metabolites, facilitating renal or biliary elimination.
What is enterohepatic circulation, and how does it affect drug levels?
Enterohepatic circulation occurs when drug conjugates excreted in bile are hydrolyzed in the intestine to release the parent drug, which can be reabsorbed—creating a reservoir that prolongs drug action.
Which transporters in hepatocytes facilitate biliary excretion of drug conjugates?
Organic cation transporters (OCTs), organic anion transporters (OATs), and P-glycoproteins (P-gp).
Name three processes by which drugs are excreted by the kidney.
Glomerular filtration, active tubular secretion, and passive reabsorption.
How can urine pH affect renal excretion of a drug?
Altered urine pH can change drug ionization: acidic urine enhances excretion of weak bases, while alkaline urine enhances excretion of weak acids, by reducing passive reabsorption.
What is the impact of decreased hepatic blood flow on drug clearance?
Reduced hepatic blood flow (due to disease or drug interactions) can impair clearance, increasing drug half-life and potential toxicity.
Describe the genetic polymorphism categories for CYP2D6.
Poor metabolizers (little/no CYP2D6 function), intermediate metabolizers (reduced function), extensive metabolizers (normal function), and ultrarapid metabolizers (multiple functional gene copies leading to increased activity).
Give one clinical consequence of being a CYP2D6 poor metabolizer.
Decreased clearance of CYP2D6 substrates (e.g., certain antidepressants) may result in higher plasma levels and increased risk of adverse effects.
What can enzyme induction by rifampicin do to warfarin therapy?
Rifampicin induces CYP450, increasing warfarin metabolism, lowering warfarin plasma levels, shortening prothrombin time, and potentially reducing anticoagulant efficacy.
How does erythromycin inhibit cyclosporine metabolism, and what is the clinical implication?
Erythromycin competitively inhibits CYP3A4, reducing cyclosporine clearance, which can lead to elevated cyclosporine levels and increased risk of toxicity in transplant patients.
Why is paracetamol overdose particularly dangerous in terms of metabolism?
When normal conjugation pathways are saturated, more is metabolized by CYP450 to a toxic reactive metabolite (NAPQI), which depletes glutathione and can cause hepatic necrosis.
Which enzyme deficiency can lead to prolonged action of suxamethonium (succinylcholine)?
Plasma cholinesterase (butyrylcholinesterase) deficiency reduces hydrolysis of suxamethonium, causing prolonged neuromuscular blockade.
How does age affect hepatic microsomal enzyme activity?
Enzyme activity declines with age, reducing metabolic clearance and necessitating dosage adjustments in elderly patients.
What changes occur during pregnancy that affect drug elimination?
Increased cardiac output and renal blood flow raise glomerular filtration rate, enhancing renal elimination of drugs; liver enzyme activity may also change.
How can obesity or increased adipose tissue affect drug distribution and metabolism?
Lipophilic drugs may distribute into fat stores, altering volume of distribution and prolonging half-life; metabolic capacity may be unchanged, leading to altered dosing requirements.
Explain how enterohepatic recirculation can lead to drug toxicity.
Repeated cycling of conjugated drug to active form in the gut can prolong systemic exposure, potentially accumulating toxic levels if clearance is impaired.
Why might two stereoisomers of a drug have different pharmacological effects?
Each stereoisomer can interact differently with enzymes and receptors, leading to differences in potency, metabolism, or toxicity.
