flashcards 1

Question 1

What does ADME stand for in pharmacokinetics?

Answer 1

ADME stands for Absorption, Distribution, Metabolism, and Excretion.

Question 2

Why is studying drug metabolism and elimination important?

Answer 2

It determines a drug’s pharmacological or toxicological activity, impacts dosing and frequency, and prevents toxic accumulation in the body.

Question 3

What is the “first-pass effect”?

Answer 3

The first-pass effect refers to the metabolism of an orally administered drug by gut and liver enzymes before it reaches systemic circulation, reducing its bioavailability.

Question 4

Name three routes by which drugs can be excreted unchanged.

Answer 4

Urine (renal), bile (biliary), and exhaled air (e.g., volatile anesthetics).

Question 5

How does lipophilicity of a drug influence its metabolism?

Answer 5

Lipophilic (non-polar) drugs tend to accumulate in membranes or fat, so they require metabolic conversion to more polar forms for renal excretion.

Question 6

What are the two major phases of drug metabolism?

Answer 6

Phase 1 (functionalization/activation) and Phase 2 (conjugation/anabolism).

Question 7

In Phase 1 metabolism, what are the three main reaction types?

Answer 7

Oxidation (mostly via CYP450), reduction, and hydrolysis.

Question 8

What is added or exposed on a drug molecule during Phase 1 metabolism?

Answer 8

A functional group, such as a hydroxyl (–OH), amino (–NH₂), or thiol (–SH) group, to create a “handle” for Phase 2 conjugation.

Question 9

Why can some Phase 1 metabolites be more toxic or carcinogenic than the parent drug?

Answer 9

Because the introduction of reactive groups may create electrophilic intermediates that can bind cellular macromolecules, leading to toxicity.

Question 10

What is the primary purpose of Phase 2 metabolism?

Answer 10

To conjugate (attach) polar moieties (e.g., glucuronic acid, sulfate, amino acids, glutathione, acetyl groups) to make metabolites more water-soluble for excretion.

Question 11

Which organ is the principal site for both Phase 1 and Phase 2 metabolism?

Answer 11

The liver.

Question 12

Name two other tissues (besides the liver) where drug metabolism can occur.

Answer 12

Intestines (gut wall) and kidneys; also lungs, skin, and nasal mucosa to a lesser extent.

Question 13

What family of enzymes catalyzes most Phase 1 oxidations?

Answer 13

Cytochrome P450 (CYP450) monooxygenase enzymes.

Question 14

In the CYP450 monooxygenase reaction, which two enzymes collaborate?

Answer 14

Cytochrome P450 enzyme and NADPH–cytochrome P450 reductase.

Question 15

What cofactor is oxidized to NADP⁺ during a CYP450-mediated reaction?

Answer 15

NADPH is oxidized to NADP⁺.

Question 16

Give one example of a drug oxidized by CYP450.

Answer 16

Nifedipine is oxidized by CYP3A4.

Question 17

How does grapefruit juice affect CYP450 activity?

Answer 17

Grapefruit juice inhibits certain CYP450 enzymes (notably CYP3A4), reducing metabolism of drugs and potentially increasing their plasma concentrations.

Question 18

What dietary component induces CYP450 enzymes?

Answer 18

Brussels sprouts (and cruciferous vegetables) can induce certain CYP450s.

Question 19

What defines a “prodrug”?

Answer 19

A compound administered in an inactive (or less active) form that requires metabolic conversion (often Phase 1) to become pharmacologically active.

Question 20

Provide one example of a prodrug and its active metabolite.

Answer 20

Aspirin (acetylsalicylic acid) is hydrolyzed to salicylic acid; aspirin is anti-platelet, salicylic acid is anti-inflammatory.

Question 21

What is glucuronidation, and which enzyme family catalyzes it?

Answer 21

Glucuronidation is the addition of glucuronic acid to a substrate (e.g., –OH, –COOH, –NH₂, –SH) by UDP-glucuronosyltransferases (UGTs), forming a glucuronide conjugate.

Question 22

What functional groups on drugs commonly undergo glucuronidation?

Answer 22

Hydroxyl (–OH), carboxyl (–COOH), amino (–NH₂), and thiol (–SH) groups.

Question 23

Which conjugation reaction uses glutathione, and what enzyme catalyzes it?

Answer 23

Glutathione conjugation uses glutathione (GSH) and is catalyzed by glutathione S-transferases (GST).

Question 24

Why is the Phase 2 conjugation step critical for excretion?

Answer 24

Conjugation dramatically increases water solubility of metabolites, facilitating renal or biliary elimination.

Question 25

What is enterohepatic circulation, and how does it affect drug levels?

Answer 25

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.

Question 26

Which transporters in hepatocytes facilitate biliary excretion of drug conjugates?

Answer 26

Organic cation transporters (OCTs), organic anion transporters (OATs), and P-glycoproteins (P-gp).

Question 27

Name three processes by which drugs are excreted by the kidney.

Answer 27

Glomerular filtration, active tubular secretion, and passive reabsorption.

Question 28

How can urine pH affect renal excretion of a drug?

Answer 28

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.

Question 29

What is the impact of decreased hepatic blood flow on drug clearance?

Answer 29

Reduced hepatic blood flow (due to disease or drug interactions) can impair clearance, increasing drug half-life and potential toxicity.

Question 30

Describe the genetic polymorphism categories for CYP2D6.

Answer 30

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).

Question 31

Give one clinical consequence of being a CYP2D6 poor metabolizer.

Answer 31

Decreased clearance of CYP2D6 substrates (e.g., certain antidepressants) may result in higher plasma levels and increased risk of adverse effects.

Question 32

What can enzyme induction by rifampicin do to warfarin therapy?

Answer 32

Rifampicin induces CYP450, increasing warfarin metabolism, lowering warfarin plasma levels, shortening prothrombin time, and potentially reducing anticoagulant efficacy.

Question 33

How does erythromycin inhibit cyclosporine metabolism, and what is the clinical implication?

Answer 33

Erythromycin competitively inhibits CYP3A4, reducing cyclosporine clearance, which can lead to elevated cyclosporine levels and increased risk of toxicity in transplant patients.

Question 34

Why is paracetamol overdose particularly dangerous in terms of metabolism?

Answer 34

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.

Question 35

Which enzyme deficiency can lead to prolonged action of suxamethonium (succinylcholine)?

Answer 35

Plasma cholinesterase (butyrylcholinesterase) deficiency reduces hydrolysis of suxamethonium, causing prolonged neuromuscular blockade.

Question 36

How does age affect hepatic microsomal enzyme activity?

Answer 36

Enzyme activity declines with age, reducing metabolic clearance and necessitating dosage adjustments in elderly patients.

Question 37

What changes occur during pregnancy that affect drug elimination?

Answer 37

Increased cardiac output and renal blood flow raise glomerular filtration rate, enhancing renal elimination of drugs; liver enzyme activity may also change.

Question 38

How can obesity or increased adipose tissue affect drug distribution and metabolism?

Answer 38

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.

Question 39

Explain how enterohepatic recirculation can lead to drug toxicity.

Answer 39

Repeated cycling of conjugated drug to active form in the gut can prolong systemic exposure, potentially accumulating toxic levels if clearance is impaired.

Question 40

Why might two stereoisomers of a drug have different pharmacological effects?

Answer 40

Each stereoisomer can interact differently with enzymes and receptors, leading to differences in potency, metabolism, or toxicity.

Question 41

Give an example of a Phase 2 conjugation that does not require prior activation (Phase 1).

Answer 41

Glutathione conjugation (via glutathione S-transferase) of electrophilic substrates does not require prior functionalization.

Question 42

How does rifampicin’s induction of CYP450 affect its own metabolism over time?

Answer 42

As rifampicin induces the enzymes that metabolize it, its own clearance increases, potentially leading to the need for dose adjustments with chronic use.

Question 43

What role do bile salt transporters play in enterohepatic circulation?

Answer 43

Bile salt transporters (e.g., OATs) concentrate hydrophilic drug conjugates into bile; bacterial enzymes in the gut can hydrolyze them, releasing the parent drug for reabsorption.

Question 44

Why is morphine’s pharmacokinetic profile influenced by enterohepatic circulation?

Answer 44

Morphine–glucuronide conjugates excreted in bile can be hydrolyzed in the intestine to free morphine, which is reabsorbed, prolonging its effect.

Question 45

Describe one way co-administration of two drugs can alter renal excretion of one.

Answer 45

If Drug A displaces Drug B from plasma proteins, free Drug B increases, leading to higher glomerular filtration and faster elimination; alternatively, Drug A might inhibit tubular secretion of Drug B, slowing its clearance.

Question 46

What is the clinical significance of polymorphisms in ethanol-metabolizing enzymes?

Answer 46

Certain populations (e.g., some East Asians) have reduced alcohol dehydrogenase or aldehyde dehydrogenase activity, leading to acetaldehyde buildup, flushing, and increased intoxication risk.

Question 47

How can a drug interaction lead to an “apparent” change in half-life without altering metabolism?

Answer 47

If one drug displaces another from tissue binding sites or plasma proteins, the volume of distribution changes, altering the apparent half-life even if metabolic clearance is unchanged.

Question 48

Why might a patient with hepatic cirrhosis require dose adjustment of highly metabolized drugs?

Answer 48

Cirrhosis reduces functional hepatic mass and blood flow, decreasing metabolic capacity and increasing drug exposure, necessitating lower or less frequent dosing.

Question 49

What is the impact of impaired renal function on Phase 2 conjugate excretion?

Answer 49

Conjugated metabolites that rely on renal elimination accumulate, potentially causing adverse effects; dose reduction may be needed.

Question 50

How does the presence of a handle (e.g., –OH, –NH₂, –SH) on a drug molecule influence its susceptibility to Phase 2 conjugation?

Answer 50

The handle provides a site for conjugating enzymes (UGTs, sulfotransferases, GSTs, etc.) to attach polar groups, facilitating water solubility and excretion.