Drug Metabolism

Question 1

What organs function in drug metabolism? (4)

Answer 1

1. Liver 20-30%
2. kidney 8%
3. intestine 6%
4. skin 1%

Question 2

What 4 factors influence drug membrane passage?

Answer 2

1. Size (smaller better)
2. Lipid solubility
3. Degree of ionization (unionized form better)
4. concentration gradient

Question 3

Drug metabolism commonly converts drugs to larger more _____ and ______ compounds that are easily excreted

Answer 3

hydrophilic, ionized

Question 4

What drugs are metabolized to more active compounds?

Answer 4

Codeine -> Morphine
Hydrocodone -> Hydromorphone

Question 5

What drugs are metabolized from inactive prodrug to active drug?

Answer 5

Omeprazole -> a sulfenamide
Enalapril -> enalaprilat
Valacyclovir -> acyclovir

Question 6

What drug is metabolized to a toxic metabolite?

Answer 6

acetaminophen -> N-Acetyl-benzoquinoneime (hepatotoxic)

Question 7

_______ inserts or unmasks a functional group on the drug that renders the molecule more water soluble

Answer 7

Phase I

Question 8

Name the 3 reactions in phase 1

Answer 8

oxidation, reduction, hydrolysis

Question 9

Describe components of the phase 1 oxidation system (4)

Answer 9

enzyme CYP450 (liver is the richest source)
cofactor NADPH
Flavoprotein NADPH-cytochrome P450 reductase
molecular O2

Question 10

Phase 1 oxidations (P450) are unlikely/likely to display zero order kinetics?

Answer 10

zero order kinetics = saturation kinetics, this is unlikely in phase 1 oxidation because cofactors are in abundant supply

Question 11

CYP450 Dependent Oxidations (3)

Answer 11

Aromatic hydroxylations
Aliphatic hydroxylations
Oxidative dealkylation

Question 12

CYP450 Independent Oxidations

Answer 12

Monoamine oxidase
Alcohol dehydrogenase
Aldehyde dehydrogenase

Question 13

2 types of phase I hydrolysis

Answer 13

1. Esterases - Ester local anesthetics, utilized in design of prodrugs (valacyclovir), Procaine metabolized to allergenic PABA
2. Amidases - amide local anesthetics

Question 14

Where are Esterases and Amidases primarily found?

Answer 14

Esterases - plasma, liver, other sites

Amidases - primarily liver and gut, less in plasma

Question 15

3 less common phase I reductions

Answer 15

Reductases:
1. Azo reduction (sulfonamides)
2. Nitro reduction (chloramphenicol, toxic intermediates)
3. Carbonyl reduction (methadone)

Question 16

“Substrates are high-energy and in limited supply, increased likelihood of depletion and zero order kinetics” What phase is this?

Answer 16

Phase II conjugations

Question 17

What enzymes and reactions are involved in phase II conjugation?

Answer 17

Enzyme - transferases
Reactions: Glucuronidation, acetylation, glutathione/glycine/sulfate conjugation

Question 18

Phase II conjugation forms highly ____ conjugate that is readily excreted via the urine

Answer 18

polar (water soluble)

Question 19

Describe what happens in phase II?

Answer 19

endogenous substrate combines with pre-existing or metabolically inserted functional group (from phase I) on the drug

Question 20

_______ reach adult values within the first few months

Answer 20

esterases

Question 21

________ _________ are microsomal enzymes in the liver, kidney, and GI tract, adult levels of activity reached by age 3-4

Answer 21

Glucuronyl transferases

Question 22

How are drugs excreted after glucuronidation?

Answer 22

Conjugates that are highly water soluble excreted via urine. Higher MW conjugates excreted in bile then feces.

Question 23

What does hydrolysis by bacterial b-glucuronidase result in?

Answer 23

free drug in the intestine can be reabsorbed and reenter circulation, enterohepatic recirculation may be a source of drug interactions (antibiotics & OCs)

Question 24

___________ form amide bond with amino group of drug, acetyl group in donated by acetyl CoA

Answer 24

N-acetyltransferases

Question 25

______ activity can display marked genetic variation in humans

Answer 25

acetylation, 50% fast 50% slow acetylators in metabolism of isoniazid (TB drug)

Question 26

Certain _________ from N-acetylation are less water soluble

Answer 26

Sulfonamides

Question 27

What is the enzyme and coenzyme in sulfate conjugation?

Answer 27

Sulfotransferases, coenzyme PAPS

Question 28

Describe sulfate conjugates (Phase II conjugation)

Answer 28

sulfate conjugates are ionized and water-soluble acids with a pKa of 1

Question 29

Glutathione conjugation via glutathione S transferases is extremely important in what process?

Answer 29

detoxification of carcinogens, pollutants, and toxic metabolites (e.g. acetaminophen)

Question 30

What is the toxic compound produced in acetaminophen metabolism? What is the treatment for overdose?

Answer 30

Toxin - reactive electrophilic compound AC produced by P450 Treatment - N-acetylcysteine inactivates AC directly

Question 31

What test determines polymorphisms in CYP2D6/ 2C19?

Answer 31

amplichip test

Question 32

CYP2D6 is involved in metabolism of what?

Answer 32

antipsychotic drugs, antidepressants, codeine/analgesics

Question 33

CYP2C19 is involved in metabolism of what?

Answer 33

Proton pump inhibitors (PPI) for peptic ulcer disease (PUD)

Question 34

5-10% of Caucasians are poor metabolizers of _____ 20% of Asians are poor metabolizers of ____

Answer 34

CYP2D6 CYP2C19

Question 35

When are effects of enzyme induction and inhibition most obvious?

Answer 35

When drugs are given orally via 1st pass effect

Question 36

What is the clinical effect of induction and inhibition dependent on?

Answer 36

Whether the metabolic reaction is inactivating/detoxifying (95%), activating (5%), or produces a toxic metabolite

Question 37

Name the 7 inducers

Answer 37

PPCREST Phenobarbital Phenytoin Carbamazepine Rifampin Ethanol St. Johns Wart Tobacco Smoke

Question 38

Name the 7 inhibitors

Answer 38

HOGFACE HIV protease inhibitors Omeprozole Grapefruit juice Fluoxetine Azole antifungals Cimetidine Erythromycin

Question 39

Induction of drug metabolism generally takes ________ hrs to see onset of effect

Answer 39

48-72 hrs

Question 40

Which enzymes are more prone to inhibition? (phase I or phase II)

Answer 40

Phase I

Question 41

When can onset of inhibition occur?

Answer 41

When effective levels in the liver are reaches, within hours

Question 42

What mechanisms cause inhibition?

Answer 42

an inhibitor can be a substrate competing for an enzyme, a compound inhibiting the synthesis of enzyme, or and allosteric inhibitor (not directly competing at active site)

Question 43

Byproducts of methanol metabolism cause an accumulation of ____ in the blood, ______, and death.

Answer 43

acid, blindness

Question 44

What is the treatment for methanol-ethylene glycol poisoning?

Answer 44

ethanol, inhibits the enzyme that produces formic acid

Question 45

How does age affect drug metabolism?

Answer 45

Perinatal - some enzymes not well developed at birth Neonates - variable development patterns Old age - decrease in phase 1 CYP450 in 1/3

Question 46

What is thought to cause decrease in phase 1 CYP450 with aging?

Answer 46

decrease in hepatic blood flow

Question 47

Why are phase II enzymes unlikely to decrease with aging?

Answer 47

transferases in other tissues can compensate

Question 48

What conditions may require dosage adjustments or drug avoidance?

Answer 48

hepatic diseases, conditions affecting liver blood flow, non-hepatic diseases, alcohol consumption

Question 49

What is zero order kinetics compared to first order kinetics?

Answer 49

In first order kinetics drug metabolism is proportional to drug dose, zero order kinetics is where a constant amount of drug is eliminated per unit time and is independent of drug dose

Question 50

What causes zero order kinetics?

Answer 50

Saturation of hepatic metabolic processes (esp. phase II conjugations), seen with few drugs at therapeutic doses and many drugs at toxic doses