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Pharm > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

What organs function in drug metabolism? (4)

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

What 4 factors influence drug membrane passage?

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

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

A

hydrophilic, ionized

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4
Q

What drugs are metabolized to more active compounds?

A

Codeine -> Morphine
Hydrocodone -> Hydromorphone

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5
Q

What drugs are metabolized from inactive prodrug to active drug?

A

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

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6
Q

What drug is metabolized to a toxic metabolite?

A

acetaminophen -> N-Acetyl-benzoquinoneime (hepatotoxic)

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7
Q

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

A

Phase I

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8
Q

Name the 3 reactions in phase 1

A

oxidation, reduction, hydrolysis

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9
Q

Describe components of the phase 1 oxidation system (4)

A

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

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10
Q

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

A

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

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11
Q

CYP450 Dependent Oxidations (3)

A

Aromatic hydroxylations
Aliphatic hydroxylations
Oxidative dealkylation

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12
Q

CYP450 Independent Oxidations

A

Monoamine oxidase
Alcohol dehydrogenase
Aldehyde dehydrogenase

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13
Q

2 types of phase I hydrolysis

A
  1. Esterases - Ester local anesthetics, utilized in design of prodrugs (valacyclovir), Procaine metabolized to allergenic PABA
  2. Amidases - amide local anesthetics
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14
Q

Where are Esterases and Amidases primarily found?

A

Esterases - plasma, liver, other sites

Amidases - primarily liver and gut, less in plasma

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15
Q

3 less common phase I reductions

A

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

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16
Q

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

A

Phase II conjugations

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17
Q

What enzymes and reactions are involved in phase II conjugation?

A

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

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18
Q

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

A

polar (water soluble)

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19
Q

Describe what happens in phase II?

A

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

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20
Q

_______ reach adult values within the first few months

A

esterases

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21
Q

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

A

Glucuronyl transferases

22
Q

How are drugs excreted after glucuronidation?

A

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

23
Q

What does hydrolysis by bacterial b-glucuronidase result in?

A

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

24
Q

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

A

N-acetyltransferases

25
Q

______ activity can display marked genetic variation in humans

A

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

26
Q

Certain _________ from N-acetylation are less water soluble

A

Sulfonamides

27
Q

What is the enzyme and coenzyme in sulfate conjugation?

A

Sulfotransferases, coenzyme PAPS

28
Q

Describe sulfate conjugates (Phase II conjugation)

A

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

29
Q

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

A

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

30
Q

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

A

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

31
Q

What test determines polymorphisms in CYP2D6/ 2C19?

A

amplichip test

32
Q

CYP2D6 is involved in metabolism of what?

A

antipsychotic drugs, antidepressants, codeine/analgesics

33
Q

CYP2C19 is involved in metabolism of what?

A

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

34
Q

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

A

CYP2D6
CYP2C19

35
Q

When are effects of enzyme induction and inhibition most obvious?

A

When drugs are given orally via 1st pass effect

36
Q

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

A

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

37
Q

Name the 7 inducers

A

PPCREST

Phenobarbital
Phenytoin
Carbamazepine
Rifampin
Ethanol
St. Johns Wart
Tobacco Smoke

38
Q

Name the 7 inhibitors

A

HOGFACE

HIV protease inhibitors
Omeprozole
Grapefruit juice
Fluoxetine
Azole antifungals
Cimetidine
Erythromycin

39
Q

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

A

48-72 hrs

40
Q

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

A

Phase I

41
Q

When can onset of inhibition occur?

A

When effective levels in the liver are reaches, within hours

42
Q

What mechanisms cause inhibition?

A

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)

43
Q

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

A

acid, blindness

44
Q

What is the treatment for methanol-ethylene glycol poisoning?

A

ethanol, inhibits the enzyme that produces formic acid

45
Q

How does age affect drug metabolism?

A

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

46
Q

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

A

decrease in hepatic blood flow

47
Q

Why are phase II enzymes unlikely to decrease with aging?

A

transferases in other tissues can compensate

48
Q

What conditions may require dosage adjustments or drug avoidance?

A

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

49
Q

What is zero order kinetics compared to first order kinetics?

A

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

50
Q

What causes zero order kinetics?

A

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

Pharm (7 decks)

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