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PHARM > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

Structural modification of the drug via oxidation, reduction, or hydrolysis:

A

Phase 1 Reactions

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2
Q

Consequences of phase 1 modifications:

A
  1. inactivation of the parent drug
  2. conversation of active drug to an active drug metabolite
  3. conversion to a toxic metabolite
  4. generation of a “reactive” metabolite
  5. conversion of an inactive drug to an active drug metabolite
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3
Q

Also called conjugation reactions because produce of phase 1 reaction is conjugated to a large, endogenous molecule:

A

Phase 2 Reactions

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4
Q

Conjugation almost always results in conversion of drug to inactive metabolite that are highly:

A

ionized, polar, hydrophilic

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5
Q

Action of drug efflux transporters regulates bioavailability, distribution, and excretion of drugs; act in concert with. phase I and II enzymes to reduce systemic exposure to xenobiotics:

A

Phase 3 Reactions

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6
Q

Contribute to endothelial barrier function:

A

Phase 3 Reactions

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7
Q

Most important site of enzymes that metabolize and transport drugs:

A

Liver - greatest concentration of metabolizing enzymes

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8
Q

T/F. Hepatic metabolism is not high enough to remove most of the drug from the portal blood passing through the liver.

A

False; hepatic metabolism IS high enough.

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9
Q

First-pass or presystemic metabolism is referring to:

A

metabolism in the liver; oral drugs transported via portal vein

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10
Q

Subcellular locations of drug metabolizing enzymes/transporters for Phase 1 enzymes, Phase 2 enzymes, and Phase 3 transporters:

A

Phase 1 enzymes: smooth endoplasmic reticulum of the liver;
Phase 2 enzymes: cytosol, enzymes are soluble (except UGTs in SER);
Phase 3 transporters: apical (luminal side) and basolateral (blood side) membranes of GI and renal tubular epithelial cells, plasma and canalicular membranes of hepatocytes

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11
Q

Cytochrome P450 Complex (CYP) is what kind of enzyme?

A

Phase 1 enzyme

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12
Q

The net result of CYP-catalyzed oxidation (hydroxylation) reaction is:

A

Drug + O2 +NADPH + H+ –> Drug-OH + H2O + NADP+

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13
Q

Nomenclature: How to name CYP gene superfamily:

A

CYP + family number + subfamily letter + individual gene number, ex: CYP1A2, CYP2D6

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14
Q

Three CYP isozymes that account for the metabolism of most drugs:

A

CYP 3A4/5, 2C8/9, 2D6

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15
Q

Amine oxidases, dehydrogenase, flavin-containing monooxygenase (FMO), reductases are what kind of enzymes:

A

Phase 1 enzymes

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16
Q

Monoamine oxidase (MAO); oxidize endogenous catecholamine neurotransmitters and synthetic analogs:

A

amine oxidases

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17
Q

Alcohol (ADH) and aldehyde (ALDH) dehydrogenases, oxidize alcohols to aldehydes and aldehydes to acids:

A

Dehydrogenases

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18
Q

Oxidizes substrates with N-, S-, P- moieties, not C, similar to CYPs but are only minor contributors to drug metabolism, can metabolize nicotine, some H2 receptor antagonists, and antipsychotics

A

Flavin-containing monooxygenase (FMO)

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19
Q

Carry out reduction of ago-, nitro-, and carbonyl groups on drug molecules, located in the liver and in anaerobic bacteria of the GI tract

A

reductases

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20
Q

Hydrolysis inactivates some parent ester drugs, but activates other ester prodrugs (bioactivation) (esterification improves oral bioavailability) with these enzymes:

A

Hydrolytic enzymes

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21
Q

Carboxylesterases, amidases, epoxide hydrolase (EH) are examples of what kind of enzymes?

A

Hydrolytic

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22
Q

Acetylcholinesterase (neurons) and butyrylcholinesterase (plasma) hydrolyze ester-containing drugs, acetylcholine and its synthetic analogs; bioactivation of lovastatin (pro-drug) inhibits formation of mevalonate (precursor for cholesterol), what enzyme is this?

A

carboxylesterases

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23
Q

This enzyme hydrolyzes amide linkages in drugs:

A

amidases

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24
Q

This enzyme hydrolyses epoxide metabolites produced by CYP-mediated metabolism of aromatic rings (epoxides are reactive metabolites):

A

epoxide hydrolase (EH)

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25
Q

Conjugation or synthetic reactions refers to these types of enzymes:

A

Phase 2 enzymes

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26
Q

Where are phase 2 enzymes mostly found and what is the exception?

A

cytosol (except UGTs in SER)

27
Q

These enzymes use reactive of functional groups on drugs or drug metabolites to covalently combine an endogenous molecule:

A

Phase 2 enzymes

28
Q

Acceptor site functional groups of Phase 2 enzymes:

A

hydroxyl, epoxide, nitrite, amine, sulfide

29
Q

Endogenous donor molecules of phase 2 enzymes:

A

glucoronic acid, sulfate, glutathione, amino acids, or acetate

30
Q

Phase 2 enzymes have what effects on drugs?

A
  1. inactivates
  2. usually makes drug more polar
  3. greater molecular weight
  4. more easily excreted in bile and urine
31
Q

UDP-glucuronyltransferase (UGT) is what type of enzyme?

A

Phase 2 enzyme

32
Q

UGT is only phase 2 enzyme found where?

A

SER (not cytosolic), it is in Cole proximity with CYPs

33
Q

T/F. UGT attaches glucuronic acid to acceptor sites (OH, NH2, COOH, sulfonamide) on drug substrates. And the enzyme produces what metabolite?

A

TRUE, produce “glucuronide conjugate” metabolite

34
Q

UGT1 and UGT2 are involved in conjugation of?

A

Drugs and bilirubin

35
Q

Attaches sulfo- groups to acceptors sites (-OH groups) on drug substrates

A

sulfotransferase (SULT); “sultan conjugate” metabolite which is very polar

36
Q

Attaches glutathione (GSH) to acceptor sites on substrates (which are often reactive metabolites of certain drugs)

A

Glutathione-S-transferase (GST); produce a “GSH conjugate” metabolite

37
Q

Attaches acetate to aromatic amine and hydrazine drug substrates:

A

N-acetyltransferase (NAT); produces an “acetylated” metabolite; two human acetylkator genes: NAT1, NAT2

38
Q

Methylates various substrates:

A

Methyltransferase (MT)

39
Q

These enzymes metabolize over 80% of all drugs:

A

NATs, GSTs, UGTs, and SULTs

40
Q

Types of Phase III Enzymes:

A

ATP Binding Cassette (ABC) Transporters, SoLute Carrier (SLC) Transporters

41
Q

Rate of metabolism can control ______ and _____.

A

Drug Efficacy and Toxicity

42
Q

What is the major source of adverse drug interactions?

A

Drug Metabolism

43
Q

8 factors influencing drug metabolism:

A

enzyme induction, enzyme inhibition, pharmacogenetics, age, nutrition and diet, disease, hormonal effects, intestinal microflora

44
Q

The increase in concentration of metabolizing enzymes or transporters following exposure to xenobiotics; up-regulation:

A

Induction

45
Q

Enzyme inducing xenobiotic examples:

A

Tobacco smoke and charbroiled foods - CYP1a (carcinogens), Ethanol - CYP2E1 (acetaminophen), St. John’s wort (herbal) - CYP3A4, MDR1

46
Q

Xenobiotic sensing receptors:

A

Inducers (enzyme induction)

47
Q

Examples of xenobiotic sensingg receptors:

A

MDR1, OATP2, UGT1A2, GSTA1

48
Q

Consequences of enzyme induction:

A
  1. diminish plasma drug levels to below therapeutic levels
  2. may increase toxic metabolites
  3. Long term chronic exposure may induce enzyme levels that never return to baseline after cessation (smoking induced expression of CYP1A)
49
Q

Diminishes rate of enzyme activity:

A

Enzyme inhibition

50
Q

Terms to describe inhibition ceasing when inhibitor eliminated vs. when inhibitors are irreversible:

A

competitive vs. non-competitive

51
Q

Consequences of inhibition:

A

drug-drug interactions when taking multiple drugs, one drug inhibits the metabolism of another

52
Q

Examples of inhibiting enzymes:

A

grapefruit juice (CYP3A4, 1A2, 2B6 in intestine), Antifungals and histamine antagonists in liver, HIV-1 protease inhibitors inhibit CYP 3A4

53
Q

Why is it important to have accurate history of all reactions and drug combinations of your patient?

A

to avoid drug-drug interactions

54
Q

Addresses the influence of genetic variations on drug responses:

A

Pharmacogenetics

55
Q

Polymorphisms- Populations with tri-modal activities of:

A

poor (gene deleted), rapid (wild type), and ultra-rapid (gene duplicated)

56
Q

Examples of Phase 1 Enzyme Polymorphisms:

A

CYP2D6 = antiarrhythmics, beta-blockers, CYP2C9 = warfarin, phenytoin, CYP2C19 = warfarin, antidepressants, CYP3A4 = few polymorphisms affect enzyme activity

57
Q

Effects of inactive or multiple CYP2D6 genes:

A

1 functional group = SLOW, exhibit toxic drug effects, 13 functional groups = RAPID, exhibit no beneficial effects of drug

58
Q

Examples of Phase II Enzyme Polymorphisms:

A

NAT2 (n-acetyl transferase-2) and UGT1A1 (glucuronidation of bilirubin)

59
Q

Difference between NAT24 vs. NAT25:

A

NAT24 = rapid acetylator (US asians) vs. NAT25 = slow acetylators (US whites and blacks)

60
Q

Gilbert’s Syndrome is related to what polymorphism:

A

UGT1A1*28, TATA Box

61
Q

A 70-80% reduction in UGT activity results in:

A

HYPERbilirubinemia leading to coronary artery disease

62
Q

The study to devise drug regimens to maximize efficacy and minimize adverse effects

A

Pharmacogenetics

63
Q

How does age influence drug metabolism?

A

The older you are, the more drugs you probably take. Therefore, start with a low dose and give very slowly to help with adverse drug effects. Use Phase II (UGT) more in elderly or those with liver disease.

64
Q

Intestinal microflora can diminish Beta-glucuronidases. T/F.

A

True, bacteria plays role.

PHARM (18 decks)

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