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Pharmacology Test 1 > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

Major Routes for Drug Elimination

A

1) excreted through KIDNEY UNCHANGED

2) biotransformation of drugs or xenobiotics

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2
Q

Major Route I

Excreted through KIDNEY UNCHANGED

A
  • pivotal role with drugs that have small molecular volumes or possess polar characteristics
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3
Q

Major Route II

Biotransformation of drugs or xenobiotics

A
  • biotransformation into more HYDROPHILIC metabolites is critical for termination of biological activity and elimination for the body
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4
Q

Drug Metabolism

A
  • biotransformation of drugs to polar and hence more readily excretable products
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5
Q

Drug Metabolizing Enzyme Groupings I vs II

A
  1. enzymes catalyze PHASE I or Functionalization Reactions

2. enzymes catalyze PHASE II or Conjugation (biosynthetic) Reactions

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6
Q

Phase I

A

Functionalization Reactions
- introduce or expose a polar functional group on the parent compound
(add handle)

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7
Q

Phase II

A

Conjugation (Biosynthetic) Reaction
- typically involve the conjugation of endogenous compounds to phase I products to yield highly polar conjugates
(add something to handle)

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8
Q

Examples of Phase I Reactions

A
  • Aliphatic hydroxylation to alcohol (add OH)
  • Aromatic hydroxylation to phenol
  • Oxidation at S (on N)
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9
Q

Sites of Drug Metabolism/Biotransformation (Tissue Level)

A
  • Liver: principal organ of drug metabolism

- other tissues include GI tract, lungs, skin, and kidneys

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10
Q

Sites of Drug Metabolism/Biotransformation (Subcellular Level)

A
  • most drug metabolizing activity occurs in the ER and the cytosol
  • Phase I Enzymes: ER of liver (microsomal enzymes)
  • Phase II Enzymes: cytosol of liver cell
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11
Q

Cytochrome P450 Mixed Function Oxidase System

A
  • major enzymatic system for Phase I drug metabolism reactions
  • metabolizes large number of environmental chemicals, food toxins, and drugs
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12
Q

P450 Oxidative Reaction Requirements

A
  • enzymes
  • cytochrome p450
  • NADPH-cytochrome P450 reductase
  • cofactor NADPH
  • ACTIVATED molecular O2
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13
Q

Cytochrome P450 Specificity

A
  • low substrate specificity and inducibility

- not high specificity; just needs high level of lipophilicity

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14
Q

Activated Oxygen

A
  • very potent oxidizing reagent
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15
Q

Most Important Phase I Enzyme

A

Cytochrome P450

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16
Q

CYP450 General Properties (LIST)

A
  • have tremendous capacity to metabolize a large number of structurally diverse chemicals
  • —- a single compound can be metabolized at different positions on the molecule
  • —- a single molecule can be metabolized by different CYPs (overlapping substrate specificities)
  • inducible by a variety of chemicals
  • —- induced by presence of substrate
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17
Q 
Phase II (Conjugation) Reactions
(description)
A
  • involves specific transferases, which typically are located in the CYTOSOL of ER
  • catalyze the coupling of an “energy-rich” (activated) endogenous substance with an exogenous or other endogenous compound
    highly polar nature promotes elimination in the urine or bile
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18
Q

Types of Phase II (Conjugation) Reactions

A
  • glucuronidation
  • acetylation
  • glutathione conjugation
  • sulfate conjugation
  • methylation and water conjugation
    etc
19
Q

Glucuronidation

Enzymes, Endogenous Reactant

A

MOST ABUNDANT\IMPORTANT Phase II
- Versatile: O-, N-, S- glucuronidations

The Enzymes: UDP-glucuronosyltransferases
Endogenous Reactant: UDP-Glucuronic Acid

20
Q 
Glutathione Conjugation
(Enzymes, Endogenous Reactant, Two Genes)
A

Phase II
- conjugation of reactive electrophilic compounds with the tripeptide glutathione is a major detoxification pathway for drugs and carcinogens

The Enzymes: Glutathione-S-transferase
Endogenous Reactant: Glutathione (Glu-Cys-Gly)
The Genes: two supergene family
--- Cytosolic GSTs: 16 genes
--- Membrane GSTs: 6 genes

v. important for detox; not enough glutathione = liver damage

21
Q

Sulphation

Enzymes, Endogenous Reactant

A

Phase II

The Enzymes: Sulphotransferase
Endogenous Reactant: PAPS (3’-Phosphoadenosine-5’-phosphosulfate)

22
Q

Isoniazid (INH)

A

Phase II reactions precede phase I reactions

23
Q

Importance of Drug Metabolism: Alter Pharmacodynamic Properties of Drugs

A
  • metabolic products are OFTEN INACTIVE or LESS ACTIVE than parent drugs
  • some metabolic products may have ENHANCED activity
  • – e.g. inactive prodrugs may convert metabolically to active drugs
24
Q

Importance of Drug Metabolism: Alter Pharmacokinetic Properties of Drugs

A
  • OFTEN DRAMATICALLY INCREASE CLEARANCE AND SHORTEN HALF LIVES
25
Q

Importance of Drug Metabolism: Affect Toxicity Properties of Drugs

A
  • USUALLY DETOXIFY

- – some metabolic products have enhanced toxic properties (acetaminophen)

26
Q

Importance of Drug Metabolism

A
  • alter pharmacodynamic properties of drugs
  • alter pharmacokinetic properties of drugs
  • affect toxicity properties of drugs
27
Q

FDA Mandate: before NDA can be applied

A

route of metabolism and enzymes involved must be known

28
Q

Factors Affecting Drug Metabolism

A
  • Genetic Factors: defects; polymorphisms
  • Non-Genetic Factors: age; sex; diseases
  • Environmental Determinants: dietary factors; environmental factors; drug-drug interactions; drugs and endogenous compound interactions
29
Q

Environmental Determinants

A
  • Dietary factors: smoking, alcohol consumption, etc
  • Environmental factors: pollutants, pesticides, etc
  • Drug-Drug interactions: inhibition or induction of drug metabolism
  • Drugs and Endogenous Compound interactions
30
Q

Genetic Factors in Drug Metabolism

A
  • contribute to large interindividual differences in metabolic rate
31
Q

N-Acetylation of Isoniazid

NAT2 mutation

A
  • genetic factors change metabolism
  • polymorphism of NAT2 gene (if 2 of “slow” NAT2) slow acetylation
  • – reducing dosage or increasing dosing interval is recommended
32
Q

Induction

3 examples

A
  • increasing the amount of enzymes -> increasing metabolism -> decreased effect
  • induce cytochrome P450 gene (making more of enzyme) and increase metabolism rates of drugs
  • charcoal-broiled food
  • cruciferous vegetables
  • induces CYP1A3 (warfarin)
33
Q

Inhibition

2 examples

A
  • inhibiting activity of enzymes
  • ** DANGEOUS: because if keep increasing level of drug to induce response you could reach toxicity***
  • increasing enzyme inhibition -> decreased metabolism -> increased effect
  • grapefruit juice (CYP3A4): cyclosporine
  • Alcohol
34
Q

Drug-Drug Interactions: Inhibition of Metabolizing Enzymes

A
  • inactivation of CYP enzymes by certain drugs
  • consequence: may impair elimination of the more slowly metabolized drug, prolong or potentiate pharmacological effects, and incidence of drug-induced toxicity
  • induce/inhibit metabolizer of other drugs
35
Q

Diseases & Effect of Drug Metabolism

A
  • acute and chronic diseases that affect LIVER function or architecture markedly diminish the metabolism of some drugs
36
Q

cyclosporine inhibition

A

grapefruit juice (CYP3A4)

37
Q

Warfarin Inhibition

A
  • charcoal-broiled food
  • cruciferous vegetables
  • induces CYP1A2
38
Q

Chlordiazepoxide and Diazepam t1/2 increase

A

hepatitis & cirrhosis

diseases that affect liver function

39
Q

Aminopyrine Impaired Oxidative Metabolism

A

cancer

40
Q

CYP3A4 and John’s Wort interaction

A

John induces CYP3A4; reduce concentration of oral contraceptives and other drugs co-administered

41
Q

How are drugs eliminated from the body?

A
  • make polar and soluble so can eliminate
42
Q

Pathways of drug elimination

A 
Phase II (conjugate)  -> elimination
Phase I (drug metabolite with modified activity / inactive drug metabolite) -> Phase II (conjugate) -> elimination

Lipophilic -> Hydrophilic

43
Q

What increases half life of chlordiazepoxide and diazepam

A

Hepatitis and Cirrhosis

44
Q

What impairs oxidative metabolism of aminopyrine

A

cancers

Pharmacology Test 1 (8 decks)

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