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Pharmacology Test 1 > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

(44 cards)

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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

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

Glucuronidation

Enzymes, Endogenous Reactant

Study These Flashcards
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)
Study These Flashcards
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

Study These Flashcards
A

Phase II

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

22
Q

Isoniazid (INH)

Study These Flashcards
A

Phase II reactions precede phase I reactions

23
Q

Importance of Drug Metabolism: Alter Pharmacodynamic Properties of Drugs

Study These Flashcards
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

Study These Flashcards
A
  • OFTEN DRAMATICALLY INCREASE CLEARANCE AND SHORTEN HALF LIVES
25
Importance of Drug Metabolism: Affect Toxicity Properties of Drugs
- USUALLY DETOXIFY | - -- some metabolic products have enhanced toxic properties (acetaminophen)
26
Importance of Drug Metabolism
- alter pharmacodynamic properties of drugs - alter pharmacokinetic properties of drugs - affect toxicity properties of drugs
27
FDA Mandate: before NDA can be applied
route of metabolism and enzymes involved must be known
28
Factors Affecting Drug Metabolism
- 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
Environmental Determinants
- 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
Genetic Factors in Drug Metabolism
- contribute to large interindividual differences in metabolic rate
31
N-Acetylation of Isoniazid | NAT2 mutation
- genetic factors change metabolism - polymorphism of NAT2 gene (if 2 of "slow" NAT2) slow acetylation - -- reducing dosage or increasing dosing interval is recommended
32
Induction | 3 examples
- 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
Inhibition | 2 examples
- 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
Drug-Drug Interactions: Inhibition of Metabolizing Enzymes
- 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
Diseases & Effect of Drug Metabolism
- acute and chronic diseases that affect LIVER function or architecture markedly diminish the metabolism of some drugs
36
cyclosporine inhibition
grapefruit juice (CYP3A4)
37
Warfarin Inhibition
- charcoal-broiled food - cruciferous vegetables - induces CYP1A2
38
Chlordiazepoxide and Diazepam t1/2 increase
hepatitis & cirrhosis | diseases that affect liver function
39
Aminopyrine Impaired Oxidative Metabolism
cancer
40
CYP3A4 and John's Wort interaction
John induces CYP3A4; reduce concentration of oral contraceptives and other drugs co-administered
41
How are drugs eliminated from the body?
- make polar and soluble so can eliminate
42
Pathways of drug elimination
``` Phase II (conjugate) -> elimination Phase I (drug metabolite with modified activity / inactive drug metabolite) -> Phase II (conjugate) -> elimination ``` Lipophilic -> Hydrophilic
43
What increases half life of chlordiazepoxide and diazepam
Hepatitis and Cirrhosis
44
What impairs oxidative metabolism of aminopyrine
cancers

Pharmacology Test 1 (8 decks)

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