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2060 Pharmacology > Module 4 Metabolism > Flashcards

Module 4 Metabolism Flashcards

1
Q

Drug Metabolism Definition

A
  • Enzyme mediated alteration of drug structure
  • Biotransformation
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2
Q

Metabolism Sites

A
  • Liver
  • Intestine
  • Stomach
  • Kidney
  • Intestinal bacteria
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3
Q

Liver Site

A
  • Primary metabolism site
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4
Q

Intestine Site

A
  • Enterocytes on gut lining metabolize
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5
Q

Stomach Site

A
  • Alcohol metabolism
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6
Q

Intestinal Bacteria SIte

A
  • Bacterial flora
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7
Q

Drug Metabolism Importance

A
  • Protection from toxins
  • Synthesize endogenous molecules
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8
Q

Endogenous Examples

A
  • Vit D synthesis
  • Bile acid synthesis
  • Cholesterol metabolism
  • Steroid hormones
  • Bilirubin
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9
Q

Therapeutic Consequences

A
  • Increase water solubility of drugs, promoting excretion
  • Inactive drugs
  • Increase drug effectiveness
  • Activate prodrugs (inactive until metabolized)
  • Increase drug toxicity
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10
Q

1st Order Kinetics

A
  • Directly proportional to free drug concentration
  • Constant fraction of drug metabolized per unit time
  • Drug concentration lower than metabolic capacity
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11
Q

0 Order Kinetics

A
  • Plasma drug concentration higher than metabolic capacity
  • Constant metabolism over time
  • Ethanol
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12
Q

First Pass Metabolism

A
  • Metabolism prior to entering circulation
  • Decrease amount of parent drug in circulation
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13
Q

Mechanisms of First Pass

A
  • Hepatocytes in lives
  • Intestinal enterocytes
  • Stomach
  • Intestinal bacteria
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14
Q

Extraction Ratio

A
  • Metabolism amount on first pass through liver
  • Determine bioavailability
  • High/low ratio characterization
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15
Q

High Extraction Ratio

A
  • Low oral bioavailability
  • High PO dose, low IV dose
  • Small changes in hepatic enzyme
  • Produce large changes to bioavailability
  • Susceptible to drug/drug interactions
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16
Q

Low Extraction Ratio

A
  • High oral bioavailability
  • PO & IV doses similar
  • Hepatic enzyme changes no effect on bioavailability
  • Not susceptible to drug/drug interactions
  • Many passes through liver
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17
Q

Metabolism Phase 1

A
  • Convert lipophilic drugs to polar molecules (OH/NH2)
  • Oxidation, reduction, hydrolysis reactions
  • Mediated by cytochrome, esterases, dehydrogenases
  • Metabolites formed more/less active or same as parent drug
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18
Q

Glucuronidation

A
  • Phase 2 metabolism
  • Addition of glucuronic acid (UGTs)
  • Create metabolite glucuronide
  • Excreted in bile/urine
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19
Q

Metabolism Phase 2

A
  • Increase polarity of lipophilic drugs by conjunction reactions
  • Addition of water soluble molecule
  • Conjugates sugar, sulfate, amino acids
  • Metabolites less active than parent drug
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20
Q

Phase 1 Intracellular Site

A
  • Localized to smooth endoplasmic reticulum (ER)
21
Q

Phase 2 Intracellular Site

A
  • Drug metabolisers on cytosol side of cell
  • Glucuronidation exception ER
22
Q

Cytochromes P-450 Drug Metabolizing Enzymes

A
  • Phase 1 of metabolizing
  • Hepatic enzymes majority
  • Oxidize drugs by adding oxygen
  • Produce water by product
23
Q

CYP Naming

A
  • 12 families
  • Sub families
  • Isozyme
24
Q

Phase 2 Metabolizing Enzymes

A
  • UDP-glucuronosyltransferases
  • Sulfotransferases (SULTs)
  • Glutathione S Transferases (GSTs)
  • N-acetyltransferases (NATs)
  • Thiopurine Methyltransferase (TPMT)
25
Q

UDP-Glucuronosyltransferases (UGTs)

A
  • Localized to smooth ER
  • Catalyze transfer of glucuronic acid (sugar) to drug
  • Polar
  • Easily excreted
  • 19 enzymes
26
Q

Sulfotransferases (SULTs)

A
  • Cytosolic
  • Catalyze transfer of sulfate group to hydroxyl group
  • Polar
  • Easily excreted
  • 11 enzymes
27
Q

Glutathione S Transferases (GSTs)

A
  • Cytosolic or microsomal
  • Catalyze transfer of glutathione molecule to drug
  • Transfer of glutathione onto a reactive
  • Metabolite less toxic
  • 20 enzymes
28
Q

N-acetyltransferases (NATs)

A
  • Cytosolic
  • Catalyze transfer of acetyl group from acetyl CoA
  • Subject to general polymorphisms
  • Cause of variability to drug response
  • 2 enzymes
29
Q

Thiopurine Methyltransferase (TPMT)

A
  • Cytosolic
  • Catalyze transfer of methyl group
  • Subject to general polymorphisms
  • Effects on drug safety
30
Q

Affecting Factors of Drug Metabolism

A
  • Age
  • Drug interactions
  • Disease state
  • Genetic polymorphisms
31
Q

Age

A
  • Expression & activity changes
  • Enzymes develop by age 2
32
Q

Drug Interactions

A
  • Enzyme inducers
  • Enzyme inhibitors
33
Q

Enzyme Inducers

A
  • Cell synthesizes enzyme in response to drug/chemical
  • Specific CYP isozymes susceptible to induction
  • Increases drug metabolism
34
Q

Consequences of Increased Metabolism

A
  • Decreased plasma concentration
  • Decreased drug activity (metabolite inactive)
  • Increased drug activity (metabolite active)
35
Q

Enzyme Inhibition

A
  • Certain natural compounds inhibit CYPs
  • Decreasing drug metabolism
36
Q

Consequences of Decreased Metabolism

A
  • Higher plasma drug concentration
  • Increased therapeutic effects of drug
  • Increased drug toxicity
37
Q

Disease State

A
  • Role in CYP activity
  • Liver, kidney, infection, inflammatory
38
Q

Genetic Polymorphisms

A
  • Genes have single nucleotide polymorphisms (SNP)
  • Change of single nucleotide in DNA
  • Affect production of drug metabolizing enzyme
39
Q

Phase 1 SNP

A
  • Metabolizes anticoagulant drug warfarin
  • Polymorphism of CYP2C9
  • Enzyme activity decrease
  • Lower dose required
40
Q

CYP2D6 Function

A
  • Metabolizes codeine to morphine
41
Q

CYP2D6 Phenotypes

A
  • Ultra-rapid metabolizer (UM)
  • Extensive metabolizer (EM)
  • Intermediate metabolizer (IM)
  • Poor metabolizer (PM)
42
Q

Extensive Metabolizers (EM)

A
  • Normal enzymatic activity
43
Q

Intermediate Metabolizers (IM)

A
  • Reduced metabolic activity
44
Q

Poor Metabolizers (PM)

A
  • Almost no metabolic activity
45
Q

Ultra-Rapid Metabolizers (UM)

A
  • Increased CYP2D6 activity
  • Multiple copies of CYP2D6 gene
46
Q

Phase 2 SNP

A
  • UGT1A1
  • Polymorphisms decrease activity
  • Glucuronidases anti-cancer compound (irinotecan)
  • Bone marrow suppression
47
Q

NAT 2

A
  • Acetylates isoniazid, caffeine & cancer chemicals
  • 23 SNP with NAT2 gene
  • Rapid/slow acetylators based on genotype
48
Q

Slow Acetylators

A
  • Susceptible to isoniazid toxicity
  • Neuropathy/hepatoxicity
  • Risk of cancer development

2060 Pharmacology (18 decks)

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