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Pharm 2060 > Module 4 > Flashcards

Module 4 Flashcards

1
Q

Metabolism

A

The enzyme mediated alteration of a drug’s structure

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2
Q

Metabolism is also referred to as…

A

Biotransformation

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3
Q

Where is metabolism found?

A

Liver, Intestine, Stomach, Kidney, Intestinal Bacteria

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4
Q

The primary site of drug metabolism is…

A

The liver

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5
Q

How does the intestine metabolize drugs?

A

The enterocytes that line the gut are our key metabolizers

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6
Q

What does the stomach metabolize?

A

Alcohol

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7
Q

Why is drug metabolism important?

A

Metabolism protects humans from a number of environmental toxins as well as playing an important role in synthesizing essential endogenous molecules

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8
Q

Exogenous

A

Things that are not natural in our body (alcohol, drugs, steak, cigarets, coffee, etc.)

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9
Q

Endogenous

A

Things that are natural in our body (vitamin D synthesis, bile acid synthesis, cholesterol metabolism, steroid hormones, bilirubin)

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10
Q

What are the consequences of drug metabolism?

A
  1. ) Increase water solubility of drugs to promote their excretion (lipo -> hydro)
  2. ) Inactive drugs (active -> inactive)
  3. ) Increase drug effectiveness (active -> more active)
  4. ) Activate prodrugs (drugs that are inactive until metabolized)
  5. ) Increase drug toxicity
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11
Q

1st Order Kinetics for Drug Metabolism

A

Drug metabolism is directly proportional to the concentration of free drug

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12
Q

What order of kinetics is “a fraction of drug metabolized per unit time”?

A

1st Order

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13
Q

What order of kinetics has more drug metabolizing enzyme then drug?

A

1st Order

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14
Q

Zero Order Kinetics

A

Drug metabolism is constant over time

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15
Q

What order of kinetics is a constant amount of drug metabolized per unit time?

A

Zero Order

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16
Q

What is a good example of a zero order kinetic drug?

A

Ethanol

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17
Q

What order of kinetics has more drug then drug metabolizing enzyme?

A

Zero Order

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18
Q

1st Pass Metabolism

A

PO drugs can undergo significant metabolism prior to entering the systemic circulation

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19
Q

First pass metabolism can occur…

A
  1. ) Hepatocytes in the liver
  2. ) Intestinal enterocytes
  3. ) Stomach
  4. ) Intestinal bacteria
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20
Q

What is the result of 1st pass metabolism

A

Decreased amount of parent drug that enters systemic circulation

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21
Q

ER stands for…

A

Extraction Ratio

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22
Q

High ER Drugs are…

A

Highly metabolized in the liver

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23
Q

High ER Drug characteristics:

A
  • Low oral bioavailability (1-20%)
  • PO doses are usually much higher than IV doses (compensating for high first metabolism)
  • Small changes in hepatic enzyme activity produce large changes in bioavailability
  • Very susceptible to drug-drug interactions
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24
Q

Low ER Drug characteristics:

A
  • Have high oral bioavailability (>80%)
  • PO doses are usually similar to IV doses
  • Small changes in hepatic enzyme activity have little effect on bioavailability
  • Not very susceptible to drug-drug interactions
  • Take many passes through the liver via the systemic circulation before they are completely metabolized
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25
Q

What are the two phases of metabolism called?

A

Phase I Metabolism, Phase II Metabolism

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26
Q

Phase I Metabolism

A

Converts lipophilic drugs to more polar molecules (unmasks polar groups like OH or NH2)

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27
Q

What types of reactions are involved in Phase I Metabolism?

A

Oxidation, reduction and hydrolysis reactions

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28
Q

What mediates phase I metabolism?

A

Cytochrome P450 enzymes, esterases and dehydrogenases

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29
Q

Metabolites from phase one are how active in comparison to the parent drug?

A

They are either more, less or equally active. It varies greatly.

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30
Q

Phase II Metabolism

A

Increase the polarity of lipophilic drugs by conjugation reactions (addition of large water soluble molecule to drug)

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31
Q

What is included in a conjugate?

A

Glucuronic acid (sugar), sulfate (SO4), acetate or amino acids (glycine)

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32
Q

Metabolites from phase II are how active in comparison to the parent drug?

A

Less active

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33
Q

What is the exception of Phase II Metabolism?

A

Morphine 6-glucuronide - more potent analgesic (pain reliever) than morphine

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34
Q

True or False: some drugs directly enter phase II metabolism?

A

True

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35
Q

Where are phase I drug metabolizing enzymes localized?

A

The smooth endoplasmic reticulum

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36
Q

Where are phase II drug metabolizing enzymes localized?

A

Predominantly in the cytosol with the exception of glucuronidation which is localized to the smooth ER

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37
Q

CYPs

A

Large family of drug metabolizing enzymes

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38
Q

In what phase are CYPs predominant?

A

Phase I Drug Metabolizing

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39
Q

The majority of drug metabolism in the body is performed by

A

Hepatic CYP enzymes

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40
Q

CYPs oxidize drugs by…

A

Inserting one atom of oxygen into the drug molecule producing water as a by product

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41
Q

How many faimilies of CYPs are there?

A

12 families, 3 accounting for the majority of drug metabolism

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42
Q

What is malnutritions effect on CYP activity?

A

Decreases activity as these enzymes require dietary protein, iron, folic acid and zinc for full activity

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43
Q

What does the A in CYP3A4 represent?

A

The sub-family

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44
Q

What does the 3 in CYP3A4 represent?

A

Family

45
Q

What does the 4 in CYP3A4 represent?

A

Isozyme

46
Q

What CYP metabolizes the largest fraction of currently marketed drugs?

A

CYP3A4

47
Q

What are the five phase II drug metabolizing enzymes:

A
  1. ) UDP-glucuronosyltransferases (UGTs)
  2. ) Sulfotransferases (SULTs)
  3. ) Glutathione S Transferases (GSTs)
  4. ) N-acetyltransferases (NATs)
  5. ) Thiopurine Methyltransferase (TPMT)
48
Q

UGTs are localized…

A

In the smooth endoplasmic reticulum

49
Q

What phase are UGTs part of?

A

Phase II

50
Q

What do UGTs catalyze?

A

The transfer of a glucuronic acid (sugar) to a drug

51
Q

Why are glucuronidated drugs more easily excreted?

A

They are more polar

52
Q

How many human UGT enzymes are there?

A

19

53
Q

What is the reaction for UGT?

A

Drug + UDP-glucuronic acid -> Drug-glucuronide + UDP

54
Q

Where are SULTs localized?

A

In the cytosol

55
Q

What phase are SULTs?

A

Phase II Drug Metabolizing enzymes

56
Q

What do SULTs catalyze?

A

The transfer of a sulphate group to a hydroxyl group of drugs

57
Q

Why are sulphated drugs more easily excreted?

A

They are more polar

58
Q

How many human SULT enzymes are there?

A

11

59
Q

What is the drug reaction for SULT?

A

Drug + sulphate -> drug-sulfate

60
Q

Where are GSTs localized?

A

Cytosol or Microsomal

61
Q

What phase are GSTs?

A

Phase II Drug Metabolizing enzymes

62
Q

What do GSTs catalyze?

A

The transfer of a glutathione molecule to a drug

63
Q

What is Glutathione (GSH)

A

Intracellular anti-oxidant

64
Q

How do GSTs render the metabolite less toxic?

A

They transfer glutathione onto a reactive/toxic drug

65
Q

How many human GSTs are there?

A

20

66
Q

GST Reaction

A

Reactive Drug + GSH -> Drug-GSH

67
Q

Where are NATs localized?

A

Cytosol

68
Q

What phase are NATs?

A

Phase II

69
Q

What do NATs catalyze?

A

The transfer of an acetyl group from acetyl CoA to a drug

70
Q

Why do NATs have a variability in drug response?

A

They are subject to genetic polymorphisms

71
Q

How many human NATs are there?

A

2: NAT 1 and NAT 2

72
Q

NAT Reaction

A

Drug + Acetyl-CoA -> Acetylated Drug + CoA

73
Q

Where are TPMT localized?

A

Cytosol

74
Q

What phase are TPMT?

A

Phase II

75
Q

What do TPMTs catalyze?

A

The transfer of a methyl group from S-adenosylmethionine to a drug

76
Q

Why do TPMTs sometimes become unsafe?

A

They are subject to genetic polymorphisms. This has a dramatic effect on safety

77
Q

TPMT Reaction

A

Drug + S-adenosylmethionine -> Drug-CH3 + Methionine

78
Q

What are the four factors that affect drug metabolism?

A
  1. ) Age
  2. ) Drug interactions (enzyme inducers and enzyme inhibitors)
  3. ) Disease state
  4. ) Genetic polymorphisms
79
Q

What is the activity of CYP in an infant?

A

Almost no activity, not until 1 year after birth

80
Q

By what age do infants have the same drug metabolizing enzymes as adults?

A

Age 2

81
Q

Enzyme Induction

A

A process where a cell synthesizes an enzyme in response to a drug or other chemical

82
Q

What is the consequence of CYP induction?

A

Increased drug metabolism

83
Q

What are the consequences of increased drug metabolism?

A
  1. ) Decreased plasma drug concentration
  2. ) Decreased drug activity (if metabolite is inactive)
  3. ) Increased drug activity (if metabolite is active)
84
Q

What is the consequence of CYP inhibition?

A

Decreased drug metabolism

85
Q

Decreased drug metabolism results in…

A
  1. ) Higher plasma drug concentration
  2. ) Increased therapeutic effect of drugs
  3. ) Increased drug toxicity
86
Q

What are 4 diseases that decrease CYP activity?

A
  1. ) Liver disease
  2. ) Kidney Disease
  3. ) Inflammatory diseases
  4. ) Infection
87
Q

What are genetic polymorphisms also known as?

A

Single Nucleotide Polymorphisms (SNPs)

88
Q

What is a SNP?

A

A change of a single nucleotide in our DNA

89
Q

What do SNPs affect?

A

Proteins

90
Q

Phase I SNPs

A

CYP2C9, CYP2D6

91
Q

CYP2C9

A

Metabolizes the anticoagulant drug warfarin

92
Q

Results of a polymorphism of CYP2C9

A

An enzyme with decreased activity, patients require a lower dose of warfarin

93
Q

What happens to a patient with CYP2C9 who is not administered a lowered dosage of warfarin?

A

Extensive bleeding

94
Q

CYP2D6

A

Metabolizes codeine to morphine. Morphine is a more potent analgesic than codeine

95
Q

What are the 4 distinct phenotypes that genetic polymorphisms causes in CYP2D6?

A
  • Ultra-rapid metabolizer (UM)
  • Extensive Metabolizer (EM)
  • Intermediate Metabolizer (IM)
  • Poor Metabolizer (PM)
96
Q

What affect do extensive metabolizers have on enzymatic activity?

A

No effect. Enzymatic activity is normal.

97
Q

Intermediate metabolizers have _____ metabolic activity?

A

Reduced

98
Q

Poor metabolizers have _____ metabolic activity

A

No

99
Q

Ultra-rapid metabolizers have _____________ CYP2D6 activity

A

Significantly increased

100
Q

Phase II SNPs

A

UGT1A1, NAT2

101
Q

What kind of compound is Glucuronidate?

A

An anti-cancer compound

102
Q

What affect do polymorphisms in UGT1A1 have on activity?

A

Decreased activity

103
Q

What risks are increased for patients with a UGT1A1 polymorphism?

A

Diarrhea and dose limiting bond marrow suppression (potentially fatal)

104
Q

NAT2

A

Acetylates the drug isoniazid (for tuberculosis), caffeine and various cancer causing chemicals

105
Q

How many different SNPs are in the NAT2 gene?

A

23

106
Q

How are patients classified as either rapid or slow acetylators?

A

Based on their genotype

107
Q

What type of acetylator is more susceptible to isoniazid toxicity?

A

Slow acetylators

108
Q

What type of acetylator is at higher risk for developing cancer?

A

Slow acetylators

Pharm 2060 (5 decks)

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