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Kinetics > 3 - Metabolism > Flashcards

3 - Metabolism Flashcards

1
Q

What is metabolism?

A

Conversion of a drug to a more polar, water soluble, ionized substance, usually w/ reduced pharmacological activity and toxicity (exception is a prodrug)

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2
Q

____ is the main organ of biotransformation

A

Liver

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3
Q

What are the sites of metabolism?

A
  • Bloodstream
  • Kidneys
  • Brain
  • Muscle tissue
  • Walls of GI tract
  • Lungs
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4
Q

What are the 2 types of hepatic metabolism? What are examples of each?

A

1) Phase 1 - oxidation, hydrolysis, reduction (in order from most to least prevalent)
2) Phase 2 - glucuronidation, acetylation, sulfation

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5
Q

What must happen to a drug to undergo phase 2 metabolism?

A

Must be activated, generally by a phase 1 reaction

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6
Q

What does it mean when an active drug is metabolized to an active metabolite?

A

Don’t have to dose as frequently

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7
Q

How are barbiturates metabolized?

A

Glucuronidation and oxidation

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8
Q

How are benzodiazepines metabolized?

A

1) N-dealkylation to biologically active metabolite
2) Hydroxylation to active metabolite
3) Glucuronidation to inactive metabolite

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9
Q

How is morphine metabolized?

A

Glucuronidation to morphine-6-glucuronide (active metabolite) or morphine-3-glucuronide (inactive metabolite)

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10
Q

How is codeine metabolized?

A

10% is demethylated to morphine

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11
Q

How are tranquilizing agents (anti-psychotic agents) metabolized?

A

Majority is oxidized, some undergoes glucuronidation

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12
Q

How is cocaine metabolized?

A

Plasma esterases

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13
Q

How is ethanol metabolized?

A

Oxidation (zero order process)

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14
Q

What is required for oxidation?

A
  • NADPH
  • Molecular oxygen
  • Heme-protein
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15
Q

Important phase 1 oxidation reactions are performed by ______ found in ______

A

Mixed function oxidases found in smooth endoplasmic reticulum

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16
Q

Why is it called cytochrome P450?

A

Absorbs light at wavelength 450 nm

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17
Q

What is the key element in the oxidative process?

A

Hemeprotein cytochrome

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18
Q

What is the difference btwn ferrous and ferric iron?

A
  • Ferrous = Fe2+

- Ferric = Fe3+

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19
Q

Which families of CYP enzymes are responsible for drug metabolism?

A

Families 1, 2, and 3

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20
Q

What are the 6 major CYP P450 isoenzymes responsible for the majority of drug metabolism in humans?

A

1) CYP1A2
2) CYP2C8/9/10
3) CYP2C18/19
4) CYP2D6
5) CYP2E1
6) CYP3A4

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21
Q

What are the substrates of CYP1A2?

A
  • Phenacetin

- Theophylline

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22
Q

What are the substrates of CYP2C8/9/10?

A
  • Hexobarbital

- Phenytoin

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23
Q

What are the substrates of CYP2C18/19?

A
  • Diazepam

- Mephenytoin

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24
Q

What are the substrates of CYP2D6?

A
  • Imipramine

- Propranolol

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25
Q

What is the substrate of CYP2E1?

A

Acetaminophen

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26
Q

What are the substrates of CYP3A4?

A
  • Erythromycin

- Cyclosporin

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27
Q

CYP____ metabolizes chemicals and toxins

A

1A2

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28
Q

Smoking induces CYP____ resulting in ____

A
  • 1A2
  • Resulting in activation of benzpyrene, a carcinogen in cigarette smoke
  • This means higher levels of drugs may be required by smokers than non-smokers
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29
Q

Which CYP enzymes exhibit genetic polymorphism?

A
  • 2C9 and 2C19
  • 2D6
  • 2E1
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30
Q

Where in the body is the majority of CYP3A4 found?

A

Gut

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31
Q

Which CYP enzymes are affected by nutrition?

A
  • 1A2
  • 2E1
  • 3A3
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32
Q

Which CYP enzyme is affected by alcohol? What does this mean?

A
  • 2E1
  • Causes glutatione depletion, leading to accumulation of NAPQ1 (lethal byproduct of acetaminophen) => severe liver damage
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33
Q

Which CYP enzymes are affected by drugs?

A
  • 1A2
  • 2C
  • 2D6
  • 3A3
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34
Q

What are the 2 major reduction reactions?

A

1) Nitro-reduction

2) Azo-reduction

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35
Q

Where are reduction reactions carried out?

A

Intestinal microflora

36
Q

Which drugs commonly undergo reduction reactions?

A

Orally administered

37
Q

Where are hydrolysis reactions and by what?

A

By respective esterases in liver or by esterases in plasma and other tissues

38
Q

What do esterases do?

A

Hydrolyze esters to alcohols and carboxylic acids

39
Q

What do phase 2 reactions involve and what do they normally result in?

A
  • Involve chemical conjugation or synthesis

- Generally increase water solubility and result in pharmacological deactivation

40
Q

What occurs in a conjugation reaction?

A

Compound/metabolite is combined w/ endogenous molecule

41
Q

Where does glucuronidation occur?

A

Endoplasmic reticulum

42
Q

Where does sulfation occur?

A

Cytosol

43
Q

Where does acetylation occur?

A

Cytosol

44
Q

Where does methylation occur?

A
  • Cytosol

- Endoplasmic reticulum

45
Q

Where does glutathione conjugation occur?

A
  • Cytosol

- Endoplasmic reticulum

46
Q

What are some factors that contribute to variability in drug response?

A
  • Genetic factors (most common)
  • Concomitant drugs (2nd most common)
  • Weight
  • Ethnicity
  • Gender
  • Diet
  • Compliance
  • Concomitant disease
47
Q

Is the CYP P450 the same in adults and children?

A

No, so children can’t be treated the same way adults are

48
Q

What could result from CYP2D6 gene duplication?

A

Lethal levels of morphine in the blood, b/c CYP2D6 metabolizes codeine to morphine

49
Q

What can accumulation of morphine in an infant cause?

A
  • CNS depression
  • Respiratory failure
  • Death
50
Q

What is the function of SLC28A3 (sodium-coupled nucleoside transporter 28A3)? Where is it found?

A
  • Transports pyrimidines, purines, and anti-cancer drugs; demonstrated role in anthracycline transport
  • Expressed throughout body, including heart
51
Q

What is the function of SLC28A3 L461L?

A

L461L is a protective allele that reduces SLC28A3 expression, reduces anthracycline uptake, and reduces generation of toxic metabolites

52
Q

What can altered glucuronidation lead to?

A

Accumulation of toxic anthracycline metabolites

53
Q

How is isoniazid metabolized and what is important about this?

A
  • Metabolized by N-acetyltransferase

- Metabolite is not active, so rate and extent of metabolism will affect efficacy of the drug

54
Q

Is total body water and extracellular fluid greater in newborns or in adults?

A

Newborns

55
Q

Do elderly individuals have more lean body mass or more body fat in relation to body weight?

A

Greater body fat

56
Q

Do newborns have increased or decreased glucuronidation reactions?

A

Decreased

57
Q

How does half life of a drug change as you age? What else changes w/ age?

A
  • High at birth, goes down as you age to an adult, and increases again in elderly
  • Vd and protein binding
58
Q

What affect can a low protein diet have on drug metabolism?

A

Decreases drug metabolizing capacity b/c of lack of amino acids

59
Q

What affect can decreased lipid intake have on drug metabolism?

A

Decreases essential fatty acids, so decreases metabolism of ethylmorphine and hexobarbitone

60
Q

What affect can a high glucose intake have on drug metabolism?

A

Inhibits barbiturate metabolism

61
Q

What affect does food have on bioavailability?

A

Increases bioavailability b/c increases splanchic (organ) blood flow which increases uptake

62
Q

Which foods are inducers of the CYP P450 system?

A
  • Charcoal broiled meats

- Smoked fish

63
Q

Which food inhibits intestinal P450 enzymes and what affect does this have on cyclosporine?

A
  • Grapefruit juice

- Increases bioavailability of cyclosporine

64
Q

Which drugs are mostly affected by the action of grapefruit juice of CYP3A?

A
  • Antihistamines
  • Benzodiazepines
  • Immunosuppressants
65
Q

What can happen if a px is taking nifedipine and terazosin for BP control and consumes grapefruit juice?

A

Px will experience hypotension b/c grapefruit juice blocks metabolism of the drugs

66
Q

What components of grapefruit juice are thought to affect CYP P450?

A
  • Flavanoids

- Furanocoumarins

67
Q

Effect of grapefruit juice appears to last for at least __ days following ingestion

A

3

68
Q

What effect does St. John’s Wort have on CYP P450?

A

Induces CYP3A

69
Q

What is St. John’s Wort used for?

A

Treating mild to moderate depression

70
Q

What is ginseng used for?

A

Normalizer, energizer, and stress reducer

71
Q

What can ginseng interact w/?

A
  • Antidepressants
  • Warfarin
  • Steroids
72
Q

What can ginko and garlic interact w/?

A

Warfarin, can increase bleeding time

73
Q

Should drugs and herbs be mixed?

A

No

74
Q

Do all drugs follow the Michaelis-Menten kinetics?

A

Yes

75
Q

What is important to note about increasing the dose of a drug that exhibits Michaelis-Menten kinetics?

A

Doubling the dose will dramatically increase the plasma concentration, likely putting it at toxic concentrations, so must be careful when increasing dose

76
Q

Why can cause a metabolite to have reduced pharmacological activity?

A
  • Metabolite is more water soluble than parent compound, so has less capacity to cross membranes
  • Metabolite has lost most of its original intrinsic pharmacological activity
77
Q

Does skin have CYP P450 enzymes?

A

Yes, can metabolize compounds in ointments

78
Q

Phase 2 reactions occur w/ _____

A

CYP P450 system

79
Q

Can a metabolite have a longer half life than its parent compound?

A

Yes

80
Q

___ has many of the same properties as morphine

A

Morphine-6-glucuronide

81
Q

Is codeine a pro-drug?

A

Yes, becomes activated into morphine through demethylation

82
Q

Since codeine is normally given w/ caffeine, would taking codeine w/ a cup of coffee increase bioavailability?

A

No

83
Q

Describe the process of P450 action

A
  • Drug binds to P450 ferric complex
  • Electron from NADPH reacts w/ the complex
  • Oxygen binds to complex
  • Free radical forms
  • Oxygen is removed
  • Drug comes off
84
Q

Why must a compound be active to undergo glucuronidation?

A

Must have a site to accept the glucuronic acid

85
Q

Is it possible to have 0% drug concentration but still have a pharmacological effect?

A

Yes b/c drug can go inside a cell into a reservoir and be sequestered later

Kinetics (4 decks)

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