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Pharmacokinetics > Metabolism > Flashcards

Metabolism Flashcards

1
Q

Define metabolism

A

Conversion of a drug to a more polar, water soluble, ionized substance usually with reduced pharmacological activity and toxicity

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2
Q

Give an example of when pharmacodynamics may not equal pharmacokinetics

A

When there is 0% blood level but still producing a pharmacological effect. (Drug is completely concentrated in organ)

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3
Q

List some sites of metabolism

A
  • bloodstream
  • kidneys
  • brain (CNS active drugs)
  • muscle tissue
  • wall of GI tract (ex. bacteria)
  • lungs
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4
Q

_____ = main organ of biotransformation

A

liver

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5
Q

What are the two types of hepatic metabolism?

A

Phase 1

Phase 2

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6
Q

List Phase 1 Metabolism processes

A
  • oxidation (most common)
  • hydrolysis
  • reduction
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7
Q

List Phase 2 Metabolism processes

A
  • glucuronidation (most common)
  • sulfation
  • acetylation
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8
Q

What type of metabolism do barbiturates undergo?

A
  • glucuronidation

- oxidation

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9
Q

What type of metabolism do benzodiazepines undergo?

A 
1st N-dealkylation (biologically active metabolite)
2nd hydroxylation (active)
3rd glucuronidation (inactive)
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10
Q

What type of metabolism does morphine undergo?

A

glucuronidation

morphine-6-glucuronide (active)
morphine-3-glucuronide (inactive)

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11
Q

What type of metabolism does codeine undergo?

A

10% demethylated to morphine

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12
Q

What type of metabolism do tranquilizing agents undergo (anti-psychotic agents)?

A
  • oxidation (majority)

- glucuronidation (some)

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13
Q

What type of metabolism does cocaine undergo?

A

plasma esterases

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14
Q

What type of metabolism does ethanol undergo?

A

oxidation (zero order process)

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15
Q

Phase 1: Oxidation:

Most _____ phase 1 reaction

A

prevalent

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16
Q

Phase 1: Oxidation:

What does it require?

A

NADPH, molecular oxygen, heme-protein

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17
Q

Phase 1: Oxidation:

Important phase 1 oxidation reactions are performed by mixed function oxidases found in the ???

A

smooth endoplasmic reticulum

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18
Q

Phase 1: Oxidation:

Key element in the oxidative process is the hemeprotein cytochrome: ??

A

cytochrome P450 enzyme system

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19
Q

Describe the mechanism of P450 action

A
  • Substrate (drug) enters the system
  • NADPH acts as an electron donor
  • chromophore absorbs at 450 nm
  • O2 is entered into the system
  • NADPH acts as an electron donor
  • H+ is added, H2O is released to form the proposed “activated oxygen” species
  • then you get the oxidized product

Substrate: R-H
Oxidized Product: R-OH

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20
Q

What is the format of isoenzymes of CYP?

A

CYPnXm

n = family
X = subfamily
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21
Q

Drug metabolism carried out by which CYP families?

A

1, 2, and 3

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22
Q

Oxidative phase 1 reactions are carried out by CYP in the presence of _____ and ______ _____

A

NADPH

molecular oxygen

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23
Q

The metabolism of drugs in humans is dominated by ___ major P-450 isoenzymes

A

six

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24
Q

What are the six major P-450 isoenzymes?

A 
CYP1A2
CYP2C8/9/10
CYP2C18/19
CYP2D6
CYP2E1
CYP3A4
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25
Q

CYP1A2:

Substrates?

A

phenacetin, theophylline

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26
Q

CYP2C8/9/10:

Substrates?

A

hexobarbital, phenytoin

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27
Q

CYP2C18/19:

Substrates?

A

diazepam, mephenytoin

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28
Q

CYP2D6:

Substrates?

A

imipramine, propranol

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29
Q

CYP2E1:

Substrates?

A

acetaminophen

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30
Q

CYP3A4:

Substrates?

A

erythromycin, cyclosporin

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31
Q

CYP1A2:

Metabolizes ____ and ______

A

chemicals

toxins

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32
Q

CYP1A2:

____ induces this enzyme, resulting in activation of benzpyrene

A

smoking

benzpyrene - carcinogen in the cigarette smoke

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33
Q

CYP2C9, CYP2C19:

exhibits genetic ________

A

polymorphism (5% of caucasians, 20% of asians are poor metabolizers)

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34
Q

CYP2C9, CYP2C19:

Inhibition of S-warfarin metabolism by _______

A

amiodarone (high prothrombin times for 3 weeks)

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35
Q

CYP2D6:

More than ___ clinical drugs metabolized by this isoform

A

80

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36
Q

CYP2D6:

Also exhibits _____

A

polymorphism (ultra rapid metabolizers needing high doses)

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37
Q

CYP3A4:

More than _____ clinical drugs metabolized by this isoform

A

150

calcium channel blockers, bnezo’s, cyclosporin, etc

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38
Q

CYP3A4:

70% of iso form present in ___

A

gut (which decreases bioavailability)

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39
Q

What major drug-metabolizing isozymes does nutrition affect?

A

1A2, 2E1, 3A3

40
Q

What major drug-metabolizing isozymes does smoking affect?

A

1A2

41
Q

What major drug-metabolizing isozymes does alcohol affect?

A

2E1

42
Q

What major drug-metabolizing isozymes does drugs affect?

A

1A2, 2C, 2D6, 3A3

43
Q

What major drug-metabolizing isozymes does somatic (liver function and size, intestinal metabolism, etc.) affect?

A

1A2, 2E1, 3A3

44
Q

What major drug-metabolizing isozymes does genetic polymorphism affect?

A

2C9, 2C19, 2D6, 2E1

45
Q

Smoking induces 1A2, therefore ____ levels of drugs may be required by smokers than non-smokers (ex. theophylline)

A

higher

46
Q

Chronic alcoholism induces ______ and glutathione depletion leading to accumulation of ____, a lethal byproduct of acetaminophen which leads to severe liver injury and possibly liver failure.

A

CYP2E1

NAPQ1

47
Q

What are the two major reduction reactions?

A

Nitro-reduction

Azo-reduction

48
Q

What carries out the reduction reactions?

A

Intestinal microflora carries out these reactions with far more efficiency than livers in mammals.

49
Q

______ = performed through respective esterases in the liver. Also by esterases in plasma and other tissues. Esterases hydrolyse esters to alcohols and carboxylic acids. Ex. procaine

A

Hydrolysis

50
Q

Hydrolysis can also be simply defined as ??

A

addition of a water molecule

51
Q

Oxidation is _____

A

losing

52
Q

Reduction is _____

A

gaining

53
Q

What do phase 2 reactions generally increase?

A

the water-solubility of a molecule

-which then results in pharmacological deactivation

54
Q

For phase 2 reactions to occur, a compound must be chemically ______.

A

active

55
Q

Phase 1 reactions make the compound chemically _____

A

active

56
Q

Is it possible to skip phase 1 metabolism and just go straight to phase 2?

A

Yes - if the compound is already chemically active

ex. sulfanilamide
ex. procainamide

57
Q

List some factors affecting drug metabolism

A
  • species
  • genetics
  • age
  • disease state
  • drug/drug interactions
  • food
58
Q

Where does glucuronidation happen?

A

endoplasmic reticulum

59
Q

Where does salvation occur?

A

cytosol

60
Q

Where does acetylation occur?

A

cytosol

61
Q

Where does methylation occur?

A

cytosol and ER (endoplasmic reticulum)

62
Q

Where does glutathione conjugation occur?

A

cytosol and ER

63
Q

Endogenous substrates involved in glucuronidation?

A

steroids
thyroxine
catecholamines
bilirubin

64
Q

Endogenous substrates involved in sulfation?

A

steroids

carbohydrates

65
Q

Endogenous substrates involved in acetylation?

A

serotonin

66
Q

Endogenous substrates involved in methylation?

A

biogenic amines

67
Q

Endogenous substrates involved in glutathione conjugation?

A

metabolites of arachidonic acid

68
Q

What does NAT-2 stand for?

A

N-acetyltransferase 2

69
Q

Since isoniazid is _____ and N-acetylisoniazid is not, the rate and extent of metabolism will affect the efficacy of the drug in treating tuberculosis (fast and slow acetylators)

A

active

70
Q

Total body water and extracellular fluid in newborn __ adult

A

>

71
Q

What happens when you become elderly?

A
  • lean body mass decreases
  • body fat increases
  • *in relation to body weight
72
Q

What happens if you’re a newborn?

A
  • low titers of hepatic microsomal enzymes

- glucuronidation reactions decrease

73
Q

Is the Vd of a drug higher or lower in newborns compared to children?

A

higher in newborns man

74
Q

____-____ is a lot longer for newborns compared to adults

A

half-life

75
Q

How does a decreased protein diet affect drug metabolizing capacity?

A

it decreases it

76
Q

How does decreased lipid intake and decreased EFA (essential fatty acids) affect metabolism of ethylmorphine & hexobarbitone?

A

decreases the metabolism

77
Q

How does high glucose intake affect barbiturate metabolism?

A

inhibits the barbiturate metabolism

78
Q

How does food increase bioavailability?

A

By increasing splanchnic blood flow

79
Q

What are charcoal broiled meats & smoked fish potent inducers of?

A

cytochrome P450 enzyme systems

80
Q

How does grapefruit juice affect P450 enzymes?

A

Grapefruit juice inhibits intestinal P450 enzymes which increases bioavailability of cyclosporine

81
Q

Grapefruit juice is a potent inhibitor of _____

A

CYP3A

82
Q

What is CYP3A responsible for?

A

the metabolism (hence excretion) of antihistamines, benzodiazepines, immunosuppressants, etc.

83
Q

Are juices safe with drugs?

A

NO - take with water

84
Q

Are herbs safe with drugs?

A

no way jose

85
Q

How long do the effects of flavonoids and furanocoumarins (found in grapefruit juice) last for?

A

at least 3 days following ingestion

86
Q

How does St. John’s wort affect CYP3A?

A

induces it

*produces sub therapeutic doses of HIV treating drugs

87
Q

What is St. John’s wort used for?

A

treating mild to moderate depression

88
Q

What is ginseng used for?

A

used as a normalizer, energizer, and stress reducer

89
Q

What does ginseng have potential interactions with?

A
  • anti-depressants (headache & mania)
  • warfarin (increased bleeding time)
  • steroids (stronger effects)
90
Q

How does Ginko, garlic interact with warfarin?

A

increases bleeding time with warfarin (risk of hemorrhages)

91
Q

What is the Michaelis-Menton Equation?

A

Rate of metabolism = VmaxC/(Km+C)

92
Q

Rate of metabolism = VmaxC/(Km+C)

What does C = ?

A

[drug]

93
Q

Rate of metabolism = VmaxC/(Km+C)

What does Vmax = ?

A

maximum rate

94
Q

Rate of metabolism = VmaxC/(Km+C)

What does Km = ?

A

Michaelis constant = 0.5 Vmax

95
Q

Most drugs follow a ____ order process

A

first

*this produces a linear graph

96
Q

Why is dealing with non-linear drugs a problem?

A

They produce a curved graph.

So when you want to double a dose, you will not be doubling the effect (it will have much more than double the effect)

*see slide 32

Pharmacokinetics (12 decks)

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