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Intro to Pharmacology > Intro to Pharmacology - Pharmacokinetics: Metabolism - CYP - Phase 1 > Flashcards

Intro to Pharmacology - Pharmacokinetics: Metabolism - CYP - Phase 1 Flashcards

1
Q

Drug metabolism, often, but not always occurs in ____ phase(s).

A

2

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2
Q

What is phase 1 of drug metabolism?
What does it reveal?
What are the reactions?

A

Reveal a reactive group: -OH, - NH2

Reactions: oxidation, reduction, hydrolysis

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3
Q

Phase II
- _______ of the reactive group with a highly _______, ______-soluble substrate (e.g. glucuronic acid)
Reactions are?

A

Conjugation of the reactive group with a highly charged, water-soluble substrate (e.g. glucuronic acid)

Reactions:

  • glucoronidation
  • acetylation
  • sulfation
  • conjugation with amino acids
  • conjugation with glutathione
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4
Q

What is the purpose of drug metabolism?

A

To get rid of the foreign compound by making the drug more polar, causing it to be excreted.

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5
Q

Which is the most common reaction of phase 1 metabolism?

A

oxidation

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6
Q

All the enzymes of phase II are of what type?

A

Transferases

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7
Q

What are the most common reactions of phase II?

A

Glucuronidation, acetylation

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8
Q

In phase 2, the transfer of a functional group is from a _________ to the drug.

A

co-enzyme

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9
Q

What are the different reactions of phase 1 metabolism and what are their enzymes’ names?

A

hydrolysis - hydrolase
reduction - reductase
oxidation - oxidase

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10
Q

If hydrolysis occurs to an ester, the enzyme is an ________.

A

esterase

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11
Q

If hydrolysis occurs to an amide, the enzyme is an ________.

A

amidase

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12
Q

Hydrolysis reactions can occur anywhere there is ______.

A

water

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13
Q

Hydrolysis generally occurs to which functional groups?

A

ester, peptide bond

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14
Q

Esters and amides are converted to what?

A

carboxylic acid, alcohols and amines

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15
Q

Esterases and amidases are found where?

What is a characteristic of these enzymes?

A

Found in plasma, liver, kidney, and intestine

Often are non-specific

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16
Q

Phase 1 - reductions

  • Only a _______ number of drugs are metabolized by reduction
  • Metabolites are more _________ and ready for phase II transformation
A

small

hydrophilic

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17
Q

Reduction of an aldehyde will yield?
Reduction of an alkene will yield?
Reduction of a ketone will yield?
Reduction of an alkyl halide yields?

A

alcohol + Hydrogen

alcohol + Hydrogen

alkene –> two extra hydrogens (both sides)

R- X –> R-H

(refer to slide 9)

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18
Q

Phase 1 - Oxidation

  • Phase 1 reactions are often catalyzed by members of the _________ _____ family
  • Other phase 1 enzymes include what?
A

cytochrome p450
alcohol DH
aldehyde DH
pseudocholinesterase

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19
Q

Low levels of aldehyde dehydrogenase leads to what?

A

alcohol intolerance

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20
Q

Low levels of pseudocholinesterase?

A

excessive effect of neuromuscular relaxants used during surgery

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21
Q

Cytochrome P450:

  • contains a _____ (__) group
  • absorbs light at ____ nm
  • many CYP: _______ distribution of activity
A

heme (Fe)
450nm
polymorphic

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22
Q

Cytochrome p450 are found in the ____ membrane.
Cytochrome p450 is _______-associated
Cytochrome p450 has ___ coenzymes. These are?

A 
ER
membrane-associated
3
- FMN
- NADPH
- FADH
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23
Q

Why do we have a multiple copies of CYPs?

A

These enzymes perform redox reactions that are important for lipid metabolism, and producing FA and steroids.

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24
Q

CYP gene family is used in what metabolism?

A

Drug and lipid

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25
Q

Regarding CYPs, how can copy number variation be changed?

A

Gain: Duplication
Loss: Heterozygous deleterious SNPs
LOH: Homozygous deletions

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26
Q

The majority of the population has what number of proteins for a CYP?

A

Two functional alleles

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27
Q

Population based dosing is based on what?

A

Two functional alelles

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28
Q

Many drugs are metabolized by hepatic ____ ____.

This enzyme is also found in the ______ _____ and can decrease ________ even before the drug reaches the _____.

A

CYP 34A
intestinal wall
decrease bioavailability before reaching the liver

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29
Q

CYP polymorphic distribution leads to what different people?

A

PM - poor metabolizer
(IM) - intermediate metabolizer
EM - extensive metabolizer
URM - ultra-rapid metabolizer

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30
Q

For a URM patient, they tend to metabolize drugs _____ and will have a _____ plasma concentration.

A

quickly

low

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31
Q

Draw the cytochrome p450 metabolism types based on polymorphism.
Indicate any other particulars.

A

Refer to slide 17

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32
Q

Describe, very briefly, personalized medicine.

A

Because there are genetic differences in drug metabolic ability, the goal is to sample a patient to determine his or her genotype, and change the dose of the drug accordingly to their metabolic profile.

33
Q

Cytochrome p450 - a ____-oxygenase reaction

A

mono

34
Q

When the drug enters, it binds to what part of Cytp450?

What happens?

A

heme portion, drug pairs with iron-coordinating with oxygen
Iron 3 oxidized to iron 2
One molecule of oxygen moves to the drug, and one goes with hydrogen to form water.

35
Q

______ ________ demonstrate decreased responsiveness to typical doses of codeine;
_____-____ _______ have suffered overdoses.

A

PM

URM

36
Q

Why would URM suffer overdoses rather than PM in regards to codeine?

A

Codeine is converted to morphine. URM can rapidly and extensively convert codeine to morphine, leading to overdoses.

37
Q

When talking about oxidation, how do we know the metabolic pathway the drug underwent?

A

During phase 1 study of pre-clinical trial, subject like monkey or healthy human takes a radiolabelled drug, excreted in urine or feces and analyzed to determine enzymes involved.

38
Q

What is the general reaction of oxidation of drugs?

A

Drug-H + O2 + 2H+ + 2 e- –> Drug-OH + H2O

39
Q

Is acetaminophen safe?

A

Yes, for the most part.
However, after phase 1 metabolism, it is converted to a toxic compound which, for the most part, is converted by phase 2 metabolism to a safe compound.

40
Q

What are the different phase 1 oxidation reactions?

A 
Aromatic
Aliphatic
Epoxidation
Oxidative de-alkylation
Oxidative de-amination
41
Q

Describe aromatic oxidation?

A

adding OH to para-position

(i.e. addition of OH to opposite side of benzene ring

42
Q

Describe aliphatic oxidation.

A

Adding OH to the end of the alkyl group (primary alcohol)

43
Q

Describe epoxidation.

A

Adding - O-group to C=C, then further into (OH)-C-C-(OH)

44
Q

Describe oxidative de-alkylation.

A

Alkyl group is removed, the hetro-atome (N, S, O) has H instead

45
Q

Describe oxidative de-amination.

A

NH2 is removed, the carbon that N-previously attached become C=O

46
Q

Look up the structure of acetaminophen and draw out the end product of N-oxidation.

A

refer to slide 23

47
Q

Look up the structure of phenobarbitone and draw out the end product of aromatic oxidation.

A

refer to slide 24

48
Q

Look up the structure of pentobarbitone and draw out the end product of aliphatic oxidation.

A

refer to slide 25

49
Q

Look up the structure of carbamazepine and draw out the end product of epoxidation.

A

refer to slide 26

50
Q

Look up the structure of Imiparmine and draw out the end product of N-oxidative dealkylation.

A

refer to slide 27

51
Q

Look up the structure of Phenacetin and draw out the product of Oxidative dealkylation.

A

refer to slide 28

52
Q

Look up the structure of Amphetamine and draw out the product of oxidative deamination.

A

refer to slide 29

53
Q

Draw out the reaction of a primary alcohol converted by ADH.

A

refer to slide 30

54
Q

Draw out the reaction of an aldehyde converted by ADH.

A

refer to slide 30

55
Q

Draw out the reaction of a secondary alcohol converted by ADH.

A

refer to slide 30

56
Q

What is the common point of all NTs?

A

Amine group

57
Q

For the NTs that have benzene rings, what is their precursor?

A

Tyrosine

58
Q

What is the basic equation of N-oxidation?

A

Drug-H + O2 + 2H+ + 2e- –> Drug-OH + H2O

59
Q

What is the basic equation of aromatic oxidation?

A

Drug-H + O2 + 2H+ + 2e- –> Drug-OH + H2O

60
Q

What is the basic equation of aliphatic oxidation?

A

Drug-H + O2 + 2H+ + 2e- –> Drug-OH + H2O

61
Q

What is the basic equation of epoxidation?

A

Drug-H + O2 + 2H+ + 2e- –> Drug-OH + H2O

62
Q

What is the basic equation of oxidative dealkylation of drugs?

A

Drug-X-CH3 + O2 –> Drug-X-CH2OH –> Drug-XH + HCHO

63
Q

In oxidative dealkylation, what is the alkyl chain attached to?

A

X = N, O or S

64
Q

Oxidative dealkylation is a ___-step process.

A

two

65
Q

In what cases would oxidative dealkylation occur more than once?

A

with tertiary amines for example

66
Q

For the drug phenacetin (slide 28), what two reactions are feasible?

A

amidase reaction

or oxidative dealkylation

67
Q

What is the basic equation of oxidative deamination?

A

Drug-NH2 + O2 –> Drug-CO-R + NH3

68
Q

ADH levels are high in what organs?

A

GI and kidney

69
Q

What is the enzyme that oxidizes the different NTs?

A

MOA - monoamine oxidase

70
Q

MOA inhibitors will lead to accumulation of what?

A

Not only serotonin but the other NTs

71
Q

What is the basic equation of MOA?

A

RCH2NH2 –> RCHO

72
Q

Draw serotonin undergoing Monoamine oxidase conversion.

A

refer to slide 32

73
Q

Induction and inhibition of CYP:

  • Some _____ or _____ types can induce or inhibit CYP activity
  • altered normally expected level of drug concentrations
  • given drugs could result in ____ or ____ pharmacological action
  • could lead to ________ _______
  • need a close monitoring mechanism
A

food or drugs
more or less
unexpected toxicity

74
Q

Grapefruit juice inhibits what?

A

Intestinal CYP34A

75
Q

What will grapefruit juice do?

A

Inhibits CYP34A, thereby increasing the amount of drug that reaches the liver and the systemic circulation

76
Q

Describe how CYP34A will reduce bioavailability.

A

Occurs prior to first-pass metabolism.

CYP34A lines intestinal tract, will oxidize the drug, making it more polar and reducing available drug.

77
Q

Does grapefruit juice affect first pass metabolism?

A

No, the enzymes there are less sensitive to grapefruit juice in the liver

78
Q

How does grapefruit juice affect Cp?

A

Increases it

79
Q

What is another compound that will reduce bioavailability of certain drugs through its activity on CYP450?

A

St. John’s Wort

Intro to Pharmacology (23 decks)

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