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Principles of Disease > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

What is drug metabolism

A

A biochemical modification of pharmaceutical substances by living organisms usually through specialized enzymatic activity

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2
Q

Why is metabolism an essential pharmacokinetic process

A

It limits the life of a substance in the body, by rendering lipid soluble and non-polar compounds to water soluble and polar compounds so that they can be excreted

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3
Q

What happens to lipid soluble substances

A

They are passively reabsorbed from renal or extra renal excretory sites back into the blood

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4
Q

What are important sites in drug metabolism

A

Liver
Lining of gut
Kidneys
Lungs

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5
Q

What happens to most drugs before excretion

A

They are metabolised

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6
Q

What is the purpose of drug metabolism

A

To increase water solubility and so aid excretion

Or to deactivate compounds (which may involve a number of steps)

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7
Q

What happens to prodrugs following metabolism

A

They are activated

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8
Q

What happens to some drugs following metabolism

A

They form active metabolites

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9
Q

Give examples of prodrugs

A

Codeine
Enalapril
Simvastatin
Sacubitril

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10
Q

What are the effects of drug metabolism

A

The loss of pharmacological activity
A decrease in activity, with metabolites that show some activity
Increase in activity, more active metabolites (activation of a prodrug)
Production of toxic metabolites

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11
Q

What can the production of toxic metabolites in drug metabolism cause

A

Direct toxicity
Carcinogenesis
Teratogenesis

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12
Q

What can metabolising enzymes be divided into

A

Families and sub-families

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13
Q

What type of specificity do metabolising enzymes have

A

Wide substrate specificity

Individual drugs can be metabolised by more than one

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14
Q

Where is enzyme activity control regulated

A

At several levels

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15
Q

How are some enzymes expressed

A

Constitutively

Some are expressed or induced in the presence of a particular substrate

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16
Q

How many phases are there in enzyme metabolism

A

2
Phase 1
Phase 2

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17
Q

What occurs in phase 1

A

Oxidation, reduction and hydrolysis reactions

It increases the polarity of the compound and provides an active site for Phase 2 metabolism

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18
Q

What enzymes super family are important metabolising enzymes

A

Cytochrome P-450 enzymes

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19
Q

How is drug specificity determined

A

By the isoform of the cytochrome P-450

Specificity tends to be relative rather than absolute

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20
Q

What are the three most important families of the cytochrome P-450 superfamily that have been identified as important in oxidative drug metabolism

A

CYP1: isoform CYP1A2
CYP2: isoform CYP2D6
CYP3: isoform CYP3A4

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21
Q

What is the drug substrate for CYP1: isoform CYP1A2

A

Theophylline

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22
Q

What is the drug substrate for CYP2: isoform CYP2D6

A

Codeine

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23
Q

What is the drug substrate for CYP3: isoform CYP3A4

A

Cyclosporine

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24
Q

What is CYP3A4

A

The major constitutive enzyme in human liver and contributes to the metabolism of a wide range of drugs

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25
Q

Where can CYP3A4 be found

A

Liver

Gut

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26
Q

What is CYP3A4 also responsible for

A

The pre-sysytemic metabolism of several drugs

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27
Q

Give examples of drugs which use CYP3A4

A

Diazepam
Methadone
Simvastatin
CCBs

28
Q

What is CYP2D6 responsible for

A

The metabolism of some antidepressants, antipsychotics and the conversion of codeine to morphine

29
Q

What is found in 5-10% of the population in regards to CYP2D6

A

Reduced or absent expression so they may be immune to the analgesic actions of codeine

30
Q

What is CYP1A2 induced by

A

Smoking so smokers will require a higher dose of theophylline than non smokers

31
Q

What is CYP1A2 important in

A

Mmetabolism of theophylline

32
Q

What does phase 2 metabolism involve

A

Conjugation

33
Q

What does conjugation do

A

Increases the water solubility and enhance excretion of the metabolised compound

34
Q

What does conjugation involve

A

The attachment of glucuronic acid, glutathione, sulphate or acetate to the metabolite generated by Phase 1 metabolism

35
Q

What does conjugation result in

A

Usually in inactivation however a small number of drug metabolites may be active

36
Q

What factors affect metabolism (8)

A 
Other drugs/herbals/natural substances
Genetics
Hepatic blood flow
Liver disease
Age
Sex
Ethnicity
Pregnancy
37
Q

How can drug metabolising enzymes be induced

A

From the increased metabolism of drugs metabolised by that enzyme which can result in decreased drug effects

38
Q

What does the induction of an enzyme involve

A

Increased synthesis and therefore increased activity

39
Q

What are common enzyme inducers

A

Alcohol
Smoking
Many drugs and herbals such as phenytoin and carbamazepine

40
Q

What can commonly used drugs herbal medicines and food stuffs do

A

Inhibit drug metabolising enzymes which may be reversible or irreversible binding to the enzyme

41
Q

What are common drugs or foods which can inhibit drug metabolising enzymes

A

Erythromycin, Clarithromycin

Grapefruit

42
Q

How long does it take for the inhibition effect to occur

A

It is immediate

43
Q

What can the wide variability in the response to drugs between individuals cause

A

Therapeutic failure or an adverse drug reaction

44
Q

How many forms are Drug metabolising enzymes are often expressed in

A

Multiple

45
Q

What does the multiple expression forms of drug metabolising enzymes cause

A

Inter-individual differences in gene expression (this is pharmacogenetics)

(Gene mutations can also occur resulting in deficiencies or absence of a particular metabolising enzyme)

46
Q

What will the lack or decreased activity of an enzyme usually result in

A

Increased drug toxicity

47
Q

What can occur when there are multiple expressions of a particular metabolising enzyme

A

Enhanced metabolism and reduced drug effect or drug resistance.

48
Q

State the 4 phenotype subpopulations of metabolizers

A 
Poor metabolizers (PM)
Intermediate metabolizers (IM)
Extensive metabolizers (EM)
Ultrarapid metabolizers (UM)
49
Q

How can the variation in phenotype subpopulations of metabolizers occur

A

Due to racial background

50
Q

What will poor metabolisers normally require

A

A smaller dose

51
Q

What will ultrarapid meatbolisers normally require

A

An increased dose

52
Q

What does CYP2C9 meatabolise

Name two of its substrates

A

16 commonly used drugs

Warfarin and phenytoin

53
Q

How many allelic varients are known for CYP2C9

A

2

54
Q

How many allelic varients are known for CYP2C19

A

8 which are all nonfunctional proteins

55
Q

Which enzymes exhibit genetic variation (name at least 2)

A 
Pseudocholinesterase
N-Acetyltransferase (isoniazid is a substrate)
Cytochrome P450 2D6
Cytochrome P450 2C19
TMPT -Thiomethylpurinetransferase
Dihydropyrimidine Dehydrogenase
56
Q

What type of enzymes does pseudocholinesterase

have

A

Typical and atypical enzymes

57
Q

What type of enzymes does N-Acetyltransferase (isoniazid is a substrate) have

A

Fast acetylation

Slow acetylation

58
Q

What happens to drug metabolising enzymes in foetuses and premature infants

A

They are either deficient or reduced (normally)

59
Q

What else can be deficient in foetuses and premature infants

A

Renal function so drug and metabolites rapidly build up to toxic levels

60
Q

How well can children metabolise drugs by the age of 2

A

More rapidly than adults

61
Q

What is the rate of metabolism by puberty

A

Greater than that of adults

62
Q

In what pharmacokinetic areas have sex-based differences been found

A

Absorption, Distribution, Metabolism, and Elimination

63
Q

What is induced in pregnancy

A

The induction of certain drug metabolizing enzymes occurs in second and third trimester

64
Q

What can have a profound effect on drug metabolism

A

Hormonal changes during development

65
Q

What parameters in the elderly can affect drug metabolism

A

Plasma protein, lean body mass and liver weight which decrease significantly
Also chronic disease is also more common so they are likely to be on multiple drug therapy

66
Q

How can race affect drug metabolism

A

There are many incidences of racial differences in the genetic expression of cytochrome P-450 isoforms

67
Q

Why is ADME important

A

To determine how to get the drug to its site of action
To determine dose and frequency
Making sure the drug is present in an effective dose
Predicting and avoiding toxicity
Making changes based on other drugs, illness or physiological factors

Principles of Disease (41 decks)

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