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All you need to know and more > 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
Where can CYP3A4 be found
Liver | Gut
26
What is CYP3A4 also responsible for
The pre-sysytemic metabolism of several drugs
27
Give examples of drugs which use CYP3A4
Diazepam Methadone Simvastatin CCBs
28
What is CYP2D6 responsible for
The metabolism of some antidepressants, antipsychotics and the conversion of codeine to morphine
29
What is found in 5-10% of the population in regards to CYP2D6
Reduced or absent expression so they may be immune to the analgesic actions of codeine
30
What is CYP1A2 induced by
Smoking so smokers will require a higher dose of theophylline than non smokers
31
What is CYP1A2 important in
Mmetabolism of theophylline
32
What does phase 2 metabolism involve
Conjugation
33
What does conjugation do
Increases the water solubility and enhance excretion of the metabolised compound
34
What does conjugation involve
The attachment of glucuronic acid, glutathione, sulphate or acetate to the metabolite generated by Phase 1 metabolism
35
What does conjugation result in
Usually in inactivation however a small number of drug metabolites may be active
36
What factors affect metabolism (8)
``` Other drugs/herbals/natural substances Genetics Hepatic blood flow Liver disease Age Sex Ethnicity Pregnancy ```
37
How can drug metabolising enzymes be induced
From the increased metabolism of drugs metabolised by that enzyme which can result in decreased drug effects
38
What does the induction of an enzyme involve
Increased synthesis and therefore increased activity
39
What are common enzyme inducers
Alcohol Smoking Many drugs and herbals such as phenytoin and carbamazepine
40
What can commonly used drugs herbal medicines and food stuffs do
Inhibit drug metabolising enzymes which may be reversible or irreversible binding to the enzyme
41
What are common drugs or foods which can inhibit drug metabolising enzymes
Erythromycin, Clarithromycin | Grapefruit
42
How long does it take for the inhibition effect to occur
It is immediate
43
What can the wide variability in the response to drugs between individuals cause
Therapeutic failure or an adverse drug reaction
44
How many forms are Drug metabolising enzymes are often expressed in
Multiple
45
What does the multiple expression forms of drug metabolising enzymes cause
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
What will the lack or decreased activity of an enzyme usually result in
Increased drug toxicity
47
What can occur when there are multiple expressions of a particular metabolising enzyme
Enhanced metabolism and reduced drug effect or drug resistance.
48
State the 4 phenotype subpopulations of metabolizers
``` Poor metabolizers (PM) Intermediate metabolizers (IM) Extensive metabolizers (EM) Ultrarapid metabolizers (UM) ```
49
How can the variation in phenotype subpopulations of metabolizers occur
Due to racial background
50
What will poor metabolisers normally require
A smaller dose
51
What will ultrarapid meatbolisers normally require
An increased dose
52
What does CYP2C9 meatabolise | Name two of its substrates
16 commonly used drugs | Warfarin and phenytoin
53
How many allelic varients are known for CYP2C9
2
54
How many allelic varients are known for CYP2C19
8 which are all nonfunctional proteins
55
Which enzymes exhibit genetic variation (name at least 2)
``` Pseudocholinesterase N-Acetyltransferase (isoniazid is a substrate) Cytochrome P450 2D6 Cytochrome P450 2C19 TMPT -Thiomethylpurinetransferase Dihydropyrimidine Dehydrogenase ```
56
What type of enzymes does pseudocholinesterase | have
Typical and atypical enzymes
57
What type of enzymes does N-Acetyltransferase (isoniazid is a substrate) have
Fast acetylation | Slow acetylation
58
What happens to drug metabolising enzymes in foetuses and premature infants
They are either deficient or reduced (normally)
59
What else can be deficient in foetuses and premature infants
Renal function so drug and metabolites rapidly build up to toxic levels
60
How well can children metabolise drugs by the age of 2
More rapidly than adults
61
What is the rate of metabolism by puberty
Greater than that of adults
62
In what pharmacokinetic areas have sex-based differences been found
Absorption, Distribution, Metabolism, and Elimination
63
What is induced in pregnancy
The induction of certain drug metabolizing enzymes occurs in second and third trimester
64
What can have a profound effect on drug metabolism
Hormonal changes during development
65
What parameters in the elderly can affect drug metabolism
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
How can race affect drug metabolism
There are many incidences of racial differences in the genetic expression of cytochrome P-450 isoforms
67
Why is ADME important
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

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