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ME2019 PART 2 > Metabolism and Pharmacokinetics > Flashcards

Metabolism and Pharmacokinetics Flashcards

1
Q

What is drug metabolism?

A

Biochemical modification of pharmaceutical sibstances by living organisms usually through specialised enzymatic activity

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2
Q

What does metabolism limit?

A

The life of a substance in the body by rendering lipid soluble and non-polar compounds to water soluble and polar compounds than can be excreted

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3
Q

What substances are excreted?

A

Water soluble

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4
Q

What substances are reabsorbed back into the blood from renal sites?

A

Lipid soluble

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5
Q

What are some sites of drug metabolism?

A

Liver

Lining of gut

Kidneys

Lungs

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6
Q

What is the purpose of drug metabolism?

A

Increase water solubility and aid excretion

Deactivate compounds

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7
Q

What are prodrugs?

A

Drugs that may be activated following metabolism

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8
Q

What are examples of prodrugs?

A

Codeine

Enalpril

Simvastatin

Sacbitril

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9
Q

What are the effects of metabolism?

A

Loss of pharmacological activity

Decrease in activity, with metabolites that show some activity

Increase in activity, more active metabolites (activation of prodrug)

Production of toxic metabolites

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10
Q

What can different kinds of toxic metabolites do?

A

Direct toxicity

Carcinogenesis (formation of a cancer)

Teratogenesis (congenital malformations produced in an embryo)

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11
Q

What is carcinogenesis?

A

Formation of a cancer

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12
Q

What is teratogenesis?

A

Congenital malformations produced in an embryo

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13
Q

What happens to a prodrug during metabolism?

A

Inactive chemical compound is coverted into its active metabolite

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14
Q

What controls the metabolism of drugs?

A

Enzymes

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15
Q

What can you say about the specificity of enzymes that metabolise drugs?

A

They have a wide range of specificity so individual drugs are often metabolised by more than one

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16
Q

How can different enzymes be expressed?

A

Constitutively (constant amounts)

In the presence of particular substance

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17
Q

What are the 2 phases of metabolism?

A

Phase 1 (activation/inactivation)

Phase 2 (conjugation products)

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18
Q

What are different phase 1 reactions?

A

Oxidation

Reduction

Hydrolysis

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19
Q

What happens during phase 1?

A

Polar groups are introduced to the molecule

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20
Q

What does increasing the polarity of compounds during phase 1 do?

A

Provides an active site for phase 2 metabolism

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21
Q

What is the most important superfamily of metabolising enzymes?

A

Cytochrome P-450

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22
Q

What does drug specificity of an enzyme depend on?

A

Which isoform of cytochrome P-450 is being used

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23
Q

What are the 3 families of the cytochrome P-450 super family used in oxidative drug metabolism?

A

CYP1

CYP2

CYP3

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24
Q

What is CYP1A2 important in the metabolism of?

A

Theophylline

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25
Q

What is CYP1A2 induced by?

A

Smoking

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26
Q

What is CYP2D6 important for the metabolism of?

A

Some antidepressants, antipsychotics and conversion of codeine to morphine

27
Q

What is CYP2D6 induced by?

A

Smoking

28
Q

Where is CYP3A4 found?

A

In the liver and the gut

29
Q

What is CYP3A4 important for?

A

Pre-systematic (first pass) metbaolism of several drugs

30
Q

What are examples of drugs that CYP3A4 is important for the metabolism of?

A

Diazepam

Methadone

Simvastatin

CCBS

31
Q

What can you say about smokers and drugs that are metabolised by the cytochrome P-450 family?

A

They require a higher dose of drugs than non-smokers to achieve the same desired effect

32
Q

What does phase 2 metabolism involve?

A

Conjugation

33
Q

What does conjugation during phase 2 do?

A

Increases water solubility and enhances excretion of the metabolised compound

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

34
Q

What does conjugation involve?

A

Attachment of glucuronic acid, glutathione, sulphate or acetate to the metabolite generated by phase 1 metabolism

35
Q

What does a endogenous molecule do during phase 2 metabolism?

A

A molecule endogenous (inside) the body donates a portion of itself to the foreign molecule (the drug)

D+ENDOX→DX+ENDO

36
Q

What does endogenous mean?

A

Inside

37
Q

What are some factors that affect metabolism?

A

Other drugs

Genetics

Hepatic blood flow

Liver disease

Age

Sex

Ethnicity

Pregnancy

38
Q

What is enzyme induction?

A

Process where a molecule (such as a drug) induces (enhances) the expression of an enzyme

39
Q

What does enzyme induction result in?

A

Increased metabolism of the drugs metabolised by that enzyme, decreasing the drug effect

40
Q

What are common enzyme inducers?

A

Alcohol

Cigarettes

41
Q

What is enzyme inhibition?

A

Substances which inhibit the expression or function of metabolising enzymes

42
Q

How may enzyme inhibitors bind to enzymes?

A

Reversibly or irreversibly

43
Q

What are some common enzyme inhibitors?

A

Cimetidine

Erythromycin

Clarithromycin

Ketoconazole

CCBS

Grapefruit

44
Q

What are possible consequences of there being a wide variation in the response to drugs between individuals?

A

Therapeutic failure

Adverse drug reactions

45
Q

What is pharmacogenetics?

A

The study of inherited genetic differences in drug metabolic pathways which affects an individual’s response to a drug

46
Q

What can gene mutations result in?

A

Deficiencies or absence of a particular metabolising enzyme

47
Q

What does decreased activity in enzymes result in?

A

Increased drug toxicity

48
Q

What does multiple expressions of a particular enzyme result in?

A

Reduced drug effect or drug resistance due to increased metabolism

49
Q

What is polymorphism?

A

Discontinuous genetic variation resulting in the occurrence of several different forms or types of individuals amount the members of a single species

50
Q

What are the 4 phenotype subpopulations of metabolisers?

A

Poor metabolisers (PM)

Intermediate metabolisers (IM)

Extensive metabolisers (EM)

Ultrarapid metabolisers (UM)

51
Q

What is CYP2C9?

A

The gene that codes for cytochrome P450 2C9

52
Q

What does cytochrome P450 2C9 do?

A

Metabolises 16 commonly used drugs such as warfarin and phenytoin

53
Q

What is CYP2C19?

A

Gene that codes for cytochrome P450 oxidase 2C

54
Q

How many allelic varients are there for cytochrome P450 oxidase 2C?

A

8

55
Q

What can you say about all the allelic variants of cytochrome P450 oxidase 2C and what does this mean for dosage of drugs?

A

They are all non-functional and so dose adjustments must be made for poor metabolisers of drugs that these enzymes act on such as S-mephenytoin

56
Q

What are some enzymes that exhibit genetic variation?

A

Pseudocholinesterase

N-Acetyltransferase

Cytochrome P450 2D6

Cytochome P450 2C19

TMPT

Dihydropyrimidine dehydrogenase

57
Q

How do infants metabolise drugs compared to adults?

A

Slower

58
Q

Why do infants metabolise drugs slower than adults?

A

Deficient enzymes

Worse renal function

59
Q

When can children metabolise drugs faster than adults?

A

At 2 and at puberty

60
Q

Why do the elderly metabolise drugs differently to adults?

A

Plasma protein

Lean body mass

Liver weight

More common chronic disease

61
Q

What is responsiveness to certain drugs different between?

A

Men and woman

62
Q

What causes a profound change to drug metabolism in woman?

A

Pregnancy

63
Q

Why may race affect drug metabolism?

A

Due to differences in genetic expression of cytochrome P450 isoforms

64
Q

Why is knowing about absorption, distribution, metabolism and excretion important?

A

Determining how to get the drug to the site of action

Determining the 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

ME2019 PART 2 (45 decks)

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