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PHAY0003 > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

What is the aim of pharmacotherapy?

A

To achieve an effective concentration of drug at its target

It depends on getting the drug into the body and to its site of action

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2
Q

What is the difference between pharmacokinetics and pharmacodynamics?

A

Pharmacokinetics is what the body does to the drug

Pharmacodynamics is what the drug does to the body

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3
Q

What is bioavailability?

A

The proportion of a an administered drug that is available in the body, this is significantly different for an orally administered drug vs a drug administered intravenously

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4
Q

Why is the bioavailability of a drug administered orally less?

A

It has to be absorbed across the GI tract and then distributed in the blood
It is vulnerable to metabolism and excretion before it reaches the site of action

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5
Q

What does ADME stand for?

A

Absorption, distribution, metabolism and excretion

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6
Q

Why is bioavailability for intravenous drugs higher?

A

They are immediately distributed, they are still vulnerable to metabolism and excretion before reaching the site of action

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7
Q

Define drug absorption

A

The passage of a drug from the site of administration into the plasma

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8
Q

What type of administration delivers drug directly into the plasma?

A

Intravenous

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9
Q

What is the most common way of drugs crossing cellular membranes?

A

Passive diffusion

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10
Q

What is the less common mode of transport for drugs and when does this happen?

A

Carrier mediated transfer, it happens when a drug is similar in structure to an endogenous molecule that has a specialised transport process, i.e uses another molecules transporter

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11
Q

Give an example of a drug that is transported using carrier mediated transport

A

L-DOPA, anti-Parkinsonian drug, it resembles the amino acid phenylalanine and so can use the amino acids transporter to cross the blood brain barrier

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12
Q

What is the main factor that determines the rate of passive diffusion of a drug across a membrane?

A

The drugs ability to dissolve in lipids

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13
Q

What are the 4 factors that affect the drugs distribution?

A

Cardiac output and regional blood flow
Permeability f membranes
Disease
Binding of drugs to plasma proteins

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14
Q

What is the main protein found in plasma?

A

Albumin

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15
Q

What type of bonding occurs between drugs and albumin?

A

Non-covalent forces

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16
Q

Give some types of molecules that binds to albumin

A

Fatty acids, hormones, ions and drugs

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17
Q

What does pharmacodynamics of a drug mainly depend on?

A

Their concentration at their targets

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18
Q

What is the plasma concentration of a drug dependent on?

A

ADME

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19
Q

What is the main factor that controls the duration of action of lipid soluble drugs?

A

Rate of metabolism

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20
Q

Why does metabolism not apply as much to polar drugs?

A

They are excreted largely unchanged

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21
Q

During metabolism, what are lipid soluble drugs converted to?

A

Water soluble metabolites

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22
Q

Where are drug metabolising enzymes found?

A

Mainly in the liver but also in the gut wall, lungs and kidney

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23
Q

What does the extent of metabolisation of a drug depend on?

A

The enzyme specificity and the similarity of a drug to the normal substrate of the enzyme

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24
Q

What are microsomes?

A

The small vesicles of endoplasmic reticulum that are formed when the liver is homogenised

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25
Q

What type of reactions do microsomes do when metabolising drugs?

A

Oxidisation, reduction, hydrolysis and conjugation (combining)

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26
Q

Where in the liver cells are metabolising enzymes found?

A

In the endoplasmic reticulum

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27
Q

Describe the structure of the liver

A

2 major lobes each consisting of many lobules

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28
Q

Describe the structure of a lobule

A

They are hexagonal structures made up of hepatocytes arranged around interconnected channels around a central vein

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29
Q

What are the 2 major vessels that supply the liver with blood?

A

Hepatic artery: oxygenated blood

Hepatic portal vein: deoxygenated blood and nutrients from the GI tract

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30
Q

What are sinusoids?

A

The spaces between hepatocytes where the vessels flow through before draining into the hepatic vein

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31
Q

What is the vessel that blood in the liver drains out from?

A

Hepatic vein

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32
Q

What happens in drug metabolism?

A

The centre of a drug molecule is made reactive so that it attaches to other polar groups making them readily excreted

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33
Q

What is the most important system in the endoplasmic reticulum?

A

The hydroxylation system

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34
Q

What is the outcome of hydroxylation of a drug molecule?

A

An OH group is added to the drug

NADPH + H+ + O2 + drug forms NADP + Drug-OH + H2O

35
Q

What enzymes carry out hydroxylation

A

Cytochrome P450 enzymes with A P450 reductase to supply energy from NADPH

36
Q

What is the cofactor in cytochrome P450 that allows hydroxylation to occur?

A

A haem molecule that contains an iron atom

37
Q

When is Phase 2 metabolism able to happen without Phase 1?

A

If the drug already has a reactive centre

38
Q

What is the outcome of Phase 2 metabolism?

A

The drug molecule undergoes a conjugation reaction using the OH added from Phase 1 to make the a more polar molecule

39
Q

When does Phase 2 metabolism not occur?

A

If the metabolite from Phase 1 is sufficiently polar to be excreted

40
Q

What is the role of the coenzyme and the enzyme in Phase 2 metabolism?

A

Coenzyme adds on the reactive group

Enzyme is the molecule that carries out this process

41
Q

Give 2 examples of conjugation reactions that are part of Phase 2 metabolism

A

Sulphation

Acetylation

42
Q

Where does glucuronic acid gets its energy to allow it to conjugate with a drug molecule in Phase 2 metabolism?

A

By binding to UDP

43
Q

In Phase 2 metabolism, where on a Glutathione molecule is the drug added?

A

On the S atom

44
Q

In Phase 2 metabolism, acetylation does not make the molecule more polar, what does it do instead?

A

Creates functional groups on drugs which can then undergo conjugation reaction

45
Q

In Phase 2 metabolism, methylation does not make the molecule more polar, what does it do instead?

A

It inactivates parts of the drug molecule using conjugation reactions so that receptor binding is inhibited and the drug is made inactive, the metabolite also becomes more water soluble

46
Q

What type of medicine is aspirin?

A

Analgesic, anti-inflammatory and anti-pyretic

47
Q

Where is aspirin metabolised to salicylate?

A

Mainly in the liver, stomach, intestinal mucosa and blood

48
Q

Which metabolite of aspirin is responsible for the anti-inflammatory, anti-pyretic and analgesic effects?

A

Salicylate

49
Q

Which metabolite of aspirin is responsible for the antiplatelet-aggregating effect?

A

Acetylsalicylate

50
Q

Which protein do aspirin and salicylate bind to in the plasma?

A

Albumin

51
Q

Which phase metabolism is the most common for metabolism of salicylate?

A

Phase 2

52
Q

What is the half life of salicylate?

A

2 hours

53
Q

What are the indications for paracetamol?

A

Mild to moderate pain

Fever

54
Q

Why is bioavailability of paracetamol increased so much with higher doses?

A

The capacity for metabolism in the liver is overwhelmed with higher doses of paracetamol, increasing the bioavailability

55
Q

What is the type of conjugation reaction that paracetamol undergoes when it is metabolised?

A

Glucuronidation

56
Q

How are hepatoxic metabolites of paracetamol synthesised?

A

By Cyp450

57
Q

How are the hepatoxic metabolites of paracetamol neutralised?

A

By conjugation with glutathione using glutathione transferase

58
Q

When do hepatoxic metabolites of paracetamol become harmful to the body?

A

If he concentration of them outweighs the amount of available glutathione which is what normally neutralises it

59
Q

What are the 3 treatments of intoxication?

A

Gastric emptying and administration of active charcoal to absorb metabolite
Administration of N-acetylcysteine to add glutathione
Haemodialysis

60
Q

How many families of CYP enzymes are there?

A

18

61
Q

How are CYP enzymes named?

A

CYP followed by a number which represents the family, followed by a letter to show the sub family and then another number for each specific enzymes

62
Q

What is the role of CYP enzymes?

A

To metabolise chemicals and substrates

63
Q

Where are Cyp P450 enzymes found?

A

In most tissues in the body

64
Q

What are CYP450 enzymes important for?

A

Steroid hormone synthesis and breakdown, cholesterol synthesis and vitamin D metabolism

65
Q

Where are CUP450 enzymes mostly found?

A

In the liver

66
Q

Which families of CYPs are responsible for metabolising 70-80% of drugs?

A

families 1-3

67
Q

What is the most important factor in determining the duration of action of a drug?

A

The rate and extent of metabolism

68
Q

What does drug metabolism potential represent?

A

The spectrum of cytochrome P450 activity present

69
Q

What are some factors that affect drug metabolism?

A

Age, sex, hormones, health, genetics, drug interactions,

70
Q

How does age affect drug metabolism?

A

Adults have higher levels of P450s than children. Less glucuronidation occurs in infants due to their lower levels of EDGT, CYP450 levels can also go down in elderly

71
Q

How does sex affect drug metabolism?

A

Rats showed a difference in drug metabolism between males and females, the rate is usually higher in males but there is no marked difference in humans

72
Q

How does health affect drug metabolism rate?

A

Diseases that affect the liver and kidney have profound effects

73
Q

What is the difference between a mutation and polymorphism?

A

Mutations occur in less than 1% of the population whereas polymorphism is more frequent than 1% of the population

74
Q

What are microsatellite repeats?

A

Regions of repeated base sequences in the promoter region of DNA

75
Q

What is copy number variation?

A

When on of the chromosomes in a pair has more than one copy of a gene

76
Q

What are the 4 major phenotypes that polymorphisms in CYP genes can lead to?

A 
Poor metabolisers (PMs)
Intermediate metabolisers (IMs)
Efficient metabolisers (EMs)
Ultra-rapid metabolisers (UMs)
77
Q

Describe PMs

A

Removed enzyme activity due to lack of functional gene, patients have 2 defective alleles of the particular CYP450 gene

78
Q

Describe IMs

A

Reduced enzyme activity, one defective allele

79
Q

Describe EMs

A

Normal enzyme activity, 2 functional gene copies

80
Q

Describe UMs

A

Increased enzyme activity, more than 2 functional copies of CYP450 gene`

81
Q

What is metabolic ratio (MR)?

A

The ratio of parent drug : metabolite

82
Q

What can the patient experience if they have a poor metaboliser?

A

Adverse Drug Reactions resulting in higher concentrations of the drug in the blood compared to a normal patient

83
Q

What is enzyme induction?

A

When the enzyme activity increases due to newly synthesised enzymes for example from other drug interactions

84
Q

How do drug and food interactions affect metabolism?

A

Drug and foods can inhibit or induce CYP enzymes resulting in a change in metabolism rate, this leads to changes in drug that enters the blood

PHAY0003 (22 decks)

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