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Session 6: Drug Metabolism Flashcards

1
Q

What is pharmacology?

A

Study of the interaction of drugs with the body

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2
Q

What is a drug?

A

Chemical substance which (once administered) produces a biological effect

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3
Q

What is medication?

A

Drug administered to body to cure or improve medical condition

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4
Q

What is pharmacokinetics?

A

What the body does to the drug (ADME)

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5
Q

What is pharmacodynamics?

A

What the drug does to the body

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6
Q

Why do drugs need to be metabolised when they enter the body?

A

Drugs are foreign to the body and are potentially toxic so they need to be deactivated and eliminated via metabolism

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7
Q

Following metabolism, most drugs usually become ___ metabolically active.

A

less

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8
Q

What are pro-drugs?

A

Some drugs may become active after metabolism

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9
Q

Give an example of a pro-drug.

A

Codeine

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10
Q

Codeine is a pro-drug and is converted to its active form: ___ when metabolised.

A

Morphine

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11
Q

What are other examples of pro-drugs?

A

Cyclophosphamide

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12
Q

How many phases are there in drug metabolism?

A

Two

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13
Q

Where does phase 1 of drug metabolism take place?

A

Liver (ER enzymes)

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14
Q

What are the main reactions within phase 1 of drug metabolism?

A
  • Oxidation
  • Reduction
  • Hydrolysis
  • Addition or exposure of reaction groups (polar groups e.g., OH, COOH, NH2) on parent drug molecule making them temporarily more reactive
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15
Q

What is the most common reaction that takes place during phase 1 of drug metabolism?

A

oxidation

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16
Q

What do some drugs have that allows them to go straight into phase two of drug metabolism?

A

polar and reactive groups e.g., morphine

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17
Q

What enzymes does phase 1 of drug metabolism mainly require?

A

Cytochrome P450 enzymes

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18
Q

What do cytochrome P450 enzymes function as?

A

monooxygenases

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19
Q

What is the overall P450-dependent oxidation reaction in phase 1 of drug metabolism?

A
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20
Q

How many CYP-450 enzymes are there?

A

around 60

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21
Q

Which families of CYP are involved in drug metabolism?

A

CYP 1-3 families involved

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22
Q

What are the two most important CYP enzyme isoforms involved in drug metabolism?

A

CYP-3A4 = ~55% of drug metabolism
CYP-2D6 = ~25% of drug metabolism

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23
Q

What are the factors affecting variability in CYP-450 activity?

A

1) Genetic variability affecting drug efficacy, risk of side effects
2) Environmental factors (diet, pesticides, other drugs)

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24
Q

Give one environmental and one genetic example of variability in CYP-450 activity.

A

1) Genetic = mutation in CYP-2D6 in African population
2) Environmental = grapefruit juice & cimetidine (inhibitors); brussels sprouts & nicotine (inducers)

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25
Q

In pregnancy, which CYP enzymes in drug metabolism are shown to have altered activity?

A

CYP-1A2 = Decreased activity (paracetamol)
CYP-2D6 = Increased activity (codeine)

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26
Q

Give examples of drugs which engage in CYP-450 INDEPENDENT oxidation in phase 1 of drug metabolism.

A

1) Suxamethonium (muscle relaxant used in anaesthesia) = hydrolysed by pseudocholineesterases

2) Ethanol = oxidised by dehydrogenases

27
Q

What does pseudocholinesterase deficiency lead to?

A

Increased sensitivity to Suxamethonium because it is metabolised by pseudocholinesterases

28
Q

Where does phase two of drug metabolism occur mainly?

A

Liver (cytosolic & ER enzymes)

29
Q

What types of groups will directly enter Phase II of drug metabolism?

A

polar and reactive groups

30
Q

What reactions does phase 2 of drug metabolism mainly encompass?

A
  • Conjugation reactions (addition of water-soluble groups to drug molecules)
31
Q

What are examples of conjugation reactions in phase 2 of drug metabolism?

A

1) Glucuronic acid conjugation (glucuronidation)
2) Sulphate or acetyl group conjugation
3) Glutathione conjugation

32
Q

In the example of morphine - in phase 2 of drug metabolism, glucuronic acid is transferred from uridine diphosphate-glucuronic acid (UDPGA) to substrate (e.g., morphine) forming…

A

Glucuronide (e.g., morphine-6-glucuronide)

33
Q

A therapeutic dose of paracetamol is metabolised in phase ___?

34
Q

A toxic dose of paracetamol is metabolised in phases…

A

one and two (both)

35
Q

What is the maximum therapeutic dose of paracetamol in 24 hours?

36
Q

What reactions does paracetamol undergo during phase two of drug metabolism at therapeutic doses?

A

Glucuronidation or sulphation conjugation reactions

37
Q

What reactions does paracetamol undergo during phase two of drug metabolism at toxic doses?

A

Glutathione or sulphation conjugation reactions - this becomes SATURATED

38
Q

What is the name of the toxic metabolite produced in the case of overdose of paracetamol in phase 1 of drug metabolism?

A

N-acetyl-p-benzo-quinoneimine (NAPQI)

39
Q

What is the treatment for paracetamol overdose?

A

N-acetyl cysteine (NAC)

40
Q

How many hours post-ingestion does paracetamol reach its 100% metabolism in the blood?

A

4 hours
bloods should be taken 4-hours post-overdose

41
Q

> ___% of alcohol is metabolised in the liver and <10% is excreted passively via urine or breath.

A

> 90% of alcohol is metabolised in the liver and <10% is excreted passively via urine or breath

42
Q

What is the main route of metabolism of alcohol?

A

via Dehydrogenase enzymes (liver)

43
Q

Aside from the main route of alcohol metabolism being dehydrogenases in the liver, what else metabolises alcohol?

A

a small amount is also metabolised by P450-2E1 enzymes in the liver or catalase enzymes in the brain

44
Q

What do alcohol dehydrogenase (ADH) enzymes do?

A

oxidises alcohol to acetaldehyde

45
Q

Acetaldehyde is then oxidised to ___ via the enzyme ___ ___.

A

acetate (acetic acid) via the enzyme aldehyde dehydrogenase (ALDH)

46
Q

In ~50% of South Asian people, one copy of ___ gene is inactive leading to Alcohol flushing syndrome.

47
Q

What is the toxic metabolite in alcohol metabolism?

A

Acetaldehyde

48
Q

What are the two main consequences of prolonged and/or excess alcohol consumption?

A

1) Liver toxicity = acetaldehyde accumulation leading to liver damage
2) Altered liver metabolism =** decreased [NAD+]** and increased acetyl-CoA

49
Q

What are biomarkers of liver damage in the blood?

A
  • Elevated ALT/AST/GTT enzymes (due to escape of the liver enzymes because of lysis of hepatocytes)
  • Elevated bilirubin (due to reduced taking up/conjugation of bilirubin leading to hyperbilirubinaemia)
50
Q

What is the effect on the liver due to acetaldehyde accumulation from alcohol?

A

1) Escape of liver enzymes (ALT, AST, gamma glutamyl transpeptidase or GTT) to the blood
2) Reduced taking up/conjugation of bilirubin = hyperbilirubinaemia
3) Reduced production of urea = hyperammonaemia
4) Reduced synthesis of proteins such as albumin, clotting factors and lipoproteins

51
Q

What is the pathogenesis of fatty liver in alcoholics?

A

1) Reduced levels of NAD+ in liver = increases fatty acid levels as they cannot be oxidised
2) Reduced levels of NAD+ in liver = increased levels of acetyl-CoA as it will not be oxidised
3) Increased fatty acid synthesis and ketone synthesis from acetyl-CoA (may lead to keto-acidosis as well)
4) Increased synthesis of triacylglycerols which CANNOT be transported from liver due to reduced synthesis of lipoproteins

52
Q

Why may alcoholics develop hypoglycaemia?

A

Reduced levels of NAD+ in liver for…
a) conversion of lactate to pyruvate (Pyruvate converted to glucose - GLUCONEOGENESIS)
b) conversion of glycerol to DHAP
So there are no substrates for de novo glucose synthesis

53
Q

Why may alcoholics develop gout?

A

Reduced levels of NAD+ in liver for conversion of lactate to pyruvate so…
1) Lactate accumulates in blood = lactic acidosis
2) Reduces kidney’s ability to excrete uric acid, so uric acid levels increase
3) Crystals of uric acid form in tissues = GOUT

54
Q

What is the drug used to treat alcohol dependence?

A

Disulfiram (Antabuse)

55
Q

What does Disulfiram inhibit?

A

Aldehyde dehydrogenase (ALDH) enzyme

56
Q

What is the effect of Disulfiram?

A

Acute sensitivity to alcohol due to toxic effects of accumulated acetaldehyde

57
Q

What is the major site of alcohol metabolism?

58
Q

Which alcohol metabolite is toxic?

A

Acetaldehyde

59
Q

Name a drug which is used to treat chronic alcohol independence.

A

Disulfiram

60
Q

List the three most common reactions involved in phase I of drug metabolism.

A

Oxidation, reduction, hydrolysis

61
Q

In phase II of drug metabolism the reactive metabolite is conjugated with a polar molecule. List the most common conjugate for the reaction.

A

Glucuronic acid

62
Q

According to the British National Formulary (BNF) what is the dose of orally administered paracetamol?

63
Q

Patient is admitted with paracetamol overdose. The paracetamol was taken within one hour of admission. What treatment is indicated?

A

Activated charcoal can be administered within one hour of ingestion - it will bind the paracetamol and prevent it from absorbing

64
Q

Patient is admitted with paracetamol overdose. The paracetamol was taken within four hours of admission. What treatment is indicated?

A

N-acetyl cysteine (IV)

Metabolism (15 decks)

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