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Session 6: Drug Metabolism Flashcards

(64 cards)

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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
In pregnancy, which CYP enzymes in drug metabolism are shown to have altered activity?
CYP-1A2 = Decreased activity (paracetamol) CYP-2D6 = Increased activity (codeine)
26
Give examples of drugs which engage in CYP-450 INDEPENDENT oxidation in phase 1 of drug metabolism.
1) **Suxamethonium** (muscle relaxant used in anaesthesia) = **hydrolysed** by **pseudocholineesterases** 2) **Ethanol** = **oxidised** by **dehydrogenases**
27
What does pseudocholinesterase deficiency lead to?
Increased sensitivity to Suxamethonium because it is metabolised by pseudocholinesterases
28
Where does phase two of drug metabolism occur mainly?
Liver (cytosolic & ER enzymes)
29
What types of groups will directly enter Phase II of drug metabolism?
polar and reactive groups
30
What reactions does phase 2 of drug metabolism mainly encompass?
- **Conjugation reactions** (addition of water-soluble groups to drug molecules)
31
What are examples of conjugation reactions in phase 2 of drug metabolism?
1) Glucuronic acid conjugation (glucuronidation) 2) Sulphate or acetyl group conjugation 3) Glutathione conjugation
32
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...
Glucuronide (e.g., morphine-6-glucuronide)
33
A therapeutic dose of paracetamol is metabolised in phase ___?
two
34
A toxic dose of paracetamol is metabolised in phases...
one and two (both)
35
What is the maximum therapeutic dose of paracetamol in 24 hours?
4g
36
What reactions does paracetamol undergo during phase two of drug metabolism at therapeutic doses?
Glucuronidation or sulphation conjugation reactions
37
What reactions does paracetamol undergo during phase two of drug metabolism at toxic doses?
Glutathione or sulphation conjugation reactions - this becomes SATURATED
38
What is the name of the toxic metabolite produced in the case of overdose of paracetamol in phase 1 of drug metabolism?
N-acetyl-p-benzo-quinoneimine (NAPQI)
39
What is the treatment for paracetamol overdose?
**N-acetyl cysteine (NAC)**
40
How many hours post-ingestion does paracetamol reach its 100% metabolism in the blood?
4 hours bloods should be taken 4-hours post-overdose
41
>___% of alcohol is metabolised in the liver and <10% is excreted passively via urine or breath.
>90% of alcohol is metabolised in the liver and <10% is excreted passively via urine or breath
42
What is the main route of metabolism of alcohol?
via Dehydrogenase enzymes (liver)
43
Aside from the main route of alcohol metabolism being dehydrogenases in the liver, what else metabolises alcohol?
a small amount is also metabolised by P450-2E1 enzymes in the liver or catalase enzymes in the brain
44
What do alcohol dehydrogenase (ADH) enzymes do?
oxidises alcohol to acetaldehyde
45
Acetaldehyde is then oxidised to ___ via the enzyme ___ ___.
acetate (acetic acid) via the enzyme aldehyde dehydrogenase (ALDH)
46
In ~50% of South Asian people, one copy of ___ gene is inactive leading to Alcohol flushing syndrome.
ALDH2
47
What is the toxic metabolite in alcohol metabolism?
Acetaldehyde
48
What are the two main consequences of prolonged and/or excess alcohol consumption?
1) **Liver toxicity** = **acetaldehyde accumulation** leading to liver damage 2) **Altered liver metabolism** =** decreased [NAD+]** and **increased acetyl-CoA**
49
What are biomarkers of liver damage in the blood?
- 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
What is the effect on the liver due to acetaldehyde accumulation from alcohol?
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
What is the pathogenesis of fatty liver in alcoholics?
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
Why may alcoholics develop hypoglycaemia?
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
Why may alcoholics develop gout?
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
What is the drug used to treat alcohol dependence?
Disulfiram (Antabuse)
55
What does Disulfiram inhibit?
Aldehyde dehydrogenase (ALDH) enzyme
56
What is the effect of Disulfiram?
Acute sensitivity to alcohol due to toxic effects of accumulated acetaldehyde
57
What is the major site of alcohol metabolism?
Liver
58
Which alcohol metabolite is toxic?
Acetaldehyde
59
Name a drug which is used to treat chronic alcohol independence.
Disulfiram
60
List the three most common reactions involved in phase I of drug metabolism.
Oxidation, reduction, hydrolysis
61
In phase II of drug metabolism the reactive metabolite is conjugated with a polar molecule. List the most common conjugate for the reaction.
Glucuronic acid
62
According to the British National Formulary (BNF) what is the dose of orally administered paracetamol?
150mg/kg
63
Patient is admitted with paracetamol overdose. The paracetamol was taken within one hour of admission. What treatment is indicated?
Activated charcoal can be administered within one hour of ingestion - it will bind the paracetamol and prevent it from absorbing
64
Patient is admitted with paracetamol overdose. The paracetamol was taken within four hours of admission. What treatment is indicated?
N-acetyl cysteine (IV)

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