Drug Metabolism and Elimination Flashcards
Describe the 2 phases of drug metabolism.
Phase 1 - introduces chemically reactive groups:
- Main process is oxidation in the liver
- Addition of oxygen molecules to drug structure
- Carried out by cytochrome P450 enzymes
- Other reactions: hydrolysis, hydration, etc
Phase 2 - increases water solubility of drug:
- Conjugates phase 1 product with endogenous substance through covalent bond formation
- E.g. glucuronidation
What is the overall goal of metabolism?
To convert lipid-soluble drugs to water-soluble molecules to prevent reabsorption by kidneys.
What type of substance is activated by metabolism?
A prodrug - e.g. enalapril, diamorphine (heroin)
Some drugs are eliminated unchanged. Name an example of this.
Digoxin
Name a drug that directly enters phase 2 metabolism. Describe how this drug is metabolised at low and high doses.
Paracetamol - enters 2 main phase 2 reactions:
- Glucuronidation
- Sulfate conjugation
When these reactions are saturated:
- Paracetamol enters phase 1 metabolism by cytochrome P450 enzymes
- This produces toxic quinone-imine, which is metabolised by phase 2 glutathione conjugation to N-acetylcysteine conjugate
The kidney glomerulus filters molecules of what size?
Molecules > 20kDa
Give the equation that describes the net excretion in the kidney.
Net excretion = filtration - reabsorption + secretion
Describe how age and genetics affect drug metabolism and excretion.
Age:
- Cyto P450 activity reduced in neonates/elderly
- GFR reduced greatly in neonates/elderly
- Increased % fat content in elderly
Genetics:
- 45% Europe and USA, 80-90% Asians fast acetylators
- 1/3000 slow metabolism by pseudocholinesterase
1 litre contains 100mg of a drug. If 10mg of the drug was removed after 1h, what is the clearance?
100ml/h
