Drug Metabolism and Excretion Flashcards
What happens when drugs are given by different routes?
- IV – immediately at max concentration, then gradually wears off over time
- i.m or s.c. – Takes a brief time to get up to max conc, then rapidly wears off
- Oral – some drugs will have a higher concentration, all take time to get up to their max concentration and then gradually wear off – will have much lower max concs than the other routes due to liver metabolism
Define Drug Metabolism
- Removal of lipid-soluble drug molecules to prevent reabsorption by kidneys
- Achieved by converting drugs into water-soluble molecules
Where are the main areas of drug metabolism?
- Liver (by CYP450)
- plasma
- lung epithelium
- intestinal epithelium
Define Drug excretion
- removal of drug/metabolites from the body
What are the main routes of drug excretion?
- Urine
- Bile/faeces
- Sweat
- Tears
- Saliva
- Exhaled air
- Milk
Why are knowing the metabolism and excretion so important?
- Dosing issues - knowing the amount of drug available at the site/ knowing the time taken for a drug to reach steady state levels (depends on half life)
- Safety issues - metabolites of drug may have their own effects / different isomers can have different effects
- Can measure metabolite concentration when looking at substance abuse
Name a drug that is activated by metabolism
Enalapril (ACE Inhibitor) - turned into its active form Enalaprilat by esterases
Describe Phase 1 metabolism
- Introduces chemically reactive groups making it more reactive
- The main process is oxidation in the liver - addition of oxygen to C,N,S atoms
What enzymes carry out Phase 1 metabolism?`
Cytochrome P450 enzymes
- They bind the drug and a molecule of oxygen
- CYP3A4/5/7 are responsible for metabolism of many drugs
Why can drug interactions occur (in terms of CYP enzymes)?
If the same enzyme metabolises a number of drugs
- the drug concentration in blood may be lower or higher than expected
Describe Phase 2 metabolism
Increases the water solubility of a drug for excretion
- conjugates the phase 1 product with an endogenous substance through the production of covalent bonds
- e.g. Glucuronidation (reaction with glucose)
What is the sequence of Drug metabolism?
Drug –> Phase 1 (e.g. hepatic oxidation) –> reactive metabolite/active drug –> Phase 2 (conjugation) –> Water soluble metabolite –> excretion
What is an exception to the normal metabolism process?
Paracetamol
- carries out phase 2 before phase 1
Describe the paracetamol metabolism process
- Paracetamol is metabolised by Phase 2 conjugation, either with glucose or sulphate to make the safe metabolites
- If glucuronidation/ sulphate conjugation is saturated, it goes down Phase 1 where it is metabolised by CYP enzymes.
- This makes NAPQI which is toxic
- Has to be conjugated by Glutathione to make a safe NAC conjugate
What effect does alcohol have on Paracetamol metabolism?
It induces (upregulates) CYP enzymes Therefore alcoholics are more likely to go down Phase 1 first This leads to glutathione stores depleting and NAPQI causing hepatocellular necrosis.
