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.
What is the main treatment for Paracetamol overdose?
N-acetylcysteine
How are drugs excreted from the kidney?
- Small molecules are filtered through the glomerulus - depends on whether drug is bound to plasma proteins
- Secretion into the tubules - molecules going through the arterioles are concentrated, making conc gradients causing the diffusion into the urine
- Some is reabsorbed back into blood - so next time there will be less bound to plasma proteins
What is an equation for excretion?
Excretion = Filtration + Secretion - Reabsorption
Define clearance
The volume of drug in the blood cleared per unit time
Define renal clearance
The volume of plasma cleared of drug per unit time in one pass through the kidney
Renal clearance example
If the plasma [drug] is 10ug/ml, and the drug is appearing in urine at 500ug/min, then the renal clearance is 50ml of plasma/min
What factors affect the metabolism and excretion of drugs?
- Age (CYP activity and GFR are reduced in neonates/elderly)
- Genetics - people may have faster enzyme activities than others
- Drug metabolising enzymes - can be induced or inhibited
- Disease - liver/ renal disease impairs metabolism
