Drug metabolism and excretion Flashcards
What is metabolism
Removal of lipid-soluble drug molecules to prevent reabsorption by kidneys
How is metabolism achieved
Converting drugs into water-soluble molecules
Where does metabolism occur
Mostly in the liver, but also in plasma, lung and intestinal epithelium
What is excretion
Removal of drug/metabolites form the body
How does excretion occur
Mostly in urine, but also via bile/faeces, sweat, tears, saliva, exhaled air and breast milk
What is clearance
The volume of plasma cleared of drug per unit time
What drug has a constant clearance
A drug that obeys first order kinetics
What is the plasma clearance for a drug that is removed by liver metabolism and kidney excretion
Plasma CL = Hepatic CL + Renal CL
What determines the amount of drug available at the site of action
Metabolism and clearance
What are safety issues when it comes to drug metabolism
- Metabolism produces new chemical entities that may have their own effect
- Components of racemic molecules (D/L isomers) may be handled differently
Why do most drugs undergo metabolism prior to removal
To increase excretion
What are prodrugs and give an example
Drugs that are activated by metabolism
e.g. enalapril into active form enalaprilat by esterases
Some drugs are eliminated unchanged, give an example
Digoxin
Phase 1 of drug metabolism
- Main process is oxidation within the liver
- Addition of oxygen molecules to carbon, nitrogen and sulphur molecules in drug structure
What is phase 1 of drug metabolism carried out by and how
Carried out by cytochrome p450 enzymes
It binds the drug to an O2 molecule
One oxygen is used to oxidise the drug, one is used to reduce water
Why is it a problem that phase 1 only used one type of enzyme
Since either the enzymes will be saturated or the rate at which the body can metabolise the drug will be slowed down since they are competing for active sites
Phase 2 of drug metabolism
Increases water solubility of drug excretion
How is phase 2 of drug
metabolism carried out and give an example
Joins the phase 1 product with an endogenous substance, normally a large molecule, through the production of stable covalent bonds
e.g. glucuronidation (reaction with glucose)
Which drug is an exception to this metabolism process and how
Paracetamol
Goes straight to phase 2 by undergoing either glucuronidation or sulphate conjugation creating one of two safe products
These are excreted quite readily by the kidney
What happens when you overdose on paracetamol
The phase 2 enzyme will be saturated making the body to undergo phase 1 metabolism, this produces a toxic intermediate (NAPQI) that covalently binds to proteins changing their structure
Phase 2 of this pathway is glutathione conjugation which is a safe molecule
Why are alcoholics more likely to have the toxic metabolite accumulated
There is an up regulation of cytochrome p450 therefore they are more likely to go down the phase 1 pathway
What does glomerulus filtration depend on
The amount of drug bound to plasma proteins
Why is it key to make drugs water-soluble
Since when molecules pass through tubules they are concentrated, creating a large concentration gradient for reabsorption
What is tubular secretion
Acid/base molecule carriers transporting molecules into tubular fluid, lower levels of unbound drug in plasma
What does excretion =
Filtration - reabsorption + secretion
What is renal clearance
The volume of plasma cleared of drug per unit time in one pass through the kidey
How does age affect drug metabolism and excretion
Cyto p450 activity reduced in neonates/elderly
glomerular filtration rate is reduced greatly in neonates/elderly
increased fat % in elderly
How does genetics affect drug metabolism and excretion
45% in Europe and USA and 80-90% of asians have fast acetylators
How does disease affect drug metabolism and excretion
Liver diseases impairs drug metabolism
Renal diseases may alter pharmokinetics
