Flashcards in Metabolism - Drug Metabolism Deck (19)
What is pharmacology, pharmokinetics and pharmodynamics?
Pharmacology - how chemical agents affect the systems of living things
Pharmacokinetics - what the body does to the drug
Pharmacodynamics - what the drug does to the body
What are the four steps of pharmacokinetics?
What are the exceptions to the rule that drug metabolites are usually inactive?
Pethidine ---> norpethidine (toxic)
Codeine ---> morphine
Way are the main reaction types in phase I of drug metabolism?
Where does phase I metabolism occur?
Liver (microsomes on the ER contain relevant enzymes)
GI tract (broken down and absorbed)
Plasma (cholinesterase in the blood breaks ester bonds)
What is the function of phase I drug metabolism?
To add or expose a reactive group on the drug molecule.
How does phase I of drug metabolism metabolise the drug and what is its importance
Uses the CYP system which requires haem containing enzymes and NADPH.
Important in ridding of toxicity.
What type of drugs may skip phase I and enter straight into phase II?
Drugs that already have a reactive group exposed
Where does phase II drug metabolism occur?
In the liver via cytosolic enzymes
What are the types of reaction in phase II metabolism?
- sulphate conjugation
- glutathione conjugation
What occurs in glucoronidation?
It uses the cofactor UDPGA
Combines metabolites of the drug with glutaronic acid (a metabolite of glucose therefore in high concentration in the liver).
What is the function of phase II metabolism?
It takes the altered drug molecule and combines it with a water soluble group so that it can be excreted via kidneys.
What are the factors affecting drug metabolism?
- polymorphisms/variation in the population
- genetic deletions can cause enzyme deficiencies
- some drugs can inhibit the enzymes that work on other drugs = slow their metabolism
- some drugs can stimulate the enzymes that work on other drugs = speed up their metabolism
How is paracetamol in normal doses metabolised?
It skips phase I and enters phase II where it is glucoronidated or sulphated.
What pathway does paracetamol take in an overdose, and why is this damaging?
It saturates the usual phase II pathway, so enters phase I and produces NAPQI.
NAPQI is toxic to liver cells.
It then undergoes glutathione conjugation in phase II
= uses up all livers glutathione defences against ROS, causing oxidative stress.
How and when is a paracetamol overdose treated?
Treated in early stages only.
Treated with N-acetyl cysteine, which can donate a H+ to act as an antioxidant.
How is alcohol metabolised and using what enzymes?
1). Alcohol is converted into acetaldehyde by alcohol dehydrogenase, which also makes NADH.
2). Acetaldehyde is converted into acetic acid by aldehyde dehydrogenase.
3). Acetic acid can be converted into acetyl CoA
What is the problem with excessive alcohol?
1). It creates excess NADH = favourable for TAG synthesis or fat deposition
- fatty liver (fatty build up)
- alcoholic hepatitis (inflamed liver)
- alcoholic cirrhosis (scar tissue)
2). Acetaldehyde is toxic to the liver cells.