Metabolism Flashcards
What is elimination the sum of?
Metabolism and excretion
Give two examples of drugs which are removed from the body unchanged
- Benzylpenicillin
2. Gentamicin
What is biotransformation?
The chemical modification of drugs and other foreign compounds (xenobiotics)
What is the main site of action for metabolism?
The liver
Give 3 examples of less important sites of action for metabolism
- Kidney
- Epithelial cells of the GIT
- The skin
What is the purpose of biotransformations?
Convert the drug into a more excretable form which the body can recognise.
What are the metabolites in comparison to the drugs
Less pharmacologically active and less toxic
What is the drug Tamoxifen (TAM) used for?
Chemotherapy drug used to treat breast cancer
What is a pro drug?
Must be modified before it is in its most active form.
How is TAM modified?
A methyl groups is removed and a hydroxyl group is added to form Endoxifen
What does the addition of a -OH group to TAM allow?
It to form an interaction with the Estrogen receptor.
What are cytochrome P450s?
A group of enzymes responsible for metabolic reactions.
Which cyt P450 adds the hydroxyl group to TAM?
CYP2D6
Which cyt P450 removes the methyl group from TAM?
CYP3A4/5
What is the primary metabolic pathway for paracetamol?
Glucuronidation
What is the toxic (to hepatocytes) intermediate formed from paracetamol?
NAPQI
How is NAPQI inactivated?
Conjugation by glutathione (will be used up if too much is taken resulting in liver failure). `
What is phase 1 biotransformation?
Modify the drug by oxidation, reduction or hydrolysis.
What is phase 2 biotranformation?
Involve the addition of a new chemical group to the drug or to its phase one metabolite - a conjugation reaction.
What is the most important phase 1 reaction?
Oxidation
What is the main organ involved in oxidation metabolism?
Liver
What is the reaction for oxidation?
RH + NADPH + H+ + O2 –> R-OH +NADP+ + H2O
What are the 6 cytochrome p450s that are used in oxidative metabolism?
CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP2E1 CYP3A4
Where is the hydroxyl group added?
Often at the site at which phase 2 takes place
How are phenactin and acetanilide converted into paracetamol?
Phenacetin –> De-alkylated
Acetanilide –> hydroxylated
What type of drugs often undergo reduction reactions?
Those containing Nitro or azo groups
What is chloroamphenicol and what reaction does it undergo?
Antibacterial eyedrop, has a nitro group which results in an amine group when metabolised.
What sort of drugs undergo hydrolysis?
Those which contain ester or amide bonds
What are the enzymes which catalyse hydrolysis called?
Esterases
What does aspirin form when hydrolysed?
Salicyclic acid and acetic acid
What does phase 1 metabolism result in?
Formation of more polar, less lipid soluble metabolites.
What is the most important phase 2 reaction?
Glucuridation
Give two other phase 2 reactions
- Sulphation
2. N-acetylation
What is glucuronidation catalysed by?
UDP-glucuronosyltransferases (UTGs)
What drugs can glucuronidation occur for?
Those containing -OH, -COOH and -NH2 groups
What drugs can sulphation occur for?
-OH and -NH2
What is the source of sulfur?
Cofactor, 3’-phosphoadenosine-5’-phosphpsulphate.
What does N-acetyl action occur for and what is it catalysed by?
-NH2 groups, N-acetyltransferases.
Give 3 classifications of drugs which act as enzyme inducers
- Anticonvulsants
- Antimicrobial agents
- Steriods
What does induction involve?
Binding of drug or doreign compound to either cytosolic or nuclear receptors and the interaction of the sensor with specific regions of DNA to switch on transcription of genes for enzymes.
What does Rifampicin do?
Reduces the expression of a large number of cytochrome P450s
What do phenytoin and carbamazepine do?
Promote the induction of the same metabolic enzymes that would metabolise themselves.
What is osteomalacia?
Some anticonvulsants increase the metabolism of vitamin D3 resulting in demineralisation of bone
What is Cimetidine?
Inhibits gastric acid, inhibits metabolic enzymes responsible for biotransformations of warfarin. Increases chance of haemorrhaging by enhancing anticoagulent effect.
