Drugs 3: Drug Metabolism Flashcards
What is the definition of drug metabolism?
Biochemical modification og pharmaceutical substances by living organisms usually through specialised enzymatic activity
What form do compounds need to be in to be excreted?
Water soluble and polar (changed from lipid soluble to water soluble)
What happens to water soluble substances?
Undergo excretion
What happens to lipid soluble substances?
they are passively reabsorbed from renal or extra renal excretory sites back into blood
Where is the main site where metabolism occurs? What are other sites? (3)
Liver
Other sites include: gut, kidneys, lungs
What is the purpose of metabolism?
- increase water solubility (to aid excretion)
2. deactivate compounds (may take several steps)
What is the name of a group of drugs which are ACTIVATED following metabolism?
Prodrugs (deactivated before metabolism and activated after metabolism)
What are 2 examples of prodrugs?
- codeine
2. enalapril
What are the 4 main effects of metabolism?
- loss of pharmacological activity
- decrease i nactivity with metabolites that show some activity
- increase in activity, more active metabolites ( prodrug activation)
- production of toxic metabolites
What can toxic metabolites cause? (3)
- direct toxicity
- carcinogenesis
- teratogenesis ( in foetus and embryo)
what 3 reactions occur in phase 1 metabolism?
- reduction
- oxidation
- hydrolysis
What occurs in phase 1 metabolism?
Polar groups are exposed, increasing molecule polarity and provides active site for phase 2.
What is the main superfamily of enzymes involved in phase 1 metabolism?
Cytochrome p-450 enzymes (their different isoforms)
Is specificity relative or absolute?
Relative
What is the drug substrate for CYP1A2 enzyme and what does it treat?
theophylline: used for COPD and asthma patients
What is CYP1A2 production induced by?
smoking
What is the drug substrate for CYP2D and what does it treat?
Codeine: pain relief
What does CYP2D convert codeine to?
morphine
What additional group of drugs does CYP2D metabolise, other than codeine? (2)
Metabolism of antidepressants and antipsychotics
What is the drug substrate for CYP3A4 and what does it treat?
Cyclosporine: immunosuppressant which is used in organ transplantations to decrease chances of organ rejection
What other drugs does CYP3A4 metabolise, outside cyclosporine?
wide range of drugs; e.g. diazepam, methadone, simvastatin, CCBS
What main event occurs in phase 2 metabolism and what does it do?
Conjugation; increases water solubility and enhances excretion of metabolised compound
What substances attach to metabolites from phase 1 during phase 2?
glucuronic acid
glutathione
sulphate
acetate
What does conjugation in phase 2 result in?
Inactivation
What are some factors which often affect metabolism? (~9)
- other drugs/herbals/natural substances
- genetics
- hepatic blood flow
- liver disease
- age
- sex
- ethnicity
- pregnancy
- state of disease
What are the most common enzyme inducers which induce metabolism?
Alcohol and smoking
What other drugs and herbals can induce metabolising enzymes?
- phenytoin
- carbamazepine
- rifampicin
- St John’s Wort
Is enzyme induction a fast or slow process?
Slow
Which antibiotics commonly inhibit drug metabolising enzymes?
- cimetidine
-erythromycin
-clarithromycin
-ketoconazole
( and CCBs (Ca channel blocker), grapefruit)
Is enzyme inhibition a fast or slow proces?
Fast
Which enzyme does grapefruit juice cause a decrease in its production?
CYP3A (drugs have a narrower therapeutic range so altered enzyme means they cannot be metabolised)
What is gene polymorphism in terms of enzymes?
Drug metabolising enzymes are often expressed in different forms, so inter-individual differences in gene expression are common
What can mutations in metabolic enzymes results in? (2)
- enhanced enzyme activity (fast metaboliser)
2. inhibited enzyme activity (slow metaboliser)
What can an abnormally fast metabolism lead to?
reduced drug effect as it will be metabolised too quickly or drug resistance
What can an abnormally slow metabolism lead to?
increased drug toxicity
What 3 enzymes commonly have polymorphisms?
- CYP2D 5
- CYP2C 9
- CYP2C 19
How many phenotype subpopulations of metabolisers does CYP2D 5 polymorphism have?
4:
- poor
- intermediate
- extensive
- ultrarapid
How many nucleotide polymorphisms does CYP2D 5 have
70 nucleotide polymorphisms
How many commonly used drugs are metabolised by CYP2D 5?
65 drugs
How many commonly used drugs are metabolised by CYP2C 9 polymorphisms?
16 drugs
what two drugs are the main 2 substrates for CYP2C 9?
- warfarin
- phenytoin
What are some examples of enzymes exhibiting genetic variation?
- pseudocholinesterase
- N-acetyltransferase
- cytochrome P450 2D6
- cytochrome P450 2C 19
- TMPT
What enzyme isoforms are expressed in racial differences between populations?
P-450 isoforms
Why is ADME important?
- det. how to get drug to site of action
- det. dose and frequency
- predicting and avoiding toxicity
- effective dose
- making changes base don other drugs/illnesses
By what age can children metabolise many more drugs much rapidly?
at 2 years old onward ( at puberty metabolism rate is greater than in adults)
