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WEEK 2:
Metabolism of drugs:
| Question | Answer |
|---|---|
| what is not readily excreted by kidneys | lipophilic drugs |
| most lipophilic drugs are metabolised into what | more polar compounds (water soluble metabolites) before they can be excreted via kidneys |
| kidneys eliminate | some small, hydrophilic drugs (and are not metabolised by liver egp penicillin) and lead to reduced renal function tissue |
| lipophilic drugs are passively reabsorbed where | across kidney tubule and therefore not excreted in urine |
| weak acids and weak bases are actively secreted into | renal tubule and rapidly excreted |
| what can be excreted via the lungs | volatile substances (primarily gaseous anaesthetics) |
| how does thalidomide differ between mice and humans | metabolism is different where mice have more 5-hydroxythalidomide compared to humans) |
| where are drugs metabolised predominantly | in liver by enzymes |
| types of reactions in metabolism (2) | phase one and phase two |
| which metabolic reactions precede the other | phase one reactions tend to precede phase two reactions |
| phase one metabolism | involves attachment of a functional group/ functionalisation (OH, COOH, NH2) or unmask an existing polar group to produce a metabolite which is more hydrophilic in nature |
| reactions involved in phase one (3) | oxidation, reduction or hydrolysis |
| type of reaction in diazepam | N-dealkylation |
| type of reaction in codeine to morphine | O-dealkylation |
| type of reaction in propranolol | aromatic hydroxylation |
| type of reaction in ibuprofen | aliphatic hydroxylation |
| type of reaction in promethazine | S-oxidation |
| oxidation | removal of hydrogen or addition of oxygen |
| enzyme involved in oxidations | microsomal enzymes (monoxygenases) |
| where are monoxygenases found | smooth endoplasmic reticulum in liver cells |
| difference between polar and non polar (lipid soluble) molecules in movement | polar molecules can cross surface membrane but less readily that non-polar (lipid soluble) molecules |
| what types of enzymes are monoxygenases | P450 enzymes |
| what do cytochrome P450 enzymes contain | haem |
| main families of cytochrome P450 (3) | CYP1, CYP2, and CYP3 |
| subfamilies of cytochrome P450 | CYP3A etc |
| if there is more than one subfamily for P450 how is it written | CY3PA4 etc |
| how many cytochrome P450's exist | 57 |
| monoxygenase P450 system in short | drug H +NASP + O2 ---(Cytochrome P450) ----> DrugOH + NADP + H20 |
| induction due to drugs etc can lead to | reduced plasma levels of drug over 1-3 week period (and reduced therapeutic action) or if metabolite is active it leads to increased toxicity |
| inhibition due to drugs etc can lead to | increased plasma concentration of drug and possible drug induced toxicity immediately |
| St John' Wort (Hypericum perforatum) induces | CYP3A4 which is responsible for speeding up metabolism of many drugs eg those used in transplants like ciclosporin |
| role of CYP3A4 | speeding up metabolism of many drugs eg those used in transplants like ciclosporin |
| what inhibits CYP3A4 | grapefruit juice |
| function of monoamine oxidase (MAO) | oxidatively deaminates a wide range of substrates produced by the body eg main neurotransmitters noradrenaline, dopamine and serotonin |
| what happens to alcohol and aldehyde in soluble fraction of liver | dehydrogenase and metabolise ehtanol along with CYP2E1 |
| flavin-containing monoxygenase system require | molecular oxygen, NADPH and flavin adenosine dinucleotide |
| types of reductions (2) | nitro reduction (chloramphenicol) and reduction dehalogenation (halothane) |
| phase 2 reactions | involve conjugation (attachment of substituent group) to a metabolite from phase 1 to form a more polar and highly ionised acid (which is easier to eliminate) |
| glucuronidation | compounds with an -OH or COOH group are conjugated with glucuronic acid using energy and the enzyme glucuronyltransferase |
| when would the drug glucuronide be excreted in bile | during enterohepatic recycling of oral contraceptives |
| sulphonation | major pathway for drugs with phenol and alcohol functional groups using enzyme sulphotransferase eg paracetemol |
| glycine conjugates drugs with | -COOH eg salicylic acid |
| acetylation | uses acetyltransferase enzyme and is a common reaction for aromatic amines (-NH2) eg sulfonamides |
| what to use to treat (antidote) to paracetamol overdose | IV acetylcysteine and is 100% effective in preventing liver damage when given within 8 hours of overdose |
| glutathione regeneration depends on | cysteine (so acetylcysteine or methionine is used in paracetamol overdose) |
| chronic excessive alcohol induces | P450 enzymes |
| what can inhibit CYP2C9 (4) | metronidazole, amiodarone, fluconazole, miconazole |
| what can induce CYP2C9 (2) | carbamazepine and rifampicin |
| what can induce CYP3A4 (2) | anti epileptics and St John's wort |
| what can inhibit CYP3A4 | erythromycin and clarithromycin |
| half life of N-dealkylation and 3-hydroxylation | 30 hours |
| half life of 3-hydroxylation | 10 hours |
| polymorphism | genetic variation in drug metabolism due to variations in genes that code for enzymes responsible for drug metabolism (single nucleotide polymorphism) |
| role of CYP2D6 | converts codeine into active morphine |
| what happens to metabolism of codeine in poor metabolisers | no analgesia |
| what happens to metabolism of codeine in ultra-rapid metabolisers | get significant side effects at normal doses (10% white population) |
| why do many people in the UK have a ultra rapid metabolism for codeine | many people in the UK lack the conjugating liver enzyme N-acetyltransferase (slow acetylators) |
| difference between japanese and UK in metabolism | many people in UK lack conjugating liver enzyme N-acetyltransferase (slow acetylators) while japanese and inuit people are fast acetylators |
| prodrug | substance that is not active itself but is converted into an active form by the body |
| azathioprine | drug widely used in IBD and is converted into the active form mercaptopurine |
| enzyme used to break down mercaptopurine | xanthine oxidase |
| xanthine oxidase is inhibited by | drug allopurinol |
| clopidogrel is converted into active form by | CYP2C19 isoenzyme |
| what competitively inhibits CYP2C19 isoenzyme | PPI omeprazole |
| why are prodrugs formulated | initial prodrug made to help overcome problems such as unpalatability or gastric irritation or increase solubility |
| diamorphine (heroin) undergoes first metabolism to | morphine |
| acetyl groups make diamorphine what | more lipid soluble and crosses BBB |
| diamorphine (heroin) is the metabolite of | morphine and morphine 6- glucuronide is the one producing analgesia/narcotic effects |
| first order metabolism | constant fraction per unit time is metabolised (so rate increases as drug concentration increases) |
| zero order metabolism | constant amount per time is metabolism - rate does not increase as drug concentration increases eg phenytoin and alcohol |
| hepatic damage can lead to | acute viral hepatitis and chronic liver disease |
Created by:
22tango
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