OzEMedicine - Wiki for Australian Emergency Medicine Doctors

see also:

• pharmacokinetics
• prescribing drugs in patients with liver impairment

• Generally, the metabolism of a drug decreases its lipid solubility by making it more polar and thus more hydrophilic, thereby facilitating excretion;

• Occur when there is a change in the drug molecule such as oxidation, reduction, or hydrolysis;

• 2 main types:
  • 1. microsomal (mainly liver):
    • i) oxgenation (O, OH, NOH, NO, SO);
    • ii) oxygenation with cleavage;
  • 2. other:
    • i) mitochondrial: monoamine oxidase;
    • ii) transmitter vesicle hydroxylases;
    • iii) cytoplasmic:
      • alcohol/aldehyde dehydrogenases;
      • xanthine oxidase → uric acid;
      • tyrosine/tryptophan hydroxylases;
    • iv) plasma:
      • diamine oxidases (eg. histaminase);
    • v) metallic (ferrous→ferric;arsenic);
    • vi) sulphides → sulphates;
    • vii) sulphydryls → sulphuric acid esters/sulphonic;

• Less common than oxidative (mainly microsomal);
• i) azo & nitro groups to amines;
• ii) dehalogenation (eg. halothane minor route only);
• iii) aldehydes to 1o alcohols (chloral to trichloroethanol);
• iv) ketones to 2o alcohols (oestrone to oestradiol);
• v) pentavalent arsenic to trivalent;
• vi) disulphides to sulphydryl derivatives;
  • (eg. disulfiram to diethyldithiocarbamic acid);

• i) alcohol esterases (blood, liver, kidney, etc):
  • cholinesterase;
  • atropine; cocaine; procaine; pethidine;
• ii) amide esterases (hydrolysed more slowly than alcohol ones):
  • procainamide; phenytoin (minor route);
• iii) hydrazides:
  • iproniazid;
• iv) glycosides - removal of glycose residues from glycosides alters their lipid/aqueous distribution & their ph/dynamic activity;

• Occur when drug is conjugated;
• i) glucuronide conjugates in hepatocytes:
  • paracetamol; morphine; steroids; salicylic acid; indocid;
  • sulphonamides; dapsone;
• ii) sulphate conjugates (sulphokinase in intest.,liver, kidney)
  • phenols (mainly intestinal mucosa or kidney(if from ph.I)
  • catechols (eg. isoprenaline) (mainly intsetinal mucosa);
  • sterols (mainly liver);
• iii) acetyl conjugates:
  • hepatic: (genetic) isoniazid, hydrallazine;
  • elsewhere: sulphanilamide; p-amino benzoic acid;
• iv) amino acid conjugates:
  • glycine: salicylic acid derivs.; nicotinic acid;
• v) methyl conjugates:
  • sympathomimetic amines; histamine; serotonin; nicotine;

• prontosil → sulphanilamide;
• chloral hydrate → trichloroethanol;
• L-dopa → dopamine;
• methyldopa → alpha methyl noradrenaline;
• cortisone → hydrocortisone;
• prednisone → prednisolone;
• glyceryl triacetate → acetic acid;

• halothane → trifluoroacetic acid;
• sulphonamides → acetylated sulphonamide conjugate → crystals;
• methanol → formaldehyde → retinopathy;

• acute ethanol → phenobarbitone; phenytoin; tolbutamide; warfarin;
• chloral hydrate → ethanol;
• disulfiram → ethanol; phenytoin; warfarin;
• warfarin → phenytoin;

====Examples of drug induction of microsomal enzymes & the drug metabolised:

• chronic ethanol ⇒ ethanol; isoniazid; phenobarbitone; phenytoin; tolbutamide; warfarin;
• carbamazepine ⇒ phenytoin; warfarin;
• griseofulvin ⇒ warfarin;
• phenobarbitone
  • ⇒ethanol; chlorpromazine; codeine; digitoxin; oestradiol; pethidine;
  • ⇒phenobarbitone; phenytoin; quinine; testosterone; thyroxine; warfarin;
• phenytoin ⇒ digitoxin; phenobarbitone; thyroxine;
• rifampicin ⇒ oestrogens, warfarin; dicoumarol;

• Most genetic variations in drug metabolism are multifactorial & have a Gaussian population distribution, but some enzyme activities have been identified as having discontinuity, thus two or more populations:
  • fast/slow acetylators: isoniazid/hydrallazine/some sulpha's;
  • phenytoin microsomal metabolism;
  • plasma pseudocholinesterase:
    • suxamethonium (autosomal codominant - 4 separate genes at 1 locus);
  • Acatalasia: tissue catalase activity <1% normal;
  • G6PD defic.: sulphonamides; etc;
  • Hb defects: sulphonamides may cause metHb in heterozygotes;
  • porphyrias: ethanol/sulpha's/osetrogens/tranquillisers/etc;
  • warfarin resistance;
  • steroid induced glaucoma;
  • mydriatics work much better in blue eyes than dark eyes!
  • malignant pyrexia;