Drug interaction

Pharmacokinetic drug interactions Absorption of drugs gastrointestinal drug absorption may be affected by concurrent use of other drugs that have a large surface area upon which the drug can be adsorbed bind or chelate (antacids and quinolones) alter gastric pH alter gastrointestinal motility consequently, sub-therapeutic plasma drug concentrations antacids adsorb drugs in gastrointestinal tract, thus reducing absorption digoxin, iron, itraconazole, ketoconazole, quinolones (ciprofloxacin, norfloxacin, enoxacin), tetracycline speed gastric emptying, thus delivering drugs to absorption sites in the intestines more quickly cholestyramine reduces absorption of oral anticoagulants antimuscarinic agents decrease gastrointestinal motility may increase bioavailability of poorly soluble drugs may reduce bioavailability of drugs that are degraded in the gut digoxin gastrointestinal absorption inhibited by antacids, kaolin-pectin, sulphasalazine increased absorption with erythromycin as a result of decreased gastrointestinal inactivation by intestinal flora cimetidine by increasing pH in the gut, absorption of other drugs (ketoconazole, itraconazole) is decreased Distribution of drugs mechanisms by which drug interactions alter drug distribution include competition for plasma protein binding displacement from tissue binding sites consequently, increased free drug concentration cimetidine may reduce hepatic blood flow, reducing first-pass metabolism of highly extracted drugs salicylate may displace drugs from plasma protein binding sites beta-blockers may reduce hepatic blood flow reducing clearance of lignocaine oral anticoagulant effect augmented by displacement from albumin by sulphonamide Metabolism of drugs stimulated or inhibited by concurrent therapy induction or inhibition of hepatic microsomal drugmetabolizing enzymes effects of enzyme induction maximal effect occur after 7-10 days require an equal or longer time to dissipate after the enzyme inducer is stopped effects of enzyme inhibition prolongation of effective duration potentiation of side effects inhibition of cytochrome P450 by drugs non-selective inhibition on oxidation by direct interaction with haem iron (cimetidine through one of the nitrogen atoms of its imidazole nucleus; ketoconazole) direct irreversible inactivation (disulphiram) reversible inhibition of demethylation by fluoroquinolone antimicrobials (ciprofloxacin) affecting metabolism of midazolam inhibition of cytochrome P450 by metabolites compounds whose oxidative products bind to haem (troleandomycin) that irreversibly bind to enzyme (secobarbitone, cyclophosphamide, chloramphenicol) that have a high affinity for the reduced (ferrous) form of CYP so that it is not available for further oxidation (nitroso metabolite of erythromycin) 2 main groups of inducers of microsomal enzymes aromatic hydrocarbons (tobacco smoke, benzene) agents that resemble phenobarbitone (such as ethanol, phenylbutazone) both groups increase protein synthesis phenobarbitone type of compounds increase P450 reductase as well increase the drugs own metabolism as well

hepatic blood flow reduction can also reduce biotransformation if this is the rate limiting factor effects of propranolol and cimetidine on lignocaine metabolism oral anticoagulant effect is augmented by inhibition of metabolism by amiodarone, ciprofloxacin, phenylbutazone, decreased metabolism by chloramphenicol, cimetidine, disulfiram, fluconazole, metronidazole, propafenone effects is decreased with enzyme induction by barbiturates, carbamazepine, glutethimide, phenytoin, primidone, rifampicin inhibit hepatic metabolism of tolbutamide, phenytoin chlorpropamide tricyclic antidepressant effect is augmented if metabolism is decreased by cimetidine metabolism is inhibited by quinidine, selective serotonin reuptake inhibitors (SSRI) effects is decreased with enzyme induction by barbiturates, carbamazepine barbiturates by inducing hepatic microsomal enzymes, increase the metabolism of beta-adrenoceptor blockers, calcium channel blockers, corticosteroids, cyclosporine, doxycycline, oestrogens, itraconazole, ketoconazole, phenothiazines, quinidine, theophylline beta-blockers that undergo extensive first-pass metabolism may be affected by drugs capable of altering this process drugs effect may be increased by decreased metabolism with concomitant administration of chlorpromazine, cimetidine, frusemide, hydralazine decrease effect by enzyme inducers barbiturates, phenytoin, rifampicin calcium channel blockers verapamil, diltiazem, nicardipine (not nifedipine) inhibit hepatic enzymes, affecting metabolism of carbamazepine, cyclosporine metabolism of diltiazem, nifedipine, and verapamil in turn subjected to induction and inhibition decreased metabolism by cimetidine increased metabolism by enzyme inducers (phenobarbitone) cimetidine inhibit microsomal enzymes (ranitidine and newer H2 blockers do not appear to do so) decreasing metabolism of diazepam (but not oxazepam, lorazepam, temazepam), lignocaine, phenytoin, quinidine, theophylline, warfarin, tricyclic antidepressants, beta-adrenoceptor blockers, calcium channel blockers, carbamazepine

digoxin metabolism is increased with enzyme inducers phenytoin via enzyme induction, increases metabolism of corticosteroids, doxycycline, methadone, mexiletine, quinidine, theophylline, verapamil metabolism is inhibited by amiodarone, chloramphenicol, fluconazole, isoniazid, miconazole metabolism is enhanced by rifampicin theophylline metabolism inhibited by benzodiazepine, diltiazem, clarithromycin, cimetidine, erythromycin, ticlopidine, verapamil, quinolone antibiotics metabolism increased by barbiturates, carbamazepine, phenytoin, rifampicin Excretion of drugs the renal excretion of weak acids or weak bases may be influenced by other drugs that affect urinary pH due to changes in ionization of the drug, thus altering its lipid solubility and therefore its ability to be absorbed back into the blood from the kidney tubule (aluminium hydroxide antacid increases salicylate excretion) for some drugs, active secretion into the renal tubules may be affected by concurrent drug therapy which alters serum drug concentrations magnesium hydroxide + aluminium hydroxide alkalinize urine to alter excretion of drugs sensitive to urinary pH (salicylates) cimetidine may inhibit renal tubular secretion of weak bases (procainamide) digoxin renal excretion susceptible to inhibition by amiodarone, diltiazem, quinidine, spironolactone salicylate interferes with renal excretion of drugs that undergo active tubular secretion (methotrexate) renal excretion dependent on urinary pH Pharmacodynamic drug interactions Potentiation and antagonism phenomena may be due to competition with other ligands at receptor sites (atropine and acetylcholine at muscarinic receptor sites) non-competitive interaction by other drugs at receptor sites interactive effects of other drugs acting at different sites the effects of temperature and pressure (on hypnotic effect of anaesthetic agents)

additive effect a second drug acting with the first drug will produce an effect equal to an algebraic summation (N2O & volatile anaesthetic agent) antimuscarinic agents: activity of augmented by combined use of more than one antimuscarinic combination of an antimuscarinic with another drug with hidden antimuscarinic actions (antihistamines) synergistic effect two drugs interact to produce an effect greater than an algebraic summation may or may not act on the same receptor (local anaesthetic agent & opioid) oral anticoagulant: effect augmented by drugs affecting clotting factor synthesis or catabolism (anabolic steroids, thyroxine, NSAIDs) inhibition of platelet function (aspirin) inhibition of function clotting factors (heparin) barbiturate augmentation of central nervous system depression with administration of other central nervous system depressants beta-blockers increase hypotensive response to first dose of prazosin increased pressor response to adrenaline with non-specific beta-blockers antagonism two drugs interact to produce an effect less than an algebraic summation (non-depolarising muscle relaxant & neostigmine) effect of beta-blockers on insulin inhibition of glucose recovery from hypoglycaemia inhibition of symptoms of hypoglycaemia, increased blood pressure during hypoglycaemia Potentiation of side effects digoxin toxicity may be induced by electrolyte imbalance hypokalaemia from potassium-depleting drugs thiazide diuretics quinidine (prolongation of QT interval leading to polymorphic ventricular tachycardia or torsade de pointes, due to hypokalaemia) risk of hypokalaemia increased by amphotericin B and corticosteroids hypoglycaemia large dose of salicylates have hypoglycaemic activity monoamine oxidase inhibitors have intrinsic hypoglycaemic activity, augmenting effects of hypoglycaemic agents

Specific drug interactions Antacids may adsorb drugs in gastrointestinal tract, thus reducing absorption digoxin, iron, itraconazole, ketoconazole, quinolones (ciprofloxacin, norfloxacin, enoxacin), tetracycline speed gastric emptying, thus delivering drugs to absorption sites in the intestines more quickly magnesium hydroxide + aluminium hydroxide alkalinize urine to alter excretion of drugs sensitive to urinary pH salicylates Oral anticoagulants effect augmented by inhibition of metabolism amiodarone, ciprofloxacin, phenylbutazone, decreased metabolism chloramphenicol, cimetidine, disulfiram, fluconazole, metronidazole, propafenone drugs affecting clotting factor synthesis or catabolism anabolic steroids, thyroxine, NSAIDs inhibition of platelet function aspirin displacement from albumin sulphonamide effects decreased by reduction in absorption cholestyramine enzyme induction barbiturates, carbamazepine, glutethimide, phenytoin, primidone, rifampicin effect on other drugs inhibition of hepatic metabolism of tolbutamide, chlorpropamide, phenytoin Tricyclic antidepressants effects augmented by decreased metabolism cimetidine inhibition of metabolism: quinidine, selective serotonin reuptake inhibitors effects decreased by enzyme induction barbiturates, carbamazepine effects on other drugs inhibition of amine uptake into postganglionic adrenergic neuron guanadrel, guanethidine potentiate antimuscarinic effects of other antimuscarinic agents increased pressor effects of adrenaline, noradrenaline, phenylephrine

Antimuscarinic agents decreased gastrointestinal motility this may increase bioavailability of poorly soluble drugs and reduce bioavailability of drugs degraded in the gut augmentation of antimuscarinic activity combined use of more than one antimuscarinic combination of an antimuscarinic with another drug with hidden antimuscarinic actions (antihistamines) Barbiturates induction of hepatic microsomal enzymes, and increase metabolism of beta-adrenoceptor blockers, calcium channel blockers, corticosteroids, cyclosporine, doxycycline, oestrogens, itraconazole, ketoconazole, phenothiazines, quinidine, theophylline augmentation of central nervous system depression with other central nervous system depressants Beta adrenergic blockers beta blockade alters response to sympathomimetics with beta agonist activity beta-blockers that undergo extensive first-pass metabolism may be affected by drugs capable of altering this process beta-blockers may reduce hepatic blood flow drugs that may increase beta-blocker effect decreased metabolism chlorpromazine, cimetidine (only for those cleared by the liver), frusemide, hydralazine drugs that may decrease beta-blocker effect enzyme inducers barbiturates, phenytoin, rifampicin NSAIDs reduces antihypertensive response indomethacin effect of beta-blockers on other drugs insulin inhibition of glucose recovery from hypoglycaemia, inhibition of symptoms of hypoglycaemia, increased blood pressure during hypoglycaemia lignocaine decrease clearance of lignocaine prazosin increased hypotensive response to first dose sympathomimetic agents increased pressor response to adrenaline, more likely to occur with non-specific beta-blockers Calcium channel blockers inhibition of hepatic enzymes by verapamil, diltiazem, nicardipine (not nifedipine), affecting carbamazepine, cyclosporine metabolism of diltiazem, nifedipine, and verapamil subject to induction and inhibition by decreased metabolism cimetidine increased metabolism enzyme inducers

Cimetidine inhibition of microsomal enzymes diazepam (but not oxazepam, lorazepam, temazepam), lignocaine, phenytoin, quinidine, theophylline, warfarin, TCA, blockers, calcium channel blockers, carbamazepine may inhibit renal tubular secretion of weak bases procainamide may reduce hepatic blood flow, thus reducing first-pass metabolism of highly extracted drugs due to increased pH in the gut decreased absorption of other drugs ketoconazole, itraconazole Digoxin susceptible to inhibition of gastrointestinal absorption kaolin-pectin, sulphasalazine increased absorption with erythromycin decreased gastrointestinal inactivation by intestinal flora toxicity may be induced by electrolyte imbalance hypokalaemia from potassium-depleting drugs inducible metabolism enzyme inducers renal excretion susceptible to inhibition amiodarone, diltiazem, quinidine, spironolactone Loop diuretics diuretics increase activity of aminoglycosides and cisplatin (augmentation of ototoxicity) oral anticoagulant lithium, propranolol (increased plasma concentrations) digoxin (potentiate digoxin-induced arrhythmias) diuretics reduce activity of sulphonylureas (hyperglycaemia) reduce diuretic response increased diuretic response thiazide diuretics NSAIDs probenecid (reduce transport into tubular lumen) Thiazide diuretics diminish the effects of anticoagulants, uricosuric agents, sulphonylureas, insulin increase the effects of anaesthetics, digoxin, lithium, loop diuretics, vitamin D quinidine (prolongation of QT interval leading to polymorphic ventricular tachycardia or torsade de pointes, due to hypokalaemia) effect of thiazide diuretics decreased by NSAIDs, bile acid sequestrants (reduce reabsorption of thiazides), methanamines (alkalinization of urine) risk of hypokalaemia increased by amphotericin B and corticosteroids

Monoamine oxidase inhibitors increased noradrenaline stored in adrenergic neuron displacement of these stores by other drugs may produce acute hypertensive response amphetamines, ephedrine, pseudoephedrine reversal of hypotensive effects of guanethidine serotonin syndrome (hyperpyrexia, coma, death) dextromethorphan, nefazodone, selective serotonin reuptake inhibitor, venlafaxine have intrinsic hypoglycaemic activity, augmenting effects of hypoglycaemic agents effects on other drugs opioids hypertension, rigidity and excitation (more with pethidine) phenylephrine also metabolized by MAOi selective serotonin reuptake inhibitor fatalities have occurred due to serotonin syndrome Phenytoin drugs whose metabolism is stimulated by phenytoin corticosteroids, doxycycline, methadone, mexiletine, quinidine, theophylline, verapamil drugs that inhibit phenytoin metabolism amiodarone, chloramphenicol, fluconazole, isoniazid, miconazole drugs that enhance phenytoin metabolism rifampicin Salicylates interferes with renal excretion of drugs that undergo active tubular secretion methotrexate salicylate renal excretion dependent on urinary pH aspirin interferes with platelet function effect augmented by heparin large dose of salicylates have hypoglycaemic activity salicylate may displace drugs from plasma protein binding sites Theophylline drugs that inhibit theophylline metabolism benzodiazepine, diltiazem, clarithromycin, cimetidine, erythromycin, ticlopidine, verapamil, quinolone antibiotics drugs that increase theophylline metabolism barbiturates, carbamazepine, phenytoin, rifampicin