102 Drugs likely to be Involved in interactions. 106 3021 Drugs that are likely to precipitate drug interactions. 105 10.2.2 Drugs that ae likely to be the objects ofdrug interactions. 105 Pharmaceutical interactions 105 Pharmacokinetic interactions 107 10.41 Absorption interactions 107 10.442 Protein binding displacement interactions 107 41043 Cellular eistibution interactions 108 40.44 Metabolism interactions 109 10.45 Excretion interactions 113 Pharmacodynamic Interactions 113 105. Direct pharmacodynamic interactions 113 41052 Indirect pharmacodynamic interactions 114 Lists of clinically Important drug interactions 117 ‘A drug interaction occurs when the elfects of one dmg are altered by the effects of another drug. We cll the drug that pre- Cipittes en interaction the gga dug nd the drug whose action is affected thei A drug interaction can result in either an increased oF @ decreased effect of the object drug: for instance, amiodarone {ahibits a cytochrome Pygy isoenzyme CYP2C%, leading t0 reduced metabolism of S(-) wartarin and increased anticongu- Iant effec, whereas carbamazepine reduces the anticoagulant Gao warfarin BY Increasing tts hepatic metabolism by cytochrome Py. Occasionally ia an interaction, the effects ofboth drug ate altered, for example in the complex interaction of phenytoin with phenobarbital ‘Although drug interactions usually resultin an adverse drug reaction, in some cases an interaction is beneficial, for example the pharmacodynamic synergy between diuretics and augiotensin-converting enzyme (ACE) inhibitors in the treat ‘ment of hypertension. 40.1 Incidence of significant drug interactions Hundreds of interactions have been described. However, rela tively few are of clinical importaic, and itis those with which ‘we shall deal here. The incidence of such reactions is hard to auge, since there are certain distinctions that are dificult to take; the distinction between the frequency with which two potentially interacting drug ae prescribed together and the fre~ quency with which clinically important interactions oecur #8 result of such prescriptions; the distinction between events that ‘occur spontancously and events that occuras a result of adverse drug effects, and the distinction between adverse drug effects that occur asa result of misuse of the drug causing the adverse effect and those that occur asthe result of a drug interaction.vanced ag, tiple lls he fe on patidece figures for cniesly 10,3 Pharmaceutical interactions sicochemical interaction, interactions kedingtotheapectc ereae, varyfrom 0 to atleast 22 percent” os 10.2 Drugs likely to be involved in é ‘importance ofa drug interaction itis possible to pre- ° 1 is the ype of drugs that ae Hl tobe vated in imposene 102-1 Drugs that are Ukely to precipitate drug ‘interactions ae 1. Drugs that oe highly aot are therefr ily to dipac objec drgs fom proten-bintng sites Such crag, | : Include apirin, phenylbutazone, sulfonamides, nd tickle (ie acetic acid a metabolite of chlor lndate and is congue, Pharenacetial interactions ate p sthsnata drug wih an intravenous infusion rugsig the sammeglion aniig thos of act of th SOTTO rrvour Tem i Pharmaceutical interactions are too numerous to remember interactions in deta. However, they canbe simply avoided by adhering tq ‘Abough ts nocalvay pone o be sure abou the cnet ‘hollowing pnp, oe ec se infison ore anton ties saline Bvep io thos so omed others are light senshive sd mus. be possible or via an Tass The olowing se ample. 2. Donot ad digs jgGuion lution han deccicor 1S prevent rapid loss of activity. These drugs are listed in Table 101, | Sodium valproate displaces phenytoin from ‘protein-binding Table 10.1 Stability of drugs in sling and dextrose solutions | sts but it also inhibits its metabolism ands thisisa complet. 7 ¢ interaction, v ae CY! Drugs that cor inhibit) the (OO) thecadaasssExamples of drugs Oats irug metabolism * indude various anticonvulsants (phenytoin, carbamazepine, > aad phenobarbital), rifampicin, dichloralphenazone (because it } Inhibition of drug metabolism “Interactions that involve inhibition of drug metabolism fall broadly spetking, intg {ep tunes: those in which the precipitant drug is ay inhibitor of mixed-function oxid; ms and ee earl ele treet neltng ntiion of drug ‘metabolism are listed in Table 10.4, and illustrative examples, ‘one of each type, are shown in Figs 10.6 and 10.7 Important examples of inhibition of drug metabolism by inhibition ofthe mixed-function oxidase ae the inhibition of are inbibition of phenytoin metabolism by isoniazid (particularly in slow acetylators, see Chapter 8, p. 81), inhibition of tolbutamide metabolism by phenylbutazone, and inhibition ‘of theophylline metabolism by quinolone and macrolide an Diotics (for example erythromycin — ‘The metabolism interaction of phenylbutazone with warfarin is complicated by the fact that't is stereoselective (see also P. 42), Phenylbutazone inhibits them ) stereoisomer and thus reduces its clearance. However, it enhances the clearance of the R(+) stereoisomer by protein 25° binding displacement (see above). Thus, although there is no overall effect on the clearance of the racemic mixture, the lini- ‘al results one of increased anticoagulant effect since the S(-) sereoismer is about five times more potent than the R(+) stereoisomer: The interactions of metronidazole and sulinpyra- zone with warfarin are also stereoselective. The interaction of sgpaialgeaoretnd -me «aptopurine san impOriant example of te effect of inhibition of «a specific metabolic pathway distinct from the mixed-function oxidase system, Resge alomucaal ree antine oss activity i inhibited: Both 6-mereaptopurine ad zatoprine (which is metabolized) by is, their metabo Tor P- turinol and their dosage requirements are reduced (see Fig. 10.7, Plasma warterin concentration (git) Prothrombin tne (6) Time) Fig, 10.6 An example of an interaction Involving inhibition of drug microsomal oxidation. Plasme warfarin concentrations andthe prothrombin time both rose after cimetidine (200 mg ts) was introduced volunters taking dally malntenance doses of warfarin, Note that the effect occured almost immediately In contrast the effect of enayme Induction (Fg. 10.5), (Adapted from Serlin et al. (1979) lancet, 317-19, with permission)Metronidaole Phenybutazore dunes a Se inate a IS I \ xi abe 4 Sat of disséram with alcohol, Alahol is meaboli=d to ih a raldtyde, whi sin uth meubolizd to carbon dixie and 4 b water (see Fig. P2, p. 480). ‘Disulfiram inhibits the metabolism of veldchyde, which accumsltesand causes an unpleasant sof seians, nding abdominal coli fshing, dizziness breath~ q esness, tachycardia, and vomiting. Disulfram has therefore ten used to try to break the drinking habit in alcohols. 4 ale “etn oampe ofa tgapeutily Peel interaction ith ing inhibition rere aa as S Minibitors benseranig ond cabidop2. t= i an Co TET STS Cops deco tbe brain, this leads to a therapeutic increas in dopamine on eapations, but peripheral decarboxylase activity diverts much Gfibe administered 1-dopa to dopamine, which cannot itself foter the brain, Dopa decarbosyase inhibitors reduce this rsipheral metabolism and do not themselesente the Brin. ‘there dopamine formation can continue uninhibited, The ther- Jpentaly effective dose of -dopa can therefore bereduced and ite peripheral adverse fet, such a hypotension, minimized, peripheral adve such as hypotension, minimized, Tbrtory interaction ase Neohol oles wl onoeiite Fee neas 7 Thera eiee _ Anbeseis aA recon bods which may inert wth MAO Ino a aur nay Ct cam antag cess etapa somes Fs coer rem cpu cite nia tee one ‘opening or thawing) ‘Theinleraction ofvon-scecve, reversible moneaseane inhibitors wit ai Tp renulis in severe Season, witch canbe fatal, The Fequence OF evens © ome «nition of MAO results in an increase in the noradrenaline sympathetic nerve endings normally it i¢ metabolized by ‘when MAO is inhibited, tyra- all and liver and reaches the contentot ben pani ingested MEAG in the gut wal: howe ‘Bin pses though he gut ‘psec clon = leases noradrenaline from is increased tres in + tyramin nerve endings and a hypertensive crisis results, ertensive crisis es ecaue it is due to excess noradrenaline, the bypertnsion donna ths interaction ean be treated eflectivey with the a- corcsoceptos antagonist phenolfnne. Since Tee we SSR BED Te ONT OT of which (MAO A) i arena or the metabol of itary tyramine, hs into aaa no ocr withthe MAO B-sclecive inhibitor see Tae Reverse inhibitors of MAA (such a masobamie, ete tceaiment of depresive illness) cause les potentiation of the elects of fear yamine than the i= versible non-selective MAO inhibitors. bem mocle = EEEDReeen2) aoe! Tine h) {107 An exemple ofan interaction involving the inhibition ofa Speci rupetabotizing enzyme, Plasma concentrations of ‘fercaptopurine (whichis metabolized by xanthine oxidase inthe fiver “andintstinl mucosa) were higher in fvepalents after preveatment ‘th allopurinol xanthine oxidase inhitite). Closed cies, with ‘Hopurino-open circles, without allopurinol. Note that the vertical scale {slogarthmic and that the changes ae therefore arg: the AUC Of mercaptopurine wasincreased sisfold by allopurinol. (Adapted From ‘nm eta (1953) Clin, Pharmacol Ther. 34, 810-17, with permission) 10.4.5 Excretion interactions © Most interactions involving drug excretion occur inthe kidneys. “The important interactions are liste in Table 10.5 and an illus: trative exarmple is sown in Fig. 10.8. ‘able 1055 Drug interactions involving altered dru object dusts) Precipltant érug(s) “Heyl antidepressants, phenobarbital thium Gentamicin ‘ativated charcoal ~ Aeetoheximide, chlorpropamide Penicilin Digoxin 2 “Methotrexate Uricosuric drugs, ion ‘and lithium are used concur- reduced sing ram concentra: Jar odin transport diuretics copiecuent tox! icity. If ‘rently, lithium doses be: ‘ion measurements asa guide, 10.5 Pharmacodynamic interactions ‘Pharmacodynamic interactions are those in which theprecipl “aliers the effect of the object drug ris sue ‘cree or tee Te Te “meractions Toay Deemer avec or indirect. The Tmpor~ tant examples are listed in Table 10.6 and dlustcative examples of the two types are shown in Figs 10.9 and 10.10. 10.5.1 Direct pharmacodynamic interactions birect pharmacodynamic interactions occur when two drugs scron the ame st (ant actén two different sites with a similar end result. (2) Antagonism at the same site ‘There are numerous examples of such interactions, some of which are therapeutically beneficial. They include the reversal of oe jgexcretion Result Enhanced excretion rate of abject drug iithiem retention = Wephrotoxiciy Hypoelycaemia Peniili retention Digoxin toxicity ‘Methoirerate toxicity Reduced urcosuriaSig an etelncese pasa Rin centrati asec om Chambers el (97 Bed. ithe the effects of with, the reversal of the actions of warfarim (©) Synergism atthe same site ‘The effects of watfarin can be increased or decreased in direct ‘synergistic interactions. The precise mechanisms of these int actions are not clear buy they may ivlve changes inthe af of warfarin for vitamin K epoxige reductase (clofibrate, o-thy- toring and anabolic steroid), alterations inthe synthesis ate of 0m 757 9 aomin ul 2 sor z p< 0.001 2 72 7 a LIAS fo Fig. 10.9 An example ofa aiect pharmacodynamic interaction. Neither doxepin (20 mg 4s) nor amitripryie (20 mgt.d.s) alone altered the Feaction time, Alcohol alone prolonged the reaction time slightly a ll times of testing ater dug administration (30,90, and 150 Howeves, the combination of elcohol with either doxepi or anitiptyine prolonged the reaction time by much more than you would expec rom the separate effects of each component of he combination, (adapted fiom Seppala et ol. (1975) Gln. Pharmacol, Ther 47, 515-23, with emission) depolarizing some antidotes {for example a : iymixin say andy quinidine a au Th ileractions are due to the melee tat th Pre Ihe motor endplate of skeletal mu , i quency of esta arhythmias when they are used in combina tion than either does alone, presumably beéause of an interaction in the specialized cardiac conducting tissues. This combination is also associated with an increased risk of heat failure, since both have negative inotropic effets on cardiac "Ts a pong the Qe onthe electocardogan can cause yntccular arrhythmia, particularly the form of poly. morphous ventricular tachycardia called torsade de pointes ‘wen drugs that have this action ace combined, the risks great ly increased. A non-cardiac drug that does this and that should not be used with antiarrhythmic drugs isthe antimalarial drug *halofantrine. This action is potentiated by hypokalaemia (see indirectinteractions below). (© Summation o-synergicm of similar affects at different sites ‘Any drug that has a depressant action on central nervous func- ‘ion will potentiate the effect of another such drug, whether or not the two drugs have elects on the same receptors. The most common example is that of alcohol with any centrally acting rug (Fig. 109), but any two centrally acting drugs may partici- pate insoch an interaction (Other examples include the numerous beneficial combina- Hions of cytotoxic drug used in the treatment of malignancies, and the use of combinations of antibiotics in the treatment of some infections, even when only one orgenism is implicated (g.in infective endocarditis and tuberculosis). 10.5.2 Indirect pharmacodynamic interactions In indirect pharmacodynamic interactions, a pharmacological, therapeuti, or toxic effect ofthe precipitant drug in some way alters the therapeutic or toxic effect ofthe object drug, but the two effec are not themselves related and do not themselves interact Se (2) Coagulation Warfarin and other anticoagulants can be involved in indirect Inggractiansin thre ways 1, Platelet aggregation, Some drugs reduce the ability of platelets to aggregate (for example salicylates, dipyridamole, sulfinpyrazone, mefenamic acd, phenylbutazone, and other non-steroidal antiinflammatory drugs). They therefore impair haemostasis if warfarin-induced bleeding occurs. Interactions oF this sort have not yet been reported with érugs that impair the binding of ADP to platelet receptors (ticlop=Guarana ‘Worn Maa Warn Incjeased anticoagulation “Thereased anticoagulation Increased antcoanulation re oe paca erage See niet Seaireaniar : Tareas : Tnseased isk aryl [apc cso ose auc pote oe Tncnerietrae ‘eg.cateum sls, viteninD) _Dugs causing Rid etention® oe i contol of hypertension or angina dine and clopidogr), Thrombocytopenia caused bythe pre-encaind, and fecinide). The common precipitant drogs in pitent drug would have a similar effect. such interactions are potasium-wasting diuretics, cortico- steroids and porgatives. The thiazide diuretics attenuate the hypoglyeaemic eects of anticoagulants (eg tpi, phenylbutazone, indomethacin, te slfomluress, Although the mechanism of his interaction s and other non-steroidal anti-inflammatory drug). tot ney sen og Ea of a : insulin secretion secondary to potasium depletion. However, Bee inci brio (or example ¢ ie fact thatthe fet of frase and Bumetanide in his E: Espiner respect is less marked is evidence against thet hypothesis, end a (©) Fluid and electrolyte balance direct interaction at the site of insulin secretion (e.g. at potass- ‘Alterations in uid and electrolyte balance can secondarily alter ium channels) cannot be ruled out, particulary in view of the effects of saane drugs. The effects of cardine glycosides are the similarity in structure between these diuretles and the enhanced by potassium depletion, ciusing digials toxicity. sulfonyiureas a | Hypokalaemia is also associated with an increased risk of “Finally, the effects of diuretics themselves may be ettenuated | sHthythmias in patienfs taking antiarshythmic drugs that pro- by uid-retaining drugs such as carbamazepine, non-steroidal Jong the QT interval (for example quinidine, proceinamide, _anti-inflammatory drugs, and phenylbutazone, ulceration, it provides site for bleeding in patients taking10.6 Lists of clinically important drug interactions Jn the previous tables in this chapter, drug interactions have been listed according to their mechanism. In Table 10.7, these Interactions are listed according to whether the effects oft ‘object drugs are potentiated (Table 107.1) or diminished (Table 10.72), Imeractions in which the effects of both drugs a Table 10,7 Clinically important drus-drug interactions inthe tres parts ofthis table, the interactions discussed in Cha they are classed not according (o mechanism but according Interactions that affect both drugs ar stein art 3 pte 10 and edn Tables 102-10.5 are heated and supplemented However a owhether the efecto ne object dr ir creased (ot or decteeed (par precipitant det) et -edrenoceporatagonsis phen sure, metonicazole ‘MAD innitors Ma inhibitors ‘Allopurno| Hypokalsenia (rei, purgatves, cetcoserids,amehot Inypercalsemia (clu salts, vitamin, quinine =pronlaco verapamil, amiodarone Cthacrnic acd fireside eta-arenoceplc antagonists, pyle [Aiodarone, anabolic steroids, choral hydrate, choranphenle, Gimetine, canbe dipyriéemale, dsufram,Othyroxe, indomethacin hetoceszae, afnamic aca, mevonidel neomycin, onphenbutazone, paractanol og tem renvoutaone uloines says shaper, feventneserties, quinones main ateoagulnt, ~~ Ghoranpherizo fate, coum Genmn ant at ios line pidonsring rugs bates sais) fests banazne aie ee tenia, msm invari, sone satbiucte came, hen a iin outcome ypeaaeria ‘ENS depression Improved antnyp ~thytnias,asystle, heat flare NS depression ~_Cargiacanhythias Risk of myopathy Reduced uiosue eect