RICHARD I. SHADER, M.D.

DOMINIC A. CIRAULO, M.D

DAVID J. GREENBLAlT, M.D.

ACADEMY OF PSYCHOSOMATIC MEDIONE

Drug interactionsinvolving psychotropic drugsABSTRACT: As polypharmacy becomes more common for psychi­atric patients, the clinician's ability to evaluate the potential fordrug-drug interactions becomes more important. Psychiatristsmust be aware of interactions not only among psychotropicdrugs, but also between these and drugs given for accompanyingor incidental medical conditions. A classification of the sites andmechanisms of drug interactions is given as an aid to concep­tualizing the problems involved.

As drug therapy takes on increasingimportance in the total manage­ment of psychiatric disorders inboth psychiatric and general hospi­tal settings and in private practice,occasions for polypharmacy be­come more common and the clini­cian is faced with the task of evalu­ating the potential for drug-druginteractions. Either therapeutic ortoxic effects can be significantlymodified when two or more drugsare administered simultaneously.Psychiatrists must be aware of in­teractions not only among thevarious psychotropic agents, butalso between these drugs and thosegiven for various accompanying orincidental medical conditions.With many new drugs being intro-

NOVEMBER 1978· VOL 19· NO II

duced, both in medicine and psy­chiatry, this may appear to be anoverwhelming task. Two factorsmake this process a bit less difficultthan it seems. First, not all interac­tions are clinically significant. Forinstance, lithium carbonate whengiven with chlorpromazine couldtheoretically result in hyperglyce­mia; this is almost never a clinicalproblem. I Second, there are a lim­ited number of mechanisms bywhich one drug may interact withanother.

For practical purposes, drug in­teractions can be arbitrarily di­vided into two principal subdivi­sions, pharmacokinetic andpharmacologic (or pharmacody­namic).2 These SUbgroups serve to

focus attention on the possible sitesof interaction as a drug moves fromits site of administration and ab­sorption to the receptor site. Phar­macokinetic processes are thosethat include transport to and fromthe receptor site and consist of ab­sorption, distribution in body tissue(including binding to plasma pro­teins), metabolism, and excretion.Pharmacologic interactions occurat biologically active sites (the re­ceptor site).

PHARMACOLOGICINTERACflONS

Because of space limitations, weshall restrict our discussion ofpharmacologic interactions, citingonly some general principles and afew less well-known examples.These interactions may result inadditive, synergistic, or antagonis­tic effects due to their action oncentral and/or peripheral receptorsites. Perhaps the most common ispotentiation of central nervous sys­tem depression, which can occurwith combinations of anticonvul­sants, ethanol, sedative-hypnotics,tricyclic antidepressants, the more

671

Drug interactions

sedating neuroleptics, monoamineoxidase inhibitors, and lithium.2

Peripheral sites can also be af­fected by drugs whose therapeuticaction is primarily central. Lithiumhas been found to potentiate theneuromuscular blocking effects ofpancuronium bromide and succi­nylcholine in man3; this is impor­tant since many depressed patientswho are candidates for electrocon­vulsive therapy (ECT) are alreadyreceiving lithium salts. Animalstudies have shown variability inthe effect of lithium on differentneuromuscular blocking agents. Inone study with dogs, lithium poten­tiated the actions of pancuronium,succinylcholine, and decametho­nium, but not those of d-tubo­curarine and gallamine, suggestingsubtle variations in the mechanisms

TMre are a limited """,be,ofmeclumisms by whichone drug may mteraet withtuIOther.

of action of these agents.45 It hasbeen suggested that lithium inhib­its acetylcholine synthesis and/orrelease at the neuromuscular junc­tion.6 This is supported by the find­ing that lithium prolongs the rever­sal time of pancuronium blockadeby neostigmine.s Lithium's actionson calcium metabolism may also beinvolved. This interaction is of ob­vious clinical importance for psy­chiatric patients undergoing surgi­cal procedures as well as for ECT.Diazepam may be involved in asimilar interaction; it has been re­ported from animal work that diaz­epam increases the magnitude andduration of the blockade producedby gallamine and d-tubocurarine,and reduces that produced by suc-

672

cinylcholine.7Other reports contra­dict these findings and suggest thatthere is no potentiation of the ef­fects of gallamine or d-tubo­curarine.8•10 The positive findingsmay be criticized on the basis of anexperimental design that did notcontrol for tachyphylaxis, so thatthe potentiation of effect may havebeen due to the administration oftwo doses of a neuromuscularblocking agent over too short a timeperiod. Although the data are cer­tainly not definitive, patients takingdiazepam who receive blockingagents during anesthesia should bewatched closely for signs of respi­ratory depression.

Another example of a pharma­cologic interaction involves papav­erine, which can antagonize the an­tiparkinsonian effect of L-dopa,presumably by blocking the effectofdopamine in the corpus striatum.Patients taking L-dopa developed arecrudescence of symptoms of par­kinsonism within one week whenpapaverine was added to theirmedication regimen at a dosage aslow as 100 mg daily. I 1.12 The thera­peutic effects of L-dopa can also belessened by chlorpromazine,l3 andL-dopa can cause clinical de­terioration in patients taking anti­psychotic agents, implying that thisdrug can antagonize the therapeu­tic action of neuroleptics (througheffects of dopamine).'w

One anecdotal report suggeststhat certain benzodiazepines mayinterfere with the action of L­dopa. 16 Some parkinsonian patientsdeteriorated after diazepam or ni­trazepam was added to their L­dopa regimen. The GADA (gammaaminobutyric acid) agonist proper­ties of benzodiazepines couldtheoretically act on dopaminergicneurons in the basal ganglia toworsen parkinsonian symp-

toms.2.16.17 Carefully designed stud­ies will have to corroborate theseinitial clinical observations beforethis can be considered a significantinteraction.

Many other clinically importantpharmacologic interactions couldbe cited; however, the remainingdiscussion in this review will belimited to pharmacokinetic in­teractions involving psychotropicdrugs. This discussion is intendedto provide the clinician with a ra­tional framework for understand­ing both known and future drug­drug interactions.

PHARMACOKINETICINTERACTIONS

Absorption

In typical clinical practice, drug in­teractions occurring at sites of ab­sorption are of concern primarilyfor substances administered via theoral route. Nevertheless, it istheoretically possible to apply someof the following considerations tosimultaneous administration ofmore than one substance intrave­nously or intramuscularly. Druginteractions that occur during ab­sorption from the gastrointestinaltract can result in a change in therate of absorption and/or in theamount of drug absorbed. Alteredserum concentrations, delayedonset of drug action, prolonged ef­fects, or altered subjective responsecan occur on the basis of an alter­ation in the absorptive processalone. Events that combine to makeup the normal process of absorp­tion-e.g., dissolution of the tabletor capsule, passage from the stom­ach to the site of absorption in thesmall intestine-are all potentialfocuses of drug interactions.

Alcohol: Many anxious patientsare likely to self-administer alco-

PSYCHOSOMATICS

hoI, and it can interact with a vari­ety of psychotropic drugs via sev­eral different mechanisms. Forexample, the coadministration ofalcohol (ethanol) with benzodiaze­pines is frequent and yet the find­ings in the literature on this in­teraction are contradictory. One ofthe major reasons for this is thatstudies of the interaction differ indosages and routes of administra­tion, resulting in variation in theirresemblance to each other and toreal life usage. This is clearly evi­dent in studies examining the in­teraction between diazepam andethanol. With ethanol concentra­tions higher than those seen in so­cial situations (ethanol was admin­istered as a pure compound),diazepam levels were higher whengiven with alcohol than withwater. IX It has been suggested thathigh intragastric concentrations ofethanol could disrupt the barrierfunction of the gastric mucosa, fa­cilitating permeability to drugs.'~·2u

In another study, higher levels ofdiazepam were found when it wasgiven with high concentrations ofethanol (50% by volume), with di­azepam tablets being dissolved orsuspended in ethanol before ad­ministration. 21 The more rapid ab­sorption that was seen could haveresulted from the drug's dissolutionin ethanol before ingestion, whichcould have circumvented the timeusually needed for drug dissolutionwithin the gastrointestinal tract.Another study found no significantdifference in plasma diazepamconcentrations between 30 minutesand four hours after dosage whenthe drug was taken with water orpure ethanol (0.8 g/kg bodyweight),22 On the other hand, astudy in our laboratory showed thatcoadministration of a typical eth­anol-containing cocktail (orange

NOVEMBER 1978 • VOL 19 • NO II

juice and vodka) tended to reducethe rate (but not the completeness)of diazepam absorption, probablyby reducing the rate of gastric mo­tility and emptying, thus delayingdiazepam dissolution and/or itsdelivery to absorptive sites in theproximal small bowel.23 Despitethis pharmacokinetic interaction, itis important to consider the poten­tial for additive (or possibly syner­gistic) sedation through effects atreceptor sites in the brain. Thepharmacologic interaction may bemore important in this instancethan the more easily studied phar­macokinetic interaction. No consis­tent effect has been noted withchlordiazepoxide (CDX) andethanol.24

Antacids: Interactions with ant­acids are another common absorp­tion phase interaction. We haveshown that the rate of absorption of

Gastric motility may be de­creased and absorption de­lIlyed by drugs the patientuses and does not freely re­port to the physician.

CDX is significantly slowed when itis given in conjunction with a mag­nesium-aluminum hydroxide ant­acid preparation.25.27 It is likely thatthe absorption rate of CDX is animportant determinant of its earlyclinical effects and that delayed ab­sorption could result in delayed orattenuated clinical response whenthe drug is used in single-dose clin­ical situations (i.e., "take this whenyou feel anxious"). Many anxiousindividuals suffer from gastrointes­tinal disturbances, and coadminis­tration of these agents is common.In vitro studies indicate that mag­nesium and aluminum hydroxides

are capable of absorbing CDX, apossible contributory mechanismto delayed absorption.26 It is alsopossible that elevation of gastricpH toward or above the pK ofCDX(4.8) reduces the dissolution rate ofthe drug by increasing concentra­tions of the poorly water-solublenonionized base. Most likely, how­ever, many antacids cause delayedgastric emptying, resulting inslowed absorption.

Clorazepate is another antianx­iety agent that may interact withantacid preparations.25 Clorazepateis essentially a pro-drug that is hy­drolyzed in the stomach to its activemetabolite, desmethyldiazepam.As the pH of the stomach rises, thisconversion is slowed. As the pHapproaches 7, the hydrolysis half­life becomes very long, suggestingthat gastric emptying may occurbefore a significant amount of theactive agent is formed. Effectivedoses of antacid given every twohours will keep the gastric pH in the4 to 6 range and it may become ashigh as 7.2 within 20 minutes ofinitial antacid dosing.2x We haverecently shown decreased bloodlevels and decreased clinical effec­tiveness from coadministered sin­gle doses of c10razepate and anantacid preparation containingmagnesium hydroxide and alumi­num hydroxide.29

Antacids can also decrease theabsorption of chlorpromazine(CPZ) and possibly other antipsy­chotic agents as well. This interac­tion has resulted in decreased con­centrations of CPZ in rat brain anddecreased serum levels in man.3UJ1

In addition, the initiation of ant­acid therapy has been reported tolead to relapse in a patient previ­ously stabilized on CPZ.3U It hasbeen suggested that gel-type antac­ids (e.g., milk of magnesia) act as a

673

physical adsorbent of CPZ, thusdecreasing its absorption.32 How­ever, it seems more likely that de­creased gastric motility and resul­tant metabolism of CPZ in the gutresult in decreased absorption ofunmetabolized CPZ.

While gut metabolism of CPZhas been shown in the rat, it has notbeen directly demonstrated inman.33 An important study thatsupports this interpretation was re­cently conducted in Norway. Pa­tients taking CPZ intramuscularlydid not form CPZ sulfoxide, aninactive metabolite. When theytook CPZ orally, varying degrees ofsulfoxidation occurred, suggestingpresystemic metabolism of CPZ(i.e., within the lumen or in the gutwall). Decreased blood levels ofCPZ have also been reported withthe coadministration of the anti­parkinsonian agent, trihexypheni­dyl, presumably the result of de­creased gastric motility due toadditive anticholinergic effects.34 Itseems likely then that food, ant­acid, and anticholinergics, whichincrease the transit time of oralCPZ in the upper GI tract, will alterthe proportion of CPZ (active) toCPZ sulfoxide (inactive) and hencealter CPZ blood levels and clinicaleffects.35

Other agents: Several drugs thatare used to treat side-effects of psy­chotropics alter gastric motility(e.g., antiparkinsonian agents,bethanechol, pilocarpine nitrate),and the effects of these drugs onabsorption of coadministered med­ications require further study.

Benzodiazepine absorption mayalso be affected by anticholinergicinfluences. Parenterally adminis­tered atropine can calise a signifi­cant short-term decrease in absorp­tion of diazepam36; however, fromthe research done to date it is not

NOVEMBER 1978 • VOL 19 • NO II

known if the total amount absorbedover 24 hours is altered (given whatwe know about the effects of foodand antacids, it seems likely thatonly rate was affected).

It is important for the clinician toremember that gastric motility maybe decreased and absorption de­layed by drugs the patient uses anddoes not freely report to the physi­cian. Such drugs range from theover-the-counter cold preparationsto cannabis.J7·3S

Absorption of some drugs suchas L-dopa, digoxin, acetaminophen,and phenylbutazone is highly sus­ceptible to changes in gastric mo­tility.39 When psychotropic agentsthat reduce gastric motility (e.g.,

Several psychoactive drugsare affected by altered tubu­lar reabsorption resultingfrom changes in urinary pH.

tricyclic antidepressants, highly an­ticholinergic phenothiazines) aregiven together with such drugs, im­paired absorption can result. Forhighly soluble, rapidly absorbeddrugs, it can be expected that theirpassage from the stomach to theabsorptive surface of the smallbowel will be the rate limiting fac­tor in absorption, and that delayedgastric emptying will have the po­tential for altering the absorptiveprocess.

Food: Finally, the effect of foodon drug absorption is often over­looked. Many drugs are absorbedmore slowly when taken with food,which is probably due to the inhib­itory effect of food on gastric emp­tying.40 Limited studies have sug­gested that administration ofhypnotic drugs with meals can slowthe rate of absorption but not nec-

Drug interactions

essarily the completeness of ab­sorption. While it is possible thatlipid substances could bind fat sol­uble hypnotics such as glutethi­mide in the gastrointestinal tractand delay absorption,41 it seemsmore likely that in the majority ofcases decreased gastroin testinalmotility results in a decreased rateof absorption or in some degree ofgut metabolism. A clinically im­portant contribution was madewhen it was shown that concomi­tant intake of food significantlylowered chlorpromazine (CPZ)concentrations in blood (unfortu­nately, CPZ sulfoxide levels werenot measured to see if they corre­spondingly rose).42

We have recently demonstratedthat coadministration of food anddiazepam resulted in considerablyslowed absorption of diazepam(i.e., decreased gastric motilitydelays delivery of the drug to itssmall-bowel absorption site); how­ever, the total diazepam absorbedfrom the single dose over 48 hourswas increased (compared with di­azepam taken with water), suggest­ing that there was greater tabletdissolution when drug and foodwere taken together.43 On theoreticgrounds, decreased motility couldalso keep the drug in increasedcontact with the small intestine, re­sulting in increased absorption.This may also be the explanationfor lithium absorption that isgreater after a meal than in thefasting state.44 For drugs that aresubject to considerable first-passmetabolism (e.g., propranolol), in­creases in splanchnic blood flow, asoccur after a meal, may also con­tribute to higher blood levels.45

Drug distribution

Drugs are reversibly bound to tis­sue and to plasma proteins. AI-

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Drug interactions

though it is possible for drug in­teractions to occur by thedisplacement of a drug from itstissue-binding sites, alterations ofthis nature are not of major impor­tance in psychopharmacology.

On the other hand, protein­binding alterations may be clini­cally significant. Most drugs are re­versibly bound to a varying extentto proteins (principally albumin). Ifa drug is highly bound to albumin,then it is more susceptible to in­teractions via this mechanism. Thisis so because highly bound drugshave a small percentage of freedrug at the receptor site, so thatsmall changes in bound drug candramatically change the amount offree drug at active sites. All chloralderivatives (chloral hydrate,chloral betaine, triclofos) are me­tabolized to trichloracetic acid,which is strongly bound to albuminand can displace other less tightlybound drugs from their protein­binding sites.4\ The result is short­term potentiation of the displaceddrug's clinical effect. For example,giving chloral hydrate to a patientwho has been stabilized on war­farin anticoagulant therapy can re­sult in an increased prothrombin­emic effect (increased prothrombintime) and bleeding.4648 Both thecoumarin anticoagulants and theindandione derivatives may in­teract in this manner.49.50 There isno absolute contraindication tousing these drugs in combination;however, the use of fturazepam oranother benzodiazepine sedative­hypnotic might be advisable forpatients taking drugs whose effectmight be inftuenced by protein­binding displacement. Other drugsthat are at certain times affected byprotein-binding displacement in­clude both phenytoin andtolbutamide.4\

678

MetaboUsmMetabolism or biotransformationis an important process in elimina­tion of drugs from the body. Thechemical reactions involved can beclassified as nonsynthetic and syn­thetic.51 Nonsynthetic processes in­volve oxidation, reduction, or hy­drolysis and may result in a changein activity of the drug (increased ordecreased). The synthetic reactionsinvolve coupling of a drug or itsmetabolite to an endogenous sub­strate (e.g., carbohydrate or aminoacids), and usually result in inac­tivation of the drug. Biotransfor­mations for the most part takeplace in the hepatic cell endoplas­mic reticulum (microsomal frac-

A.ddition ofthiazides couldreduce the totlll doMlge ofIithiJlm required.

tion). As in absorption, drug in­teractions that alter metabolisminvolve normal processes of bio­transformation. Very simply, theycan be classified into interactionsinvolving either enzyme inductionor metabolic inhibition.

Enzyme induction: Definite en­zyme-inducers are barbiturates,glutethimide, and alcoho1.4u2.54Drugs that are affected by coad­ministration of enzyme-inducersundergo more rapid metabolism,which results in diminished clinicaleffect; this can be reversed severaldays to several weeks after the en­zyme-inducer is stopped. Drugs soaffected include oral anticoagu­lants, vitamin D, corticosteroids,phenylbutazone, and tolbuta­mide.33,4I,46.5055 Other drugs thatpossibly are affected are digitoxin,phenytoin, methyldopa, chlor­promazine, tricyclic antidepres-

sants, rifampin, and doxy­cycline.2.41.56.57

Some neuroleptic agents may in­teract with phenytoin via thismechanism. A mentally retardedadult male treated with phenytoin400 mg per day had a blood level of10 Itg/ml after ten days of treat­ment.58 After three months' therapywith loxapine, a phenytoin levelgreater than 7.5ltg/ml could not beachieved with doses as high as 460mg per day. After loxapine wasdiscontinued, phenytoin levels roseto 16.5ltg/ml ten days later despiteconstant dosage. Carbamazepine,which is structurally related to lox­apine, is also known to decreaseblood levels of phenytoin.2 Whilestimulated metabolism due to he­patic enzyme induction may be themechanism responsible for this in­teraction, other factors could alsobe important. Both loxapine andcarbamazepine are highly anticho­linergic and this may diminish gas­tric emptying and motility, render­ing phenytoin less available forabsorption.

Epileptic patients may be partic­ularly susceptible to enzyme-in­duction interactions because oftheir exposure to such drugs as car­bamazepine, phenobarbital, andphenytoin. The clearance value ofclorazepate was recently found tobe higher in a group of epilepticpatients (treated with various anti­convulsants) compared with exist­ing data on normal volunteers.59

With a reported increased preva­lence of seizure disorders amonginmates of jails and prisons, druginteractions of this type may beimportant for that population.60

The clinical effects of enzyme in­duction can be managed by carefultitration of dosage and monitoringof blood levels of drugs known tobe affected by inducing agents.

PSYCHOSOMATICS

However, if possible, a noninduc­ing drug should be substituted.Benzodiazepines, which undermost circumstances have no clini­cally important inducing effects,might be substituted for barbitu­rates in some instances.41

Metabolic inhibition: Manydrugs are known to decrease themetabolism of coadministereddrugs. Typically, these interactionslead to increased serum levels. Insome cases this may result in en­hanced clinical effect, but not with­out the risk of increased toxicity.These interactions may also influ­ence individual pathways of bio­transformation. For example,methylphenidate competes withimipramine for hydroxylation, re­sulting in increased demethylationof imipramine to desipramine.61

Phenothiazines and other antipsy­chotics may have a similar effect ontricyclic antidepressants. Perphen­azine, haloperidol, and chlorprom­azine have been shown to decreasethe excretion of imipramine andnortriptyline, but flupentixol didnot affect imipramine excretion.56 Itthus appears that some neurolep­tics inhibit the metabolism of tri­cyclic antidepressants.

Phenytoin reacts with a numberof psychotropic drugs via themechanism of altered metabolism.Clonazepam, a newly marketedbenzodiazepine derivative withmarked anticonvulsive properties,may alter phenytoin levels. Al­though the general trend of thedata indicates that phenytoin levelsrise when clonazepam is added tothe regimen, the opposite resultshave also been reported.2.62.66 Theanecdotal nature of the reports aswell as polypharmacy in many ofthese patients may partially explainsuch discrepancies. Other reportssuggest that diazepam, chlordiaz-

NOVEMBER 1978 • VOL 19 • NO II

epoxide, and nitrazepam can ele­vate phenytoin levels in theblood.2.67.69 Although there hasbeen a reported elevation of phe­nytoin levels in the presence ofchlorpromazine or prochlorpera­zine, this interaction has not beenadequately substantiated.2.67 Amore certain interaction is betweendisulfiram and phenytoin. Disul­firam can elevate serum levels ofphenytoin, and several case reportsof toxicity appear in the litera­ture.70.71 Disulfiram can also pro­long the half-life and reduce theclearance of chlordiazepoxide byinterfering with demethylation.72

Other benzodiazepines requiringthis metabolic step would be likelyto interact in a similar manner, un­less this is offset by changes in thedistribution of the drug. For pa­tients taking disulfiram, the short­or intermediate-acting benzodiaze­pines (e.g., oxazepam, lorazepam),which require only glucuronideformation prior to elimination, maybe more predictable drugs to use.

Excretion

Renal excretion of drugs can be animportant mechanism by which in­teractions occur. For this to be thecase, the drug or an active metabo­lite must be appreciably eliminatedby the kidney. The three compo­nents of urinary excretion­glomerular filtration, tubular reab­sorption, and active tubularsecretion-may all be focuses ofdrug interactions.

Glomerular filtration involvesthe filtering of non-proteinbounddrugs, so potential for interactionsexists when a highly bound drug isdisplaced by another drug. Onceagain, chloral derivatives have thepotential to act in this manner. Al­though there are several drugs thatinteract by competing for the tubu-

lar transport system (i.e., active tu­bular secretion), none are of partic­ular importance in clinicalpsychopharmacology. On the otherhand, several psychoactive drugsare affected by altered tubularreabsorption resulting fromchanges in urinary pH. For exam­ple, acetazolamide for sodium bi­carbonate may enhance the excre­tion of tranylcypromine or lithium,while acidic substances such as am­monium chloride, ascorbic acid, ormethenamine mandelate may en­hance the excretion of imipramine,amitriptyline or amphetamines.

One of the most important in­teractions involving renal excretion

Patients taking diazepamwho receive blocking agentsduring anesthesia should bewatched closely for signs ofrespiratory depression.

is that which occurs between lith­ium and diuretics. The thiazidediuretics have been shown to de­crease lithium clearance and ele­vate serum lithium levels, whichcould possibly lead to toxicity.73.75 Ithas been suggested that a 40% re­duction in daily lithium dose isneeded to maintain customaryblood levels when a patient is tak­ing 500 mg of chlorothiazidedaily.76 It is known that initiallyduring thiazide treatment sodiumexcretion exceeds sodium intake.74

However, this is followed by acompensatory increase in sodiumreabsorption in the proximal tu­bule. Since lithium is primarilyreabsorbed in the proximal tubulewith sodium, thiazide treatmentmay lead to an increase in thereabsorption of lithium, a decreasein lithium clearance, and symptoms

679

Dr. Shader is director of the Psychopharmacology Research Laboratory. Massachu­setts Mental Health Center and Harvard Medical School and associate professor ofpsychiatry at Harvard Medical School. Dr. Ciraulo is research psychiatrist at theLaboratory and clinical instructor in psychiatry at Harvard. and Dr. Greenblatt ischief of the Clinical Pharmacology Unit. Massachusetts General Hospital andassistant professor of medicine at Harvard. Reprint requests to Dr. Shader. 74Fenwood Road. Boston. MA 02/l5.

Drug interactions

of toxicity. Any diuretic that pro­motes the excretion of sodium andpotassium has the potential for in­ducing toxicity (decreased potas­sium levels could lead to increasedmyocardial irritability).77 Furose­mide has also been reported to in­teract with lithium.78.79 Althoughdata on the potassium-sparingdiuretics are limited, there is someevidence that lithium reabsorptionis blocked, promoting lithium di­uresis.8o.s1 There is no absolute con­traindication to using lithium inconjunction with a thiazide diuret­ic. In fact, one group has recom­mended that this combination beused to treat the lithium-induceddiabetes insipidus-like syndrome.76

It has also been suggested that theaddition of thiazides could reducethe total dosage of lithium requiredfor an individual patient, possiblyreducing the likelihood of adverseeffects from long-term, high-dose

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lithium treatment. In light of cur­rent data on renal lesions asso­ciated with impaired concentratingability in those patients receivingchronic lithium treatment,82,83 athorough renal evaluation shouldbe obtained before embarking onthis course of treatment. Otherdrugs that enhance renal excretionof lithium are sodium bicarbonate,aminophyllin, acetazolamide, urea,and mannitol.

ConclusionPolypharmacy-the use of combi­nations of drugs-may be of thera-

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peutic benefit in some patients, butnot without an increased likelihoodof adverse effects and drug interac­tions. There are a limited numberof mechanisms by which drugs mayinteract with each other, Althoughthe determination of the primarysite of interaction is often arbitrary,this classification provides a usefulway of conceptualizing the prob­lem of drug-drug interactions. 0

Supporled in pari by USPHS GranlMH 12279.

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