Cardiac drug-psychotropic drug update

Update: Drug-Psychotropic Drug Interactions

Cardiac drug–psychotropic drug update�

James J. Strain, M.D.a,*, Anwarul Karim, M.D.a, Gina Caliendo, Pharm. D., R.Ph.b,Jeffrey D. Alexis, M.D.c, R. Sandlin Lowe, III, M.D.a, Valentin Fuster, M.D., Ph.D.b

aDivision of Behavioral Medicine and Consultation Psychiatry, Mount Sinai–NYU Medical Center/Health System, New York, NY, USAbDepartment of Pharmacy, Mount Sinai Hospital, New York, NY, USA

cCardiovascular Institute, Mount Sinai - NYU Medical Center/Health System, New York, NY, USA

Abstract

This is an update from the report—Cardiac Drug and Psychotropic Drug Interactions: Significance and Recommendations—publishedin this journal in November-December 1999. As mentioned in that article there has been an explosion of new drugs both in psychiatry andcardiology without a sufficient understanding of their potential interactions. Also there is a need for methods to update drug interactions onan ongoing basis. This report describes: 1) examples of actual adverse interactions from clinical cases that move beyond some of thehypothesized contraindications included in the 2000 millennium publication; 2) confirmation of previous adverse interactions reported ifthey strengthen the earlier findings; 3) listing of new drugs, e.g., sildenafil (viagra) now commonly prescribed by psychiatrists andcardiologists; 4) reports explaining and/or refining mechanisms of adverse interactions; and 5) cautions and important associated phenom-enon of either a cardiac or a psychotropic drug, e.g., valproic acid and cases of life-threatening pancreatitis. Methods of publicizing the newknowledge of cardiac drug–psychotropic drug interactions, e.g., the Internet and web sites are described. © 2002 Elsevier Science Inc. Allrights reserved.

Keywords:Cardiac drugs; Psychotropic drugs; Drug interactions; Adverse drug reactions; Update methods.

1. Introduction

A large percentage of symptoms in patients are related todrug interactions and toxicity. Better identification and un-derstanding of these effects will lead to improved patientcare. With the ongoing development of new drugs, newinteractions are surely to be seen. In December 1999 ourgroup publishedCardiac Drug and Psychotropic Drug In-teractions: Significance and Recommendations[1]. Thisarticle was sent to every medical school in the world by theauthors assisted by grants from the Malcolm Gibbs Foun-dation, Inc. and donors to the Liaison Psychiatry ResearchFund at the Mount Sinai School of Medicine, NY, USA.During the last year, new drugs were approved for clinicaluse, new interactions were identified, and data confirminghypothesized interactions were described. The study groupexamined the updates of key reference sources from the last

quarter of 1999 until the present to discern the interactionsbetween a group of commonly employed cardiac drugs andpsychotropic medications (Tables 1 and 2).

The drugs selected for review were from: 1) the 1999Redbook list of the 200 most often prescribed drugs in theUnited States; and 2) those most commonly employed bythe Cardiovascular Institute and the Division of BehavioralMedicine and Consultation Psychiatry (Mount Sinai–NYUMedical Center/Health System). The disciplines of the in-vestigators were: cardiologists (JA, VF), pharmacist-druginformation specialist (GC), psychiatrists (JJS, RSL), and aresearch assistant (AK). The search strategy utilized: 1)MEDLINE (PubMed) employing the cardiac drug name, thepsychotropic drug name, and the term “interaction;” 2)Hanston’s Drug Interaction Analysis and ManagementText (July 2001 quarterly updated version) [2]; 3)DrugInteractions Facts(quarterly updated version) [3,4]; 4)MICROMEDEX Drug-dex[5]; 5) American Hospital For-mulary Service Drug Information[6]; and 6) Food andDrug Administration (MedWatch)(Dear Doctor Letters andnew labeling) (www.fda.gov/medwatch) for (1999, 2000and 2001, July). (Citations regarding children, reports inforeign languages or about food, animals, in-vitro experi-

� This work was funded by the Malcolm Gibbs Foundation, Inc., NewYork, NY, USA.

* Corresponding author. Tel.:�1-212-659-8728; fax:�1-212-369-6817.

E-mail address: [email protected] (J.J. Strain).

General Hospital Psychiatry 24 (2002) 283–289

0163-8343/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved.PII: S0163-8343(02)00184-6

ments, analgesics and naturalistic treatment interactionswere excluded). Obviously, these sources do not necessarilyinclude all information regarding drug–drug interactions.

This communication reports examples of actual adverseinteractions from clinical cases that move beyond some ofthe hypothesized contraindications included in the 2000millennium publication [1]. Second, confirmation of previ-ous adverse interactions are reported if they strengthen theearlier findings. Third, new drugs, e.g., sildenafil (viagra),now commonly prescribed by psychiatrists and cardiolo-gists, and its interactions are reported. Fourth, reports ex-plaining mechanisms of adverse interactions or refinementof mechanisms of action of a specific drug are included inthis update. And, fifth, reports of cautions and importantassociated phenomenon or side effects of either a cardiac ora psychotropic drug, e.g., valproic acid and cases of life–threatening pancreatitis reported in both children and adultsreceiving this medication (Abbot letter to physicians—FDAMedWatch, July 2000) [7].

1.1. Significance levels: rating systems

The first three levels of the Drug Interactions Factsrating system was employed [3,4]: “1 � Major : The effects

are potentially life-threatening or capable of causing perma-nent damage; 2 � Moderate: The effects may cause adeterioration in a patient’s status. Additional treatment, hos-pitalization or extension of hospital stay may be necessary;and 3 � Minor : The effects are usually mild; consequencesmay be bothersome or unnoticeable, but should not signif-icantly affect the therapeutic outcome. Additional treatmentis usually not required [3,4].”

Significance level 1 requires the clinician to documentwhy he/she is prescribing this combination, and to use bothdrugs only if there is no other way to manage the patient.Drug combinations producing an interaction with a Signif-icance level 1 are combinations that result in serious andpotentially life threatening adverse effects such as arrhyth-mia. Obviously, if this combination is to be used the drug(s)in question must be prescribed with an explanation as to theneed for their concurrent use and cautious monitoring em-ployed. The optimum choice, if possible, is to use anotherdrug to avoid Significance level 1 interactions. With Sig-nificance level 2, the potential interaction must be docu-mented and the clinical outcome(s) must be monitored care-fully so that unacceptable, pernicious reactions may behalted as soon as possible. Again, it is often better to useanother drug when possible. In any event, it is incumbent

Table 1Commonly prescribed cardiac drugs

AdenosineAmilorideAmiodaroneAmlodipineAspirinAtenololAtorvastatinAtropineBenazeprilBisoprololBretyliumBumetanideCandesartanCaptoprilCarvedilolCerivastatinCholestyramineClonidineClopidogrelColestipolCoumadinDigoxinDiltiazemDisopyramideEnalaprilFelodipineFlecainideFlolanFluvastatinFurosemideGemfibrozilHeparinHydralazineHydrochlorothiazide

IbutilideIsordilLabetalolLevophedLidocaineLisinoprilLosartanLovastatinMetolazoneMetoprololMexiletineMinoxidilNadololNeosynephrineNicardipineNifedipineNimodopineNitroglycerinPravastatinPrazosinProcainamidePropafenonePropranololQuinidineSimvastatinSotalolSpironolactoneTerazosinTiclopidineTocainideTorsemideTriamtereneVerapamil

Table 2Commonly prescribed psychotropic medications

AmantadineAmitriptylineAmphetamineAlprazolamAmobarbitalBenztropineBupropionBuspironeButalbitalCarbamazepineChoral HydrateChlordiazepoxideChlorpromazineCitalopramClomipramineClonazepamClozapineDesipramineDextroamphetamineDiazepamDiphenhydramineDivalproex sodiumDonepezilFluoxetineFluphenazineFluvoxamineGabapentinHaloperidolImipramineLamotrigineLithiumLorazepamLoxapine

MeprobamateMethylphenidateMirtazapineMolindoneNefazadoneNortriptylineOlanzapineOxazepamPargylineParoxetinePemolinePerphenazinePhenobarbitalQuetiapineRisperidoneSertindoleSertralineSildenafilSodium AmytalTacrineTemazepamThioridazineThiothixeneTrazodoneTranylcypromineTriazolamTrifluperazineTrihexyphenydilValproic acidVenlafaxineZaleplonZolpidem

284 J.J. Strain et al. / General Hospital Psychiatry 24 (2002) 283–289

upon the clinician to provide careful documentation thatadverse effects were considered when using this drug com-bination and the physician had knowledge of potential ad-verse consequences. It is also mandatory to communicate tothe patient’s health care providers the potential interactionsand adverse outcomes. Significance level 3 may not pre-clude the use of a specific drug, but clinical decision-makingneeds to consider whether the untoward side effects, (e.g.,nausea, rash, etc.) could be avoided by another drug choice.Again, the potential interaction and its mechanism shouldbe documented in the patient’s medical chart and patient’shealth care providers need to be informed.

Facts and Comparisons utilizes a five point significanceclassification [6]:

1. Avoid combination—risk always outweighs benefit.2. Usually avoid combination—use combination only

under special circumstances.3. Minimize risk—take action as necessary to reduce

risk.4. No action needed—risk of adverse outcomes appears

small.5. No interaction—evidence suggests no interaction.

For this communication level 4 and level 5 were notused, and only levels 1–3 were employed.

2. Cardiac drug–psychotropic drug interactions

2.1. Case support of previously (1999) hypothesized(potential) interactions

Cholestyramine/Valproic AcidSignificance level 2: ModerateAdvice to Practitioner: Cholestyramine interferes with

the gastrointestinal absorption of valproic acid, which re-duces the concentration and therapeutic effects of valproicacid.

Action: Administer valproic acid at least three hoursbefore, but not within three hours following cholestyra-mine. Monitor the patient’s clinical response and adjustthe dose of valproic acid accordingly.

2.2. Confirmation of previously reported adverseinteractions (1999)

Nifedipine/FluoxetineSignificance level 2: ModerateAdvice to Practitioner: Occasionally, there are increased

calcium blocker effects when fluoxetine is administeredsimultaneously. Although there are no clinical data avail-able, since nefazodone is a more potent inhibitor of cytro-chrome P3A4 than fluoxetine, it could also inhibit the me-tabolism of nifedipine, verapamil, and other calciumblockers. There is a question if this interaction would applyto other SSRIs.

Action: monitor for increased effects of calciumblockers if fluoxetine is also prescribed.

Propafenone/FluoxetineSignificance level 2: ModerateAdvice to Practitioner: Fluoxetine increases the concen-

tration of propafenone, and thereby markedly delays cardiacconduction leading to increased likelihood of pro-arrhyth-mia. Since fluoxetine inhibits the cytrochrome P2D6 en-zyme system, which is the metabolic pathway forpropafenone, its concentration may be increased. Givenfluoxetine’s and its active metabolite, norfluoxetine longhalf-life, their effects may appear only after a period of timewith the concomitant administration of propafenone. Simi-larly, it is necessary to observe and monitor the patient fora sufficient period of time after fluoxetine is withdrawnbecause propafenone’s concentration would decrease.

Action: Select antidepressants that do not inhibit cy-tochrome P2D6, for example, citalopram, nefazadone,venlafaxine. At the least, if this combination is pre-scribed, the patient should be monitored for heart rateand increased QRS duration.

Quinidine/FluvoxamineSignificance level 2: ModerateAdvice to Practitioner: Fluvoxamine coadministered

with quinidine produces a modest increase in quinidineconcentration with possible toxicity by fluvoxamine’s inhi-bition of the cytochrome P3A metabolism of quinidine. Forthe same reason nefazodone would be expected to have aneven greater effect on quinidine than fluvoxamine.

Action: Alternative antidepressants should be consid-ered that do not affect cytochrome P3A4 metabolism,e.g., venlafaxine, paroxetine. Or, another antiarrhyth-mic could be employed, e.g., procainamide that is notmetabolized by the cytochrome P3A4 enzyme system.Monitor EKG for prolonged QT and increased quini-dine concentrations. Due to marked pro-arrhythmiaquinidine should be avoided if possible.

2.3. Newly reported drug interactions since 1999

Amiloride/LithiumSignificance level 2: ModerateAdvice to Practitioner: Caution is needed when lithium

and diuretics are combined because the sodium loss mayreduce the renal clearance of lithium leading to toxicity.

Action: monitor lithium levels during the first weekafter starting amiloride or discontinuing it.

Atenolol/VerapamilSignificance level 2: ModerateAdvice to Practitioner: It is reported that the effects of

both drugs can be decreased by their concomitant use. It isuncertain if the mechanism(s) is an additive or synergistic

285J.J. Strain et al. / General Hospital Psychiatry 24 (2002) 283–289

occurrence. It is known that verapamil can diminish oxida-tive metabolism for certain beta blockers.

Action: it is essential to monitor cardiac functioningand adjust (decrease) the dose of both drugs as required.

Atorvastatin/Hydantoins (Phenytoin)Significance level 2: ModerateAdvice to Practitioner: The therapeutic effect of atorva-

statin may be decreased resulting in its diminished thera-peutic efficacy. The possible mechanism for the reduction inatorvastatin is its increased metabolism as a result of thepresence of hydantoins.

Action: The patient should be monitored for clinicalresponse and if the atorvastatin appears to be decreasedwith diminished clinical effectiveness, then a change topravastatin is suggested since it is less likely to interactwith phenytoin.

Atorvastatin/NefazodoneSignificance level: 1 MajorAdvice to Practitioner: Nefazodone is a known inhibitor

of cytrochrome P3A4 and atorvastatin is a substrate of thesame enzyme. Myopathy and rhabdomyolysis have oc-curred in patients with HMG-CoA reductase inhibitorsalone, or in conjunction with nefazodone.

Action: Monitor for signs and symptoms of myopathyand rhabdomyolysis. Monitor creatine kinase (CK) lev-els and discontinue use if CK levels show a markedincrease, or if myopathy or rhabdomyolysis occurs.

Carvedilol/FluoxetineSignificance level 2: ModerateAdvice to Practitioner: Fluoxetine increases the plasma

concentrations of carvedilol; although the clinical signifi-cance is uncertain, increased hypotension or bradycardiamay result. Since fluoxetine is a cytrochrome 2D6 inhibitorand can diminish the metabolism of R-carvedilol greaterthan the S form, an increase of carvedilol’s alpha and�-blocking effects may be seen.

Action: First an alternative SSRI should be consid-ered, e.g., citalopram or nefazodone which do not inhibitcytochrome P2D6. Or, a beta blocker that does notemploy cytochrome P2D6 metabolism, e.g., metoprololcould be considered. Monitor alpha or �-blocking ef-fects if carvedilol and fluoxetine are administered simul-taneously.

Clopidogrel/PhenobarbitalSignificance level: Non specifiedAdvice to Practitioner: There are no data to predict the

reaction from the concomitant administration of these twodrugs. However, since clopidogrel may interfere withCYP2C9 enzymes, and phenobarbital is partially metabo-lized by the same enzyme system, an adverse reaction mayone day be reported and this is a potential reaction to becognizant of.

Action: observe for changes that may occur fromcoadministration

Digoxin/FluoxetineSignificance level 2: ModerateAdvice to practitioner: the mechanism for increased

digoxin toxicity when fluoxetine was added to a previouslystabilized patient is unknown.

Action: Although this is from one case report in a 93year old female, the increased use of SSRI for depressionin the elderly should be cautiously undertaken when thepatient is on digoxin.

Diltiazem/BuspironeSignificance level 2: ModerateAdvice to Practitioner: Diltiazem increases the concen-

tration of buspirone. Diltiazem inhibits CYP3A4 enzymesthat may result in an increase in the bioavailability ofbuspirone and enhance its plasma concentration. In studiesthe increase in buspirone varied from 3.3 to 7.4 times.Coadministration of buspirone with verapamil, diltiazem,erythromycin and itraconazole substantially increased theplasma concentration of busprione.

Action: The use of dihydropyridine calcium channelblockers could prevent this reaction, or the use of ananxiolytic drug that does not employ cytochrome P3A4enzymes, e.g., lorazepam, diazepam. Monitor for in-creased buspirone effects, e.g., sedation.

Flecainide/ParoxetineSignificance level 2: ModerateAdvice to Practitioner: Although there are no data avail-

able related to the combined use of flecainide and parox-etine, concern does prevail in that paroxetine is a potentinhibitor of cytochrome P2D6 which is how flecainide ismetabolized. Therefore, it would not be surprising that atsome point an adverse reaction will be reported by theirconcomitant use.

Action: Monitor QRS duration. Doses may have to bereduced. Caution should prevail in the concomitant useof these two drugs. Exercise testing can be used to assessincreased cardiac effects of flecainide. Prolongation ofQRS duration with exercise indicates high risk of proar-rhythmia.

Lovastatin (Pravastatin)/NefazodoneSignificance level 2: ModerateAdvice to Practitioner: Myopathy and rhabdomyolysis

have occurred in patients treated with lovastatin and nefa-zodone simultaneously. Nefazodone is a potent inhibitor ofcytrochrome P3A4 and lovastatin is a substrate of cytro-chrome P3A4. Elevated CPK levels have also been reportedwith the simultaneous use of nefazodone and pravastatin,which is also, a substrate of cytochrome P3A4.

Action: Carefully monitor serum CPK levels if nefa-zodone is used in combination with lovastatin or prav-


astatin. This combination should be discontinued ifthere is a significant rise in CPK, or if rhabdomyolsisoccurs.

Mibefradil/TriazolamSignificance level 2: ModerateAdvice to Practitioner: Mibefradil markedly increases

the plama concentrations of triazolam probably secondaryto its potent inhibition of cytochrome P3A4. Thus thepharmcokinetic effects on triazolam are to enhance andprolong its effects.

Action: prescribe another hypnotic and try to avoidusing mibefradil and triazolam concomitantly.

Nefazodone/SildenafilSignificance level 2: ModerateAdvice to Practitioner: Nefazodone and Sildenafil use

the same cytochrome P450 metabolic pathways. Therefore,the practitioner must know that either drug may have lesseffect than expected for the dosage administered.

Action: Attempt to use an alternative antidepressant.If you need to employ nefazodone with sildenafil, insureblood levels and/or effectiveness is monitored routinelyto achieve expected result.

Nitrates/SildenafilSignificance level 1: MajorAdvice to Practitioner: Current warnings advise that

sildenafil should not be taken with any nitrate containingdrugs, e.g., nitroglycerin. Sildenafil inhibits phosphodiester-ase-5 (PDE-5) that is found in the corpus cavernosum and inthe systemic vasculature. Sildenafil causes a decrease insystemic arterial pressure and a synergistic and often majordecrease in systemic arterial pressure in the presence oforganic nitrates (nitric oxide donors).

Action: Do not concomitantly administer nitrate con-taining medications and sildenafil. Although other vaso-dilating agents have different pharmacology, it may beprudent to avoid agents that cause vasodilation whenadministering sildenafil until more information is avail-able. In addition, patients’ cardiac status needs to beevaluated when administering any erectile dysfunctiontreatment that may have systemic vasodilatory proper-ties that may potentially lower blood pressure. Patientsmay require exercise treadmill testing to determine iferectile dysfunction patients with coronary artery dis-ease may achieve the physiologic work load (4–6 meta-bolic equivalents) associated with sexual intercourse [14].

Verapamil/OxcarbazepineSignificance level 2: ModerateAdvice to Practitioner: Co-administered verapamil and

oxcarbazepine has resulted in a 20% reduction in the plasmalevel of the 10-monohydroxy metabolite of oxcarbaxzeinethat possesses pharmacological activity. The clinical signif-icance of this interaction has not been determined as yet.

Action: monitor clinical effectiveness of oxcarbaz-epine when coadministered with verapamil.

Warfarin/BarbituratesSignificance level 1: MajorAdvice to Practitioner: Warfarin’s clinical efficacy is

reduced with the addition and concomitant utilization ofbarbiturates. The mechanism may be the enhanced meta-bolic rate from the induction of hepatic microsomal en-zymes by the barbiturates. Addition of barbiturates to war-farin will decrease its clinical effectiveness, while thewithdrawal of barbiturates from the anticoagulant will in-crease its effectiveness and produce toxicity.

Action: It is necessary to monitor anticoagulant ther-apy when adding or discontinuing barbiturates as eitherinsufficient or excessive anticoagulation activity may oc-cur. It is important to monitor patients for severalweeks. Benzodiazepines would have less effect on war-farin.

Warfarin/FluvoxamineSignificance level 2: ModerateAdvice to Practitioner: Low dose fluvoxamine can inter-

act significantly with warfarin in the elderly and the effectmay persist for up two weeks after stopping the antidepres-sant.

Action: monitor the effects on warfarin, e.g., increaseof international normalized ration, when it is combinedwith fluvoxamine.

Warfarin/QuetiapineSignificance level 2: ModerateAdvice to Practitioner: A recent case report suggests that

quetiapine may competitively inhibit cytochrome p450 3A4and cytochrome 2C9, resulting in increased warfarin activ-ity. Interactions of this type present problems when theenzyme-altering drugs are added to a previously stable pa-tient. Interactions due to this mechanism may take a fewdays to two weeks to become evident or dissipate, as it maytake some time before the enzyme alteration occurs orresolves.

Action: When quetiapine is added to a previouslystable regimen of warfarin, warfarin activity may beincreased. When warfarin is added to a regimen con-taining quetiapine, no intervention would be required,as the dose of warfarin would be determined by pro-thrombin times or international normalized ratios.Monitor prothrombin times and/or international nor-malized ratios.

2.4. Explanatory mechanisms for drug or drug–druginteractions

Angiotensin converting enzyme inhibitors(ace)/desipramine

Significance level 2: ModerateAdvice to Practitioner: Tricyclic antidepressants de-


crease ACE function, especially desipramine that displacesACE from its receptors. Fluoxetine or tranycypromine donot change ACE levels [9].

Action: monitor carefully if ace and desipramine areused concomitantly.

Atenolol/FluvoxamineSignificance level: Not applicableAdvice to Practitioner: Because atenolol is renally ex-

creted fluvoxamine added to it did not affect the plasmaconcentration of atenolol. In contrast fluvoxamine doeshave an impact upon metoprolol and propranolol (both ofwhich are metabolized hepatically).

Action: note the difference in reaction when fluvox-amine administered concomitantly with atenolol thenwhen it is with metoprolol and propanolol.

Metoprolol/DiphenhydramineSignificance level 2: ModerateAdvice to Practitioner: Diphenhydramine inhibits the

metabolism of metoprolol because of the alteration of me-tabolizers of cytochrome P2D6. Consequently the negativechronotropic and inotropic effects of the drug are prolonged[10].

Action: monitor the combined use of metroprolol anddiphenhydramine for adverse chronotropic and inotro-pic effects.

2.5. Cautions and important associated phenomenon

Valproic Acid“Cases of life-threatening pancreatitis have been re-

ported in both children and adults receiving depakote. Someof the cases have been described as hemorrhagic with rapidprogression from initial symptoms to death” (Dear DoctorLetter, Abbott Laboratories, July 2000) [7].

Thioridazine“Mellaril has been shown to prolong the QTc interval in

a dose related manner, and drugs with this potential, includ-ing mellaril, have been associated with torsade de pointes–type arrthymias and sudden death. Mellaril is indicated onlyfor schizophrenic patients who fail to show an acceptableresponse to adequate courses of treatment with other anti-psychotic drugs. Mellaril is contraindicated with certainother drugs, including fluvoxamine, propranolol, pindolol,any drug that inhibits the cytochrome p450 2D6 isoenzyme,e.g., fluoxetine and paroxetine and agents known to prolongthe QTc interval. Mellaril is contraindicated in patients withreduced levels of the cytochrome–P450 2D6 isozyme aswell as in patients with congenital long QT syndrome or ahistory of cardiac arrhythmias. A baseline EKG is sug-gested, and serum potassium should be normalized beforestarting treatment and patients with a QTc interval greaterthan 450 msec should not receive mellaril and it should bediscontinued in patients with a QTc interval over 500 msec.

. . . . ” (Novartis Dear Doctor Letter July 7, 2000; FDA/MedWatch 2000) [11].

SildenafilSildenafil and the interactions with the SSRIs has been

reviewed, including the psychopharmacology of sildenafil,possible interactions with SSRIs, side effects, risks, and theneed for concomitant psychological counseling [12]. Impor-tant papers address the issues of management of sexualdysfunction in patients with cardiovascular disease: Recom-mendations of the Princeton Consensus Panel [13], Ameri-can College of Cardiology/American Heart Association [14].

ZaleplonZaleplon the newest benzodiazepine receptor agonist,

has the shortest half-life of available agents. Zaleplon im-proves sleep latency, duration and sleep quality, particularlyin the elderly. It does not appear to cause rebound insomnia,residual sedation, or adversely affect psychomotor function.Patients should be ready to go to sleep immediately uponthe drug’s ingestion. Zaleplon appears to be helpful to thosewith difficulty falling asleep, and those who experiencenext-day drowsiness with the more long acting hypnoticagents. There were no interactions noted from the searchstrategies employed with the cardiac drugs listed (Table 1).

Ziprasidone“QT Prolongation and Risk of Sudden Death.A study directly comparing the QT/QTc prolonging ef-

fect of ziprasidone with several other drugs effective in thetreatment of schizophrenia was conducted in patient volun-teers. In the first phase of the trial, ECGs were obtained atthe time of maximum plasma concentration when the drugwas administered alone. In the second phase of the trial,ECGs were obtained at the time of maximum plasma con-centration while the drug was coadministered with an in-hibitor of the CYP450 3A4 metabolism of the drug. . . .

Nevertheless, ziprasidone’s larger prolongation of QTclength compared to several other antipsychotic drugs raisesthe possibility that the risk of sudden death may be greaterfor ziprasidone than for other available drugs for treatingschizophrenia. This possibility needs to be considered indeciding among alternative drug products. . . .

Ziprasidone use should be avoided in combination withother drugs that are known to prolong the QTc interval.Ziprasidone should also be avoided in patients with congen-ital long QT syndrome and in patients with a history ofcardiac arrhythmias [17].”

3. Conclusion

We have previously reported several methods to keepup-to-date, including the instruments that are currentlyavailable to accomplish this (see introduction) [1]. As thisupdate illustrates new drugs have appeared, new interac-


tions have been reported, and confirmatory data on previ-ously described hypotheses are now known. This unfoldingof knowledge of cardiac drug - psychotropic drug interac-tions illustrates the importance of methods of surveillance toensure that new information is current, accurate, and avail-able. It is our intent to have the earlier interactions as wellas those described in this paper available on the Internet ona web site (www.microcares.com), and as a part of thedictionaries in a computerized medical record—MICRO-CARES [15]. This would allow medical students, houseofficers, fellows, and attendings in psychiatry, cardiologyand primary care to have immediate access to this essentialinformation.

Non psychiatric physicians, e.g., cardiologists, primarycare physicians, internists, would be expected to have theirpatients on medical drugs. They are also frequent prescrib-ers of psychotropic medications for behavioral and mentaldisorders as well. Psychiatrists often consult with medicallyill patients on a variety of medications and to which they areadding a psychotropic prescription. It is incumbent thatphysicians of all disciplines know the interactions listedabove, (and those in the previous article) before they pre-scribe psychotropic medications to the medically ill whereconcomitant medication use may lead to adverse and attimes life threatening interactions [1].

Although there is a new journal to be launched in 2001—American Journal of Cardiovascular Drugs: Drugs, De-vices and Other Interventions—it does not necessarily in-clude or emphasize cardiac drug–psychotropic druginteractions [16].

References

[1] Strain JJ, Caliendo G, Alexis JD, Lowe RS, III, Karim A, LoigmanM. Part II: Cardiac drug, and psychotropic drug interactions: signif-icance, and recommendations. Gen Hosp Psychiatry 1999;21:408–29.

[2] Hansten PD, Horn JR, Koda-Kimble MA, Young LY, (editors). Druginteractions, and analysis, and management. Facts and comparisons.St Louis, MO, Quarterly Update 2000.

[3] Tatro DS, editor. Drug interaction facts. Facts, and comparisons. St.Louis, MO 1998. Quarterly Update 1999.

[4] Sewester CS, Olin B, Hebel SK, et al., (editors). Drug facts andcomparisons. Facts and comparisons. St. Louis, MO 2000, MonthlyUpdate July 2001.

[5] Micromedex Drugdex, Micromedex, Volume 97. Englewood, NewJersey, 2000.

[6] McEvoy GK, editor. American Hospital Formulary Service DrugInformation. American Society of Health System Pharmacists. Be-thesda, MD, 2000.

[7] Dear Doctor Letter. Important change in the labeling of depakote.Abbott Laboratories, 2001.

[8] Mahmood I, Sahajwall C. Clinical pharmacokinetics, and pharmaco-dynamics of buspirone, an anxiolytic drug. Clin Pharmacokint 1999;36(4):277–87.

[9] Gard PR, Mandy A, Sutcliffe MA. Evidence of a possible role ofaltered angiotensin function in the treatment, but not etiology, ofdepression. Biol Psychiatry 1999;45(8):1030–4.

[10] Hamelin BA, Bouayad A, Methot J, Jobin J, Desgagnes P, Poirier P,Allaire J, Dumesnil J, Turgeon J. Significant interaction between thenonprescription antihistamine diphenhydramine, and the CYP2D6substrate metoprolol in health men with high or low CYP2D6 activ-ity. Clin Pharmacol Ther 2000;67(5):466–77.

[11] Dear Doctor Letter. Important changes to the prescribing informationfor mellaril (thioridazine HCL). Novartis Pharmaceuticals Corpora-tion, East Hanover, New Jersey, July 7, 2000.

[12] Rosenberg KP. Sildenafil J. Sex Marital Therapy 1999;25:271–9.[13] DeBusk R, Drory Y, Goldstein I, et al. Management of sexual dys-

function in patients with cardiovascular disease: recommendations ofthe Princeton Consensus Panel. Am J Cardiol 2000;86:62F–68F.

[14] Cheitlin MD, Hutter AM Jr, Brindis RG. ACC/AHA expert consensusdocument. Use of sildenafil (Viagra) in patients with cardiovasculardisease. American College of Cardiology/American Heart Associa-tion. J Am Coll Cardiol 1999;33:273–82.

[15] Hammer JS, Strain JJ, Friedberg A, Fulop G. Operationalizing abedside pen entry notebook clinical database system in consultation-liaison psychiatry. Gen Hosp Psychiatry 1995;17:165–72.

[16] American Journal of Cardiovascular Drugs. Drugs, Devices, andOther Interventions. Adis International Inc. 860 Town Center Drive,Langhorne, PA 19047, USA.

[17] Physicians’ desk reference. 56th edition, Medical Economics Com-pany, Inc. Montvale, NJ, p. 2689, 2002.


Documents

Cardiac drug-psychotropic drug update