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Dual intoxication with diazepam and

amphetamine: This drug interaction probably

potentiates myocardial ischemia

Boris Starcevic, Mario Sicaja *

Invasive Cardiology Unit, Department of Internal Medicine, University Hospital Dubrava, Av. Gojka Suska 6,

10000 Zagreb, Croatia

Received 5 December 2006; accepted 7 December 2006

Summary Drug-induced myocardial infarction is not a common phenomenon and the underlying mechanism has beenrelated with the coronary artery spasm in the majority of cases. It is mainly related to illicit substances such ascocaine, ecstasy, LSD and amphetamine. According to the findings in the literature it is most likely that myocardialischemia due to amphetamine abuse is a result of combined mechanisms which include coronary artery vasospasm, andin lesser extent thrombus formation or direct myocardial toxicity. Diazepam is also usually found as a substance ofabuse. Recent findings indicate that diazepam exerts an inhibitory activity on different isoforms of the enzyme cyclicnucleotide phosphodiesterase which can be found in the heart muscle and also show that diazepam potentate thepositive inotropic effect of both noradrenaline and adrenaline, which subsequently leads to increase in myocardialcontractility. We propose that dual intoxication with amphetamine and benzodiazepine potentate their effects oncardiac tissue and coronary arteries which results in larger myocardial injury.

c 2007 Elsevier Ltd. All rights reserved.

Introduction

Drug poisoning with amphetamine and other non-specific adrenergic agonists (e.g. cocaine, ephed-

rine) are very common in everyday clinicalpractice [1,2]. Clinical manifestations usually in-volve symptoms of physical stimulation (hyperac-tivity, irritability, delirium, psychosis, mydriasis,

hyperpyrexia, hypertension, and arrhythmias). Lesscommon manifestations include acute renal fail-ure, seizures, CNS hemorrhage, coma, and drug-in-duced myocardial infarction [3].

Drug-induced myocardial infarction is not a com-mon phenomenon and the underlying mechanismhas been related with coronary spasm in the major-ity of cases [4,5]. Coronary artery spasm is the ma-jor cause of acute coronary events including druginduced myocardial infarction and arrhythmia inthe young people [5]. The underlying mechanismof increased vasospastic susceptibility of the coro-naries in some people is still quite unclear, and to

0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved.doi:10.1016/j.mehy.2006.12.033

* Corresponding author. Tel.: +385 1 290 24 44; fax: +385 1 28636 95.

E-mail address: mario.sicaja@zg.htnet.hr (M. Sicaja).

Medical Hypotheses (2007) 69, 377380

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date there is no predictive marker for the severityof the spastic attack, and its recurrence [6,7]. Druginduced myocardial infarction secondary tocoronary spasm in teenagers is mainly related to il-licit substances such as cigarette smoking, mari-juana smoking, alcohol intake, butane inhalation,cocaine, ecstasy, LSD and amphetamine [8]. Diaze-

pam is also usually found as a substance of abuse[9]. It depresses mental and respiratory functionwhen taken in overdose. Fatalities are rare, butmixed overdoses are common [9].

In this paper, we propose that dual intoxicationwith amphetamine and benzodiazepine potentatetheir effects on cardiac tissue and coronary arter-ies which results in larger myocardial injury.

Amphetamine a well known cause ofcardiac complications

Amphetamine is phenylisopropylamine which isimportant, because of its misuse as a stimulant[10]. It is relatively easy to synthesize which isprobably the main reason of its wide-spread usageamong teenagers as an illegal substance [11]. Itsperipheral actions are mediated primarily throughthe release of catecholamine and activation ofthe sympathetic nervous system [10]. As a conse-quence of acute amphetamine intoxication cardio-vascular symptoms, including chest pain,palpitations, and dyspnea are common [10]. Sev-

eral cardiovascular complications have been asso-ciated with amphetamines [1216]. The mostcommon short-term effects are tachycardia andhypertension. In addition, vascular spasm of thecoronary arteries, myocardial infarction, pulmon-ary hypertension, cardiac dysrhythmias, cardiomy-opathy, myocarditis, and necrotizing vasculitishave also been reported [14,15]. According to therecent findings in the literature, it is most likelythat myocardial ischemia due to amphetamineabuse is a result of combined mechanisms which in-clude coronary artery vasospasm, and in lesser ex-

tent thrombus formation or direct myocardialtoxicity [1722].

Diazepam and new effects on cardiactissue

Endogenous noradrenaline and adrenaline aremajor agents of sympathetic nervous system, andare severely potentiated by amphetamine usage[10]. They increase cardiac contractility by

enhancing cAMP production through beta-adrener-gic receptor [23], but also have a vasoconstrictiveeffect on coronary artery vessels [24].

On the general basis diazepam is considered toprimary exert a cardiodepressant effect which isa consequence of centrally mediated decrease incardioregulatory outflow of the sympathetic ner-

vous system [25]. It is not so very well known thatit is also reported that diazepam produce some po-sitive inotropic effects on myocardium [26,27],which have been related to catecholamines re-leased from sympathetic nerve terminals locatedin the heart [28].

Recent experimental results demonstrated thatdiazepam exerts an inhibitory activity on differentisoforms of the enzyme cyclic nucleotide phospho-diesterase (PDE), including the types 1, 2, 3 and 4,which are present in the heart tissue and are in-volved in the hydrolysis of the cyclic AMP [29]. Mar-in et Hernandez also showed that diazepam

potentiates the positive inotropic effect of bothnoradrenaline and adrenaline, as well as that ofthe endogenous noradrenaline-releasing agenttyramine in electrically driven right ventricularstrips of rat [30]. This effect of diazepam is notattributed to an increase in the amount of nor-adrenaline release at the presynaptic level, but itis a direct effect of his inhibitory activity on en-zyme cyclic nucleotide phosphodiesterase, whichcauses increase in cellular concentrations of cAMP,which subsequently leads to increase in myocardialcontractility [30]. Diazepam overdose can produce

a toxic serum concentration in blood, and cardiacsympathomimetic-like effects on atrioventricularconduction were also reported [31]. Previouslypublished studies clearly showed that diazepampotentiates the positive inotropic effect of iso-prenaline and dopamine in the myocardium, alsostressing the role of cAMP [32,33].

Emerging issues of peripheral benzodiazepinereceptors are also interesting. Peripheral-type ben-zodiazepine receptors (PBRs) are abundant in thecardiovascular system [34]. In the cardiovascularlumen, PBRs are present in platelets, erythrocytes,lymphocytes, and mononuclear cells. In the wallsof the cardiovascular system, PBR can be found inthe endothelium, the striated cardiac muscle, thevascular smooth muscles, and the mast cells. Thesubcellular location of PBR is primarily in mito-chondria [34]. Even though exact function of PBRsis not very well known, PBRs in blood vessel wallsappear to take part in responses to trauma suchas ischemia [34]. Several studies also showed thatacute stress increases the density of PBRs in theheart tissue [34]. The irreversible PBR antagonist,SSR180575, was found to reduce damage corre-

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lated with ischemia [34]. Several mechanisms wereproposed. In example, inhibition of apoptosis bydecreasing mitochondrial permeability transitionpore was connected with the effects of antagonistacting at PBRs [34]. Furthermore, findings of AkarFG et al. directly linked mitochondrial benzodiaze-pine receptor agonist with recovery of the mito-

chondrial inner membrane potential which is thekey determinant of post ischemic functional recov-ery of the heart and showed that it has failed toprevent arrhythmias, in contrast to mitochondrialbenzodiazepine receptor antagonist, 40-chloro-diazepam [35]. When they applied 40-chlorodiaze-pam throughout ischemia-reperfusion protocol, itprevented reperfusion arrhythmias [35].

Conclusion

Here we hypothesize that combined effect of diaz-epam and amphetamine will result in enhancementin the resulting myocardial injury and increasedcardiac mortality due to prolonged coronary arteryspasm and increased cardiac contractility. Abovedescribed mechanisms of diazepam on heart tissue,and well known amphetamine effects which resultin increased oxygen demand and reduced oxygensupply should be potentiated when administeredtogether. Usually, in every day clinical practiceagitation associated with amphetamines abuse istreated with diazepam [36]. In the light of our the-ory we would also challenge this therapeutic ap-

proach, especially if the myocardial lesion cannot be excluded, while we believe that it can leadto severe myocardial ischemia-reperfusion injury.Although, it may be open for discussion, whetherthe effects of diazepam are masked or attenuatedwith other endogenous ligands and are exclusivelydue to its effect on enzyme cyclic nucleotide phos-phodiesterase and mitochondrial benzodiazepinereceptor, the dual intoxication of diazepam andamphetamine warrants studies in animal modelsand their interpretation for the possible clinicalrelevance.

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