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Proarrhythmic effects of non cardiac drugs are not widely studied. Such
events are still isolated even if in the last 3 years some drugs (cisapride) have been evaluated in clinical
perspective1-3 and others in experimental studies on animal or laboratory models (isolated tissues or hearts) in
order to evaluate if electrophysiologic changes and/or ionic metabolism derangements due to these drugs could
explain the proarrhythmic effects4,5.
An overview on this subject was published in 19936 but the progressive and strong increase of new therapeutic
substances in all the specialities, the growing trend to prescribe drugs and therefore the great possibility to find
patients in polypharmacological therapy constrain to a meticulous surveillance and constant up-to-date.
There are some official recommendations like for cisapride from FDA, WHO and Janssen Pharmaceutical but more
and more frequent are the isolated descriptions of adverse effects, often without the required echo and diffusion
considering that some different drugs can have metabolic, pharmacokinetic and pharmacodynamic interferences
and therefore often can have proarrhythmic effects only if used in association.
The recent observation of ventricular hyperkinetic arrhythmias in two patients treated with cisapride for
gastro-esophageal disorders induced us to an up-to-date review of this argument.
Man 64 years old treated with cisapride 10 mg once a day and Al-Mg hydroxide for gastroesophageal disorders.
After 2 week of treatment he started to feel episodes of heart beat irregularity with dizziness. He was hospitalized
and performed ambulatory 24-hour electrocardiographic monitoring that revealed isolated ventricular premature
beats and one episode of ventricular tachycardia but echocardiography, sovraaortic arteries echotomography,
cycloergometric stress test, myocardial stress scintigraphy, head-up tilt test and haematological examination,
included thyroid function, were completely normal. After drug suspension the patient was asymptomatic and a
new 24-hour electrocardiographic monitoring revealed just few isolated premature ventricular beats.
Gastroenterological drugs – H2-antagonist
In 1986 was published a review on H2-antagonists cimetidine and ranetidine7 regarding some cases signalled
among 1970 and 1986: 10 pts treated with cimetidine showed hypokinetic arrhythmias (sinus bradicardia, AV
dissociation and 4 cases of asystole), 2 cases of ventricular fibrillation and 1 pt with paroxismal supraventricular
tachicardia induced by the association with dopamine (neither cimetidine neither dopamine if separately used
induced arrhythmias). On the other hand pts treated with ranetidine showed just few episodes of sinus
bradicardia. Authors ascribed the proarrhythmic effects of H2-antagonists to 3 mechanisms: 1. different degree of
cardiac H2-receptors stimulation and block; 2. genetic predisposition (uncommon) to the cardiac action of
H2-antagonists; 3. H2-antagonists vagomimetic effect. We want to point out H2-antagonists interference on
cytocrome P450 metabolism, action that, like for other drugs, had a very important role in the genesis of
proarrhythmic effect. This hypothesis could explain the different proarrhythmic action of cimetidine, that has a
stronger interference on hepatic cytocrome P450, in comparison with ranetidine8.
Gastroenterological drugs - Cisapride
Cisapride is a prokinetic agent that facilitates gastrointestinal motility by a significant increase of lower
esophageal sphincter pressure and improvement of gastric emptying. The mechanism of action is attributable to
enhancement of the release of acetylcholine at the myenteric plexus. Cisapride is widely used for treatment of
gastroesophageal reflux disease in adults, children and premature newborns. 11000 (approximately 19%) of more
than 58000 premature newborns admitted to the neonatal intensive care units were treated with cisapride1 and
in Grosseto district (216000 inhabitants) cisapride prescriptions have been 25226 in 1998. Since the first years from
its use were described arrhythmias during cisapride therapy2 so that were started surveillance programs
expecially in newborns and children1-3. Among February 1995 and June 1998 the Janssen Pharmaceuticals,
cisapride productor, send to american physicians 3 letters to alert them on the use of this drug in patients treated
with drugs that prolong QT interval or with described proarrhythmic effect or in patients with renal or hepatic
insufficiency or with arrhythmogenic heart disesase: the same directions were reported on product information
label. Cardiologist attention to this problem was recently excited by a letter to the Italian Journal of Cardiology9.
Cisapride induced arrhythmias seem to have a broad spectrum: were described sinus bradicardia, II degree AV
block, supraventricular and ventricular ectopic beats up to torsades de pointes and sudden death2. Moreover
many Authors2,3 pointed out the presence, in patients treated with this drug, of prolonged QT and
afterdepolarizations. Experiments performed in isolated guinea pig hearts demonstrated that cisapride induced a
significant increase in monophasic action potential duration determined at 90% (MAPD90) and this drug resulted
to be a strong inhibitor of the rapid component of the cardiac delayed rectifier current (IKr)4. Cisapride
proarrhythmic effect depend upon: 1. plasmatic drug’s level; 2. biotrasformation capacity clearly linked to
cytocrome P4503A4 activity; 3. concurrent use of other drugs (imidazole, antifungal derivatives, macrolide
antibiotics, cimetidine et cetera) that inhibits cytocrome P4503A4 metabolism or in any case prolong QT interval
(diuretics, anthiarrhythmics, triciclic antidepressant et cetera); 4. reduced clearance (hepatic and or renal
insufficiency, heart failure); 5. concomitant heart disease. Moreover recent researches on dogs suggest that the
female sex hormone 17 beta-estradiol is an important risk factor of cisapride induced arrhythmias10. It seems
from other experiments on guinea pig and rabbit that a structurally related drug, mosapride, doesn’t have
electrophysiological features of relevance for induction of torsades de pointes like that of cisapride11.
Central nervous system agents - Tricyclic antidepressants (TCAs)
The cardiovascular effects of therapeutic and toxic levels of TCAs have been studied in adults and children12,13
and experimentally in animals and isolated tissues5,14,15. Besides orthostatic hypotension they can induce P-R,
Q-T and QRS prolongation5,15 and afterdepolarizations. Since more than 30 years there are many descriptions of
dangerous conduction trouble till complete heart block12 or life-trheatening ventricular arrhythmias12. Action
mechanism of TCAs seems to be the same of Class IA antiarrhythmic drugs that is Na fast channels block (INa).
Furthermore imipramine blocks the outward delayed rectifier K+ (Ik) and Ca2 (ICa) currents in guinea pig
ventricular myocites. Moreover whereas in bovine and guinea pig preparations imipramine shortens the MAP
duration it lengthens the MAP in rabbit and rat atrium5. The antiarrhythmic activity of imipramine and
nortriptyline was documented few years ago12 so that it has been used in clinical trials on prevention of
post-infarction arrhythmias together encainide, flecainide and moricizine13 but imipramine was less effective
and more frequently induced adverse effects.
Central nervous system agents - Tetracyclic antidepressant and anti-MAO
Maprotiline, a tetracyclic antidepressant that prolong QRS, induced supraventricular and ventricular tachycardia
and cardiac arrest expecially if overdosed6 and a proarrhythmic effect has also been shown for MAO inhibitors.
The mechanism is not certain but could be related to an increase of catecholamine level6.
Central nervous system agents - Selective serotonin reuptake inhibitors (SSRIs)
At least 3 reports described in past years ventricular ectopy and heart block during trazodone therapy6 but a
recent literature revision pointed out that SSRIs have significant advantages over TCAs producing fewer
cardiotoxic, anticholinergic and antisthaminergic effects6. However the results of some animal studies are not so
clear cut and Pacher et al5 recently demonstrated that fluoxetine and citalopram inhibited cardiac Na+ and Ca++
channels like they found for TCAs and these effects could explain the cardiac side effects described (bradycardia
in chronic therapy and atrial fibrillation in overdose). The Authors suggest that fluoxetine and citalopram may
have antiarrhythmic (class I+IV type) as well proarrhythmic properties due to impairment of AV or intraventricular
conduction and shortening of repolarization. Drugs therapeutic plasmatic levels generally don’t have
proarrhythmic effects but higher concentration can induce Na+ and Ca++ channels block and then cardiac
arrhythmias. Fluoxetine plasmatic level seems to correlate with: 1. metabolism reduction for aging, cardiac,
hepatic or renal insufficiency; 2. interference with other drugs metabolized by Cytocrome P4502D6 system
(antiarrhythmics, beta-blockers, litium, TCAs, neuroleptic drugs); 3. strong proteic binding and lipophylia.
Proarrhythmic effect of TACs and SSRIs is different from a quantitative and not qualitative point of view: SSRIs
seem to have a better therapeutic index.
Central nervous system agents - Ansiolitics
We didn’t find any report of arrhythmias during chronic therapy with diazepam even if Kumagai et al16
demonstrated in 20 patients, studied with electrophysiologic examination before and after intravenous infusion
of diazepam 0.2 mg/kg, significant shortening of the sinus cycle lenght and improvement in AV node conduction
and concluded that diazepam may influence the inducibility of supraventricular reentrant tachycardia
incorporating the AV Node.
Central nervous system agents - Neuroleptics
It has been sperimentally demonstrated14 in isolated spontaneously beating Purkinje fibers of guinea pig hearts
that some neuroleptic drugs like cloropromazine, thioridazine, trifluoperazine may be responsible for a rare
occurrence of early afterdepolarization in presence of hypokalemia.
Antimicrobial
Pentamidine, an old antiprotozoal, has been recently used in infectious deseases complicating AIDS. Recently
Wharton et al17 described 2 pts with AIDS and pneumocystis Carinii in whom torsades de pointes developed in
absence of any other cardiac and non cardiac predisposing factor and pointed out that other 2 cases of the same
arrhythmia during pentamidine therapy were been brought to their attention. QT lenghtening and ST-T
abnormalities were described in 23% of cases of Kala-azar during pentamidine treatment6. Wharton et al
proposed, as cause of proarrhythmic effect of this drug, its structural similarity to procainamide and also to its
high tissue and myocardial levels.
Amantadine
Antiviral drug used also in Parkinson’s disease. There is in literature just one report of torsade di pointes in a
young woman with an intentionale amantadine overdose6. Arrhythmia could be due to an extreme presynaptic
inhibition of catecholamine uptake: moreover there is a structural similarity with TCAs.
Eritromicine
There are many clinical reports6 associating long QT and torsades de pointes with eritromicine therapy.
Proarrhythmic effect of this and other macrolide antibiotics develops often when other drugs are
contemporaneously administered (quinidine18, disopiramide6, cisapride9). Two mechanisms have been
suggested to be responsable of arrhythmogenic action: 1. decreased cardiac contractility6; 2. hypokaliemia by
promotion of intracellular efflux of K+6. We want to emphasize again the role of cytocrome P4503A4. Finally in
the review of Martyn et al6 were reported 2 cases of ventricular tachycardia due to trimethoprim-sulfametoxazole
and cases of torsade de pointes with syncope due to clorochina.
Antihystaminics – Anti-H1
Astemizole and terfenadine are commonly prescribed drugs with over 2.5 millions astemizole prescriptions filled
in 1995 in USA19. Both drugs have been reported to induce QT prolongation and torsades de pointes and both
have been shown to block delayed rectifier K+ channels. Proarrhythmic action of astemizole is principally due to
its major metabolite desmethylastemizole that blocks with great affinity the repolarizing K+ current. This
metabolite, in vitro experiments, blocks iKr at concentrations that have been considered as therapeutic19.
Experimental study in dogs show that enhanced cardiotoxic effects of astemizole in ischemic hearts may be due
to increased activation delay in ischemic regions and increased effective refractory period dispersion in the
ventricle21. Terfenedine’s metabolite on the contrary do not block K+ channels19,20. For this drug it has been
demonstrated a dose related increase in QTc interval slightly superior in patients with heart disease than in
health ones. In absence of metabolic modifiers, such as ketoconazole or other drugs that inhibit the cytocrome
P450 system, the effect on QTc interval of the approved terfenedine dose (60 mg twice daily) is represented by
a lenghtening of 6-12 msec. Wether this slight terfenedine related increase translates to any increase risk of
torsade de pointes or sudden death is not known20. A recent experimental study of Carmeliet22 comparing
terfenedine and cetirizine seems to show that this last has minor effects on K+ currents and Author conclude
that the occurence of cardiac arrhythmias is therefore unlikely with this drug.
Drugs acting on respiratory system
A significant tachycardizing effect and a more slight but significant increase in mean hourly PVB frequency has
been described in patients with heart disease treated with association of beta 2 agonists and xantinic drugs
(theopylline, enprophylline)23.
Anaesthetic drugs
Many anaesthetic agents have been associated with arrhythmic events but in this case proarrhythmic action may
be exacerbated by perioperative events such as stress, catecholamines, autonomic imbalance, coexisting
medication etc6. Halotane has been traditionally considered to produce intraoperative arrhythmias because it
sensitizes the heart to the catecholamines action but it suppresses the arrhythmias associated with digitalis
intoxication. Actually the effect of halotane on ventricular arrhythmias depend upon the specific mechanisms
responsible for the arrhythmias. Halotane antagonizes arrhythmias due to abnormal automaticity and triggered
activity induced by afterdepolarizations whose mechanism depends upon Ca++ influx. This drug may be
beneficial in reentrant VT but, as all other antiarrhythmic agents, can be proarrhythmic24. Experimental studies
indicate that bupivacaine can induce arrhythmias just with low concentration expecially during ischemia; higher
concentrations seem to have antiarrhythmic effects even during ischemia25.
Miscellaneous
Steroids can increase catecolamine level: this is the most important mechanism suggested in case of arrhythmias
after steroid administration6. Probucol appears to have specie-specific proarrhythmic effects. In humans it
demonstrated, despite measurable increases in QT interval, lack of any casual link with arrhythmias6. Just one
case of VT with syncope has been described with pyridostigmine perhaps due to reentrant mechanism promoted
by anticholinesterasic action of this drug26.
Ketanserine reduce the calcium independent component of the transient outward potassium current (ITO).
Blockade of ITO could explain the proarrhythmic action of Ketanserine in vivo27. Fluconazole and ketoconazole,
antimicotic drugs, can induce metabolic derangement of many proarrhythmic substances bringing on their
plasmatic increase.
For other drugs (acetylsalicylic acid28, glibenclamide28, organophosphates6, saturated fatty acids30, aerosol
propellants31, oxygen free radicals32, endotheline33, cocaine34) experimental researches confirmed a possible
proarrhythmic action but we didn’t find any report of this effect in human beings.
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