Clozapine tachycardia

Tacf7ycard/a- Tachycardia, which may be sustained, also has been observed in approximately 25% of patients taking clozapine. 

There are two classes of a-adrenergic receptors, aj and a2. Agents with the greatest affinity for aj blockade are chlorpromazine, thioridazine, and risperidone. There are no known beneficial effects associated with a -adrenergic receptor antagonism. However, aj-adrenergic receptor blockade can lead to hypotension, dizziness, and reflex tachycardia (Table 26.2). a2 Blockade is modest for most agents except for risperidone and clozapine. As with aj receptors, there are no benefits that have yet to be associated with a2 receptor... 

Cardiovascular effects. Hypotension and tachycardia occur in most patients taking clozapine. Cases of potentially fatal myocarditis and dilated cardiomyopathy have been reported in association with clozapine (Kilian et al. 1999). Myocarditis typically occurred within 3 weeks of starting clozapine, but cardiomyopathy may not be apparent for several years. Although rare, treatment-emergent myocarditis and cardiomyopathy occur at a reportedly higher incidence with clozapine than with other antipsychotics (Coulter et al. 2001). The mechanism by which clozapine may cause myocarditis has not been established, but some authors have speculated that clozapine may cause an immunoglobuhn E (IgE)-mediated type 1 hypersensitivity reaction (Kihan et al. 1999) or a hypereosinophilic syndrome (Hagg et al. 2001). 

Clozapine has also been compared with risperidone in 60 treatment-resistant patients with schizophrenia in India (16). There was clinical improvement (a more than 20% reduction from baseline PANSS scale scores) in 80% of the clozapine-treated patients and 67% of the risperidone-treated patients. The predominant adverse effects with clozapine (n = 30) were tachycardia (77%), hypersalivation (60%), sedation (60%), weight gain (43%), and constipation (30%) one patient had a seizure. The adverse effects of risperidone (n = 30) were constipation (50%), dry mouth (47%), weight gain (43%), akathisia (37%), insomnia (33%), tachycardia (30%), and impotence (27%). The final mean daily doses after 16 weeks of treatment were 343 mg for clozapine and 5.8 mg for risperidone. 

A 44-year-old man with no significant cardiac history was given clozapine and 12 days later had bibasal crackles in the chest and ST segment elevation in leads V2 and V3 of the electrocardiogram. He then developed ventricular tachycardia and needed resuscitation. He also developed atrial fibrillation for 24 hours, which subsequently resolved. 

A 22-year-old man developed atypical neuroleptic malignant syndrome while taking clozapine (104). He vomited and was sweating and agitated but afebrile, with mild hypertension (maximum 156/96 mmHg) and a tachycardia, with marked increases in white blood cell count (32 x 109/1), neutrophils (25 x 109/1), and creatine kinase (1442 IU/1) a similar syndrome occurred while he was taking haloperidol. 

Since the adverse effects of clozapine may be more common in children than adults, perhaps reflecting developmental pharmacokinetic differences, clozapine and its metabolites, norclozapine and clozapine-N-oxide, have been studied in six youths aged 9-16 years, with childhood onset schizophrenia (222). Dose-normalized concentrations of clozapine did not vary with age and were similar to reported adult values. Clinical improvement in five patients correlated with serum clozapine concentrations, and clinical response and total number of common adverse effects (sialorrhea, n = 5 tachycardia, n = 4 sedation, n = 1 enuresis, n = 1) correlated with norclozapine concentrations. One child had a reduced neutrophil count (1.1 x 109/1) and another child had increased hepatic transaminases. 

A 40-year-old man who took 3-4 g of clozapine became unconscious, with constricted pupils, sinus tachycardia, and twitching peak clozapine and norclozapine concentrations were 3.5 mg/1 and 0.7 mg/1 respectively, with secondary peaks at about 36 hours (240). Recovery was uneventful, and he was well 2 days after admission. 

A 20-year-old woman presented 6 hours after taking clozapine 3500 mg (242). She had unexpectedly prolonged tachycardia and somnolence, and recovered only after the serum clozapine concentration began to fall after a 4-day plateau. 

Tachycardia is the most common cardiovascular adverse effect of clozapine, and atrial fibrillation has also been reported (SEDA-22, 57) (20). 

It is generally considered that clozapine has little or no potential to cause tardive dystonia it has even been speculated that it may be an effective therapy for this adverse effect (SEDA-21, 53). The efficacy of clozapine in severe dystonia was therefore assessed in an open trial in five patients (74). All had significant improvement nevertheless, aU had adverse effects, such as sedation and orthostatic hypotension in one case persistent symptomatic orthostatic hjrpotension and tachycardia limited treatment. 

Of 524 inquiries received by the National Poisons Information Service concerning new neuroleptic drugs over 9 months, only 45 cases involved overdose with a single agent (olanzapine, n — 10 clozapine, n — 8 risperidone, n — 10 sulpiride, n = 16) (503). There were no deaths or cases of convulsions. Cardiac dysrhythmias occurred only with sulpiride. Symptoms were most marked with clozapine most patients had agitation, dystonia, central nervous system depression, and tachycardia. Most of the patients who had taken risperidone were asymptomatic. 

Clozapine, which is associated with higher risk of agranulocytosis and seizures, is indicated (25 mg once or twice daily) only in the management of schizophrenic patients who fail to respond adequately to standard antipsychotic drug treatment. On the other hand, it is relatively free from extrapyramidal side effects such as parkinsonism. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces as inactive demethylated, hydroxylated, and N-oxide derivatives. Clozapine has anticholinergic properties and causes tachycardia, and hence poses a serious risk for a patient with compromised cardiovascular function (see also Table 23). 

The antimuscarinic action of clozapine and thioridazine can cause tachycardia and enhance the peripheral and central effects (confusion, delirium) of other anticholinergic agents, such as the tricyclic antidepressants and antiparkinson agents. 

Physical examination revealed tachycardia with irregular heart rate, shallow respiration, decreased bowel sounds, dilated pupils, and hypertheimia. An ECG revealed a widened QRS complex with diffuse T wave changes. If this patient had taken a drug overdose the most likely causative agent was (A) Clozapine Fluoxetine Lithium Thioridazine Zolpidem... 

A. Mild intoxication causes sediation, small pupils, and orthostatic hypotension. Anticholinergic manifestations include dry mouth, absence of sweating, tachycardia, and urinary retention. Paradoxic ly, clozapine causes hypersalivation through an unknown mechanism. 

Beale MD, Pritchett JT, Kellner CH. Suimventricular tachycardia in a patient receiving ECT, clozapine, and caffeine. Convuls Ther ( 994) 10,228-31. 

The manufacturer of moclobemide noted that in 1992 there were data available from 110 patients given moclobemide 150 to 400 mg daily with various antipsychotks, namely acepromazine, aceprometazine, alimemazine, bromperidol, chlorpromazine, chlorprothixene, clothiapine, clozapine, cyamemazine, flupen-thixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, penfluridol, pipamperone, prothipendyl, sulpiride, thioridazine, or zuclopenthixoL There was no evidence of any clinically relevant interactions. There was, however, some evidence that hypotension, tachycardia, sieepiness, tremor and constipation were more common, suggesting synergistic adverse effects. ... 

Drag overdose Fatal and non-fatal cases of clozapine overdose have been reported [SED-15, 833 SEDA-32, 98]. The minimal dose for severe poisoning and the factors that influence acute human clozapine intoxication have been studied in 73 cases of acute clozapine monointoxication reported to the Swiss Toxicological Information Center [94 ]. The most common symptoms were central nervous system depression (63%), tachycardia (40%), restlessness/agitation (16%), confusion/disorientation (15%), dysarthria (15%), arterial hypertension (11%), bradykinesia (9.6%), respiratory depression... 

Resting tachycardia with chest pain/heart failure = stop clozapine, transfer to ED... 

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