Bethanidine sulfate: efficacy in prevention of ventricular tachyarrhythmias during programmed stimulation. Report of a multicenter study of 56 patients.

Twelve cardiac electrophysiology centers conducted an open label prospective trial of bethanidine sulfate, an oral bretylium analog, for the prevention of ventricular tachyarrhythmias during programmed electrical stimulation. The study group included 56 patients (44 men, 12 women; mean age 60 years; 55 with structural heart disease). Sixteen patients had both ventricular tachycardia and fibrillation, 30 had ventricular tachycardia alone and 10 had ventricular fibrillation alone. Programmed stimulation on no antiarrhythmic drugs induced sustained ventricular tachycardia in 46 patients, nonsustained ventricular tachycardia in 4 patients and ventricular fibrillation in 6 patients. During programmed ventricular stimulation after 59 trials of 20 to 30 mg/kg body weight of oral bethanidine (acute dosing in 40 patients, and divided dosing over 24 hours in 19 patients), no ventricular tachyarrhythmias were inducible in 6 patients (11%), sustained ventricular tachycardia was converted to nonsustained ventricular tachycardia in 3 patients (5%), ventricular tachyarrhythmias remained inducible in 39 patients (70%) and spontaneous ventricular tachyarrhythmias occurred more frequently in 4 patients (7%). Side effects prevented repeat testing in four patients. The 10 patients presenting with only ventricular fibrillation appeared to have a higher response rate: no ventricular tachyarrhythmias were inducible in 2 patients and sustained ventricular tachycardia was converted to nonsustained ventricular tachycardia in 2 patients. Despite protriptyline administration in 54 of 59 bethanidine trials, symptomatic hypotension occurred in 30 trials (51%). In conclusion, the efficacy of bethanidine for preventing ventricular tachyarrhythmias as assessed by programmed stimulation is low. Patients presenting with only ventricular fibrillation may have a more favorable response to bethanidine sulfate. Symptomatic hypotension occurs frequently despite concomitant use of protriptyline.

Antiarrhythmic and electrophysiologic actions of bethanidine sulfate in primary ventricular fibrillation or life-threatening ventricular tachycardia.

Antiarrhythmic and electrophysiologic actions of bethanidine sulfate, a chemical analog of bretylium tosylate, were studied using programmed cardiac electrical stimulation in 14 survivors of out-of-hospital cardiac arrest unassociated with acute myocardial infarction. Before bethanidine sulfate was administered sustained ventricular tachyarrhythmias (VT) were inducible in 11 patients and reproducible nonsustained VT was induced in 3 patients. Bethanidine sulfate shortened sinus cycle length and absolute and relative ventricular refractory periods measured during sinus rhythm, but did not alter ventricular effective refractory period measured during ventricular pacing. Bethanidine sulfate prevented inducible VT in 8 patients (57%), increased the number of extrastimuli needed to induce VT in 2 patients, and was ineffective in 4 patients. In contrast, in only 1 of 26 trials with other conventional and investigational antiarrhythmic drugs in these patients was VT prevented. Orthostatic hypotension was a prominent side effect of bethanidine sulfate therapy, but could be reversed in most patients by concomitant administration of protriptyline. Five patients in whom bethanidine sulfate was effective in the laboratory have been treated chronically (400 to 600 mg 4 times daily), and all are alive at 3 to 40 months. In the remaining 9 patients, 8 were treated empirically because no drug was effective in the laboratory and 1 was treated with quinidine, which appeared to be protective during testing. Four of these 9 patients, including the patient treated with quinidine, died suddenly during follow-up. Thus, although bethanidine sulfate therapy is difficult to initiate because of orthostatic hypotensive side effects, it may be useful in treating patients at high risk of recurrent cardiac arrest.

Antiarrhythmic action of bethanidine.

Studies were performed in 20 patients with symptomatic ventricular tachycardia (VT) to determine the efficacy of bethanidine compared with procainamide in preventing VT induced by programmed electrical stimulation. Before administering bethanidine, 5 to 10 mg/kg, the patients received 15 mg of protriptyline orally 24 and 2 hours before electrophysiologic studies to prevent the orthostatic hypotensive effects of bethanidine. Sustained VT (VT not spontaneously stopping) was induced in 8 and nonsustained VT (10 beats or more, terminating spontaneously) was induced in 4 patients. Bethanidine, 5 mg/kg, protected in 7 patients, and 10 mg/kg protected 1 additional patient. Procainamide, 1,000 and 1,500 mg intravenously, protected 8 of 16 patients. Bethanidine prevented VT induction in 50% of the patients not protected by procainamide. Bethanidine facilitated VT induction in 3 patients, while procainamide facilitated VT induction in 1 patient. Four patients with symptomatic VT have received bethanidine therapy for an average of 11 +/- 1.3 months, without clinical recurrence of their VT. Concomitant administration of protriptyline attenuated the acute hemodynamic changes caused by bethanidine and chronic combined therapy of protriptyline and bethanidine abolished the severe orthostatic changes in blood pressure caused by bethanidine. These studies show that bethanidine is effective in preventing VT induction and, thus, its use may not be restricted only to cases of primary ventricular fibrillation.

Bethanidine sulfate in paroxysmal ventricular tachycardia: toxicity and antifibrillatory actions.

Programmed ventricular stimulation was used to test oral bethanidine sulfate in 10 patients with life-threatening ventricular arrhythmias. These patients had previously documented, recurrent, sustained ventricular tachycardia (VT) and/or ventricular fibrillation (VF) complicating stable heart disease. During control electrophysiologic studies, VT could be induced in all 10 patients: 6 with nonsustained VT, 3 with sustained VT, and 1 with VT/VF. After control, bethanidine 20-30 mg/kg was administered orally and beginning 60 minutes later, programmed ventricular stimulation was repeated. After bethanidine administration, VT could be induced in nine patients; in four, the VT was essentially unchanged from that induced during control studies. In four others, worse VT was induced after bethanidine. The remaining two patients had a potentially beneficial response to the drug. Bethanidine was poorly tolerated: seven patients had symptomatic orthostatic hypotension that persisted for several days despite concurrent protriptyline therapy. Furthermore, in four patients, spontaneous VT or VT/VF occurred 3-8 hours after the last dose. Nausea, vomiting, flushing, and blood pressure elevation were also noted. Bethanidine sulfate in the dosages used usually does not prevent the induction of VT by programmed ventricular stimulation and frequently causes serious toxicity. These findings suggest that the drug would be ineffective and poorly tolerated for long-term therapy in patients with serious ventricular arrhythmias.

Exertional hypotension due to postganglionic sympathetic blocking drugs.

Debrisoquine, guanethidine and bethanidine may produce troublesome hypotensive symtoms related to exertion. Thirteen patients with such symptoms were exercised on a treadmill and the response of blood pressure and heart rate was compared to that of thirty patients without these symptoms, who were exercised to the same extent. There was a slight drop of systolic and diastolic pressures on standing in both groups, but after exertion there was a significantly greater drop of systolic pressure in the group with symptoms than in the asymptomatic group. The diastolic pressure after exertion was significantly lower in the group with symptoms. It was impossible to predict from the standing blood pressure levels at rest which patients would develop hypotensive symptoms after exertion. All three drugs had a similar negative chronotropic effect at rest and on exercise. It is suggested that patients are exercised during control of hypertension in order to identify those prone to exertional hypotension. Patients with such hypotension should be exercised on each attendance before the blood pressure is measured. Treatment other than postganglionic sympathetic blocking drugs should be employed whenever possible in patients with milder hypertension.

Acute electrophysiologic effects of bethanidine sulfate in patients with ventricular tachycardia or fibrillation.

Ten patients with a history of ventricular tachycardia or ventricular fibrillation underwent electrophysiologic study with programmed stimulation before and 90 minutes after oral administration of bethanidine sulfate, 20 mg/kg. Mean plasma bethanidine concentration was 2.62 +/- 2.2 (+/- SD) micrograms/ml at the start of repeat testing. This dose of bethanidine produced no effect on sinus node function, atrioventricular conduction, or atrial or ventricular refractoriness. Ventricular tachycardia or fibrillation, inducible in all patients during the control study, could still be initiated by ventricular stimulation in 9 of 10 patients after bethanidine. Bethanidine suppressed the ability to initiate an arrhythmia in one patient with ventricular fibrillation during control stimulation. Orthostatic hypotension was seen in all patients despite pretreatment with the tricyclic antidepressant, protriptyline, 15 mg every 8 hours. The results suggest that bethanidine has few electrophysiologic effects and is of limited efficacy during electrophysiologic testing in patients with life-threatening ventricular arrhythmias.

Abrupt discontinuation of antihypertensive therapy.

The abrupt cessation of antihypertensive medication is usually without immediate consequence but may be associated with symptoms and signs of enhanced sympathetic activity, severe hypertension, morbid ischemic cardiovascular events, or death. This syndrome is more common after discontinuation of high doses of centrally acting antiadrenergic and beta-adrenergic blocking drugs or combination antihypertensive therapy, but it also occurs with numerous antihypertensive agents. Predisposing factors include ischemic heart disease, severe hypertension, renovascular or high renin hypertension, and high doses of multiple antihypertensive drugs. Gradual tapering of antihypertensive medications over seven to ten days will prevent symptoms and marked elevation of blood pressure. Should a discontinuation syndrome develop, re-administration of the drug previously discontinued is the most appropriate treatment.

Relationship of psychological factors to failure of antihypertensive drug treatment.

Personality traits and pretreatment symptoms of 69 hypertensive patients were documented with self-administered questionnaires. Thirteen patients (19%) dropped out during 12 months of treatment. Five of these were lost from follow up and eight failed to tolerate their allotted medication. In this series treatment failure did not seem dependent on the type of drug used, but was linked with a high suspiciousness level and a high pretreatment symptom score. Both measures varied independently of one another and a select group of 10 patients who scored highly on both, had a failure rate of 60%. Our results suggest that hypertensives with an increased predisposition to drug treatment failure can be identified at the pretreatment stage. Recognition of such individuals should assist in their routine clinical management and in the design of antihypertensive drug trials.

A comparison and an investigation of a potential synergistic effect of labetalol and bethanidine in patients with mild hypertension.

1 The effects of labetalol, bethanidine and combined treatment with both drugs were compared in a within-patient randomized cross-over study in mild essential hypertension. Attention was directed to whether or not labetalol and bethanidine differed in their pattern of effect on arterial BP and whether evidence of synergism was apparent. 2 At the doses used labetalol significantly lowered systolic and diastolic BPs and heart rate lying, sitting, standing and after exercise. The dose of bethanidine used did not affect heart rate significantly while lowering systolic and diastolic BPs only after exercise and less clearly on standing. Combined treatment lowered BPs on standing and after exercise and heart rate after exercise. 3 The type and frequency of side-effects were similar with bethanidine and labetalol but were much less with combined treatment. 4 No evidence of synergism was observed.

Factors predisposing to postural hypotensive symptoms in the treatment of high blood pressure.

Symptoms due to orthostatic and exertional hypotension occurred in 23-4 per cent of 448 hypertensive patients treated with guanethidine, debrisoquine, or bethanidine. Symptoms were significantly more frequent in patients treated with guanethidine than in those treated with bethanidine or debrisoquine. Women rather than men and patients with radiological evidence of cardiomegaly, electrocardiographic evidence of left ventricular hypertrophy, or ST/T wave changes, developed these symptoms significantly more often than other patients. A raised blood urea was found more frequently in patients with postural hypotensive symptoms. Characteristically guanethidine produced early morning postural hypotensive symptoms, wheras hypotensive symptoms caused by bethanidine and debrisoquine occurred at other times of the day and particularly one to two hours after tablet ingestion. Debrisoquine and guanethidine had a significantly greater negative chronotropic effect than bethanidine. It is suggested that negative chronotropic effects of these drugs may potentiate hypotensive symptoms in patients with cardiovascular, renal, or cerebrovascular disease. It should be possible to minimize symptoms of postural hypotension by attention to predisposing factors and selection of treatment accordingly.

Dihydroergotamine: an effective treatment for postural hypotension due to antihypertensive drugs (ganglion-blocking agents excepted).

In this study the effect of DHE on postural hypotension induced by major antihypertensive drugs was evaluated in 40 patients. 30 patients were treated with methyldopa, five with guanoxan sulphate and five with bethanidine sulphate. To obtain a more accurate picture of the effectiveness of DHE and to test the reproducibility of its effect, each patient was observed during five separate, successive periods: in the first period the antihypertensive agent was given alone; in the second period it was given along with placebo; in the third period it was given with DHE; in the fourth period the antihypertensive agent was given alone again; and in the fifth period it was again given with DHE. In the third and in the fifth period, DHE was administered at the same time as the antihypertensive agent in a dose of 9-15 mg/24 h (3-5 mg three times daily). The first dose was given 1 h before rising, and the daily dosage was progressively increased. The beneficial effect of DHE on postural hypotension was evaluated by assessing the clinical symptoms in a semiquantitative manner and by measuring the arterial blood pressure and heart rate in a recumbent and standing position. The results were classified as follows: excellent, good, moderate and no response. In most cases, DHE was found to be an effective drug for the treatment of postural hypotension, an improvement in clinical symptoms being noted in 57.5% of patients tested (excellent and good results). In these patients the standing arterial blood pressure showed a significant response (p less than 0.01). DHE did not interfere with the therapeutic effect of the antihypertensive agents. Furthermore, DHE did not affect the heart rate, nor did it give rise to any adverse reactions.

Patterns of blood-pressure during chronic administration of postganglionic sympathetic blocking drugs for hypertension.

Continuous recording of intra-arterial blood pressure in 11 ambulant patients taking postganglionic blocking drugs for the treatment of hypertension has shown an alternating pattern of high pressures at rest and very low pressures associated with exertion during normal daily activities. In 4 patients there was evidence of decreased cerebral or myocardial blood-flow during hypotensive episodes. It is suggested that these agents may predispose towards cerebral and myocardial infarction.

Antiarrhythmic drug therapy. Recent advances and current status.

A number of conventional and newer antiarrhythmic agents are available for the treatment and prophylaxis of ventricular tachycardia and sudden death. Using a multifaceted approach of programmed electrical stimulation studies, drug level determinations, exercise tolerance testing, and 24-hour ambulatory electrocardiographic monitoring, the physician can identify those patients who require therapy and then predict the likelihood of efficacy with each antiarrhythmic agent. This approach affords evaluation of both aspects of the sudden death equation-ectopy frequency (triggering mechanism) and vulnerability to development of sustained ventricular tachycardia (substrate). After institution of therapy, careful follow-up is necessary to document sustained drug efficacy and detect side effects. Serious adverse reactions necessitate a change in antiarrhythmic therapy, as opposed to lowering drug dosage to an ineffective level. The unacceptably high incidence of sudden death due to electrical instability can be reversed only by a rigorous and dedicated long-term approach to the management of serious ventricular arrhythmias.

Psychiatric side effects of antihypertensive drugs other than reserpine.

The psychiatric side effects of the major antihypertensive drugs other than reserpine are reviewed, including centrally acting drugs such as methyldopa and clonidine, peripheral adrenergic drugs such as guanethidine, beta-adrenoceptor blockers such as propranolol, and diuretics. Problems with differential diagnosis and with the interpretation of case reports make assessment of psychiatric side effects difficult. Sedation and sleep disturbances are the most common side effects, occurring with methyldopa, clonidine, and propranolol. Only methyldopa is clearly associated with depression. Other reported effects are toxic confusional states and psychotic reactions. These are rare, however, and no clear patterns of development have been recognized.