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Cadralazine is a peripheral arteriolar vasodilator which, unlike hydralazine or dihydralazine, has a protected hydrazino group. In hypertensive patients the optimal effect, based on the antihypertensive efficacy to tolerability ratio, is seen after a 15mg dose when the drug is administered as monotherapy. When administered in combination with other antihypertensive agents, a 10mg daily dosage seems appropriate. Noncomparative trials have shown that, in patients who had failed to respond adequately to a β-blocker and/or diuretic, the addition of cadralazine 10 to 30mg once daily reduced systolic/diastolic blood pressure by 11 to 19%/13 to 22%. This antihypertensive effect becomes evident over a 2- to 6-week period of therapy and persists during longer term administration.
Comparative studies have shown that cadralazine is superior to placebo, and has a similar blood pressure lowering effect to hydralazine, dihydralazine and prazosin in patients not controlled by β-blocker and/or diuretic but who continued to receive these treatments. Similarly, cadralazine and chlorthalidone were equally effective in reducing blood pressure in resting hypertensive patients but cadralazine shows an advantage in reducing the pressor response in exercising patients.
Cadralazine is well tolerated when administered with a β-blocker or diuretic. Most adverse effects become less frequent and severe with continued use, occur more frequently at dosages of 20 mg/day or more, and do not generally require withdrawal of therapy. Manifestations of the drug’s vasodilating properties such as headache, asthenia, dizziness, palpitations and flushing are the most commonly reported symptoms during cadralazine monotherapy, but these may be reduced during combination therapy. The drug does not appear to induce a systemic lupus-like erythematosus syndrome, as may occur with hydralazine, but additional clinical experience is required to completely exclude this possibility.
In conclusion, because of its efficacy as a second- or third-line antihypertensive agent, its simple once daily dosage regimen and favourable risk: benefit ratio, cadralazine may have a useful role, particularly in those hypertensive patients who do not respond adequately to established antihypertensive treatments. However, the therapeutic potential of cadralazine cannot be clearly established until the present limited clinical base is expanded to include comparisons with other classes of vasodilating drugs (ACE inhibitors and calcium antagonists), and its utility in the management of other indications such as severe hypertension during pregnancy has been adequately explored.
Cadralazine administered as a single oral 7.5 to 30mg dose reduces systolic and diastolic blood pressure in patients with essential hypertension by up to 20/25%, with a 15mg dose producing an optimum effect. Lowering of blood pressure is thought to be mediated via reduction of peripheral vascular resistance as a result of arterial smooth muscle relaxation; peripheral vascular resistance is reduced by 20 to 30% after a single cadralazine dose in hypertensive patients. Cadralazine produces reflex tachycardia which persists but tends to diminish during long term treatment, and it also increases cardiac output by about 16% in elderly hypertensive patients during long term therapy. The drug does not seem to cause significant sodium or water retention and, like other vasodilators, stimulates the renin-angiotensin system. Cadralazine appears to have a profound vasodilatory effect on renal blood vessels which enables renal blood flow and renal function to be maintained despite a marked fall in systemic blood pressure.
Cadralazine is rapidly absorbed in healthy volunteers, and in patients with hypertension or chronic heart failure. Peak plasma concentrations of 130, 210 and 379 μg/L occurred after administration of 5, 10 and 20mg doses in healthy volunteers and similar concentrations were reported in hypertensive patients (224 and 568 ug/L following 15 and 30mg doses). After 12 hours, cadralazine is almost undetectable in plasma. Following absorption, cadralazine undergoes limited metabolism to at least 7 metabolites, one of which, the hydrazinopyridazine metabolite, has antihypertensive activity.
About 70 to 80% of an oral dose is recovered unchanged in urine within 24 hours. Faecal recovery represents about 5% of recovered drug. Elimination of cadralazine appears to be delayed in patients with hypertension or chronic heart failure compared with that reported in healthy volunteers; this may be due to impaired renal function in these patients.
Cadralazine has not been studied in large numbers of patients and comparative studies are few. Nonetheless, encouraging results from noncomparative studies show that cadralazine administered as a 10 to 30 mg/day dosage reduced supine and standing blood pressures when given as a second- or third-line antihypertensive therapy in hypertensive patients who had previously failed to respond satisfactorily to 0-blockers and/or diuretics and who continued to receive this therapy. Blood pressure reductions of 11 to 19%/13 to 22% have been reported in such patients and at least 70%, and in some cases 100%, of patients achieved target blood pressure (diastolic blood pressure ⩽ 95mm Hg). The antihypertensive effects of cadralazine were apparent within 2 weeks of starting treatment, persisted during longer term administration and were significantly superior to placebo.
Combined treatment with a vasodilator plus a diuretic or 0-blocker is significantly more effective than β-blocker monotherapy. Cadralazine and chlorthalidone show a similar antihypertensive efficacy in resting hypertensive patients who were also receiving a β-blocker. Both drugs reduce blood pressure within 2 weeks and this effect is maintained during treatment of up to 6 months. However, during exercise testing cadralazine is clearly superior to chlorthalidone in reducing the pressor response.
In comparative clinical trials, cadralazine, hydralazine, dihydralazine and prazosin were similarly effective in hypertensive patients who had inadequate blood pressure control with previous diuretic or β-blocker therapy.
Cadralazine is well tolerated when administered with a diuretic and/or β-blocker with most adverse effects being mild to moderate in nature, occurring more frequently at higher dosages (⩾ 20 mg/day), becoming less frequent with prolonged treatment, and rarely requiring withdrawal of therapy.
The most common adverse effects are typical of a drug which produces peripheral vasodilation and include headache, asthenia, dizziness, oedema, palpitations and flushing; these generally may be less frequent and severe during combination therapy. Other less common symptoms are formication, dyspnoea, gastralgia, nausea and insomnia. Cadralazine appears to be better tolerated than dihydralazine and does not appear to produce a systemic lupus erythematosus-like syndrome in patients who had developed the syndrome under hydralazine treatment. However, more patients need to be treated with the drug before this possibility can be definitely excluded. Cadralazine has no clinically relevant effects on renal or thyroid function, routine laboratory tests, or ECG.
Dosage and Administration
As a second- or third-line antihypertensive agent the usual oral dosage of cadralazine is 10 to 20mg once daily.
KeywordsHypertensive Patient Chronic Heart Failure Atenolol Essential Hypertension Prazosin
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