Labetalol is a combined alpha- and beta-adrenoceptor blocking agent for oral and intravenous use in the treatment of hypertension. It is a nonselective antagonist at beta-adrenoceptors and a competitive antagonist of postsynaptic alpha 1-adrenoceptors. Labetalol is more potent at beta that at alpha 1 adrenoceptors in man; the ratio of beta-alpha antagonism is 3:1 after oral and 6.9:1 after intravenous administration. Labetalol is readily absorbed in man after oral administration, but the drug, which is lipid soluble, undergoes considerable hepatic first-pass metabolism and has an absolute bioavailability of approximately 25%. There are no active metabolites, and the elimination half-life of the drug is approximately 6 hours. Unlike conventional beta-adrenoceptor blocking drugs without intrinsic sympathomimetic activity, labetalol, when given acutely, produces a decrease in peripheral vascular resistance and blood pressure with little alteration in heart rate or cardiac output. However, like conventional beta-blockers, labetalol may influence the renin-angiotensin-aldosterone system and respiratory function. Clinical studies have shown that the antihypertensive efficacy of labetalol is superior to placebo and to diuretic therapy and is at least comparable to that of conventional beta-blockers, methyldopa, clonidine and various adrenergic neuronal blockers. Labetalol administered alone or with a diuretic is often effective when other antihypertensive regimens have failed. Studies have shown that labetalol is effective in the treatment of essential hypertension, renal hypertension, pheochromocytoma, pregnancy hypertension and hypertensive emergencies. In addition, preliminary studies indicate that labetalol may be of value in the management of ischemic heart disease. The most troublesome side effect of labetalol therapy is posture-related dizziness. Other reported side effects of the drug include gastrointestinal disturbances, tiredness, headache, scalp tingling, skin rashes, urinary retention and impotence. Side effects related to the beta-adrenoceptor blocking effect of labetalol, including asthma, heart failure and Raynaud's phenomenon, have been reported in rare instances.

1 This was a multicentre, double-blind, parallel study in 216 patients with mild to moderate (supine diastolic blood pressure = 95-115 mm Hg) essential hypertension. 2 After a 4-week placebo washout, patients were randomized to placebo or lisinopril 1.25, 5, 20 or 80 mg once daily for 6 consecutive weeks. Supine and erect blood pressure was measured 24 h postdose at the end of weeks -2, 0, 2, 4, and 6. 3 There was a linear dose-response relationship for both supine and erect blood pressure. Diastolic blood pressure reductions in the lisinopril 20 and 80 mg day-' groups were significantly greater than in the placebo or lisinopril 1.25 and 5 mg day-' groups. 4 Lisinopril, at doses up to 80 mg day-', was well tolerated.

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Two trials were conducted on the effects of adding alpha-adrenoreceptor blockers to the therapy of hypertensive patients already receiving a beta-adrenoreceptor blocking drug with or without a diuretic. The first trial was a single-blind study in which 6 patients receiving long-term combination therapy were crossed from prazosin, 6 to 15 mg/day, to a dose of indo ram in 10 times as large. There was significant bradycardia but little change in blood pressure. The second trial was a double-blind randomized crossover study in which 15 patients completed an 8-wk period of treatment with each of the alpha blockers, administered in random sequence with an intervening 2-wk washout period. Dosage was titrated for optimal antihypertensive effect.The final mean dosages were 76 mg /day for indoramin and 8.2 mg /day for prazosin; the dose ratio was 9.3: I. Both drugs reduced erect systolic blood pressure. Prazosin, but not indoramin, reduccd exercise systolic and diastolic pressures. Indoramin lowered supine and exercise pulse rates. Neither drug affected peak expiratory flow rate or plasma renin activity. Analysis of individual responses in supine diastolic blood pressure showed that there were 9 prazosin and 8 indoramin responders, while 9 of the 21 subjects in the 2 trials failed to respond to either drug. Central side effects were more prominent with indoramin. The combination of one or other of these alpha-adrenoreceptor blockers with preexisting beta-adrenoreceptor blockade improved blood pressure control in 57% of the patients.Indoramin and prazosin are post junctional alpha-adrenoreceptor blocking drugs 4 • 9 which lower blood pressure. 7. 13 Prazosin has been used extensively in the treatment of hypertension and has proved effective alone or in combination with other antihypertensive drugs, particularly beta-adrenoreceptor blockers. '2 Indoramin differs from prazosin in its capability to block histamine and 5-hydroxytryptamine receptors' and has been shown to have cardioinhibitory' and bronchodilator 3 properties. Given alone in sufficient dosage to control the blood pressure of hypertensive patients, indoramin has induced a high incidence of somnolence 5 ; its possible role in combination therapy has not been fully evaluated.

Guanabenz is acutely natriuretic and diuretic in saline expanded animals. In man, guanabenz has not resulted in sodium retention as seen with other comparable antihypertensives. To directly define the action of guanabenz on sodium and water excretion in man, we performed clearance studies during water diuresis on eight hypertensive subjects under metabolic balance conditions. Each subject underwent three studies: 1) baseline study: no drug, a water diuresis study; this was followed by a saline load (= 2% BW); 2) acute study (24 hr after baseline): 16 mg guanabenz PO; and 3) chronic study: after one week of guanabenz 8 mg PO BID. In the acute guanabenz studies there were: 1) no changes in GFR or ERPF; 2) an increase in both sodium excretion and fractional sodium excretion; 3) a rise in free H2O clearance (CH2O) and (CH2O/GFR) X 100%. These findings were not sustained in the chronic guanabenz studies. We conclude that in man (preconditioned with prior saline loading) guanabenz is acutely natriuretic and water diuretic. These effects are due to decreased tubular sodium and water reabsorption, probably related to inhibition of alpha adrenergic activity. The data are consistent with selectively reduced renal sympathetic activity affecting sodium transport and provide a basis for the absence of edema and sodium retention associated with guanabenz therapy.

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We compared the safety of a new dihydropyridine calcium entry blocker, isradipine, with an equipotent dose of diltiazem in 174 mild hypertensives (diastolic blood pressure [DBP] 95 to 105 mm Hg). After appropriate washout and placebo periods, patients were randomly assigned to receive either 1.25 mg isradipine twice daily (Group I) or 40 mg diltiazem thrice daily (Group D). If DBP remained above 90 mm Hg, doses were increased to a maximum of 5 mg isradipine twice daily or 120 mg diltiazem thrice daily. Active therapy was given for a total of 12 weeks. Only 18 patients (nine from each group) did not complete the protocol. The patients were well-matched at baseline with a mean BP of 149/100 mm Hg for those who were randomized to isradipine and completed the protocol and 153/99 mm Hg for the diltiazem group. The responses to each drug were excellent with 72% of the isradipine patients and 73% of the diltiazem group having DBP less than 90 mm Hg at the completion of the study. Of the 156 patients who completed the protocol, only 18 patients (ten in Group I and eight in Group D) failed to respond. Both drugs were well-tolerated. No adverse reactions were reported by 68 percent of the patients in Group I and 65% of those in Group D. The most common side effect was headache (9.0% in Group I and 7.8% in Group D) followed by fatigue (5.2% in Group I and 3.9% in Group D). Age and race did not predict response to either agent but men responded slightly better to diltiazem than women. We conclude that isradipine and diltiazem are equally well tolerated and can be used successfully as a monotherapy to treat hypertension in a wide variety of patients.