Labetalol: a review of its pharmacology and therapeutic use in hypertension.

Labetalol is an orally active adrenoceptor blocking drug which is a competitive antagonist at both alpha- and beta-adrenoceptor sites. Its beta-blocking effects resemble those of propranolol, but its overall haemodynamic effects are akin to those of a comination of propranolol and an alpha-adrenoceptor blocking drugs such as phenoxybenzamine. Unlike with conventional beta-adrenoceptor blocking drugs, acute administration of labetalol reduces peripheral vascular resistance and blood pressure and has little effect on cardiac output. Theoretically, labetalol has advantages over beta-adrenoceptor blocking drugs alone in the treatment of hypertension, but any real advantage, particulary in mild or moderate hypertension, has yet to be conclusively demonstrated in therapeutic trials. Labetalol may be particularly useful in some patients whose blood pressure is not adequately controlled by beta-adrenoceptor blocking drugs alone or combined with a diuretic, but possibly at the expense of a postural hypotensive effect. Postural hypotension is the most troublesome side-effect, occasionally necessitating withdrawal of therapy, but severe side-effects such as are seen with effective antihypertensive dosages of phenoxybenzamine do not occur with labetalol.     

Interactions of NSAIDs with diuretics and beta-blockers mechanisms and clinical implications

Indomethacin attenuates the antihypertensive effect of both thiazide diuretics and beta-adrenoceptor blocking drugs. The mechanisms of these interactions are poorly understood but sodium and water retention, suppression of plasma renin activity, alterations in adrenoceptor sensitivity and impaired synthesis of vasodilator prostaglandins may all contribute to this effect. Other non-steroidal anti-inflammatory drugs (NSAIDs) may share this property of indomethacin but sulindac, which is a selective inhibitor of extrarenal prostaglandin synthesis, appears not to. This may have important clinical and theoretical implications. Clinicians must beware of this potential interaction in any patient receiving treatment for hypertension. NSAIDs may also inhibit the natriuretic response to diuretics with resultant adverse effects in patients with heart failure and other forms of oedema. NSAIDs may also have adverse nephrotoxic effects which may be exacerbated by diuretic therapy.     

Long-term therapy of arterial hypertension with nifedipine given alone or in combination with a beta-adrenoceptor blocking agent

Summary The antihypertensive effect of nifedipine during long-term therapy was investigated in 5 patients receiving nifedipine as the sole drug and in 10 patients who had nifedipine in combination with a beta-adrenoceptor blocking drug. Nifedipine monotherapy was problematic because of side-effects and development of resistance to therapy after a few months. In patients who received the combined therapy significant and stable blood pressure reductions were maintained during the whole observation period (12–33 months). However, the occurrence of peripheral oedema in 4 of the patients necessitated the addition of a thiazide diuretic. It is concluded that nifedipine is not a first choice drug for the long-term treatment of arterial hypertension. When given in addition to a beta-blocker it is well tolerated and powerful but fluid retention may occur and if not counteracted by a diuretic it will limit the antihypertensive potential of the drug.     

Nisoldipine. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of angina pectoris, hypertension and related cardiovascular disorders

Nisoldipine is an orally administered calcium entry blocking drug structurally related to nifedipine. In limited clinical trials it has been shown to be effective and relatively well tolerated in the treatment of patients with chronic stable angina pectoris and mild to moderate essential hypertension. As for all dihydropyridine-calcium antagonists, its major properties include potent peripheral and coronary vasodilation and improvement in myocardial oxygen supply relative to demand. These actions occur without depression of cardiac conduction or left ventricular function. Short term clinical trials have shown nisoldipine to produce both symptomatic and objective improvements in patients with chronic angina of effort and have suggested a benefit in vasospastic angina. A small number of comparative trials indicate that nisoldipine is equally as effective as nifedipine. In addition, in combination with beta-adrenoceptor blockade nisoldipine appears to offer additional benefit compared with beta-blockade alone and is well tolerated. In patients with mild to moderate essential hypertension nisoldipine monotherapy, in 1 or 2 daily doses, has maintained blood pressure control and has also been a useful addition to diuretics and beta-adrenoceptor blocking drugs in patients with poorly controlled disease. Side effects appear to be dose related, generally mild and transient, and are primarily those resulting from potent peripheral vasodilation - headache, flushing and pretibial or ankle oedema. Although studies to date are promising, there are no published long term studies (greater than 1 year) of nisoldipine in comparison with other calcium entry blockers and other drugs currently in clinical use for the treatment of angina pectoris or hypertension. Until such studies are completed the exact place of nisoldipine in the treatment of these diseases remains to be established.     

Indapamide. A review of its pharmacodynamic properties and therapeutic efficacy in hypertension

Indapamide is an orally active sulphonamide diuretic agent. Although some evidence appears to indicate that the antihypertensive action of indapamide is primarily a result of its diuretic activity, only a limited diuresis occurs with the usual antihypertensive doses of 2.5 mg daily, and in vitro and in vivo data suggest that it may also reduce blood pressure by decreasing vascular reactivity and peripheral vascular resistance. In mild to moderate hypertension it is as effective as thiazide diuretics and beta-adrenergic blocking agents in lowering blood pressure when used as the sole treatment. Indapamide has been successfully combined with beta-adrenergic blocking agents, methyldopa, and other anti-hypertensive agents. While such findings need confirmation, it appears that indapamide shares the potential with other diuretic agents to induce electrolyte and other metabolic abnormalities, although it may do so with less frequency or severity. Thus, indapamide appears to offer a suitable alternative to more established drugs as a 'first-line' treatment in patients with mild to moderate hypertension. Whether it differs significantly from other diuretics when used as antihypertensive therapy, either in its mode of action or its side effect profile, needs further clarification.     

Effect of diuretic, beta-adrenoceptor blocking agent and their combination on elevated blood pressure and serum potassium: a cross-over study.

1. The antihypertensive effect of a new beta-adrenoceptor blocking agent, trimepranol (10--14 mg/twice daily), chlorthalidone (50 mg every second day) and their combination was studied in eighteen patients with mild to moderate essential hypertension. In a controlled randomized cross-over study the drugs were given for 6 week periods. 2. A significant and equal decrease in blood pressure was achieved both with trimepranol and chlorthalidone, whereas their combination was significantly more effective. 3. Trimepranol significantly antagonized the chlorthalidone-induced hypokalemia. 4. The results favor the use of diuretic or diuretic-beta-adrenoceptor blocker combination over beta-adrenoceptor blocker monotherapy in the treatment of mild to moderate hypertension.     

Pinacidil monohydrate—a novel vasodilator: Review of preclinical pharmacology and mechanism of action

Pinacidil dose-dependently decreased blood pressure in normotensive, renal hypertensive, spontaneously hypertensive, and neurogenic hypertensive rats; in anesthetized cats; and in normotensive and renal hypertensive dogs by a mechanism associated with decreased total peripheral resistance and reflex tachycardia. Pinacidil was 2–4-fold more potent as an antihypertensive than hydralazine. Antihypertensive activity of pinacidil was not modified by α, β, cholinergic, or histaminergic receptor antagonists and was not associated with calcium channel blockade, activation of cyclooxygenase, or formation of the vasodilator, adenosine. In vitro, pinacidil relaxed blood vessels contracted with several agonists by a mechanism that was independent of an intact endothelium, did not increase either CAMP or cGMP, and was approximately 700 times more potent than minoxidil or hydralazine. Thus, pinacidil is a direct-acting vasodilator, whereas minoxidil and hydralazine must be metabolized to a vasoactive species or exert some indirect effect for anithypertensive activity in vivo. Pinacidil lowered blood pressure in decerebrated cats, and only trace amounts of radiolabeled pinacidil distributed to the brain, suggesting minimal central effects. Pinacidil was rapidly absorbed after oral administration in rats, dogs, and man, showing a plasma half-life of approximately 30 min in all three species with peak plasma levels within 30 to 60 min. The major biotransformation product of pinacidil in rats, dogs, and man was pinacidil-N-oxide; and renal excretion was the main elimination pathway for both agents. Pinacidil-N-oxide was less potent than pinacidil as an antihypertensive agent and showed approximately 10–100-fold less vasodilation than pinacidil in vitro. In summary, pinacidil is a clinically effective novel antihypertensive agent that nonselectively inhibits contractile responses of arterial and other smooth muscle.     

Preliminary evaluation of pinacidil in hypertension

In a balanced single-blind placebo controlled study in six hypertensive patients treated with diuretic and beta-adrenoceptor blocker, a single oral dose of 10 mg pinacidil lowered blood pressure significantly, by a maximum of 26/13 mm Hg lying and 15/12 mm Hg standing at 3 h. The duration of action was less than 6 h. Chronic treatment of four patients (mean dose 20 mg twice daily for 3--7 weeks) lowered blood pressure by only 15/7 mm Hg. All four patients experienced side-effects of the type often observed during treatment with potent vasodilators. In the formulation studied pinacidil is unlikely to offer any advantage over the antihypertensive drugs currently available.     

Acute hemodynamic effects of pinacidil in hypertensive patients with and without propranolol pretreatment

To study the systemic and regional hemodynamic effects of the new antihypertensive agent pinacidil, the authors administered intravenously two doses of pinacidil (0.1 mg/kg) to patients with hypertension after 3 days of randomized, double-blind pretreatment with either propranolol or placebo. Pinacidil administration decreased systemic arterial pressure and total peripheral vascular resistance in both groups of patients. It also decreased pulmonary artery wedge pressure, and increased cardiac output, heart rate, and plasma norepinephrine levels; the changes in cardiac output and heart rate were attenuated by propranolol pretreatment. In addition, propranolol-pretreated patients responded to pinacidil with a decrease in forearm blood flow. In contrast, pinacidil administration exerted no significant effects on right atrial pressure, stroke volume, or mean pulmonary arterial pressure alone or in combination with propranolol. The results show that pinacidil is a potent arterial dilator but has little effect on the venomotor tone in patients with hypertension.     

Arterial hypertension: second-line treatment. Try other single-agent treatments

(1) Reliable evidence supports the use of thiazide diuretics (chlortalidone or hydrochlorothiazide) as first-line treatment for uncomplicated arterial hypertension. (2) When patients fail to reach blood pressure targets with well-conducted treatment with thiazide diuretics, or this treatment is poorly tolerated, what are the best second-line options? To answer this question, we reviewed the available evidence, based on our standard in-house methodology. (3) We found no published trials specifically designed to evaluate second-line antihypertensive treatments in cardiovascular prevention. There were no available trials of dual- versus single-agent therapy after failure of a thiazide diuretic. (4) When the blood pressure target is not reached, inadequate drug efficacy is only one of several possible causes. Various other factors affecting blood pressure should also be investigated. (5) Dual-agent therapy carries an increased risk of adverse effects and drug interactions compared to monotherapy. (6) There is no consensus among clinical practice guidelines on second-line antihypertensive therapy. However, to minimise the risk of adverse effects, it is clearly better to select single-agent therapy with a drug that has been shown to prevent cardiovascular events in first-line treatment of otherwise healthy hypertensive patients. Possible options include: angiotensin-converting-enzyme inhibitors, angiotensin II antagonists, calcium channel blockers or betablockers. In patients over the age of 60, betablockers seem less effective that the other drugs in preventing strokes. (7) There is too little evidence to choose a specific third-line combination rather than another. However, any adverse effects that the patient experienced during prior treatments should be taken into account.     

Pinacidil,a new vasodilator,in the treatment of mild to moderate essential hypertension

Summary Twenty three patients with essential hypertension who were uncontrolled on diuretic and/or -receptor antagonist therapy were treated additionally with the vasodilator, pinacidil, in an open study. Significant reduction in mean blood pressure was achieved. Supine and erect systolic and diastolic blood pressure fell by 44/25 mmHg and 37/24 mmHg respectively over the study period of 12 weeks. Side-effects such as dizziness, headache, facial flushing and mild oedema were experienced by 10 patients during the study, all of which were mild and transient and did not require withdrawal from pinacidil therapy. Pinacidil is an effective and well tolerated agent in the treatment of essential hypertension.     

Evaluation of indoramin added to oxprenolol and bendrofluazide as a third agent in severe hypertension.

1 Indoramin, an alpha-adrenoreceptor blocking agent has been given as a third agent to patients with severe hypertension treated with adequate doses of a beta-adrenoceptor blocking drug and a thiazide diuretic. 2 A further fall in blood pressure followed the addition of indoramin. With 75 mg twice daily this was on average a fall of 12% of mean arterial pressure in the supine position, 16% standing an 17% after exercise. 3 The rise in blood pressure caused by isometric exercise was not altered by indoramin. 4 Indoramin slowed the heart rate. On 75 mg twice daily the reduction was 14% at rest and 19% after exercise. 5 Side effects of indoramin were sedation, sleep disturbance and vivid dreams.     

Antihypertensive and renal haemodynamic effects of atenolol and nadolol in elderly hypertensive patients.

As little is known of the antihypertensive efficacy or renal haemodynamic effects of beta-adrenoceptor blocking drugs in the elderly we studied two such drugs, atenolol and nadolol, in elderly hypertensive patients. Ten patients took part in a placebo-controlled double-blind study of atenolol and 10 received nadolol in a single-blind placebo-controlled study. Treatment phases lasted 12 weeks for atenolol or 10 weeks for nadolol. Blood pressure, effective renal blood flow and glomerular filtration rate data obtained at the end of each treatment phase were analysed. Atenolol lowered mean arterial pressure (mean +/- s.e. mean) from 129.9 +/- 1.5 to 108.2 +/- 2.3 mm Hg (P less than 0.01) while it increased mean effective renal blood flow 512.5 +/- 86.6 to 646.0 +/- 116.1 ml min-1 1.73 m-2 (P less than 0.05). Nadolol reduced mean arterial pressure from 133.2 +/- 2.0 to 113.5 +/- 3 mm Hg (P less than 0.001) but reduced mean effective renal blood flow from 558.8 +/- 32.2 to 446.0 +/- 26.9 ml min-1 1.73 m-2 (P less than 0.05). Glomerular filtration did not alter significantly with either drug. We conclude that beta-adrenoceptor blocking drugs are effective antihypertensive agents in the elderly but have disparate effects on effective renal blood flow perhaps because of differences in cardioselectivity. These data suggest that comparative studies with thiazide diuretics and beta-adrenoceptor blocking drugs are warranted in elderly hypertensives.     

Effect of pinacidil on blood pressure,plasma catecholamines and plasma renin activity in essential hypertension

Summary Pinacidil, a new cyanoguanidine derivative, is an antihypertensive agent with arteriolar vasodilating properties, which acts on precapillary resistance vessels. A trial was carried out in 30 patients with essential hypertension WHO I-II. The treatment period was divided into three phases. Hydrochlorothiazide (HCTZ) and amiloride were administered for 4 weeks in Phase 1 and supine and standing blood pressure decreased significantly. During Phase 2 pinacidil was added to HCTZ/amiloride for the following 3 months. A further significant reduction in blood pressure was obtained. In the next period of treatment (Phase 3) patients were divided into two groups. For 1 month Group A (15 patients) received pinacidil alone and Group B (15 patients) received HCTZ/amiloride. Conventional laboratory blood tests in all patients remained unchanged during treatment. Reported side effects during Phase 2 were headache (2 patients), dizziness (3 patients), palpitations (2 patients) and ankle oedema (2 patients). Plasma renin activity was slightly increased at the end both of Phases 1 and 2. Plasma catecholamines were increased but not significantly at the end of Phase 2 as compared to Phase 1. The results indicate that pinacidil is effective in lowering blood pressure in mild to moderate essential hypertension.     

Adult hypertension: reducing cardiovascular morbidity and mortality

(1) Since our last review of treatments for arterial hypertension in 1999 (Prescrire International no.41), many new data have been published and new antihypertensive drugs have appeared on the market. (2) The working definition of hypertension is unchanged, namely blood pressure of at least 160/95 mm Hg in the general population, and at least 140/80 mm Hg in patients with diabetes and a history of stroke; these figures must be found on several occasions using a standardised method, with the patient at rest. (3) The goals of antihypertensive therapy are to reduce mortality and cardiovascular events, and not simply to drive blood pressure below a fixed (and often controversial) threshold. (4) Some drug and non drug interventions have a positive risk-benefit balance in the long term. (5) When antihypertensive drug therapy is needed, trials based on clinical endpoints show that it is best to start treatment with a single drug. (6) New data support the use of certain thiazide diuretics (chlortalidone, or hydrochlorothiazide if chlortalidone is not available) as first line treatment for most hypertensive patients, including non diabetic adults, diabetic adults, elderly subjects (over 65 years), and stroke patients. Some betablockers and angiotensin-converting-enzyme inhibitors (ACE inhibitor) are second-line alternatives. (7) Assessment of other antihypertensive drugs has also progressed since 1999, including indapamide (thiazide-like diuretic), amlodipine, diltiazem and verapamil (calcium channel blockers), lisinopril (ACE inhibitor), and losartan and valsartan (angiotensin II antagonists). However, these drugs are not as thoroughly evaluated as thiazide diuretics, betablockers and some ACE inhibitors.     

Antihypertensive efficacy of pinacidil — Automatic ambulatory blood pressure monitoring

Summary Forty-three patients with mild essential hypertension were randomized into two double-blind studies: pinacidil vs. placebo or pinacidil vs. hydralazine. Pinacidil (62±18 mg/day) decreased office systolic and diastolic blood pressures from 145 to 137 mm Hg and from 98 to 89 mm Hg, respectively, after 6 weeks of therapy. Similarly, hydralazine (128±28 mg/day) reduced supine systolic blood pressure from 140 to 134 mm Hg and supine diastolic blood pressure from 93 mm Hg to 84 mm Hg. Significant tachycardia was not noted with either drug. Ambulatory blood pressure was monitored for 24 h during the placebo-washout and efficacy phases with both pinacidil and hydralazine. Mean 24-h blood pressure was 128 systolic and 81 diastolic with pinacidil and 121 systolic and 76 diastolic with hydralazine. Reduction in awake hypertensive diastolic blood pressure was significant for both pinacidil and hydralazine. Normal sleep diastolic blood pressure was not reduced by pinacidil but was reduced by hydralazine. Side-effects with both drugs included edema, headache, and palpitations. These data demonstrate that pinacidil is as effective an antihypertensive agent as hydralazine.     

Transdermal clonidine. A preliminary review of its pharmacodynamic properties and therapeutic efficacy

The clonidine transdermal therapeutic system (TTS) is a cutaneous delivery device which provides therapeutically effective doses of clonidine at a constant rate over 7 days. In clinical trials it reduces blood pressure in patients with mild to moderate hypertension as effectively as oral clonidine but with greater stability of blood pressure control. Most patients find the transdermal system more convenient than oral treatments, and compliance may be improved. The side effects known to occur with orally administered clonidine, dry mouth and sedation in particular, are also produced with transdermal administration, but possibly at a lower incidence than during oral treatment. A proportion of patients experience adverse skin reactions with the transdermal system. At this stage of its development, transdermal clonidine has not been adequately compared with other 'standard' antihypertensive treatments such as diuretics or beta-adrenoceptor blocking drugs. However, despite the lack of such comparative studies, transdermal clonidine represents a worthwhile new approach to antihypertensive therapy, particularly in terms of patient convenience.     

The management of hypertension in the overweight and obese patient: is weight reduction sufficient?

The management of hypertension in the overweight and obese patient is a frequently encountered but under investigated clinical problem. The conventional management of such patients involves weight reduction with dietary therapy or a combined approach with dietary and anti-obesity drug therapy. However, long-term weight reduction, which is necessary to sustain blood pressure (BP) control, is not feasible in over 80% of patients. Anti-obesity therapy with orlistat has inconsistent effects on BP and may benefit only patients who have uncontrolled or non-medicated hypertension. Anti-obesity therapy with sibutramine may be associated with a modest worsening of BP control. Consequently, antihypertensive drug therapy is often required to supplement a weight reduction programme, and also in patients with severe hypertension or hypertension-associated end-organ damage. Treatment with a thiazide diuretic should be considered as first-line antihypertensive drug therapy in overweight and obese patients. ACE inhibitors or non-dihydropyridine calcium channel antagonists are reasonable alternatives where clinically indicated, or they can be used in combination with a thiazide diuretic if treatment with the diuretic alone is insufficient. If such treatment is inadequate for BP control, the addition or substitution of an alpha- or beta-adrenoceptor antagonist may be considered, although the latter can be associated with weight gain. Concurrent disease is an important determinant of first-line and supplementary antihypertensive drug therapy. Additional studies are needed to determine the long-term (>1 year) efficacy and safety of antihypertensive and anti-obesity management strategies in the overweight and obese hypertensive patient.     

Labetalol: A Review of Its Pharmacology,Pharmacokinetics, Clinical Uses and Adverse Effects

Labetalol is a combined alpha- and beta-adenoceptor blocking agent for oral and intravenous use in the treatment of hypertension. It is a nonselective competitive antagonist at beta-adrenoceptors and a competitive antagonist of postsynaptic alpha₁-adrenoceptors. Labetalol is more potent at beta than at alpha₁ 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.     

Antihypertensive effect of a non-selective (propranolol) and a cardioselective (metoprolol) beta-adrenoceptor blocking agent at rest and during exercise.

1 The antihypertensive effects at rest and during physical exercise of the non-selective beta-adrenoceptor blocker propranolol and the cardioselective beta-adrenoceptor blocker metoprolol were compared in a double-blind cross-over study. 2 Eighteen patients with mild hypertension entered the trial. One patient was withdrawn from the study due to side effects on both drugs. 3 The two beta-adrenoceptor blockers were compared using doses earlier shown to have the same beta-adrenoceptor blocking potency, as measured by their effect on exercise tachycardia in healthy men. 4 Arterial blood pressure was reduced to the same extent by propranolol and metoprolol at rest as well as during submaximal work. 5 It is concluded that the antihypertensive effect of beta-adrenoceptor blockers is mainly mediated through blockade of the beta 1-adrenoceptors.