SynopsisPinacidil is an orally administered antihypertensive drug that acts via direct relaxation of vascular smooth muscle to produce peripheral vasodilatation and a reduction in blood pressure without significant direct effects on cardiac electrophysiology. Pinacidil is unrelated to other antihypertensive drugs in clinical use, either in structure or mechanism of action. It belongs to a new class of agents called ‘potassium channel openers’ which act via potassium efflux to hyperpolarise cell membranes, indirectly causing a net reduction in intracellular calcium that leads to relaxation of vascular smooth muscle.Pinacidil is indicated in the management of essential hypertension. In clinical trials of up to 1 year, duration, pinacidil administered twice daily in a controlled release capsule formulation has been shown to achieve adequate blood pressure control both in previously untreated patients and in those with blood pressure inadequately controlled by &bgr;-adrenoceptor blocking drugs or thiazide diuretics. In long term (up to 1 year) comparative studies pinacidil was at least as effective as hydralazine, prazosin or nifedipine in maintaining blood pressure control. Pinacidil may also have a potential use in the treatment of patients with secondary renal hypertension.Clinical trials to date have usually allowed the addition of a thiazide diuretic and/or &bgr;-adrenoceptor blocking drug to enhance the efficacy of pinacidil and/or to reduce the incidence of adverse effects.The main adverse effects of pinacidil treatment, which result from its peripheral vasodilator activity, are headache, oedema, palpitations and tachycardia. Although the over-all incidence of adverse effects is quite high, they are usually mild, transient in nature and respond to a reduction in dose. Nevertheless, these effects may occasionally be severe, necessitating withdrawal from therapy.Thus, pinacidil is an effective antihypertensive drug for the treatment of mild to moderate essential hypertension. Despite its novel mechanism of action pinacidil causes adverse effects typical of peripheral vasodilators; during long term use with twice daily administration of the controlled release capsule formulation, the addition of a diuretic is often necessary to attenuate peripheral oedema and maintain adequate control of blood pressure. Further long term controlled trials are needed to determine the precise role of pinacidil relative to that of the angiotensin converting enzyme (ACE) inhibitors and calcium channel blocking drugs.Pharmacodynamic PropertiesPinacidil is a peripheral vasodilator belonging to a novel class of drugs known as ‘potassium channel openers’. The opening of potassium channels in smooth muscle cells results in potassium efflux and a negative shift in the resting membrane potential, causing hyperpolarisation of the cells at rest. The net result is a decrease in intracellular calcium and relaxation of smooth muscle, particularly in the vasculature.The primary haemodynamic effect of pinacidil is peripheral vasodilatation leading to significant decreases in both systolic and diastolic blood pressures and a reflex increase in heart rate. These effects are dose related over the range of oral doses of pinacidil of 10 to 37.5mg. Administration of a conventional tablet formulation provides a rapid onset of action, with a maximum antihypertensive effect in 1 to 3 hours and a return to baseline values within 6 hours. This short duration of action prompted the development of a controlled release capsule formulation containing micropellets of pinacidil, which extends the duration of the antihypertensive effect to between 8 and 12 hours. Pinacidil in this formulation has been administered twice daily in most of the clinical trials.Single dose intravenous administration of pinacidil (0.2 mg/kg) to patients with hypertension or cardiovascular disease produced a significant decrease in systemic vascular resistance (28 to 40%), resulting in a decrease in systolic and diastolic blood pressures in the order of 20%, and reflex increases in heart rate (11 to 36%) and cardiac index (25 to 29%). The effects on cardiac haemodynamics could be abolished by &bgr;-adrenoceptor blockade, indicating that they are the result of arteriolar vasodilatation and not of any direct cardiostimulatory effect of pinacidil. Cardiac haemodynamic effects appear to be attenuated during long term oral therapy. Although pinacidil has demonstrated negative inotropic activity in animal models, the plasma concentrations required would probably not be achieved clinically and thus any marked effect on action potential duration or cardiac contractility would be unlikely.The potent effect of pinacidil in reducing systemic vascular resistance would be expected to result in a reflex increase in sympathetic outflow, an increase in plasma renin and aldosterone release and retention of sodium and water. In hypertensive patients such effects have been demonstrated following acute administration of the drug. However, the effects of long term therapy are more variable and their quantification is confounded by the frequent concomitant administration of both thiazide diuretics and &bgr;-adrenoceptor blocking drugs. Thus, the extent of the effect of long term pinacidil monotherapy on these parameters remains unclear.Pharmacokinetic PropertiesThe oral bioavailability of the controlled release capsule formulation of pinacidil in healthy volunteers is 57%. The parent compound undergoes rapid metabolism with 25% of a systemically available dose found in plasma as the major metabolite, pinacidil-N-oxide, and 17% found as other unidentified metabolites. TheN-oxide metabolite also has blood pressure-lowering activity but has approximately one-quarter the potency of pinacidil.The maximum plasma concentration of pinacidil increases linearly with dose in the range 12.5 to 75mg, the ‘average’ plasma concentration being 268 &mgr;g/L for each 1 mg/kg bodyweight of pinacidil administered. The peak plasma concentration of the rapidly released pellets occurs at approximately 1 hour, with a further peak from the slow release portion of the formulation at 4 to 6 hours. The area under the plasma concentration-time curve (AUC) is also linearly related to dose. Accumulation of pinacidil has not been demonstrated with long term administration of the drug.The volume of distribution of pinacidil after an intravenous infusion is in the order of 1.1 to 1.4 L/kg, and plasma protein binding was approximately 39% over a range of plasma pinacidil concentrations of 43 to 435 &mgr;g/L in one study, although binding of 60 to 65% was reported in another.Metabolism and elimination of pinacidil involve hepatic biotransformation via the cytochrome P450 enzyme system followed by renal excretion of metabolites. The appearance in plasma of the major metabolite, pinacidil-N-oxide, is rapid, with a peak plasma concentration (at 4 hours) and AUC which are linearly related to dose. The accumulation of theN-oxide metabolite has been demonstrated in both healthy volunteers and in hypertensive patients during long term pinacidil therapy and is directly related to increasing age and deteriorating renal function.The 24-hour urinary excretion values range from 1.3 to 6.9% for pinacidil and 25.1 to 68.3% for the metabolite. Faecal excretion as determined from animal data appears not to be significant.The elimination half-lives of pinacidil and pinacidil-N-oxide with the controlled release formulation are in the order of 1 to 3 and 4 hours, respectively. The clearance of both parent compound and major metabolite is reduced with increasing age and the peak plasma concentration of metabolite rises as creatinine clearance decreases. Liver disease also increases the plasma concentration and the elimination half-life of pinacidil and pinacidil-N-oxide, and impaired hepatic oxidising ability leads to reduced recovery of metabolite in the urine.A linear correlation between plasma concentration of pinacidil and decrease in blood pressure has been demonstrated in several studies using single oral doses of pinacidil and in some long term trials over 1 to 3 months. However, other studies have not confirmed this relationship, indicating that other factors may be involved in the determination of antihypertensive response in the long term.Therapeutic TrialsThe efficacy of pinacidil in the treatment of mild to moderate essential hypertension has been demonstrated in several short term noncomparative and controlled clinical trials and in a few longer studies of more than 12 months' duration. Some studies utilised pinacidil as monotherapy, although in the great majority a diuretic and/or &bgr;-adrenoceptor blocking drug was added. These drugs had failed to control blood pressure adequately in most patients prior to the studies. The daily dose of pinacidil in individual studies ranged from 20 to 100mg (mean range 32 to 57mg) and the average reduction in pressures achieved ranged from 9 to 44mm Hg systolic and 7 to 25mm Hg diastolic in the supine position and from 25 to 37mm Hg systolic and 13 to 24mm Hg diastolic in the erect position. The duration of effect with the controlled release formulation appeared to make twice daily dosing practicable, although continuous ambulatory blood pressure recording demonstrated a gradual rise in blood pressure from 6 hours after the dose of pinacidil and a loss of blood pressure control prior to the next dose in some patients. The addition of a thiazide diuretic was found to improve efficacy and to alleviate the common adverse effects of oedema and weight gain. Tolerance to the antihypertensive effects of pinacidil did not occur during the studies and there was no rebound hypertensive effect when therapy with pinacidil was abruptly withdrawn, blood pressure readings slowly returning toward pretreatment levels over a 1- to 2-week period.Blood pressure control with pinacidil, usually combined with a diuretic and/or adrenoceptor blocking drug, was also achieved over a prolonged period (mean 43 weeks) in a small number of patients with hypertension secondary to renal disease. No tolerance occurred and tachycardia, oedema and weight gain were not a problem.When compared with placebo pinacidil monotherapy was significantly more effective, controlling blood pressure to target levels in 67 to 87% of patients. Concomitant administration of pinacidil with hydrochlorothiazide was also more effective than the diuretic plus placebo. Furthermore, the incidence of adverse effects of the combination of pinacidil with a diuretic was less than that when pinacidil was administered alone.Pinacidil has been compared with hydralazine in a number of randomised double-blind parallel or crossover trials. Pinacidil was at least as effective, and in some studies was more effective than hydralazine in providing continued blood pressure control for periods of up to 12 months. All of the studies allowed the concomitant use of a thiazide diuretic and/or &bgr;-adrenoceptor blocking drug to enhance efficacy or reduce adverse effects. Indeed, in some studies only a limited response was noted with pinacidil monotherapy, the success rate rising markedly with the addition of the allowed medications. In a comparative trial, however, these drugs were added more frequently to pinacidil treatment to control adverse effects, while they were more often added to hydralazine therapy to enhance efficacy.In studies comparing pinacidil and prazosin the drugs were generally of similar efficacy in achieving blood pressure control. While monotherapy did achieve adequate results in most patients, the response to pinacidil was limited by the appearance of adverse effects related to vasodilatation, necessitating the addition of hydrochlorothiazide or propranolol to maintain efficacy. Similar results have been found in a small number of trials comparing pinacidil with nifedipine, verapamil or methyldopa, although no firm conclusions concerning relative efficacy can be drawn until further studies in large groups of patients have been conducted. Studies comparing pinacidil with ACE inhibitors have not been reported.Because pinacidil has often been combined with a thiazide diuretic the antihypertensive efficacy of combination therapy relative to that of either drug alone has specifically been addressed. Both hydrochlorothiazide and pinacidil administered as monotherapy were capable of lowering blood pressure, while the combination was more effective in this regard than either agent alone. Overall, the optimum daily dosage range of pinacidil alone was 25 to 50mg; this could be reduced by the addition of hydrochlorothiazide 25mg daily. The incidence of oedema was clearly reduced by combination therapy.Adverse EffectsThe most commonly reported adverse effects of pinacidil - headache, palpitations, tachycardia and dizziness - are related to its potent peripheral dilating properties. These effects, which are common, occur early in treatment and are dose related. They are alleviated by a reduction in dosage, and sometimes resolve spontaneously. Peripheral oedema, occurring later in treatment, has been reported in 25 to 50% of patients and is also related to dose. Addition of a thiazide diuretic markedly decreases the incidence of these vasodilatory effects and usually allows treatment with pinacidil to continue, although patient withdrawals of 11 to 20% have been reported in studies which enrolled reasonable numbers of patients.Other relatively common adverse effects of pinacidil therapy include weight gain, asymptomatic T wave changes on the electrocardiogram (31%) and hypertrichosis (6.4%) which resolves once the drug is discontinued. Other adverse effects noted sporadically include tiredness, postural hypotension, flushing, nasal congestion and depression.Few changes attributable to the drug have been noted in biochemical or haematological parameters during treatment with pinacidil. The development of positive antinuclear factor antibodies (ANA) has occurred in a number of patients but was not accompanied by any clinically obvious adverse effects. Pinacidil appears to have a salutary effect on serum lipids, reducing total cholesterol and triglycerides and the low density lipoprotein (LDL) fraction, while increasing the high density lipoprotein (HDL) fraction. This effect is blunted by the addition of hydrochlorothiazide and/or propranolol such that the overall effect of the combination on lipid levels is usually not significant.Drug InteractionsDrugs such as cimetidine which inhibit the enzymes of the hepatic cytochrome P450 system may delay the elimination of pinacidil, while enzyme-inducing drugs such as phenytoin and phenobarbital can increase the rate of elimination of pinacidil. Probenecid also may delay the excretion of pinacidil and pinacidil-N-oxide.Dosage and AdministrationThe initial dosage of pinacidil in the treatment of mild to moderate essential hypertension should be 12.5mg twice daily, with slow increases until the desired antihypertensive effect is achieved. The maximum daily dose varies in different countries, being 25mg twice daily in the US and 37.5mg twice daily in Europe. The usual maintenance dose is 12.5 to 25mg twice daily. It is seldom necessary to increase the total dose above 100mg daily. Dosage adjustment may be necessary in elderly patients, in those with renal or hepatic dysfunction and in patients receiving concomitant diuretics and/or &bgr;-adrenoceptor blocking drugs.The addition of a thiazide diuretic is recommended to ensure the maintenance of blood pressure control throughout the dosing interval with a twice daily dosage regimen and to control vasodilatory adverse effects.