Pinacidil

Abstract

Pinacidil 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 hyperpolarize 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 beta-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 beta-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 overall 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.

Pharmacodynamics and Pharmacokinetics of Pinacidil in Normotensive Volunteers after Repeated Doses of a New Slow-release Tablet Formulation

“…In particular, the maximum plasma concentrations after the last dose, the area under the plasma concentration curve in the interval between doses at steady-state and the mean residence time met Westlake's statistical criteria for bioequivalence (> 20 %). Whereas most of the pharmacokinetic parameters were also similar to those previously measured after single oral doses [2,7]. the values of the half-life of elimination were greater than those we found after single administration of the same oral dose to healthy subjects [7].…”

“…Venous blood samples were drawn at the following times: on the morning of days 0, 1, 2, 3, 4, 5, 6, and at the following times on day 7: 0 (immediately before the drug administration), 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 36 h after drug administration. The sampling schedule was selected on the basis of previous human pharmacokinetic studies [2,7]. Blood samples (5 ml) were drawn by venipuncture from antecubital veins and collected into two plastic tubes containing heparin and centrifuged (within 5 min) at 4 °C at 1200 x g for 10 min.…”

ATP-Sensitive Potassium Channel Openers and 2,3-Dimethyl-2-Butylamine Derivatives

“…KCOs have not been associated with tachyphylaxis to the antihypertensive effect or rebound hypertension on abrupt withdrawal [98]. Vegh reported that one particular KCO given at one dose level and administered by a particular route is unlikely to increase the risk of ventricular fibrillation under conditions of myocardial ischemia or reperfusion unless marked systemic antihypertension occurs [99].…”

“…In contrast, the compound (94) with a methyl group decreases the potassium currents, whereas the compounds with benzyl or 2-hydroxy-5-chlorobenzyl groups have no effects on the potassium currents. Analysis of (84), (90), and (98) indicates that for the carbonyl on the branched substituent group of the 2,3 and 4-position, the order of intensity of changes in the potassium current is (90) > (84) > (98).…”

Ocular Hypotensive Effects of the ATP-Sensitive Potassium Channel Opener Cromakalim in Human and Murine Experimental Model Systems

“…K ATP channel openers are already in clinical use for various non-ocular disorders including systemic hypertension and ischemic heart diseases. [ 42 – 45 ] Recently, we have shown that several major K ATP channel openers (e.g. diazoxide, nicorandil) have ocular hypotensive properties in human and animal model systems.…”