Studies on circulatory effects of clonidine and papaverine

Abstract

This thesis describes studies on the circulatory pharmacology of clonidine and papaverine, which have i n common a hypotensive action but have entirely opposite peripheral· vascular effects. The nature of clonidine's local action on blood vessels and its effect on vascular responsiveness to catecholamines was examined in man and animals. In normotensive man, intra-arterial clonidine caused cutaneous vasoconstriction in the forearm and hand which was mediated by adrenergic alpha receptors. Intravenous clonidine caused a sustained fall in blood pressure and heart rate, and an increase in the vascular resistance of the hand during and briefly after the i nfusion . Chronic antihypertensive treatment with clonidine also resulted in a fall in blood pressure and heart rate .and an increase in hand vascular resistance. The cardiovascular effects of intraarterial and intravenous noradrenaline were increased by both intravenous and chronicclonidine. Experiments with animal isolated vascular preparations from normotensive animal s confirmed t ha t acute clonidine causes a direct rather than an indirect adrenergic alpha receptor stimulation and that it has the properties of a partial agonist. Chronic administration to rats did not cause arterial or venous smooth muscle supersensitivity to noradrenaline, methoxamine or potassium chloride, nor did this treatment have any obvious effect on the monoamine fluorescence in these vessels. The doses used in these animals, though insufficient to cause a fall in blood pressure, were more than double those which had previously been shown to decrease vascular responsiveness to vasoconstrictors and vasodilators in the cat. In contrast, chronic reserpine and chronic guanethidine treatment did cause vascular supersensitivity and also catecholamine depletion. Since the animal studies failed to demonstrate vascular supersensitivity after chronic clonidine, it is suggested that the increased responses to noradrenaline observed in the human studies resulted from the additive stimulant effects of clonidine and noradrenaline at the adrenergic receptor, rather than true vascular supersensitivity. The second drug whose effects on the human were examined was papaverine. It was confirmed that, in contrast to clonidine, intraarterial papaverine has a vasodilator effect on the human hand and forearm. Papaverine was also administered intravenously and orally to determine whether the doses recommended for oral administration produce blood levels capable of causing vasodilatation. Intravenous infusion resulted in an increase in heart rate, occasional ectopic beats and an increase i n forearm blood flow, all of which were of brief duration. Plasma concentrations of the drug reached peak values during or shortly after the infusion and then declined rapidly to about half peak values within thirty minutes. The onset and duration of cardiovascular effects correlated well with plasma concentrations. In chronic studies papaverine in a sustained release formulation was administered daily. The plasma level at the end of a week with each of the two doses was only about one sixth of that associated with vasodilator effects after intravenous administration. With the lower dose there was no consistent change i n the heart rate or blood flow to the hand or forearm though the reflex vasoconstriction in the hand in response to the Valsalva manoeuvre was potentiated. The higher dose consistently reduced forearm blood flow and reflex responses were not consistently changed. At neither dose level was there any correlation between the plasma concentration and the cardiovascular effect in an individual subject. It was concluded that papaverine lacks significant vasodilator effects when given orally, even in doses five to ten times those which cause vasodilatation and cardiac effects when given intravenously, and the failure to achieve adequate plasma concentrations of the drug is the most probable cause for this finding.