YSP Clonidine Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of action: The hypotensive effect of Clonidine is produced mostly by its central effect or reducing sympathetic drive. In this respect, Clonidine differs from previously used anti-hypertensives. Clonidine neither depletes major catecholamine stores nor acts as a ganglion blocking agent. The specific and different mode of action of Clonidine leads to benefits such as reduced incidence of postural hypotension and only rarely an effect on libido.
The central action of Clonidine is ascribed mainly to an action on the bulbar structures of the central nervous system, particularly the sympathetic cardio-accelerator and constrictor mechanisms. This central action leads to decreased sympathetic outflow. Peripheral effects of Clonidine include both vasodilatation and vasoconstriction in various vascular beds, and alpha- and possible beta-adrenomimetic effects. A transient rise in blood sugar occurs following large doses of Clonidine. In addition, a small transient pressor effect (5-10 mmHg systolic blood pressure) lasting approximately five minutes may occur following intravenous use. These effects reflect the alpha-adrenomimetic action of Clonidine. The peripheral effects of Clonidine generally require isolated organ type preparations for their demonstration, as in the intact animal or man, the central action predominates.
Clinical Trials: No data available.
Pharmacokinetics: Absorption and distribution: The pharmacokinetics of clonidine is dose-proportional in the range of 75-300 micrograms. Clonidine is well absorbed from the gastrointestinal tract and undergoes a minor first pass effect. Peak plasma concentrations are reached within 1-3 hours after oral administration. The duration of action varies from 6-12 hours, the duration of action being longer in the milder hypertensives. The plasma protein binding is 30-40%.
Metabolism and excretion: The terminal elimination half-life of clonidine has been found to range from 9-26 hours in patients with normal renal function. With impaired renal function, it has been reported to increase to 18-48 hours.
The metabolic pathway of clonidine involves cleavage of the imidazolidine ring and the hydroxylation of the phenyl ring. Five metabolites have been identified in man and include para-hydroxy-clonidine and dichlorophenylguanidine.
Two-thirds of an administered dose is excreted in the urine (about half of which is unchanged Clonidine) and the remainder is excreted in the faeces.
The antihypertensive effect is reached at plasma concentrations between about 0.2 and 2.0 ng/mL in patients with normal renal function. The hypotensive effect is attenuated or decreases with plasma concentrations above 2.0 ng/mL.
Given intravenously, Clonidine is effective within five minutes, has a maximum hypotensive action within 20 to 30 minutes, and the effect lasts for several hours. Following intramuscular administration, Clonidine is effective within 5 to 10 minutes. The maximum hypotensive effect is reached after 75 minutes, and the duration of action is approximately 5 hours.