Clonidine is an α-adrenergic agonist which also has some α-adrenergic antagonist effects. The antihypertensive effect of clonidine is thought to be due to central α₂-adrenergic stimulation, which results in a decreased sympathetic outflow to the heart, kidneys, and peripheral vasculature and thus decreased peripheral vascular resistance, decreased systolic and diastolic blood pressure and decreased heart rate. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact and therefore orthostatic symptoms are mild and infrequent. Acute studies with clonidine in humans have demonstrated a moderate reduction (15 to 20%) of cardiac output in the supine position with no change in the peripheral resistance; at a 45° tilt there is a smaller reduction in cardiac output and a decrease of peripheral resistance. During long-term therapy, cardiac output tends to return to control values, while peripheral resistance remains decreased. Slowing of the pulse rate has been observed in most patients given clonidine, but the drug does not alter normal hemodynamic response to exercise.

Clonidine acts relatively rapidly. The patient's blood pressure declines within 30 to 60 minutes after an oral dose, the maximum decrease occurring within 2 to 4 hours. The plasma level of clonidine peaks in approximately 3 to 5 hours and the plasma half-life ranges from 12 to 16 hours. The half-life increases up to 41 hours in patients with severe impairment of renal function. Following oral administration about 40 to 60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 50% of the absorbed dose is metabolized in the liver.

Other studies in patients have provided evidence of a reduction in plasma renin activity and in the excretion of aldosterone and catecholamines, but the exact relationship of these pharmacologic actions to the antihypertensive effect has not been fully elucidated.

Prolonged treatment with clonidine in animals causes a decrease in the responsiveness of the vascular smooth muscle to catecholamines and angiotensin. The change in vascular response may be of importance in explaining the chronic hypotensive effect in man.

Acute administration of clonidine stimulates the release of growth hormone in children and adults, but the drug does not produce sustained elevation of growth hormone during chronic administration.