RiteMED Clonidine Mechanism of Action

Pharmacology: Pharmacodynamics: Clonidine, an imidazoline derivative, is a central alpha-adrenergic stimulant that inhibits sympathetic cardio-accelerator and vasoconstrictor centers. Stimulation of alpha-adrenergic receptors in the brain stem results in reduced sympathetic outflow from the central nervous system (CNS) and a decrease in peripheral resistance, renal vascular resistance, heart rate, and blood pressure. Renal blood flow and glomerular filtration rate remain essentially unchanged.
Clonidine lowers blood pressure to essentially the same extent in both supine and standing patients; thus, orthostatic effects are mild and infrequent. However, the underlying hemodynamic effects differ with the position of the patient. Administration of a single dose of clonidine to supine patients results in decreased cardiac output and stroke volume but total peripheral resistance remains unchanged. In patients in standing position or 45° tilt, a smaller decrease in cardiac output occurs and total peripheral resistance is decreased, but stroke volume is maintained. Prolonged therapy results in circulatory adjustments, so that the blood pressure lowering effect of clonidine largely results from reduced peripheral resistance. Rapid intravenous (IV), but not oral or intramuscular (IM), administration of clonidine produces direct stimulation of peripheral alpha₂-adrenergic receptors, resulting in transient vasoconstriction and an increase in systolic and diastolic blood pressure.
Blood pressure declines within 30 to 60 minutes after an oral clonidine dose, the maximum decrease occurring within 2 to 4 hours.
Tolerance to the antihypertensive effect of clonidine may develop in some patients, necessitating a reevaluation of therapy.
Pharmacokinetics: Clonidine is well absorbed from the gastrointestinal tract and does not exhibit a first pass effect. Peak plasma clonidine levels occur within 3 to 5 hours after oral dosing; plasma half-life is 12 to 16 hours and the elimination half-life is 6 to 24 hours.
Clonidine is rapidly and extensively distributed into tissues and crosses the blood brain barrier, as well as the placenta barrier. The plasma protein binding of clonidine is 30 to 40%.
Clonidine is metabolized in the liver. In humans, four metabolites have been detected but only one, the inactive p-hydroxyclonidine, has been identified.
The mean plasma half-life of clonidine is about 13 hours ranging between 10 to 20 hours in patients with normal renal function; the half-life increases up to 41 hours in patients with impaired renal function. About 40 to 60% of the absorbed dose is recovered in the urine as unchanged drug in 24 hours. About 20% of the total dose is excreted with the feces.
The antihypertensive effect is reached at plasma clonidine concentrations between 0.2 and 1.5 ng/mL in patients with normal excretory functions. A further increase in the plasma levels will not enhance the antihypertensive effect.
Neither food nor the race of the patient influences the pharmacokinetics of clonidine.