CLONIDINE

Closely related structurally to the imidazoline nasal decongestants is clonidine and other developed analogues. Clonidine was originally synthesized as a vasoconstricting nasal decongestant but, in early clinical trials, was found to have dramatic hypotensive effects—in contrast to all expectations for a vasoconstrictor. Subsequent pharmacological investigations showed that clonidine not only has some α1-agonist (vasoconstrictive) properties in the periphery but also that it is a powerful α2-adrenergic agonist and exhibits specific binding to nonadrenergic imidazoline binding sites in the CNS (mainly in the medulla oblongata) causing inhibition of sympathetic output (sympathoinhibition). Because of its peripheral activity on extraneuronal vascular postsynaptic α2B-receptors, initial doses of clonidine may produce a transient vasoconstriction and an increase in blood pressure that is soon overcome by vasodilation as clonidine penetrates the blood-brain barrier and interacts with CNS α2A-receptors.

Clonidine is used in various forms of hypertonic diseases and for relieving hypertonic crises. It is also used in ophthalmological practice for treating wide-angle glaucoma.

Antihypertensive.

Clonidine is used in various forms of hypertonic illnesses and for stopping hypertensive attacks. It is also used in ophthalmological practice for open-angle glaucoma.

Catapres (Boehringer Ingelheim).

Clonidine (Catapres) is effective orally and is used primarily for the treatment of moderate hypertension. It is structurally related to the α-adrenoceptor antagonists phentolamine and tolazoline. Clonidine, however, is not an α-blocker, but is actually an α-agonist. Its antihypertensive effectiveness appeared paradoxical until it was recognized that clonidine activated central 2-receptors, thus reducing sympathetic outflow to the periphery.

Clonidine differs from 2-arylimidazoline α 1-agonists mainly by the presence of o-chlorine groups anda NH bridge. The O-chlorine groups afford better activitythan O-methyl groups at α2 sites. Importantly, clonidinecontains a NH bridge (aminoimidazolines) instead of CH2bridge in 2-arylimidazoline. Clonidine is an example of a (phenylimino) imidazolidine derivative that possesses central α2-selectivity. The α1: α2 ratio is 300:1. Under certain conditions, such as intravenous infusion,clonidine can briefly exhibit vasoconstrictive activityas a result of stimulation of peripheral α-receptors.However, this hypertensive effect, if it occurs, is followedby a much longer-lasting hypotensive effect as a result ofthe ability of clonidine to enter into the CNS and stimulate α2-receptors located in regions of the brain such as thenucleus tractus solitarius. Stimulation of these α2-receptorsbrings about a decrease in sympathetic outflow from theCNS, which in turn leads to decreases in peripheral vascularresistance and blood pressure. Bradycardia is also producedby clonidine as a result of a centrally induced facilitationof the vagus nerve and stimulation of cardiacprejunctional α2-receptors. These pharmacological actionshave made clonidine quite useful in the treatment ofhypertension.

Clonidine is a selective α2-adrenergic agonist. Clonidine has expressed hypotensive action, which is associated with a reduction of general peripheral vascular resistance, reduced frequency of cardiac beats, and a reduction of cardiac output. The mechanism of action of clonidine is caused by stimulation of α2-adrenoreceptors of the inhibitory structures of the brain as well as a reduction of sympathetic impulses to the blood vessels and brain.

Clonidine has an oral bioavailability of more than 90%, with a pKa of 8.3 and a log P(exp) of 1.56. It also is absorbed when applied topically to the eye. Clonidine is well absorbed percutaneously following topical application of a transdermal system to the arm or chest. Following application of a clonidine transdermal patch, therapeutic plasma concentrations are attained within 2 to 3 days. Studies have indicated that release of clonidine from the patch averages from 50 to 70% after 7 days of wear. Plasma clonidine concentrations attained with the transdermal systems generally are similar to twice-daily oral dosing regimens of the drug. Percutaneous absorption of the drug from the upper arm or chest is similar, but less drug is absorbed from the thigh. Replacement of the transdermal system at a different site at weekly intervals continuously maintains therapeutic plasma clonidine concentrations. Following discontinuance of transdermal therapy, therapeutic plasma drug concentrations persist for approximately 8 hours and then decline slowly over several days; over this time period, blood pressure returns gradually to pretreatment levels.
Blood pressure begins to decrease within 30 to 60 minutes after an oral dose of clonidine, with the maximum decrease in approximately 2 to 4 hours. The hypotensive effect lasts up to 8 hours. Following epidural administration of a single bolus dose of clonidine, it is rapidly absorbed into the systemic circulation and into cerebrospinal fluid (CSF), with maximal analgesia within 30 to 60 minutes. Although the CSF is not the presumed site of action of clonidinemediated analgesia, the drug appears to diffuse rapidly from the CSF to the dorsal horn. After oral administration, clonidine appears to be well distributed throughout the body, with the lowest concentration in the brain. Clonidine is approximately 20 to 40% bound to plasma proteins, and it crosses the placenta. The plasma half-life of clonidine is 6 to 20 hours in patients with normal renal function and 18 to 41 hours in patients with impaired renal function. Clonidine is metabolized in the liver to its inactive major metabolite, 4-hydroxyclonidine, and its glucuronide and sulfate conjugates (10–20%). In humans, 40 to 60% of an oral or IV dose of clonidine is excreted in urine as unchanged drug within 24 hours. Approximately 85% of a single dose is excreted within 72 hours, with 20% of the dose excreted in feces, probably via enterohepatic circulation.

An acute intravenous injection of clonidine may produce a transient pressor response that apparently is due to stimulation of peripheral vascular α-receptors. The pressor response does not occur after oral administration, because the drug’s centrally mediated depressor action overrides it.
The decrease in blood pressure produced by clonidine correlates better with a decreased cardiac output than with a reduction in peripheral vascular resistance. The reduction in cardiac output is the result of both a decreased heart rate and reduced stroke work; the latter effect is probably caused by a diminished venous return.
Renal blood flow and glomerular filtration are not decreased, although renal resistance is diminished. Like α-methyldopa, it is a useful agent for hypertension complicated by renal disease. Plasma renin activity is reduced by clonidine, presumably as a result of a centrally mediated decrease in sympathetic stimulation of the juxtaglomerular cells of the kidney.

The primary indication for clonidine use is in mild and moderate hypertension that has not responded adequately to treatment with a diuretic or a β-blocker. Since clonidine causes sodium and water retention and plasma volume expansion, it generally is administered in combination with a diuretic.A vasodilator can be added to the clonidine–diuretic regimen in the treatment of resistant forms of hypertension. Such drug combinations can be quite effective, since the reflex increases in heart rate and cardiac output that result from vasodilator administration are reduced or negated by clonidine-induced decreases in heart rate and cardiac output.
For severely hypertensive patients, clonidine has been used in combination with a diuretic, a vasodilator, and a β-blocker. Some care must be taken, however, because the coadministration of clonidine and a β-blocker may cause excessive sedation. Clonidine is especially useful in patients with renal failure, since its duration of action is not appreciably altered by renal disease and it does not compromise renal blood flow.

It is estimated that about 7% of patients receiving clonidine discontinue the drug because of side effects. Although the symptoms are generally mild and tend to subside if therapy is continued for several weeks, as many as 50% of the patients complain of drowsiness and dryness of mouth. Other untoward effects include constipation, nausea or gastric upset, and impotence. These effects are characteristic of interference with the functioning of the sympathetic nervous system.
A potentially dangerous effect is rebound hypertension, which follows abrupt withdrawal of clonidine therapy. This posttreatment hypertension appears to be the result of excessive sympathetic activity. The genesis of the syndrome is not well understood. A contributing factor may be development of supersensitivity in either the sympathetic nerves or the effector organs of the cardiovascular system due to the clonidine-caused chronic reduction in sympathetic activity.Thus, when the drug is abruptly withdrawn, an exaggerated response to “normal” levels of activity may occur. If treatment with clonidine is terminated gradually, rebound hypertension is unlikely. Patients should be warned of the danger of abruptly discontinuing clonidine treatment.

Clonidine is a selective α2-adrenergic agonist that exhibits pronounced hypotensive action that is associated with a reduction of overall peripheral vascular resistance, decline in frequency of cardiac contraction, and reduced cardiac output. Clonidine is the drug of choice for treating various degrees of hypertension when used in combination with oral diuretics.

Clonidine is of interest in veterinary medicine as a diagnostic agent to determine growth hormone deficiency or pheochromocytoma in dogs, and as an adjunctive treatment for refractory inflammatory bowel disease, particularly in cats. It is being investigated in a variety of species as an epidural adjunct with or without opiates in the treatment of severe pain or for surgical procedures using epidural anesthesia.

Clonidine is well absorbed after oral administration. Peak plasma levels occur between 2 and 4 hours after drug administration and correlate well with pharmacological activity.The plasma half-life in patients with normal renal function is 12 hours. Urinary excretion of clonidine and its metabolites accounts for almost 90% of the administered dose, and fecal excretion accounts for the rest. Approximately 50% of an administered dose is excreted unchanged; the remainder is oxidatively metabolized in the liver.