Description: Clonidine is an oral and topical antihypertensive agent as well as an epidural agent for refractory cancer pain. It is similar to guanabenz in mechanism of action, although clonidine is less expensive. Synthesized in the early 1960s for use as a nasal decongestant, clonidine was serendipitously found to produce hypotension, bradycardia, and sedation at remarkably low doses. Clonidine is used mainly in the treatment of hypertension, but has been used successfully in a variety of other conditions off-label, including attention-deficit hyperactivity disorder (ADHD), opiate withdrawal, nicotine withdrawal, vascular headaches, diabetic diarrhea, glaucoma, ulcerative colitis, Gilles de la Tourette's syndrome, and for hot flashes. Clonidine is not considered a first-line agent in ADHD due to the potential for toxic cardiac effects and the availability of safer and more effective agents (i.e., methylphenidate, amphetamines).[8391] [8397] However, some experts recommend clonidine as an adjunct to stimulants in children with ADHD and comorbid tic disorders (i.e., Tourette's syndrome) or aggressive behavior.[8394] [8395] Single doses of clonidine have been used in the diagnosis of pheochromocytoma. Clonidine is effective in the treatment of severe pain in cancer patients refractory to opiate agonists.[2083] Epidural clonidine seems to be more effective in patients with neuropathic pain rather than visceral pain. Use of epidural clonidine has resulted in decreases in opiate requirements when used in combination with epidural opiate agonists and increases the duration of response to anesthetic agents used in peripheral nerve blocks. Clonidine is available as an oral preparation, a transdermal system, and an injection for epidural use. Clonidine has been used in the United States since FDA approval was given in 1974. The epidural injection (Duraclonฎ) was approved in early 1997.

Mechanism of Action: Clonidine is an agonist at presynaptic alpha2-receptors in the medulla, specifically, the nucleus tractus solitarius (i.e., the depressor area of the vasomotor center of the medulla oblongata). Stimulation of these receptors results in the inhibition of sympathetic outflow and tone. Suppression of efferent sympathetic pathways decreases vascular tone in the heart, kidneys, and peripheral vasculature; lowers peripheral resistance; and reduces blood pressure. Reflex tachycardia usually does not occur. Instead, stimulation of the central alpha-receptors by clonidine results in a reciprocal increase in vagal tone, causing an increase in baroreceptor activity and bradycardia. Clonidine is also a partial agonist at presynaptic alpha2-adrenergic receptors of peripheral nerves in vascular smooth muscle, however, this site of action contributes little, if anything, to its antihypertensive effects. Doses higher than those required to lower blood pressure are necessary to demonstrate agonism at this peripheral site. Further, it has been shown that alpha2-agonists that cannot penetrate the blood-brain barrier do not effectively lower blood pressure. Agonism at peripheral presynaptic alpha2-receptors may interfere with the peripheral regulation of norepinephrine.[1308]

Intravenous administration or large oral doses of clonidine also can stimulate alpha1-receptors in peripheral vascular smooth muscle, resulting in acute vasoconstriction and a transient increase in blood pressure. An accurate correlation between clonidine's plasma concentrations and its antihypertensive effects is evident only at lower plasma concentrations. Higher plasma concentrations of clonidine will result in reduced antihypertensive activity because of the increased contribution of the pressor effect.

Inhibition of sympathetic outflow by clonidine results in a variety of pharmacodynamic effects. In the supine position, decreased sympathetic tone reduces heart rate (HR), mean arterial pressure (MAP), cardiac output (CO), and stroke volume (SV), with essentially no change in the total peripheral resistance (TPR), renal blood flow (RBF), renal plasma flow (RPF), glomerular filtration rate (GFR), urinary potassium excretion, or renal vascular resistance (RVR). Urinary sodium and chloride excretion are increased, however. Thus, the principal antihypertensive effect in the supine position is related to the reduction in cardiac output secondary to the reduced stroke volume and heart rate.

In the erect position (45-degree tilt), clonidine reduces MAP, CO, HR, and TPR, with no significant change in stroke volume. Cardiac output due to clonidine decreases less in hypertensive patients than in normal patients, and the antihypertensive effects of the drug appear to be related to a reduction in both cardiac output and TPR, with the effects of the reduced TPR predominating in the erect position. Renin and aldosterone output are reduced. Clonidine appears to decrease catecholamine excretion during prolonged therapy, but it does not deplete catecholamine stores. As an antihypertensive, clonidine reduces LVH and does not cause detrimental effects on glucose tolerance, although sexual dysfunction is a significant problem.

Clonidine is used to treat hypertension and the subsequent decline of renal function in patients with scleroderma renal crisis (SRC). SRC is associated with elevated peripheral renin concentrations. Clonidine reduces plasma renin activity by reducing sympathetic activity while increasing parasympathetic activity.

Because of clonidine's ability to inhibit sympathetic outflow, it has been used successfully to manage withdrawal from opiate agonists,[254] ethanol,[255] or nicotine; and 'hot flashes' associated with menopause. By inhibiting intrarenal vasoconstriction, clonidine has been used to offset cyclosporine-induced nephrotoxicity.[256] Since pheochromocytomas are not under neurologic control, clonidine has been used successfully to differentiate the presence of these tumors from other hypertension-associated disease states.[257]

Clonidine administered epidurally produces a dose-dependent analgesia that is not antagonized by opiate antagonists. By preventing pain signal transmission to the brain, clonidine produces analgesia at presynaptic and postjunctional alpha2-adrenoceptors in the spinal cord. Yohimbine, an alpha2-adrenoreceptor antagonist, will partially reverse the analgesic and sedation effects of epidural clonidine with no effect on clonidine-induced changes in blood pressure or heart rate. Clonidine-induced analgesia occurs only in body regions innervated by spinal segments where analgesic concentrations of clonidine are present. Clonidine enhances epidural or peripheral nerve blocks by blocking the conduction of C and A delta fibers and increasing potassium conductance in neurons and causing local vasoconstriction decreasing the elimination of the local anesthetic.[2084]

Pharmacokinetics: Clonidine is administered epidurally, orally and via transdermal patch. Clonidine is rapidly and completely absorbed following oral administration; bioavailability approaches 100%. Blood pressure begins to decrease within 30—60 minutes, with maximal hypotensive effects occurring in 2—4 hours. Therapeutic plasma concentrations of clonidine are attained 2—3 days after transdermal application. Following epidural administration, peak clonidine plasma and cerebrospinal fluid concentrations were achieved in 19 and 26 minutes, respectively. Clonidine is highly lipid soluble and distributes widely throughout the body tissues, including the central nervous system. Epidurally administered clonidine distributes into plasma via the epidural veins. The CSF elimination half-life of clonidine is 1.3 hours. Fifty percent (50%) of a circulating dose is metabolized in the liver to inactive compounds. Unchanged drug (45%) and its metabolites are excreted in the urine and feces. Antihypertensive effects of clonidine last up to 8 hours following oral administration and up to 7 days following transdermal application. The elimination half-life of the drug ranges from 6—24 hours, with a mean of approximately 12 hours. Compared to men, women had a lower mean plasma clearance, longer mean plasma half-life, and higher mean peak concentration of clonidine in the plasma and CSF. Half-life can be increased in patients with renal failure. The pharmacokinetics of epidural clonidine in children 1—9 years of age is similar to adults.[2085]

The clonidine transdermal system consists of a patch, or 0.2 mm thick film, that contains four layers of a microporous polypropylene membrane. This patch holds a reservoir of clonidine that is released and absorbed across the skin at a constant rate over a 7-day period. Application of the transdermal system results in therapeutic plasma concentrations of the drug within 2—3 days, and replacing patches at weekly intervals will maintain therapeutic plasma clonidine levels. Therapeutic effects persist for 8 hours following discontinuance, then gradually decline over several days.

254. Gold MS, Pottash C, Sweeney DR et al. Opiate withdrawal using clonidine. JAMA 1980;243:343—6.

255. Manhem P, Nilsson LJ, Moberg AL et al. Alcohol withdrawal: effects of clonidine treatment on sympathetic activity, the renin-aldosterone system, and clinical symptoms. Alcohol Clin Exp Res 1985;9:238—43.

256. Luke J, Luke DR, Williams LA et al. Prevention of cyclosporine-induced nephrotoxicity with transdermal clonidine. Clin Pharm 1990;9:49—53.

257. Bravo EL, Tarazi RC, Fouad FM et al. Clonidine-suppression test. N Engl J Med 1981;305:623—6.

1308. Lowenthal DT, Matzek KM, MacGregor TR. Clinical pharmacokinetics of clonidine. Clin Pharmacokin 1988;14:287—310.

2083. Eisenbac JC, DuPen S, Dubois M et al. Epidural clonidine for intractable cancer pain. Pain 1995:61:391—9.

2084. Eisenach JC, DeKock M, Kilmscha W. alpha2-Adrenergic agonist for regional anesthesia. A clinical review of clonidine (1984—1995). Anesthesiology 1996;85:655—74.

2085. Ivani G, Bergendahl HT, Lampugnani E et al. Plasma levels of clonidine following epidural bolus injection in children. Acta Anaesthesiol Scand 1998;42:306—11.

8391. Rappley MD. Clinical practice. Attention deficit-hyperactivity disorder. N Engl J Med. 2005;352:165—73.

8394. Hazell PL, Stuart JE. A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children. J Am Acad Child Adolesc Psychiatry. 2003;42:886—94.

8395. Tourette's Syndrome Study Group. Treatment of ADHD in children with tics: a randomized controlled trial. Neurology. 2002;58:527—36.

8397. Fenichel RR. Post-marketing surveillance identifies three cases of sudden death in children during treatment with clonidine and methylphenidate. J Child Adolesc Psychopharm 1995;5:155—156.

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