化合物信息

Drug Groups

approved

Description

Clonidine, an imidazoline-derivative hypotensive agent is a centrally-acting α₂-adrenergic agonist. It crosses the blood-brain barrier and acts in the hypothalamus to induce a decrease in blood pressure. It may also be administered as an epidural infusion as an adjunct treatment in the management of severe cancer pain that is not relieved by opiate analgesics alone. Clonidine may be used for differential diagnosis of pheochromocytoma in hypertensive patients. Other uses for clonidine include prophylaxis of vascular migraine headaches, treatment of severe dysmenorrhea, management of vasomotor symptoms associated with menopause, rapid detoxification in the management of opiate withdrawal, treatment of alcohol withdrawal used in conjunction with benzodiazepines, management of nicotine dependence, topical use to reduce intraocular pressure in the treatment of open-angle and secondary glaucoma and hemorrhagic glaucoma associated with hypertension, and in the treatment of attention-deficit hyperactivity disorder (ADHD). Clonidine also exhibits some peripheral activity.

Indication

May be used as an adjunct in the treatment of hypertension, as an epidural infusion as an adjunct treatment in the management of severe cancer pain that is not relieved by opiate analgesics alone, for differential diagnosis of pheochromocytoma in hypertensive patients, prophylaxis of vascular migraine headaches, treatment of severe dysmenorrhea, management of vasomotor symptoms associated with menopause, rapid detoxification in the management of opiate withdrawal, treatment of alcohol withdrawal used in conjunction with benzodiazepines, management of nicotine dependence, topical use to reduce intraocular pressure in the treatment of open-angle and secondary glaucoma and hemorrhagic glaucoma associated with hypertension, and in the treatment of attention-deficit hyperactivity disorder (ADHD).

Pharmacology

Clonidine is an α-adrenergic agent that acts specifically on α₂-receptors. α₂-receptors regulate a number of signaling pathways mediated by multiple G_i proteins, Gα_i1, Gα_i2, and G&alpha_i3. Stimulation of α₂-receptors mediates effects such as inhibition of adenylyl cyclase, stimulation fo phospholipase D, stimulation of mitogen-activated protein kinases, stimulation of K⁺ currents and inhibition of Ca²⁺ currents. Three G-protein coupled α₂-receptor subtypes have been identified: α_2A, α_2B, and α_2C. Each subtype has a unique pattern of tissue distribution in the central nervous system and peripheral tissues. The α_2A-receptor is widely distributed throughout the central nervous system; it is found in the locus coeruleus, brain stem nuclei, cerebral cortex, septum, hypothalamus, and hippocampus. α_2A-receptors are also expressed in the kidneys, spleen, thymus, lung and salivary glands. The α_2C-receptor is primarily expressed in the central nervous system, including the striatum, olfactory tubercle, hippocampus and cerebral cortex. Low levels of the α_2C-subtype are also found in the kidneys. The α_2B-receptor is located primarily in the periphery (kidney, liver, lung and heart) with low levels of expression in the thalamic nuclei of the central nervous system. The α_2A- and α_2C-receptors are located presynaptically and inhibit the released of noradrenaline from sympathetic nerves. Stimulation of these receptors decreases sympathetic tone, resulting in decreases in blood pressure and heart rate. Sedation and analgesia is mediated by centrally located α_2A-receptors, while peripheral α_2B-receptors mediate constriction of vascular smooth muscle. α_2A-Receptors also mediate essential components of the analgesic effect of nitrous oxide in the spinal cord. Clonidine stimulates all three α₂-receptor subtypes with similar potency. Its actions in the nervous system decreases blood pressure in patients with hypertension and decreases sympathetic overactivity in patients undergoing opioid withdrawal. Clonidine is also a potent sedative and analgesic and can prevent post-operative shivering in intensive and post-operative care. Its use in differential diagnosis of pheochromocytoma owes to the fact that hypertension in patients with pheochromocytoma is refractory to antihypertensive treatment with clonidine.

Toxicity

Oral LD₅₀ is 150 mg/kg in rat and 30 mg/kg in dog. Symptoms of overdose include constriction of pupils of the eye, drowsiness, high blood pressure followed by a drop in pressure, irritability, low body temperature, slowed breathing, slowed heartbeat, slowed reflexes, and weakness.

Affected Organisms

Biotransformation

Hepatic. Metabolized via minor pathways. The major metabolite, p-hydroxyclonidine, is present in concentrations less than 10% of those of unchanged clonidine in urine. Four metabolites have been detected, but only p-hydroxyclonidine has been identified.

Absorption

Well absorbed following oral administration. Bioavailability following chronic administration is approximately 65%.

Half Life

6-20 hours; 40-60% is excreted in urine unchanged, 20% is excreted in feces. Less than 10% is excreted by p-hydroxyclonidine.

Protein Binding

20-40%, primarily to albumin

References

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