Indirect-acting antiadrenergic agents
Centrally acting alpha2 agonists
The drugs discussed in this section act within the CNS to reduce the firing of sympathetic neurons. Their primary use is hypertension.
Why are we discussing centrally acting drugs in a unit on peripheral nervous system pharmacology? Because the effects of these drugs are ultimately the result of decreased activation of alpha- and beta-adrenergic receptors in the periphery. That is, by inhibiting the firing of sympathetic neurons, the centrally acting agents decrease the release of NE from sympathetic nerves, and thereby decrease activation of peripheral adrenergic receptors. Hence, although these drugs act within the CNS, their effects are like those of the direct-acting adrenergic receptor blockers. Accordingly, it seems appropriate to discuss these agents in the context of peripheral nervous system pharmacology, rather than presenting them in the context of CNS drugs.
Clonidine
Clonidine [Catapres, Catapres-TTS, Jenloga] is a centrally acting alpha2 agonist with two approved indications: hypertension and severe pain. For treatment of hypertension, the drug is sold as Catapres and Jenloga. For treatment of pain it’s sold as Duraclon. Use for hypertension is discussed here. Use against pain is discussed in Chapter 28.
Mechanism of antihypertensive action
Clonidine is an alpha2-adrenergic agonist that causes “selective” activation of alpha2 receptors in the CNS—specifically, in brainstem areas associated with autonomic regulation of the cardiovascular system. By activating central alpha2 receptors, clonidine reduces sympathetic outflow to blood vessels and to the heart.
Pharmacologic effects
The most significant effects of clonidine concern the heart and vascular system. By suppressing the firing of sympathetic nerves to the heart, clonidine can cause bradycardia and a decrease in cardiac output. By suppressing sympathetic regulation of blood vessels, the drug promotes vasodilation. The net result of cardiac suppression and vasodilation is decreased blood pressure. Blood pressure is reduced in both supine and standing subjects. (Note that the effect of clonidine on blood pressure is unlike that of the peripheral alpha-adrenergic blockers, which tend to decrease blood pressure only when the patient is standing.) Because the hypotensive effects of clonidine are not posture dependent, orthostatic hypotension is minimal.
Therapeutic uses
Clonidine has two approved applications: treatment of hypertension (its main use) and relief of severe pain (see Chapter 28). Investigational uses include treating attention-deficit/hyperactivity disorder (ADHD), managing opioid withdrawal, facilitating smoking cessation, and treating Tourette’s syndrome, a CNS disease characterized by uncontrollable tics and verbal outbursts that are frequently obscene.
Adverse effects
Drowsiness.
CNS depression is common. About 35% of patients experience drowsiness; an additional 8% experience outright sedation. These responses become less intense with continued drug use. Patients in their early weeks of treatment should be advised to avoid hazardous activities if alertness is impaired.
Xerostomia.
Xerostomia (dry mouth) is common, occurring in about 40% of patients. The reaction usually diminishes over the first 2 to 4 weeks of therapy. Although not dangerous, xerostomia can be annoying enough to discourage drug use. Patients should be advised that discomfort can be reduced by chewing gum, sucking hard candy, and taking frequent sips of fluids.
Rebound hypertension.
Rebound hypertension is characterized by a large increase in blood pressure occurring in response to abrupt clonidine withdrawal. This rare but serious reaction is caused by overactivity of the sympathetic nervous system, and can be accompanied by nervousness, tachycardia, and sweating. Left untreated, the reaction may persist for a week or more. If blood pressure climbs dangerously high, it should be lowered with a combination of alpha- and beta-adrenergic blocking agents. Rebound effects can be avoided by withdrawing clonidine slowly (over 2 to 4 days). Patients should be informed about rebound hypertension and warned not to discontinue clonidine without consulting the prescriber.
Abuse.
People who abuse cocaine, opioids (eg, morphine, heroin), and other drugs frequently abuse clonidine as well. Why? Because at high doses, clonidine can cause subjective effects—euphoria, sedation, hallucinations—that some individuals find desirable. In addition, clonidine can intensify the subjective effects of some abused drugs, including benzodiazepines, cocaine, and opioids. Since clonidine costs less than these drugs, the combination allows abusers to get high for less money.
Preparations, dosage, and administration
Clonidine hydrochloride is available in oral and transdermal formulations. Oral clonidine is available in standard tablets (0.1, 0.2, and 0.3 mg) marketed as Catapres, and in modified-release tablets (0.1 mg) marketed as Jenloga. Transdermal clonidine [Catapres-TTS] is available in 2.5-, 5-, and 7.5-mg patches that deliver 0.1, 0.2, and 0.3 mg/24 hr, respectively.
The pharmacology of guanabenz [Wytensin] and guanfacine [Tenex] is very similar to that of clonidine. Like clonidine, both drugs are indicated for hypertension. In addition, guanfacine, marketed as Intuniv, is used for ADHD (see Chapter 36). Benefits in hypertension derive from activating brainstem alpha2-adrenergic receptors, an action that reduces sympathetic outflow to the heart and blood vessels. The result is a reduction in cardiac output and blood pressure. Both drugs have the same major adverse effects as clonidine: sedation and dry mouth. In addition, both can cause rebound hypertension following abrupt withdrawal. Guanabenz is available in 4- and 8-mg tablets. Dosing is begun at 4 mg twice daily and can be increased to 32 mg twice daily. For treatment of hypertension, guanfacine is available in 1- and 2-mg tablets. The usual dosage is 1 mg/day, taken at bedtime to minimize daytime sedation. Preparations and dosage for ADHD are presented in Chapter 36.
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