Indirect-acting antiadrenergic agents

CHAPTER 19


Indirect-acting antiadrenergic agents


The indirect-acting antiadrenergic agents are drugs that prevent the activation of peripheral adrenergic receptors, but by mechanisms that do not involve direct interaction with peripheral receptors. There are two categories of indirect-acting antiadrenergic drugs. The first group—centrally acting alpha2 agonists—consists of drugs that act within the central nervous system (CNS) to reduce the outflow of impulses along sympathetic neurons. The second group—adrenergic neuron-blocking agents—consists of drugs that act within the terminals of sympathetic neurons to decrease norepinephrine (NE) release. With both groups, the net result is reduced activation of peripheral adrenergic receptors. Hence, the pharmacologic effects of the indirect-acting adrenergic blocking agents are very similar to those of drugs that block adrenergic receptors directly.




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.


Clonidine is a widely used antihypertensive drug. Why? Because it’s both effective and safe. Except for rare instances of rebound hypertension, the drug is generally free of serious adverse effects. Dosing is done orally or by transdermal patch.




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






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





Guanabenz and guanfacine


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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Jul 24, 2016 | Posted by in NURSING | Comments Off on Indirect-acting antiadrenergic agents

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