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Cardiovascular Pharmacology Concepts

Richard E. Klabunde, PhD

Clinical Disorders:

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Centrally Acting Sympatholytics

Preganglionic and postganglionic autonomic nerves and their innervation of heart and blood vessels

General Pharmacology

The sympathetic adrenergic nervous system plays a major role in the regulation of arterial pressure. Activation of these nerves to the heart increases the heart rate (positive chronotropy), contractility (positive inotropy) and velocity of electrical impulse conduction (positive dromotropy). The norepinephrine-releasing, sympathetic adrenergic nerves that innervate the heart and blood vessels are postganglionic efferent nerves whose cell bodies originate in prevertebral and paraveterbral sympathetic ganglia. Preganglionic sympathetic fibers, which travel from the spinal cord to the ganglia, originate in the medulla of the brainstem. Within the medulla are located sympathetic excitatory neurons that have significant basal activity, which generates a level of sympathetic tone to the heart and vasculature even under basal conditions. The sympathetic neurons within the medulla receive input from other neurons within the medulla (e.g., vagal neurons), from the nucleus tractus solitarius (receives input from peripheral baroreceptors and chemoreceptors), and from neurons located in the hypothalamus. Together, these neuronal systems regulate sympathetic (and parasympathetic) outflow to the heart and vasculature.

Sympatholytic drugs can block this sympathetic adrenergic system are three different levels. First, peripheral sympatholytic drugs such as alpha-adrenoceptor and beta-adrenoceptor antagonists block the influence of norepinephrine at the effector organ (heart or blood vessel). Second, there are ganglionic blockers that block impulse transmission at the sympathetic ganglia. Third, there are drugs that block sympathetic activity within the brain. These are called centrally acting sympatholytic drugs.

Centrally acting sympatholytics block sympathetic activity by binding to and activating alpha22)-adrenoceptors. This reduces sympathetic outflow to the heart thereby decreasing cardiac output by decreasing heart rate and contractility. Reduced sympathetic output to the vasculature decreases sympathetic vascular tone, which causes vasodilation and reduced systemic vascular resistance, which decreases arterial pressure.

Therapeutic Indications

Centrally acting α2-adrenoceptor agonists are used in the treatment of hypertension. However, they are not considered first-line therapy in large part because of side effects that are associated with their actions within the brain. They are usually administered in combination with a diuretic to prevent fluid accumulation, which increases blood volume and compromises the blood pressure lowering effect of the drugs. Fluid accumulation can also lead to edema. Centrally acting α2-adrenoceptor agonists are effective in hypertensive patients with renal disease because they do not compromise renal function.

Specific Drugs

Several different centrally acting α2-adrenoceptor agonists are available for clinical use:  (Go to www.rxlist.com for specific drug information)

Clonidine, guanabenz and guanfacine are structurally related compounds and have similar antihypertensive profiles. α-methyldopa is a structural analog of dopa and functions as a prodrug. After administration, α-methyldopa is converted to α-methynorepinephrine, which then serves as the α2-adrenoceptor agonist in the medulla to decrease sympathetic outflow.

Side Effects and Contraindications

Side effects of centrally acting α2-adrenoceptor agonists include sedation, dry mouth and nasal mucosa, bradycardia (because of increased vagal stimulation of the SA node as well as sympathetic withdrawal), orthostatic hypotension, and impotence. Constipation, nausea and gastric upset are also associated with the sympatholytic effects of these drugs. Fluid retention and edema is also a problem with chronic therapy; therefore, concurrent therapy with a diuretic is necessary. Sudden discontinuation of clonidine can lead to rebound hypertension, which results from excessive sympathetic activity.

Revised 03/15/07

DISCLAIMER: These materials are for educational purposes only, and are not a source of medical decision-making advice.