Alpha-Adrenoceptor Agonists (α-agonists)

General Pharmacology

Alpha-adrenoceptor agonists (α-agonists) bind to α-receptors on vascular smooth muscle and induce smooth contraction and vasoconstriction, thus mimicking the effects of sympathetic adrenergic nerve activation to the blood vessels.

Vascular smooth muscle has two types of alpha-adrenoceptors: alpha₁ (α₁) and alpha₂ (α₂). The α₁-adrenoceptors are the predominant α-receptor located on vascular smooth muscle. Depending on the tissue and type of vessel, there are also α₂-adrenoceptors found on the smooth muscle. Both receptor subtypes are linked to a Gq-protein, which activates smooth muscle contraction through the IP₃ signal transduction pathway. There are also α₂-adrenoceptors located on the sympathetic nerve terminals that inhibit the release of norepinephrine and therefore act as a feedback mechanism for modulating the release of norepinephrine.

Alpha-agonists constrict both arteries and veins; however, the vasoconstrictor effect is more pronounced in the arterial resistance vessels. Constriction of the resistance vessels (small arteries and arterioles) increases systemic vascular resistance, whereas constriction of the venous capacitance vessels increases venous pressure.

Specific Drugs and Therapeutic Uses

Most α-agonists are relatively selective for either α₁ or α₂-adrenoceptors. In addition to the drugs listed below, there are other sympathomimetic drugs that have α-agonist properties in addition to their β-adrenoceptor agonist properties. These drugs include the naturally occurring catecholamines, dopamine, epinephrine and norepinephrine, as well as catecholamine analogs such as dobutamine. (Go to www.rxlist.com for specific drug information).

α₁-adrenoceptor agonists (systemic vasoconstrictors)

• methoxamine

• phenylephrine
• oxymetazoline
• tetrahydralazine
• xylometazoline

Methoxamine and phenylephrine are used as pressor agents in treating hypotension and shock. Oxymetazoline, tetrahydralazine, xylometazoline and some preparations of phenylephrine are used as nasal decongestants.

α₂-adrenoceptor agonists (centrally-acting vasodilators; Click here for details)

• clonidine
• guanabenz
• guanfacine
• α-methyldopa

The α₂-adrenoceptor agonists are used very occasionally as centrally-acting sympatholytic vasodilators for the treatment of hypertension.

Side Effects and Contraindications

Alpha₁-agonists can cause headache, reflex bradycardia, excitability, and restlessness. Because alpha₁-agonists produce systemic vasoconstriction, the work of the heart increases. If the coronary circulation is impaired, as in patients with coronary artery disease, the decrease in myocardial oxygen supply/demand ratio can precipitate angina. Preparations used as nasal decongestants can cause a rebound effect (increased congestion) after a couple days of use.

Side effects of centrally acting α₂-adrenoceptor agonists include sedation, dry mouth and nasal mucosa (because of increased vagal activity), bradycardia, 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