Centrally Acting Adrenergic Drugs

The use of agents that directly affect the peripheral component of the sympathetic nervous system represents an important approach to the treatment of hypertension. A second approach to modifying sympathetic influence on the cardiovascular system is through inhibition or reduction of CNS control of blood pressure. Several widely used medications act by stimulating a2-receptors, which in the CNS reduces sympathetic outflow to the cardiovascular system and produces a hypotensive effect.

Methyldopate Hydrochloride, USP. Methyldopate hydrochloride, l-3-(3,4-dihydroxyphenyl)-2-methylala-nine ethyl ester hydrochloride (Aldomet ester hydrochlo-ride), a-methyldopa, lowers blood pressure by inhibiting the outflow of sympathetic vasoconstrictor impulses from the brain. Early studies had suggested that the hypotensive action of a-methyldopa was a result of the peripheral properties of the drug as a decarboxylase inhibitor or a false transmitter.

The current hypothesis concerning the hypotensive activity of methyldopa involves the CNS as the site of ac tion.57 Methyldopa, on conversion to a-methylnorepineph-

rine, acts on a2-adrenergic receptors to inhibit the release of norepinephrine, resulting in decreased sympathetic outflow from the CNS and activation of parasympathetic outflow.

Methyldopa is used as a step 2 agent and is recommended for patients with high blood pressure who are not responsive to diuretic therapy alone. Methyldopa, suitable for oral use, is a zwitterion and is not soluble enough for parenteral use. The problem was solved by making the ester, leaving the amine free to form the water-soluble hydrochloride salt. It is supplied as a stable, buffered solution, protected with antioxidants and chelating agents.

Clonidine Hydrochloride. Clonidine hydrochloride, 2-[(2,6-dichlorophenyl)imino]imidazolidine monohydrochlo-ride (Catapres), was the first antihypertensive known to act on the CNS. It was synthesized in 1962 as a derivative of the known a-sympathomimetic drugs naphazoline and tolazoline, potential nasal vasoconstrictors, but instead it proved to be effective in the treatment of mild-to-severe hypertension.

Clonidine hydrochloride acts by both peripheral and central mechanisms in the body to affect blood pressure. It stimulates the peripheral a-adrenergic receptors to produce vasoconstriction, resulting in a brief period of hypertension. Clonidine hydrochloride acts centrally to inhibit the sympathetic tone and cause hypotension that is of much longer duration than the initial hypertensive effect. Administration of clonidine hydrochloride thus produces a biphasic change in blood pressure, beginning with a brief hypertensive effect and followed by a hypotensive effect that persists for about 4 hours. This biphasic response is altered by dose only. Larger doses produce a greater hypertensive effect and delay the onset of the hypotensive properties of the drug. Clonidine hydrochloride acts on a2-adrenoreceptors located in the hindbrain to produce its hypotensive action. Clonidine hydrochloride also acts centrally to cause bradycardia and to reduce plasma levels of renin. Sensitization of baroreceptor pathways in the CNS appears to be responsible for the bradycardia transmitted by way of the vagus nerve. The central mechanism that results in decreased plasma renin is not known, however. The hypotensive properties of clonidine in animals can be blocked by applying a-adrenergic blocking agents directly to the brain.58

Clonidine hydrochloride has advantages over antihyper-tensive drugs such as guanethidine monosulfate and pra-zosin hydrochloride, in that it seldom produces orthostatic hypotensive side effects. It does, however, have some sedative properties that are undesirable; it also may cause constipation and dryness of the mouth.

Clonidine hydrochloride is distributed throughout the body, with the highest concentrations found in the organs of elimination: kidney, gut, and liver. Brain concentrations are low but higher than plasma concentrations. The high concentration in the gut is caused by an enterohepatic cycle in which clonidine hydrochloride is secreted into the bile in rather high concentrations. The half-life in humans is about 20 hours. Clonidine hydrochloride is metabolized by the body to form two major metabolites, p-hydroxy-clonidine and its glucuronide. p-Hydroxyclonidine does not cross the blood-brain barrier and has no hypotensive effect in humans.

Clonidine (Catapres)

Guanabenz Acetate. Guanabenz acetate, [(2,6-dichloro-benzylidene)amino]guanidine monoacetate (Wytensin), is a central a2-adrenergic agonist that reduces the release of norepinephrine from the neuron when stimulated. The effect of the drug results in decreased sympathetic tone in the heart, kidneys, and peripheral blood vessels. The drug does not produce orthostatic hypotension.

Guanabenz ci


Guanfacine Hydrochloride. Guanfacine hydrochloride, N- (aminoiminomethyl)-2,6-dichlorobenzeneacetamide (Tenex), is structurally related to clonidine hydrochloride and guanabenz acetate and shares many of their pharmacological properties. The drug has a longer duration of action than either clonidine hydrochloride or guanabenz acetate. It lasts up to 24 hours. It also requires much longer (8-12 hours) for a peak effect to occur after the drug is administered.

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