Agents Depleting Neurotransmitter Stores

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Hypertension Causes and Treatment

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Folk remedies prepared from species of Rauwolfia, a plant genus belonging to the Apocynaceae family, were reported as early as 1563. The root of the species Rauwolfia serpentina has been used for centuries as an antidote to stings and bites of insects, to reduce fever, as a stimulant to uterine contractions, for insomnia, and particularly for the treatment of insanity. Its use in hypertension was recorded in the Indian literature in 1918, but not until 1949 did hypotensive properties of Rauwolfia spp. appear in the Western literature.51 Rauwolfia preparations were introduced in psychiatry for the treatment of schizophrenia in the early 1950s, following confirmation of the folk remedy reports on their use in mentally deranged patients. By the end of the 1960s, however, the drug had been replaced by more efficacious neurotropic agents. Reserpine and its preparations remain useful in the control of mild essential hypertension.

The effects of reserpine do not correlate well with tissue levels of the drug. The pharmacological effects of reserpine were still present in animals when it could no longer be detected in the brain.52 Reserpine depletes catecholamines and serotonin from central and peripheral neurons by interfering with the uptake of these amines from the cytosol into the vesicles and granules.53,54 As a consequence, norepinephrine cannot be stored intraneuronally in adrenergic neurons, and much of the norepinephrine in the cytosol is metabolized by monoamine oxidase (MAO) (Fig. 19.13). The binding of reserpine to the storage vesicle membrane is

Figure 19.13



• Action of reserpine at adrenergic nerve

Figure 19.13



• Action of reserpine at adrenergic nerve firm, and as a result, the storage granule is destroyed, reducing the ability of the nerve to concentrate and store norepinephrine. Because reserpine acts on both central and peripheral adrenergic neurons, its antihypertensive effects may result from neurotransmitter depletion from both of these sites.

Chemical investigations of the active components of r. serpentina roots have yielded several alkaloids (e.g., aj-maline, ajmalicine, ajmalinine, serpentine, and serpentinine). Reserpine, which is the major active constituent of Rauwolfia,55 was isolated in 1952 and is a much weaker base than the alkaloids just mentioned. Reserpinoid alkaloids are yohimbine-like bases that have an additional functional group on C-18. Only three naturally occurring alkaloids possess reserpine-like activity strong enough for use in treating hypertension: reserpine, deserpidine, and rescinnamine.

Reserpine is absorbed rapidly after oral administration. Fat tissue accumulates reserpine slowly, with a maximal level reached between 4 and 6 hours. After 24 hours, small amounts of reserpine are found in the liver and fat, but none is found in the brain or other tissues. Reserpine is metabolized by the liver and intestine to methyl reserpate and 3,4,5-trimethoxybenzoic acid.

Powdered Rauwolfia Serpentina, USP. Rauwolfia (Raudixin, Rauserpal, Rauval) is the powdered whole root of r. serpentina (Benth). It is a light tan to light brown powder, sparingly soluble in alcohol and only slightly soluble in water. It contains the total alkaloids, of which reserpine accounts for about 50% of the total activity. Orally, a dosage of 200 to 300 mg is roughly equivalent to 500 fig of reserpine. It is used in the treatment of mild or moderate hypertension or in combination with other hypotensive agents in severe hypertension.

Reserpine, USP. Reserpine (Serpasil, Reserpoid, RauSed, Sandril) is a white to light yellow, crystalline alkaloid, practically insoluble in water, obtained from various species of Rauwolfia. In common with other compounds with an indole nucleus, it is susceptible to decomposition by light and oxidation, especially when in solution. In the dry state, discoloration occurs rapidly when reserpine is exposed to light, but the loss in potency is usually small. In solution,

reserpine may break down with no appreciable color change when exposed to light, especially in clear glass containers; thus, color change cannot be used as an index of the amount of decomposition.

Reserpine is effective orally and parenterally for the treatment of hypertension. After a single intravenous dose, the onset of antihypertensive action usually begins in about 1 hour. After intramuscular injection, the maximum effect occurs within approximately 4 hours and lasts about 10 hours. When it is given orally, the maximum effect occurs within about 2 weeks and may persist up to 4 weeks after the final dose. When used in conjunction with other hypotensive drugs in the treatment of severe hypertension, the daily dose varies from 100 to 250 fig.

Guanethidine and Related Compounds. Guanethidine has been classified traditionally as an adrenergic blocking agent because it can prevent the release of norepinephrine from postganglionic neurons in response to adrenergic stimulation. Guanethidine and other compounds discussed in this section have other actions on catecholamine metabolism and can cause significant depletion of these amines in adrenergic neurons. They do not interfere with release of epinephrine from the adrenal medulla.

Guanethidine Monosulfate, USP. Guanethidine monosulfate, [2-(hexahydro-1 (2H)-azocinyl)ethyl]guani-dine sulfate (Ismelin sulfate), is a white, crystalline material that is very soluble in water. It was one of a series of guanidine compounds prepared in the search for potent an-titrypanosomal agents. There is an absence of CNS effects, such as depression, because the drug is highly polar and does not easily cross the blood-brain barrier. Guanethidine monosulfate produces a gradual, prolonged fall in blood pressure. Usually, 2 to 7 days of therapy are required before the peak effect is reached, and usually, this peak effect is maintained for 3 or 4 days. Then, if the drug is discontinued, the blood pressure returns to pretreatment levels over a period of 1 to 3 weeks. Because of this slow onset and prolonged duration of action, only a single daily dose is needed.

Guanethidine monosulfate is metabolized by microsomal enzymes to 2-(6-carboxyhexylamino)ethylguanidine and guanethidine n-oxide (Fig. 19.14). Both metabolites have very weak antihypertensive properties. Guanethidine monosulfate is taken up by the amine pump located on the neuronal membrane and retained in the nerve, displacing norepinephrine from its storage sites in the neuronal granules. The displaced norepinephrine is metabolized to ho-movanillic acid by mitochondrial MAO, depleting the nerve ending of the neurotransmitter. The usefulness of guanethi-dine monosulfate also resides in the fact that once it is taken up by the nerve, it produces a sympathetic blockade by inhibiting release of nonepinephrine that would occur on neuronal membrane response to stimulation29 by the nerve action potential. Guanethidine monosulfate stored in the granules is released by the nerve action potential but has very low intrinsic activity for the adrenergic receptors on the postjunctional membrane. Moderate doses for a prolonged period or large doses may produce undesirable side effects by causing neuromuscular blockade and adrenergic nerve conduction blockade.

Guanadrel Sulfate. Guanadrel sulfate, (1,4-dioxas-piro[4.5]dec-2-ylmethyl)guanadine sulfate (Hylorel), is similar to guanethidine monosulfate in the manner in which it reduces elevated blood pressure. It acts as a postganglionic adrenergic blocking agent by displacing norepinephrine in adrenergic neuron storage granules, thereby preventing release of the endogenous neurotransmitter on nerve stimulation. Guanadrel sulfate has a much shorter half-life (10 hours) than guanethidine monosulfate, whose

Structure Guanethidine Oxide
Figure 19.14 • Metabolism of guanethidine monosulfate.

half-life is measured in days. In the stepped-care approach to hypertension, guanadrel sulfate is usually a step 2 agent.


The principal clinical use of a-adrenergic antagonists is in the treatment of catecholamine-dependent hypertension. Classic drugs such as phentolamine and phenoxybenzamine are nonspecific-blocking agents of both a1- and a2-receptors on the presynaptic membrane of the adrenergic neuron. Specific antagonists of a1-receptors are effective antihypertensive agents by blocking the vasocontricting effect on smooth muscle and not interfering with the activation of a2-receptors on the adrenergic neuron, which when activated inhibit further release of norepinephrine.

Prazosin Hydrochloride. The antihypertensive effects of prazosin hydrochloride, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl)piperazine monohydrochloride (Minipress), are caused by peripheral vasodilation as a result of its blockade of ^-adrenergic receptors. In ligand-binding studies, prazosin hydrochloride has 5,000-fold greater affinity for a1-receptors than for some a2-adrenergic receptors.56

Prazosin Solubility

Prazosin hydrochloride is readily absorbed, and plasma concentrations reach a peak about 3 hours after administration. Plasma half-life is between 2 and 3 hours. Prazosin hydrochloride is highly bound to plasma protein; it does not cause adverse reactions, however, with drugs that might be displaced from their protein-binding sites (e.g., cardiac glycosides). It may cause severe orthostatic hypertension because of its ^-adrenergic blocking action, which prevents the reflex venous constriction that is activated when an individual sits up from a prone position.

Terazosin Hydrochloride. Terazosin hydrochloride, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(tetrahydro-2-furoyl)piperazine monohydrochloride (Hytrin), is a structural congener of prazosin hydrochloride. It possesses similar selective properties of specifically inhibiting a1-adrenergic receptors. The drug is slightly less potent than prazosin hydrochloride. Terazosin hydrochloride has a halflife of approximately 12 hours, which is much longer than that of prazosin. This lends itself to a once-daily dose to control hypertension in many patients.

Doxazosin. Doxazosin, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl)piperazine (Cardura), is a quinazoline compound that selectively inhibits the ^-subtype of ^-adrenergic receptors. This agent is very useful in the management of hypertension associated with pheochromocytoma.

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