Adrenergic Neuron-Blocking Agents

ADRENERGIC NEURON-BLOCKING AGENTS

These drugs lower blood pressure by preventing normal physio-logic release of norepinephrine from postganglionic sympathetic neurons.

Guanethidine

In high enough doses, guanethidine can produce profound sym-pathoplegia. The resulting high maximal efficacy of this agent made it the mainstay of outpatient therapy of severe hypertension for many years. For the same reason, guanethidine can produce all of the tox-icities expected from “pharmacologic sympathectomy,” including marked postural hypotension, diarrhea, and impaired ejaculation. Because of these adverse effects, guanethidine is now rarely used.

Guanethidine is too polar to enter the central nervous system.

Guanadrel is a guanethidine-like drug that is available in the USA. Bethanidine and debrisoquin, antihypertensive agents not available for clinical use in the USA, are similar.

A. Mechanism and Sites of Action

Guanethidine inhibits the release of norepinephrine from sympa-thetic nerve endings (see Figure 6–4). This effect is probably responsible for most of the sympathoplegia that occurs in patients. Guanethidine is transported across the sympathetic nerve mem-brane by the same mechanism that transports norepinephrine itself (NET, uptake 1), and uptake is essential for the drug’s action. Once guanethidine has entered the nerve, it is concentrated in transmitter vesicles, where it replaces norepinephrine. Because it replaces norepinephrine, the drug causes a gradual depletion of norepinephrine stores in the nerve ending.

Because neuronal uptake is necessary for the hypotensive activ-ity of guanethidine, drugs that block the catecholamine uptake process or displace amines from the nerve terminal  block its effects. These include cocaine, amphetamine, tricyclic antidepressants, phenothiazines, and phenoxybenzamine.

B. Pharmacokinetics and Dosage

Because of guanethidine’s long half-life (5 days), the onset of sym-pathoplegia is gradual (maximal effect in 1–2 weeks), and sym-pathoplegia persists for a comparable period after cessation of therapy. The dose should not ordinarily be increased at intervals shorter than 2 weeks.

C. Toxicity

Therapeutic use of guanethidine is often associated with symp-tomatic postural hypotension and hypotension following exercise, particularly when the drug is given in high doses. Guanethidine-induced sympathoplegia in men may be associated with delayed or retrograde ejaculation (into the bladder). Guanethidine com-monly causes diarrhea, which results from increased gastrointesti-nal motility due to parasympathetic predominance in controlling the activity of intestinal smooth muscle.

Interactions with other drugs may complicate guanethidine therapy. Sympathomimetic agents, at doses available in over-the-counter cold preparations, can produce hypertension in patients taking guanethidine. Similarly, guanethidine can produce hyper-tensive crisis by releasing catecholamines in patients with pheo-chromocytoma. When tricyclic antidepressants are administered to patients taking guanethidine, the drug’s antihypertensive effect is attenuated, and severe hypertension may follow.

Reserpine

Reserpine, an alkaloid extracted from the roots of an Indian plant, Rauwolfia serpentina, was one of the first effective drugs used on alarge scale in the treatment of hypertension. At present, it is rarely used owing to its adverse effects.

A. Mechanism and Sites of Action

Reserpine blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines, probably by interfering with the vesicular membrane-associated transporter (VMAT, see Figure 6–4). This effect occurs throughout the body, resulting in depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons. Chromaffin granules of the adrenal medulla are also depleted of catecholamines, although to a lesser extent than are the vesicles of neurons. Reserpine’s effects on adrenergic vesicles appear irreversible; trace amounts of the drug remain bound to vesicular membranes for many days.

Depletion of peripheral amines probably accounts for much of the beneficial antihypertensive effect of reserpine, but a central component cannot be ruled out. Reserpine readily enters the brain, and depletion of cerebral amine stores causes sedation, mental depression, and parkinsonism symptoms.

At lower doses used for treatment of mild hypertension, reser-pine lowers blood pressure by a combination of decreased cardiac output and decreased peripheral vascular resistance.

Pharmacokinetics and Dosage

Toxicity

At the low doses usually administered, reserpine produces little postural hypotension. Most of the unwanted effects of reserpine result from actions on the brain or gastrointestinal tract. High doses of reserpine characteristically produce sedation, lassitude, nightmares, and severe mental depression; occasionally, these occur even in patients receiving low doses (0.25 mg/d). Much less frequently, ordinary low doses of reserpine produce extrapyramidal effects resembling Parkinson’s disease, probably as a result of dopamine depletion in the corpus striatum. Although these central effects are uncommon, it should be stressed that they may occur at any time, even after months of uneventful treatment. Patients with a history of mental depression should not receive reserpine, and the drug should be stopped if depres-sion appears.Reserpine rather often produces mild diarrhea and gastrointes-tinal cramps and increases gastric acid secretion. The drug should not be given to patients with a history of peptic ulcer.