Therapeutic use of guanethidine is often associated with symptomatic postural hypotension and hypotension following exercise, particularly when the drug is given in high doses. Guanethidineinduced sympathoplegia in men may be associated with delayed or retrograde ejaculation (into the bladder). Guanethidine commonly causes diarrhea, which results from increased gastrointestinal 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-thecounter cold preparations, can produce hypertension in patients taking guanethidine. Similarly, guanethidine can produce hypertensive crisis by releasing catecholamines in patients with pheochromocytoma. When tricyclic antidepressants are administered to patients taking guanethidine, the drug’s antihypertensive effect is attenuated, and severe hypertension may follow.
Reserpine, an alkaloid extracted from the roots of an Indian plant, Rauwolfia serpentina, was one of the first effective drugs used on a large 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 nor-epinephrine, 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, reserpine lowers blood pressure by a combination of decreased cardiac output and decreased peripheral vascular resistance.
B. Pharmacokinetics and Dosage
See Table 11–2.
C. 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 depression appears.
Reserpine rather often produces mild diarrhea and gastrointestinal cramps and increases gastric acid secretion. The drug should not be given to patients with a history of peptic ulcer.
The detailed pharmacology of αand β-adrenoceptor blockers is presented in Chapter 10.
Of the large number of β blockers tested, most have been shown to be effective in lowering blood pressure. The pharmacologic properties of several of these agents differ in ways that may confer therapeutic benefits in certain clinical situations.