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Chapter: Modern Pharmacology with Clinical Applications: Antihypertensive Drugs

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Drugs that Interfere with Norepinephrine Storage

Reserpine (Serpasil) is the prototypical drug interfering with norepinephrine storage.

DRUGS THAT INTERFERE WITH NOREPINEPHRINE STORAGE

Reserpine (Serpasil) is the prototypical drug interfering with norepinephrine storage. Reserpine lowers blood pressure by reducing norepinephrine concentrations in the noradrenergic nerves in such a way that less norep-inephrine is released during neuron activation. Reserpine does not interfere with the release process per se as does guanethidine.

Under normal circumstances, when an action poten-tial invades the sympathetic nerve terminal, a portion ofthe released norepinephrine is recycled. This event re-quires two successive steps: (1) transfer of norepineph-rine across the neuronal membrane into the cytosol by an energy-dependent carrier-mediated active process, and (2) transfer of the recaptured amine from the cy-tosol into the noradrenergic storage vesicles, where it is stored until needed. Reserpine inhibits only the second uptake process. As a consequence of this inhibition of vesicular uptake, norepinephrine cannot be stored in-traneuronally, and much of the cytosolic amine is me-tabolized by MAO.

In addition to impairing norepinephrine storage and thereby enhancing its catabolism, reserpine impairs the vesicular uptake of dopamine, the immediate precursor of norepinephrine. Since dopamine must be taken up into the adrenergic vesicles to undergo hydroxylation and form norepinephrine, reserpine administration im-pairs norepinephrine synthesis. The combined effects of the blockade of dopamine and norepinephrine vesicular uptake lead to transmitter depletion.

Reserpine also interferes with the neuronal storage of a variety of central transmitter amines such that sig-nificant depletion of norepinephrine, dopamine, and 5-hydroxytryptamine (serotonin) occurs. This central transmitter depletion is responsible for the sedation and other CNS side effects associated with reserpine ther-apy. The depletion of brain amines also may contribute to the antihypertensive effects of reserpine.

The chief use of reserpine is in the treatment of mild to moderate hypertension. As with other sympathetic depressant drugs, tolerance to the antihypertensive ef-fects of reserpine can occur, owing to a compensatory increase in blood volume that frequently accompanies decreased peripheral vascular resistance. Reserpine, therefore, should be used in conjunction with a diuretic.

Because of its sedative properties, reserpine offers special benefit to hypertensive patients who exhibit symp-toms of agitated psychotic states and who may be unable to tolerate therapy with phenothiazine derivatives.

The most troublesome untoward effects of treat-ment with reserpine involve the CNS. Sedation and de-pression are the most common, although nightmares and thoughts of suicide also occur. Reserpine treat-ment, therefore, is contraindicated in patients with a his-tory of severe depression. The occasional report of re-serpine-induced extrapyramidal symptoms, which are similar to those seen in patients with Parkinson’ s dis-ease, is believed to be a result of dopamine depletion from neurons in the CNS.

Peripheral nervous system side effects are the result of a reserpine-induced reduction of sympathetic func-tion and unopposed parasympathetic activity; symp-toms include nasal congestion, postural hypotension, di-arrhea, bradycardia, increased gastric secretion, and occasionally impotence. Because of the increased gas-tric secretion, reserpine is contraindicated for patients with peptic ulcer. In patients with little cardiac reserve, reserpine must be administered with caution because of its ability to interfere with sympathetic stimulation of the heart.

 

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