CLINICAL PHARMACOLOGY
The combined antihypertensive actions of methyclothiazide and deserpidine result in a total clinical antihypertensive effect which is greater than can ordinarily be achieved by either drug given individually.
Methyclothiazide
The diuretic and saluretic effects of methyclothiazide result from a drug-induced inhibition of the renal tubular reabsorption of electrolytes. The excretion of sodium and chloride is greatly enhanced. Potassium excretion is also enhanced to a variable degree, as it is with the other thiazides. Although urinary excretion of bicarbonate is increased slightly, there is usually no significant change in urinary pH. Methyclothiazide has a per mg natriuretic activity approximately 100 times that of the prototype thiazide, chlorothiazide. At maximal therapeutic dosages, all thiazides are approximately equal in their diuretic/natriuretic effects.
There is significant natriuresis and diuresis within 2 hours after administration of a single dose of methyclothiazide. These effects reach a peak in about 6 hours and persist for 24 hours following oral administration of single dose.
Like other benzothiadiazines, methyclothiazide also has antihypertensive properties, and may be used for this purpose either alone or to enhance the antihypertensive action of other drugs. The mechanism by which the benzothiadiazines, including methyclothiazide, produce a reduction of elevated blood pressure is not known. However, sodium depletion appears to be involved.
Deserpidine
The pharmacologic actions of deserpidine are essentially the same as those of other active rauwolfia alkaloids. Deserpidine probably produces its antihypertensive effects through depletion of tissue stores of catecholamines (epinephrine and norepinephrine) from peripheral sites. By contrast, its sedative and tranquilizing properties are thought to be related to depletion of 5-hydroxytryptamine from the brain. The antihypertensive effect is often accompanied by bradycardia. There is no significant alteration in cardiac output or renal blood flow. The carotid sinus reflex is inhibited, but postural hypotension is rarely seen with the use of conventional doses of deserpidine alone.
Deserpidine, like other rauwolfia alkaloids, is characterized by slow onset of action and sustained effect which may persist following withdrawal of the drug.
Pharmacokinetics and Metabolism
Methyclothiazide
Methyclothiazide is rapidly absorbed and slowly eliminated by the kidneys as intact drug but primarily as an inactive metabolite. Additional information on the pharmacokinetics is not known at this time.
Deserpidine
Information is limited on the human pharmacokinetics of the rauwolfia alkaloids. Rauwolfia alkaloids appear to be widely distributed in body tissues, especially adipose tissue. They also cross the blood-brain barrier. Rauwolfia alkaloids are extensively metabolized. The unchanged alkaloid and the metabolites are excreted slowly in urine and feces.
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