The Mode of Action of Chlorothiazide in Hypertension: With Special Reference to Potentiation of Ganglion-Blocking Agents

Mechanism of the Altered Blood Pressure Responsiveness Produced by Chlorothiazide *

“…Such a position has been taken by Wilkins, Hollander and Chobanian (2,3). Evidence from this and other laboratories, however, indicates that the initial antihypertensive effect of chlorothiazide is a consequence of plasma and total extracellular fluid contraction resulting from the saluretic action of the drug (1,4,5). The evidence supporting this view follows.…”

“…The evidence supporting this view follows. 1) The period of falling blood pressure parallels the salt loss and plasma volume reduction and does not precede or follow it (5,6). 2) Massive administration of salt (average 25 g per day), sufficient partially to overcome the saluretic effect of the drug, tends to reverse the antihypertensive effect (6).…”

How do thiazide and thiazide-like diuretics lower blood pressure?

“…37 At first sight, the blood pressure lowering action of thiazides seems obvious; diuretics will cause a reduction in plasma volume, diminish venous return and depress cardiac output and blood pressure. This mechanism does seem sufficient to explain most or all of the reduction in blood pressure seen in hypertensive subjects following acute administration of thiazides, [38][39][40][41][42] and re-expansion of plasma volume by infusion of dextran, with or without sodium, restores blood pressure to pre-treatment levels. 39,40 In association with the fall in cardiac output following acute administration of thiazide, there is a rise in total peripheral vascular resistance (TPR) that is mediated largely by the sympathetic nervous system (SNS) 43 and activation of the reninangiotensin-aldosterone system.…”

“…This mechanism does seem sufficient to explain most or all of the reduction in blood pressure seen in hypertensive subjects following acute administration of thiazides, [38][39][40][41][42] and re-expansion of plasma volume by infusion of dextran, with or without sodium, restores blood pressure to pre-treatment levels. 39,40 In association with the fall in cardiac output following acute administration of thiazide, there is a rise in total peripheral vascular resistance (TPR) that is mediated largely by the sympathetic nervous system (SNS) 43 and activation of the reninangiotensin-aldosterone system. 44,45 Activation of the SNS may persist after chronic use, 43 but variability in reflex responses may contribute to differences in blood pressure lowering, at least in the short term.…”

Chlorothiazide. How the thiazides evolved as antihypertensive therapy.

“…20 The effect of their pilot chlorothiazide studies that were soon followed by the work of Laragh et al, 21 Dollery et al, 22 and many others was explosive. An avalanche of publications attesting to the efficacy and safety of chlorothiazide (Diuril) evoked a chemical effort in the worldwide pharmaceutical industry that could not be kept up with.…”