Low dose Sequential nephron blockade may improve BP control in resistant hypertension

Resistant hypertension is defined as uncontrolled blood pressure i.e. more than 140/90 (130/80 in diabetics) with maximum dose of three different class of antihypertensive drugs of this one diuretics is mandatory. Hypertensive patient whose blood pressure is controlled with four or more antihypertensive drugs are called controlled resistant hypertensive.

Around 14% of patients with hypertension are having resistant hypertension. Patient with uncontrolled BP are prone for CVA, IHD, heart failure and CKD. So optimal control of blood pressure is important.  Patient with resistant hypertension are volume overloaded so adding an optimum diuretics reduces chance of uncontrolled blood pressure.

Diuretics and site of action
Recently published study by Bobrie et al shows benefits adding diuretics which act at multiple levels in nephron. The rationale for low-dose sequential nephron blockade is to neutralize the effects of intrarenal compensatory increases in sodium reabsorption at unblocked sites along the nephron triggered by the use of high-dose diuretics acting at a single site. Apart from this low dose of diuretics reduces chance of side effects.

 Bobrie et al  study was prospective, randomized, open blinded endpoint study of 167 patients. At base line after treatment of 4 weeks with irbesartan 300 mg/day, hydrochlorothiazide 12.5 mg/day and amlodipine 5 mg/day, ambulatory blood pressure was more than 135/85. These were randomized to sequential nephron blocked n=82 Vs sequential rennin-angiotensin system blockade n=85. Spironolactone 25 mg/day in or ramipril 5 mg/day in were added for 4 weeks respectively to sequential diuretic and RAAS blocked group respectively.

At 12 weeks, the mean difference of ambulatory blood pressure in daytime was 10/4 mmHg between sequential diuretic and RAAS group (95% confidence interval: 7-14/2-7; P < 0.001/P = 0.0014)
Ambulatory blood pressure of less than 135/85 was achieved in 58% in sequential diuretics group as compared 20% in sequential RAAS blocked. If this is confirmed by larger trials than it may reduce prevalence of resistant hypertension by 5-6%

Diuretics and site of action.

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