Diuretics in hypertension

McVeigh G, Galloway D, Johnston D. The case for low dose diuretics in hypertension comparison of low and conventional doses of cyclopenthiazide. BMJ 1988 297(6641) 95-8. 

Wilhelmsen L, Berglund G, Elmfeldt D, Fitzsimons T, Holzgreve H, Hosie J, Hornkvist PE, Pennert K, Tuomilehto J, Wedel H. Beta-blockers versus diuretics in hypertensive men main results from the HAPPHY trial. J Hypertens 1987 5(5) 561-72. 

The adverse effects of thiazide and thiazide-like diuretics on male sexual function include reduced libido, erectile dysfunction, and difficulty in ejaculating. The exact incidence of sexual dysfunction in patients taking diuretics is poorly documented, perhaps because of the personal nature of the problem and the reluctance of patients and/or physicians to discuss it. However, these abnormalities have been reported with incidence rates of 3-32%. The true incidence of sexual dysfunction probably lies closer to the lower end of this range (119). In a meta-analysis of 13 randomized, placebo-controlled trials conducted over a mean of 4 years the NNH (number needed to harm) for erectile impotence with thiazide diuretics in hypertension was 20 and the relative risk was 5.0 (120). 

Papademetriou V. Diuretics in hypertension clinical experiences. Eur Heart J 1992 13(Suppl G) 92-5. 

NichoUs MG. Age-related effects of diuretics in hypertensive subjects. J Cardiovasc Pharmacol 1988 12(Suppl 8) S51-9. 

In general, class II and III calcium channel blockers are used to treat hypertension as an alternative to diuretics. In hypertensive patients over 55 years old and those of African origin of any age calcium channels blockers or diuretics are now the dmgs of first choice. 

Amiloride is used with thiazide or loop diuretics in hypertension, in congestive heart failure, in digitalis-induced hypokalemia, and in arrhythmias resulting from hypokalemia. Inappropriate use of amiloride may cause hyperkalemia (potassium >5.5 mEq/L), which may be fatal if not corrected, and may be more deleterious in elderly individuals and in patients with diabetes mellitus and renal impairment. The symptoms of hyperkalemia include fatigue, flaccid paralysis of the extremities, paresthesias, bradycardia, ECG abnormalities, and shock. Amiloride is not metabolized but is contraindicated in anuria, acute or chronic renal insufficiency, or in diabetic nephropathy. It should not be used with potassium preparations, and should be used cautiously with ACE inhibitors because these agents cause hyperkalemia. 

REGIMEN FOR ADMINISTRATION OF THE THIAZIDE-CLASS DIURETICS IN HYPERTENSION When a thiazide diuretic is used as the sole antihypertensive drug (monotherapy), its dose-response curve for lowering blood pressure in patients with hypertension should be... 

With the availability of newer drugs that are both effective and well tolerated, the use of reserpine has diminished because of its CNS side effects. Nonetheless, there has been some interest in using reserpine at low doses, in combination with diuretics, in hypertension therapy, especially in the elderly. Reserpine is used once daily with a diuretic, and several weeks are necessary to achieve a maximum effect. The daily dose should be limited to 0.25 mg or less, and as little as 0.05 mg/day may be effective when a diuretic is also used. Reserpine is considerably less expensive than many other antihypertensive drugs thus, it is still used in developing nations. 

Calcium channel blockers cause more pronounced lowering of blood pressure in hypertensive patients than in normotensive individuals. Generally, all calcium channel blockers cause an immediate increase in PRA during acute treatment in patients having hypertension but PRA is normalized during chronic treatment despite the sustained decrease in blood pressure. These agents also do not generally produce sodium and water retention, unlike the conventional vasodilators. This is because they produce diuretic effects by direct actions on the kidney. 

Diuretics are needed to return to normal the expanded extracellular volume that other antihypertensive agents produce, such as fluid retention and blood volume expansion, via compensatory mechanisms of the body. The loss of efficacy of antihypertensive agents can be restored if a diuretic is used concomitandy. In the treatment of hypertension, high ceiling or loop diuretics, such as furosemide, ethacrynic acid, and bumetanide, are no more efficacious than the thiazide-type of diuretics. In fact, these agents cause more side effects, such as dehydration, metaboHc alkalosis, etc, and therefore, should not be used except in situations where rapid elimination of duid volume is cleady indicated. 

Methyldopa is effective in mild, moderate, and severe hypertension but a thiazide-type diuretic is needed to overcome the fluid retaining side effect. Methyldopa has been shown to prevent and induce regression of ventricular hypertrophy in hypertensive patients. The principal side effects are sedation, drowsiness, nasal congestion, fluid retention, and in rare occasions, hemolytic anemia. 

ACE inhibitors do not completely block aldosterone synthesis. Since this steroid hormone is a potent inducer of fibrosis in the heart, specific antagonists, such as spironolactone and eplerenone, have recently been very successfully used in clinical trials in addition to ACE inhibitors to treat congestive heart failure [5]. Formerly, these drugs have only been applied as potassium-saving diuretics in oedematous diseases, hypertension, and hypokalemia as well as in primary hyperaldosteronism. Possible side effects of aldosterone antagonists include hyperkalemia and, in case of spironolactone, which is less specific for the mineralocorticoid receptor than eplerenone, also antiandrogenic and progestational actions. 

Two types of diuretics are used for volume management in HF thiazides and loop diuretics. Thiazide diuretics such as hydrochlorothiazide, chlorthalidone, and metolazone block sodium and chloride reabsorption in the distal convoluted tubule. Thiazides are weaker than loop diuretics in terms of effecting an increase in urine output and therefore are not utilized frequently as monotherapy in HF. They are optimally suited for patients with hypertension who have mild congestion. Additionally, the action of thiazides is limited in patients with renal insufficiency (creatinine clearance less than 30 mL/minute) due to reduced secretion into their site of action. An exception is metolazone, which retains its potent action in patients with renal dysfunction. Metolazone is often used in combination with loop diuretics when patients exhibit diuretic resistance, defined as edema unresponsive to loop diuretics alone. 

Explain the mechanism of action of diuretics in congestive heart failure and hypertension... 

Potassium-sparing diuretics are often coadministered with thiazide or loop diuretics in the treatment of edema and hypertension. In this way, edema fluid is lost to the urine while K+ ion balance is better maintained. The aldosterone antagonists are particularly useful in the treatment of primary hyperaldosteronism. 

Furosemide and ethacrynic acid preserve glomerular filtration rate and are, therefore, the diuretic agents of choice in hypertensive patients with impairment of kidney function(17,18,... 

In vitro studies suggest that the GRK4 SNPs impair the function of receptors, increase blood pressure, and impair the diuretic and natriuretic effects of dopamine Dj-like agonist stimulation. Inappropriate desensitization of the dopamine D, receptor in renal proximal tubules in hypertension may result in the decreased ability of the kidney to eliminate a sodium chloride load—a key risk factor in the development of hypertension. 

Amlodipine and nifedipine are dihydropyridine calcium-channel blockers. Amlodipine differs from nifedipine in that it has a longer duration of action and can therefore be given once daily, unlike nifedipine. Both are indicated in hypertension and angina and tend to cause ankle oedema that does not respond to diuretic therapy. Neither amlodipine nor nifedipine are available as spray formulations. 

Rasilez contains aliskiren, which is a renin inhibitor used in hypertension as monotherapy or in combination with other antihypertensives. It is to be used with caution in patients taking concomitant diuretics, on a low-sodium diet or who are dehydrated and in patients with a glomerular filtration rate less than 30 mL/minute. Aliskiren may cause diarrhoea as a side-effect and it should be administered with or after food. It exists in two dosage strengths, 150 mg and 300 mg. 

Thiazide diuretics act on the beginning of the distal convoluted tubule by inhibiting sodium re-absorption. Thiazide diuretics are indicated in hypertension, and at higher doses to relieve oedema caused by heart failure. Thiazide diuretics lead to hyponatraemia and hypokalaemia. They may cause hypercalcaemia and are therefore avoided in patients with this condition. 

Reserpine is used for treating hypertension however, it is not the drug of choice because of a number of side effects. A number of drugs combined with other hypertensive agents— diuretics in particular—are based on reserpine. Reserpine is prescribed under a number of names, including serpasil, brinerdin, diupres, and others. 

Moreover, whether or not hypertension is caused by an elevated level of renin or other reasons, angiotensin-converting enzyme inhibitors lower both systolic and diastolic arterial pressure in hypertensive patients, and their effects are enhanced by diuretics. Angiotensin-converting drugs of this series (captopril, enalapril) are effective antihypertensive drugs used both independently and in combination with other drugs to treat all types of hypertension as well as to treat cardiac insufficiency. 

Adjunctive treatment with thiazide or loop diuretics in CHF or hypertension to Help restore normal serum potassium in patients who develop hypokalemia on the kaliuretic diuretic prevent hypokalemia in patients who would be at particular risk if hypokalemia were to develop (eg, digitalized patients or patients with significant cardiac arrhythmias). 

Hydralazine and dihydralazine are predominantly arterial vasodilators which cause a reduction in peripheral vascular resistance but also reflex tachycardia and fluid retention. They were used in the treatment of hypertension, in combination with a -blocker and a diuretic. Long-term use of these compounds may cause a condition resembling lupus erythematodes with arthrosis, dermatitis and LE-cells in the blood. This risk is enhanced in women and in patients with a slow acetylator pattern. When combined with the venous vasodilator isosorbide (an organic nitrate) hydralazine was shown to be mildly beneficial in patients with congestive heart failure (V-HEFT I Study). Hydralazine and dihydralazine have been replaced by other therapeutics, both in hypertension treatment and in the management of heart failure. 

The therapeutic efficacy of ATi-receptor blockers in hypertensive disease is well documented. The ATi-blockers are assumed to be as effective as various classes of well-known antihypertensives, such as jS-blockers, diuretics, ACE-inhibitors and calcium antagonists. A major advantage of the ATi-blockers may be their favourable pattern of side-effects, which so far does not appear to differ from the use of placebo. In particular the fact that ATi-blockers do not cause cough (in contrast to the ACE-inhibitors) appears to be an advantage. 

Fig. 7. Sites of action of the major classes of diuretic drugs used in fluid retention states and in hypertension.

Padilla MC, Armas-Hernandez MJ, Hernandez RH, Israili ZH, Valasco M. Update of diuretics in the treatment of hypertension. Am J Ther 2007 14 154-60. 

Salvetti A, Ghiadoni L. Thiazide diuretics in the treatment of hypertension an update. J Am Soc Nephrol 2006 17(4 Suppl 2) S25-9. 

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