Thiazide diuretics therapy with

Potassium is the second most abundant cation in the body and is found primarily in the intracellular fluid. Potassium has many important physiologic functions, including regulation of cell membrane electrical action potential (especially in the myocardium), muscular function, cellular metabolism, and glycogen and protein synthesis. Potassium in PN can be provided as chloride, acetate, and phosphate salts. One millimole of potassium phosphate provides 1.47 mEq of elemental potassium. Generally, the concentration of potassium in peripheral PN (PPN) admixtures should not exceed 80 mEq/L (80 mmol/L). While it is safer to also stick to the 80 mEq/L (80 mmol/L) limit for administration through a central vein, the maximum recommended potassium concentration for infusion via a central vein is 150 mEq/L (150 mmol/L).14 Patients with abnormal potassium losses (e.g., loop or thiazide diuretic therapy) may have higher requirements, and patients with renal failure may require potassium restriction. 

The results of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was the deciding evidence that the JNC7 used to justify thiazide diuretics as first-line therapy." It was designed to test the hypothesis that newer antihypertensive agents (an a-blocker, ACE inhibitor, and dihydropyridine CCB) would be superior to thiazide diuretic therapy. The primary objective was to compare the combined end point of fatal coronary heart disease and nonfatal myocardial infarction. Other hypertension-related complications (e.g., heart failure and stroke) were evaluated as secondary end points. This was the largest hypertension trial ever conducted and included 42,418 patients aged 55 years and older with hypertension and one additional cardiovascular risk factor. This prospective, double-blind trial randomized patients to chlorthalidone (a thiazide diuretic), amlodipine (dihydropyridine CCB), doxazosin (a-blocker), or lisinopril (ACE inhibitor) for a mean follow-up of 4.9 years. 

Diuretics, such as those of the thiazide type, have been the cornerstone of first-line antihypertensive treatments for decades. However, popularity and use have eroded as a result of increases in sudden death in patients on diuretic therapy, and unfavorable effects on blood Hpids profile, ie, increasing cholesterol and triglyceride. These effects have been impHcated as possible causes for the lack of decrease in the mortaUty rate resulting from acute MI in patients treated with a diuretic (187,240,241). However, diuretics do protect against stroke and CHF. 

Acutely, diuretics lower BP by causing diuresis. The reduction in plasma volume and stroke volume associated with diuresis decreases cardiac output and, consequently, BP. The initial drop in cardiac output causes a compensatory increase in peripheral vascular resistance. With chronic diuretic therapy, the extracellular fluid volume and plasma volume return almost to pretreatment levels, and peripheral vascular resistance falls below its pretreatment baseline. The reduction in peripheral vascular resistance is responsible for the long-term hypotensive effects. Thiazides lower BP by mobilizing sodium and water from arteriolar walls, which may contribute to decreased peripheral vascular resistance. 

Blockers (without ISA) are first-line therapy in chronic stable angina and have the ability to reduce BP, improve myocardial consumption, and decrease demand. Long-acting CCBs are either alternatives (the nondihy-dropyridines verapamil and diltiazem) or add-on therapy (dihydropy-ridines) to /1-blockers in chronic stable angina. Once ischemic symptoms are controlled with /1-blocker and/or CCB therapy, other antihypertensive drugs (e.g., ACE inhibitor, ARB) can be added to provide additional CV risk reduction. Thiazide diuretics may be added thereafter to provide additional BP lowering and further reduce CV risk. 

Therapy of congestive heart failure. By lowering peripheral resistance, diuretics aid the heart in ejecting blood (reduction in afterload, pp. 132, 306) cardiac output and exercise tolerance are increased. Due to the increased excretion of fluid, EEV and venous return decrease (reduction in preload, p. 306). Symptoms of venous congestion, such as ankle edema and hepatic enlargement, subside. The drugs principally used are thiazides (possibly combined with K+-sparing diuretics) and loop diuretics. 

In multidrug therapy, it is necessary to consider which agents rationally complement each other. A p-blocker (bradycardia, cardiodepression due to sympathetic blockade) can be effectively combined with nifedipine (reflex tachycardia), but obviously not with verapamil (bradycardia, cardiodepression). Monotherapy with ACE inhibitors (p. 124) produces an adequate reduction of blood pressure in 50% of patients the response rate is increased to 90% by combination with a (thiazide) diuretic. When vasodilators such as dihydralazine or minoxidil (p. 118) are given, p-blockers would serve to prevent reflex tachycardia, and diuretics to counteract fluid retention. 

Diuretics - Generally initiate therapy with a thiazide or other oral diuretic. Thiazide-type diuretics are drugs of choice hydrochlorothiazide or chlorthalidone are generally preferred. Reserve loop diuretics for selected patients. This therapy alone may control many cases of mild hypertension. Consider treating diuretic-induced hypokalemia (less than 3.5 mEq/L) with potassium supplementation or by adding a potassium-sparing diuretic to therapy. 

Thiazide diuretics are effective antihypertensive agents in black hypertensive patients and studies suggest that they cause a greater decrease in blood pressure in black patients than in whites. The better hypotensive response in black hypertensive patients is probably due to the fact that, in comparison with whites, more black patients have an expanded intracellular volume and low plasma renin activity. In developing countries, in which the majority of black people live, the cost of therapy is important. Thiazide diuretics are because of their low cost important baseline drugs in the treatment of hypertension. 

Captopril, as well as other ACE inhibitors, is indicated in the treatment of hypertension, congestive heart failure, left ventricular dysfunction after a myocardial infarction, and diabetic nephropathy. In the treatment of essential hypertension, captopril is considered first-choice therapy, either alone or in combination with a thiazide diuretic. Decreases in blood pressure are primarily attributed to decreased total peripheral resistance or afterload. An advantage of combining captopril therapy with a conventional thiazide diuretic is that the thiazide-induced hypokalemia is minimized in the presence of ACE inhibition, since there is a marked decrease in angiotensin Il-induced aldosterone release. 

When diuretic therapy is indicated for the treatment of primary hypertension, the thiazide-type compounds (e.g., chlorothiazide, hydrochlorothiazide) are generally the drugs of choice. They can be used alone or in combination with other antihypertensive agents Approximately 30% of patients with mild hypertension may be treated effectively with thiazide therapy alone. 

The p-blockers are quite popular antihypertensive drugs. They are well tolerated, and serious side effects are seldom observed. When used alone over several weeks, p-blockers produce a signihcant reduction in blood pressure in approximately 30% of patients with mild to moderate hypertension. Thus, -blockers can be employed as a first step in the management of high blood pressure. However, they are often used in conjunction with a diuretic when therapy with a single agent is not satisfactory. The combination of a p-blocker, thiazide diuretic, and vasodilator provides signihcant control of moderate to severe hypertension in approximately 80% of patients. 

Calcium and magnesium homeostasis is altered by chronic diuretic therapy. Loop diuretics increase the urinary excretion of Ca2+ and can lead to stone formation. Thiazide administration, on the other hand, has the opposite effect and causes frank hypercalcaemia in some patients. Both thiazide and loop drugs increase the urinary loss of Mg2+ and this has been associated with cardiac arrythmias in the elderly. 

Approximately two thirds of kidney stones contain Ca2+ phosphate or Ca2+ oxalate. Many patients with such stones exhibit a defect in proximal tubular Ca2+ reabsorption that causes hypercalciuria. This can be treated with thiazide diuretics, which enhance Ca2+ reabsorption in the distal convoluted tubule and thus reduce the urinary Ca2+ concentration. Salt intake must be reduced in this setting, since excess dietary NaCI will overwhelm the hypocalciuric effect of thiazides. Calcium stones may also be caused by increased intestinal absorption of Ca2+, or they may be idiopathic. In these situations, thiazides are also effective, but should be used as adjunctive therapy with other measures. 

Therapy with hydrochlorothiazide, up to 50 mg twice daily, or chlorthalidone, 50-100 mg daily, is recommended. Loop diuretics such as furosemide and ethacrynic acid should not be used because they increase urinary calcium excretion. The major toxicity of thiazide diuretics, besides hypokalemia, hypomagnesemia, and hyperglycemia, is hypercalcemia. This is seldom more than a biochemical observation unless the patient has a disease such as hyperparathyroidism in which bone turnover is accelerated. Accordingly, one should screen patients for such disorders before starting thiazide therapy and monitor serum and urine calcium when therapy has begun. 

Since changes in glucose balance after diuretics tend to be reversible on withdrawal, measures of carbohydrate homeostasis should be assessed after several months of thiazide treatment to detect those few patients who experience significant glucose intolerance (353). With this approach, the small risk of diabetes mellitus secondary to diuretic therapy can be minimized. 

Following a single oral dose of 100 mg of spironolactone, peak serum concentrations of the drug occur within 1-2 hours, and peak serum concentrations of its principal metabolites are attained within 2-4 hours [65,67,75-77], When administered alone, spironolactone has a gradual onset of diuretic action, with the maximum effect being reached on the third day of therapy [65]. The delay in onset may result from the time required for adequate concentrations of the drug or its metabolites to accumulate [65]. When a thiazide diuretic is used concomitantly with spironolactone, diuresis usually occurs on the first day of therapy [65]. 

Therapeutic uses Thiazide diuretics decrease blood pressure in both the supine and standing positions postural hypotension is rarely observed, except in elderly, volume-depleted patients. These agents counteract the sodium and water retention observed with other agents used in the treatment of hypertension (for example, hydralazine). Thiazides are therefore useful in combination therapy with a variety of other antihypertensive agents including (3-blockers and ACE inhibitors. Thiazide diuretics are particularly useful in the treatment of black or elderly patients, and in those with chronic renal disease. Thiazide diuretics are not effective in patients with inadequate kidney function (creatinine clearance less than 50 mls/min). Loop diuretics may be required in these patients. 

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