Adverse Effects of Diuretics

The most serious side effects of diuretics are fluid depletion and electrolyte imbalance.13,88 By the very nature of their action, diuretics decrease extracellular fluid volume as well as produce sodium depletion (hyponatremia) and potassium depletion (hypokalemia). Hypokalemia is a particular problem with the thiazide and loop diuretics, but occurs less frequently when the potassium-sparing agents are used. Hypokalemia and other disturbances in fluid and electrolyte balance can produce serious metabolic and cardiac problems and may even prove fatal in some individuals. Consequently, patients must be monitored closely, and the drug dosage should be maintained at the lowest effective dose. Also, potassium supplements are used in some patients to prevent hypokalemia. 

Fluid depletion may also be a serious problem during diuretic therapy. A decrease in blood volume may cause a reflex increase in cardiac output and peripheral vascular resistance because of activation of the baroreflex (see Chapter 18). This occurrence may produce an excessive demand on the myocardium, especially in patients with cardiac disease. Decreased blood volume may also activate the renin-angiotensin system, thereby causing further peripheral vasoconstriction and increased cardiac workload. Again, the effects of fluid depletion may be especially serious in patients with certain types of heart failure. 

Loop and thiazide diuretics may also impair glucose and lipid metabolism, and it has been suggested that high doses of these agents may predispose some patients to type 2 diabetes mellitus.1,13 Although the exact risk of such metabolic disturbances is not known, the long-term use of these drugs has been questioned.67 Nonetheless, concerns about metabolic side effects can be minimized if low doses are administered.13 

Other less serious, but bothersome, side effects of diuretic therapy include gastrointestinal disturbances and weakness-fatigue. Orthostatic hypotension may occur because of the relative fluid depletion produced by these drugs. Changes in mood and confusion may also occur in some patients. 

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Adverse effects of diuretics are excessive potassium and hydrogen ion loss leading to hypokalaemia and metabolic alkalosis. Hypokalaemia enhances the toxic effects of cardiac glycosides. 

ADVERSE EFFECTS AND PRECAUTIONS Adverse effects of diuretics see Chapter 28) determine tolerance and adherence. Erectile dysfunction is a troublesome adverse effect of thiazide diuretics physicians should inquire specifically regarding its occurrence. Albeit uncommon, gout may be a consequence of the hyperuricemia induced by these diuretics. Either of these adverse effects is reason to consider alternative therapies. Hydrochlorothiazide may cause rapidly developing, severe hyponatremia in some patients. Thiazides inhibit renal Ca " excretion, occasionally leading to hypercalcemia although generally mUd, this can be more severe in patients subject to hypercalcemia, such as those with primary hyperparathyroidism. The thiazide-induced decreased Ca excretion may be used therapeutically in patients with osteoporosis or hypercalciuiia. 

Electrolyte balance Hypokalemia and hyponatremia are well-recognized adverse effects of diuretics, and the EIDOS and DoTS descriptions are shown in Figure 1. 

Potassium-sparing by diuretic agents, particularly spironolactone, enhances the effectiveness of other diuretics because the secondary hyperaldosteronism is blocked. This class of diuretics decreases magnesium excretion, eg, amiloride can decrease renal excretion of potassium up to 80%. The most important and dangerous adverse effect of all potassium-sparing diuretics is hyperkalemia, which can be potentially fatal the incidence is about 0.5% (50). Therefore, blood potassium concentrations should be monitored carehiUy. 

Furosemide, torsemide, and bumetanide are sulfonamide derivatives, hence chemically related to the thiazides. They share the thiazides adverse effects of serum uric acid elevation and diabetogenic potential. Ethacrynic acid (Edecrin) is chemically unrelated to other diuretics and does not appear to have diabetogenic potential. 

All loop diuretics, with the exception of ethacrynic acid, are sulfonamides. Therefore, skin rash, eosinophilia, and less often, interstitial nephritis are occasional adverse effects of these drugs. This toxicity usually resolves rapidly after drug withdrawal. Allergic reactions are much less common with ethacrynic acid. 

Hyponatremia is an important adverse effect of thiazide diuretics. It is due to a combination of hypovolemia-induced elevation of ADH, reduction in the diluting capacity of the kidney, and increased thirst. It can be prevented by reducing the dose of the drug or limiting water intake. 

Adverse effects The adverse events associated with (3 blockers may be avoided by starting treatment at very low doses. However, treatment can be associated with complaints of fatigue and weakness, which usually resolve in a few weeks, Sometimes it is necessary to decrease the dose of the (3 blocker or diuretic. Symptomatic bradycardia is another serious adverse effect of (3 blockers, and requires a decrease in the dose or sometimes cardiac pacing to allow the use of this vital medication, Hypotension is another potential side effect however, it is rarely seen as the therapy is started with a very low dose (3,25 mg twice a day for carvedilol, I mg for bisoprolol and 12,5 mg for extended release metoprolol). The administration of ACE inhibitor and diuretic at a different time of day than the (3 blocker can... 

Aspirin, paracetamol, and hydrocortisone are used to control febrile reactions of amphotericin. Patients with a history of adverse effects with amphotericin should be prophylactically treated with antipyretics and hydrocortisone. Antiemetics and pethidine also are used for the treatment of adverse effects of amphotericin. With sodium supplements and hydration therapy, damage to the kidney can be reduced. If conventional amphotericin is not well tolerated by the patient, colloidal carriers can be used as alternative options. Administration of amphotericin with a nephrotoxic drug, such as cyclosporin, may further increase toxicity. Diuretics and anticancer drugs should be avoided with amphotericin. 

Exaggerated pharmacological effects of diuretics to decrease sodium and water retention can result in complications relating to ion changes important in congestive heart failure. Possible adverse effects include the following ... 

Adverse effects Thiazide diuretics induce hypokalemia and hyperuricemia in 70% of patients, and hyperglycemia in 10% of patients. Serum potassium levels should be monitored closely in patients who are predisposed to cardiac arrhythmias (particularly individuals with left ventricular hypertrophy, ischemic heart disease, or chronic congestive heart failure) and who are concurrently being treated with both thiazide diuretics and digitalis glycosides (see p. 160). Diuretics should be avoided in the treatment of hypertensive diabetics or patients with hyperlipidemia. 

Q8 In addition to the intended therapeutic effects, thiazide diuretics can have adverse effects of hypokalaemia, hyperglycaemia and hyperuricaemia. These are not often observed when the usual low dose of thiazide is used. If the dosage is increased, the therapeutic effect is not greatly enhanced, but the likelihood of adverse effects increases considerably. It is therefore better to change to a more powerful agent, such as a loop diuretic, than to increase the dose of the thiazide. 

POTASSIUM-SPARING DIURETICS ANTIVIRALS-PROTEASE INHIBITORS Possibly t adverse effects of eplerenone with nelfinavir, ritonavir (with or without lopinavir) and saquinavir Inhibition of CYP3A4-mediated metabolism of eplerenone Avoid concomitant use... 

The adverse effects of radioiodine are as for iodism, above. In the event of inadvertent overdose, large doses of sodium or potassimn iodide should be given to compete with the radioiodine for thyroid uptake and to hasten excretion by increasing iodide turnover (increased fluid intake and a diuretic are adjuvants). 

Considering the widespread use of diuretics over a long period (chlorothiazide was introduced in 1957) their safety record is remarkable, and reports of adverse effects of any significance with the best-known drugs of this type are uncommon. 

The loss of potassium caused by diuretics is their most intensively debated adverse effect, and the extent and significance of the problem has long been disputed. The effect of diuretics on potassium balance and their chnical consequences have been reviewed extensively (50-52,65,100-102). The risks of diuretic-induced hypokalemia have been greatly exaggerated (50,65,102). A fall in plasma potassium is common, but sound studies have consistently showed that diuretics do not deplete body potassium or cause potassium deficiency during longterm therapy in hypertensive patients (50). 

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). 

Reviews of the age-related effects of diuretics in hjrper-tensive subjects (161,162) have concluded that symptomatic adverse reactions are not more frequent in older patients and some trials have suggested a lower frequency... 

Andersson OK, Gudbrandsson T, Jamerson K. Metabolic adverse effects of thiazide diuretics the importance of normokalaemia. J Intern Med Suppl 1991 735 89-96. 

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