Diuretics tolerance development

Alcohol inhibits the release of vasopressin (antidiuretic hormone see Chapter 29) from the posterior pituitary gland, resulting in enhanced diuresis. The volume loading that accompanies imbibing complements the diuresis that occurs as a result of reduced vasopressin secretion. Alcoholics have less urine output than do control subjects in response to a challenge dose with ethanol, suggesting that tolerance develops to the diuretic effects of ethanol. Alcoholics withdrawing from alcohol exhibit increased vasopressin release and a consequent retention of water, as well as dilutional hyponatremia. 

Psychoeducation of the patient and family is required to avoid the development of hopelessness in both the patient and family, and the clinician. Comparing these strategies with other treatments of medical disorders can be useful to help patients and their families understand the medication plan and to improve compliance with and tolerance of treatment. In this instance the example of hypertension is appropriate diuretics may be used alone, or combined with other antihypertensives in different trials, according to response. 

Acetazolamide is a diuretic whose main action is the inhibition of carbonic anhydrase (see Chapter 15). Mild acidosis in the brain may be the mechanism by which the drug exerts its antiseizure activity alternatively, the depolarizing action of bicarbonate ions moving out of neurons via GABA receptor ion channels may be diminished by carbonic anhydrase inhibition. Acetazolamide has been used for all types of seizures but is severely limited by the rapid development of tolerance, with return of seizures usually within a few weeks. The drug may have a special role in epileptic women who experience seizure exacerbations at the time of menses seizure control may be improved and tolerance may not develop because the drug is not administered continuously. The usual dosage is approximately 10 mg/kg/d to a maximum of 1000 mg/d. 

The carbonic anhydrase inhibitors, of which acetazol-amide (rINN), a non-competitive inhibitor, is the prototype, are not suitable for normal diuretic use, because tolerance soon develops. However, they are well suited to brief intermittent use, particularly in the relief of glaucoma and in the prevention of acute mountain sickness. Acetazolamide and methazolamide (rINN) should be used with caution in the long-term control of glaucoma because of its serious systemic adverse effects. However, brinzolamide (rINN) and dorzolamide (rINN) are available for long-term topical administration. 

A 12-year-old girl with neuroblastoma and normal renal function developed severe hypercalcemia while receiving isotretinoin 160 mg/m /day (61). Her hypercalcemia resolved with hydration, diuretic therapy, and temporary withdrawal of isotretinoin. Despite a dosage reduction to 80 mg/m /day, severe hypercalcemia recurred during the next treatment cycle. Further treatment with isotretinoin was made tolerable by shortening the duration of the remaining cycles. 

Parker JD, Parker AB, Farrell B, Parker JO. Effects of diuretic therapy on the development of tolerance to nihoglycerin and exercise capacity in patients with chronic stable angina. Chculation 1996 93 691-696. 

For those patients with normal to moderately impaired renal function, the cornerstone of initial treatment of hypercalcemia is volume expansion to increase urinary calcium excretion (see Table 49-6). Patients with severe renal insufficiency usually do not tolerate volume expansion they may be initiated on therapy with calcitonin. Patients with symptomatic hypercalcemia are often dehydrated secondary to vomiting and polyuria thus rehydration with saline-containing fluids is necessary to interrupt the stimulus for sodium and calcium reabsorption in the renal mbule. ° Rehydration can be accomplished by the infusion of normal saline at rates of 200 to 300 mL/h, depending on concomitant conditions (primarily cardiovascular and renal) and extent of hypercalcemia. Adequacy of hydration is assessed by measuring fluid intake and output or by central venous pressure monitoring. Loop diuretics such as furosemide (40 to 80 mg IV every 1 to 4 hours) or ethacrynic acid (for patients with sulfa allergies) may also be instiffited to increase urinary calcium excretion and to minimize the development of volume overload from the administration of saline (see Table 49-6). Loop diuretics such as furosemide... 

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. 

P receptor antagonists do not usually cause salt and water retention, and diuretic administration is not necessary to avoid edema or the development of tolerance. However, diuretics do have additive antihypertensive effects when combined with /5 blockers. The combination of a /5 receptor antagonist, a diuretic, and a vasodilator is effective for patients who require a third drug. /5 Adrenergic receptor antagonists are preferred drugs for hypertensive patients with conditions such as myocardial infarction, ischemic heart disease, or congestive heart failure. 

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. 

Magnesium- and phosphate-containing preparations are tolerated reasonably well by most patients. However, they must be used with caution or avoided in patients with renal insufficiency, cardiac disease, or preexisting electrolyte abnormalities, and in patients on diuretic therapy. Patients taking >45 mL of oral sodium phosphate as a prescribed bowel preparation may experience electrolyte shifts that pose a risk for the development of symptomatic dehydration, renal failure, metabolic acidosis, hypocalcemic tetany, and even death in medically vulnerable populations. 

The risk of ACE inhibitor-induced renal impairment in patients with or without renovascular disease can be potentiated by diuretics. " In an analysis of 74 patients who had been treated with captopril or lisinopril, reversible acute renal failure was more coimnon in those who were also treated with a diuretic (furosemide and/or hydrochlorothiazide) than those who were not (11 of 33 patients compared with 1 of 41 patients). Similarly, in a prescription-event monitoring study, enalapril was associated with raised creatinine or urea in 75 patients and it was thought to have contributed to the deterioration in renal function and subsequent deaths in 10 of these patients. However, 9 of these 10 were also receiving loop or thiazide diuretics, sometimes in high doses. Retrospective analysis of a controlled study in patients with hypertensive nephrosclerosis identified 8 of 34 patients who developed reversible renal impairment when treated with enalapril and various other antihypertensives including a diuretic (furosemide or hydrochlorothiazide). In contrast, 23 patients treated with placebo and various other antihypertensives did not develop renal impairment. Subsequently, enalapril was tolerated by 7 of the 8 patients without deterioration in renal function and 6 of these patients later received diuretics. One patient was again treated with enalapril with recurrence of renal impairment, but discontinuation of the diuretics (furosemide, hydrochlorothiazide, and triamterene) led to an improvement in renal function despite the continuation of enalapril. ... 

Tolerance to the diuretic action of caffeine was demonstrated more than 50 years ago and was shown to develop on chronic caffeine intake so that the clinical significance of hypokalemia and calciuria is difficult to evaluate. Although controversial, some epidemiological studies have implicated caffeine in the increased risk for poor calcium retention. For calcium intakes lower than 750 mg per day, increased rate of bone loss and lower bone density were reported. However, it has been suggested that the effect on bone of high caffeine intake requires a genetic predisposition toward osteoporosis. In individuals who ingest calcium recommended daily allowances, there is no evidence of any effect of caffeine on bone status and calcium economy. 

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