Pitfalls in Diuretic Use – Metabolic Adverse Reactions Iwan Darmansjah, MD Some commonly used diuretics • Thiazides and Thiazide analogs – Bendroflumethiazide, hydrochlorothiazide, indapamide • Loop diuretics – Furosemide, bumetanide, torasemide (long half-life) • Potassium-sparing diuretics – Amiloride, spironolactone, triamterene • Carbonic anhydrase inhibitors – Acetazolamide (specific use) • Adverse reactions to diuretics well known – Elderly people most affected • Mainly prescribed for hypertension and cardiac insufficiency • Thiazide as antihypertensive should not be called “diuretic”, because of the small doses used, and is not diuretic. URINARY ELECTROLYTE COMPOSITION DURING DIURESIS Volume pH Na+ K+ Cl+ HCO3- (ml/min) (mM) Control 1 6 50 15 60 1 Mannitol 10 6.5 90 15 110 4 Acetazolamide 3 8.2 70 60 15 120 Benzothiadiazides 3 7.4 150 25 150 25 (thiazides) High-celling diuretics 8 6 140 10 155 1 Potassium-sparing 2 7.2 130 5 110 15 diuretics Aminophylline 3 6 150 15 160 1 Source : Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 8 th ed. 1999 Loop-diuretic as Fluid-mover • Furosemide increases urine vol 8 x Normal • Thiazide (diuretic dose) 3xN • Potassium-sparing diuretic 2 xN Main Indications of furosemide • Removing edema fluid from: – Feet and legs, ascites, pulmonary interstitial and alveoli, whole body tissue edema • Acute and chronic Heart Failure • Forced diuresis HCT dose • As diuretic: 50-100 mg • As antihypertensive dose much smaller: – 6.25 mg (as in Lodoz) –12.5 mg/day – No problem of hyponatremia, nor hypokalemia • No need of routine K supplementation • Most metabolic adverse reactions of thiazide was reported from the 70’s – late 80’s, when the doses used were large (50-100 mg/day or more). Hyponatremia • Hyponatremia is the most frequent electrolyte abnormality among diuretic (all diuretics) users. It may be fatal. • Furosemide has the strongest natriuretic effect, and therefore the most frequent adverse reaction. • Factors: age, female, malnutrition, renal failure, combination with NSAID, ACE-inhib. • When severe renal failure: hyperkalemia, hyperphosphatemia, hyperuricemia. . Hypokalemia • Hypokalemia is the most feared among furosemide, and even low-dose thiazide users. • This fear is unfounded and results in overuse of K salts as a preventive in all patients receiving long term furosemide, which may result in hyperkalemia. Nature of Adverse Reactions • Hyponatremia: (when mild, asymptomatic) • Postural hypotension • Weakness, vomiting, mental confusion, coma, convulsion • Neurological complication when < 120 mmol/L • Hypokalemia: • Cardiac arrhytmia (QRS widening) • Excessive water loss (dehydration) Drugs that may alter K levels • Hypokalemia – Thiazide as a diuretic (not if used as antihypertensive) – Loop diuretic – Mineralocorticoids (fludrocortisone) – Cathartics – Adrenergics, theophylline (high dose) • Hyperkalemia – KCL tablets – Potassium –sparing diuretics – ACE-inhibitors – NSAID (especially when renal impairment) Some Mechanisms (1) • ACE-inhib may increase serum K by: – Reducing angiotensin-II mediated release of aldosterone, which reduces K excretion in the distal tubules. • Fludrocortisone produces hypokalemia by – increasing K renal excretion with Na absorption in the distal tubule. Some Mechanisms (2) • Adrenergics: stimulate K uptake by muscles redistribution of K (usually mild) • Furosemide depends on renal excretion; Bumetanide does not, because metabolized Treatment of Hyponatremia • Slow infusion of isotonic or hypertonic NaCl solution. • Restriction of water intake. • Precaution: when checking K level, one should include Na. Treatment of Hypo- and Hyper-kalemia • Severe hypo- or hyper-kalemia must be treated fast with cardiac monitoring. • Hypo: Slow infusion of KCL solution. • Hyper: Infusion of glucose and insulin (stimulates K uptake in the cell) – Also: anion exchange resin to bind K ion. Conclusion • Diuretics are beneficial for many diseases • It may also cause fatal adverse reactions (elderly!) • Monitoring of electrolyte levels are needed • Judicious use is warranted E-mail: <firstname.lastname@example.org> Homepage: <http://www.iwandarmansjah.web.id> Thank you !