DIURETICS+II

Diuretics are drugs that increase the excretion of solutes (mainly NaCl) and water. In general, the primary goal of diuretic therapy is to reduce ECF volume in order to lower blood pressure or rid the body of excess interstitial fluid (edema). The following is a summary of the essentials of the clinical pharmacology of diuretics.  Loop diuretics > > > >> > >> > >> Thiazide & Thiazide-like Diuretics > > > Potassium-Sparing Diuretics   
 * || [[image:http://www.thedrugmonitor.com/diuretics.gif align="center"]] ||
 * [|The Basics] || [|diuretics|Loop Diuretics] || [|Thiazide Diuretics] || [|K-Sparing Diuretics] ||
 * [|Dosage] || [|Side Effects] || [|Drug Interactions] || [|Diuretic Resistance] ||
 * [|Mannitol] ||
 * Diuretic Class (site and mechanism of action) || Main Indications || Other Uses ||
 * **Osmotic Diuretics** Freely filterable, non-reabsorbable osmotic agents like mannitol, glycerol, and urea act primarily on the proximal tubule to reduce the reabsorption of H2O and solutes including NaCl. || To treat or prevent Acute Renal Failure (see [|mannitol] below) || To reduce intra-cranial or intra-ocular pressure. ||
 * **Loop Diuretics** Furosemide, Bumetanide, Torsemide, and Ethacrynic Acid inhibit the Na+/ K+/ 2Cl- cotransport system in the thick ascending limb of Henle's loop (ALH). || Hypertension, CHF (in the presence of renal insufficiency or for immediate effect). ARF, CRF, ascites, and nephrotic syndrome || Acute Pulmonary Edema. To enhance urinary excretion of chemical toxins Hypercalc**emia** ||
 * **Thiazide** Chlorothiazide, hydrochlorothiazide, etc. inhibit NaCl cotransport in early distal convoluted tubule (DCT). || Hypertension Congestive Hear Failure (CHF) Idiopathic Hypercalci**uria** (renal calculi) || Nephrogenic Diabetes Insipidus (prevent further urine dilution from taking place in the DCT) CRF ||
 * **K+-Sparing Diuretics** Spironolactone competitively blocks the actions of aldosterone on the cortical collecting ducts (CCDs) Amiloride and Triamterene inhibit the Na+/K+ pump by reducing Na+ entry across the luminal membrane of the CCDs. || Chronic Liver Disease: To treat 2dary hyper-aldosteronism due to hepatic cirrhosis complicated by ascites. CHF: to counteract the hypokalemic effect of other diuretics. || Primary hyperaldosteronism (Conn's syndrome) ||
 * **Carbonic Anhydrase Inhibitors** Acetazolamide, Methazolamide, and Dichlorphenamide inhibit CA in luminal membrane of **proximal tubule**, reducing proximal HCO3-reabsorption. || To reduce intraocular pressure in glaucoma To lower [HCO3]p in "mountain sickness" To raise urine pH in cystinuria || Periodic paralysis Adjunctive therapy in epilepsy ||
 * Loop diuretics include furosemide (Lasix®), bumetanide (Bumex®), and torsemide (Demadex®).
 * They are often described as "high ceiling" diuretics due to their high diuretic potential; they can cause up to 20% of the filtered load of NaCl & H2O to be excreted in the urine.
 * Act by inhibiting the Na+- K+-2Cl- cotransporter in the thick ascending limb of the loop of Henle. They also interfere with the reabsorption of K +, Ca++, and Mg++ in the loop.
 * Loop diuretics are indicated in the treatment of following conditions:
 * 1) Fluid overload / edema: Congestive heart failure, acute pulmonary edema, hepatic ascites, nephrotic syndrome, renal failure, etc
 * 1) Hypertension, especially when accompanied by renal impairment
 * 1) Acute treatment of hypercalcemia.
 * || **Bumetanide** (Bumex®) || **Furosemide** (Lasix®) || **Torsemide** (Demadex®) ||
 * **Equivalent Dose**, mg || 1 || 40 || 20 ||
 * **Bioavailability** (po/iv dose ratio) || 85% (1) || 60% (1.5 ) || 85% (1) ||
 * **Elimination Route** (half-life) || Met.; Renal (60 - 90 min) || Mainly Renal (1 hr; 9 hrs in ESRD) || Hepatic Met. (3 hrs; 7 hrs in cirrhosis) ||
 * **Onset of action, min** (po / iv) || 40 / 5 || 40 / 5 || 40 / 10 ||
 * **Duration (po) (hrs)** || 4 || 6 || 6 ||
 * **Usual Adult Oral Dosage** || 0.5 - 2.0 mg qd -bid || 20 - 80 mg qd - bid || 10 - 40 mg qd - bid ||
 * Include: chlorothiazide, hydrochlorothiazide (HCTZ), benzthiazide, cyclothiazide, indapamide, chlorthalidone, bendroflumethizide, metolazone, etc
 * Exert their diuretic effect by inhibiting the Na+ - Cl- cotransport in the early distal convoluted tubules.
 * They elicit a weaker diuretic response compared to the loop diuretics as illustrated by the dose-response curves below, where the response (y axis) is expressed as the percetage of the filtered Na load that is excreted
 * Increase the loss of K and Mg, but reduce Ca excretion (may Þ hypercalcemia).
 * They are **indicated** for:
 * 1) Hypertension (1st line therapy for mild to moderate HTN). They also exert a vasodilatory effect. In fact, on chronic use, their diuretic effect may become insignificant due to a compensatory increase in fractional Na reabsorption in the proximal tubules. However, their vasodilatory action persists and may account for most of their beneficial effect in the management of chronic hypertension.
 * 2) Mild heart failure
 * 3) In combination with loop diuretics, for severe, resistant edema (especially metolazone)
 * 4) Idiopathic hypercalciuria
 * 5) Nephrogenic diabetes insipidus (DI). They prevent the urine from being diluted further in the distal convoluted tubules. This alleviates the hypernatremia that accompanies DI.
 * They include amiloride, triamterene, and spironolacton.
 * They are weak diuretics that exert their action mainly on the collecting ducts.
 * **Amiloride** and **triamterene** act by blocking the Na+ channels in the luminal membrane of the //principal cells// of the cortical collecting ducts. This reduces the Na+ entry through the luminal membrane and hence the net reabsorption of NaCl.
 * **Spironolactone** (Aldactone) is a competitive aldosterone antagonist at the cytosolic receptor level.
 * Potassium-sparing diuretics are used in the following:
 * 1) To prevent hypokalemia induced by loop or thiazide diuretics
 * 2) 2dary hyperaldosteronism due to hepatic cirrhosis & ascites.
 * 3) Primary hyperaldosteronism (Conn's syndrome)
 * Main Side Effects of Diuretics ||
 * **Osmotic Diuretics** Acute expansion of ECFV and increased risk of pulmonary edema; Acute rise in serum K+ Nausea and vomiting; headache. ||
 * **Loop Diuretics** Hypokalemia; hypomagnesemia; hyponatremia; **hypovolemia**; Hyperuricemia Metabolic alkalosis (partly due to ECFV contraction); Ototoxicity and diarrhea (mainly with ethacrynic acid) ||
 * **Thiazide** **Depletions**: hypokalemia; hyponatremia; hypovolemia; **Retentions**: Hyperuricemia due to enhanced urate reaborption and hypercalcemia due to enhanced Ca++ reaborption Metabolic alkalosis (hypochloremic) Metabolic: hyperglycemia (insulin resistance); hyperlipidemia. Hypersensitivity (fever, rash, purpura, anaphylaxis); interstitial nephritis. ||
 * **K+ - Sparing Diuretics** Spironolactone: **hyperkalemia**, gynecomastia, hirsutism; menstrual irregularities; testicular atrophy (with prolonged use). Amiloride: **hyperkalemia,** glucose intolerance in diabetic pts. Triamterene: **hyperkalemia**; megaloblastic anemia in pts with liver cirrhosis. ||
 * **Carbonic Anhydrase Inhibitors** Metabolic acidosis (due to HCO3 depletion) Drowsiness, fatigue, CNS depression, and paresthesia. ||
 * Dosage of Diuretics ||
 * **Furosemide** || neonates || p.o. || 1-4 mg/kg/dose, 1-2 times daily ||
 * || iv/im || 1-2 mg/kg/dose q 12-24 hrs ||
 * children || p.o./iv/im || 1-2 mg/kg/dose q 6-12 hrs ||
 * adults || p.o./iv/im || 20-80 mg/day divided q 6-12 hrs ||
 * **Bumetanide** || < 6 mos || p.o./iv/im || doses not established ||
 * > 6 mos || p.o./iv/im || 0.015 mg/kg/dose qd or qod; max 0.1 mg/kg/dose ||
 * adults || p.o. || 0.5-2 mg/dose 1-2 times daily ||
 * || iv/im || 0.5-1 mg/dose ||
 * **HCTZ** || < 6 mos || p.o. || 2-3.3 mg/kg/dose divided bid ||
 * > 6 mos || p.o. || 2 mg/kg/day divided bid ||
 * adults || p.o. || 25-100 mg/day in 1 or 2 doses ||
 * **Chlorthiazide** || < 6 mos || p.o. || 20-40 mg/kg/d divided bid ||
 * || iv || 2-8 mg/kg/day divided bid ||
 * > 6 mos || p.o. || 20 mg/kg/day divided bid ||
 * || iv || 4 mg/kg/day ||
 * adults || p.o. || 500 mg - 2 g divided in 1 or 2 doses ||
 * || iv || 100-500 mg/day ||
 * **Metolazone** || children || p.o. || 0.2-0.4 mg/kg/day divided q 12-24 hr ||
 * adults || p.o. || edema: 5 -10 mg/dose q 24 hrs ||
 * || p.o. || HTN: 2.5-5 mg/dose q 24 hrs ||
 * **Spironolactone** || children || p.o. || 1.5-3.5 mg/kg/day divided q6 - 24 hrs ||
 * adults || p.o. || 25-400 mg/day in 1-2 divided doses ||
 * **Metolazone** || children || p.o. || 0.2-0.4 mg/kg/day divided q 12-24 hr ||
 * adults || p.o. || edema: 5 -10 mg/dose q 24 hrs ||
 * || p.o. || HTN: 2.5-5 mg/dose q 24 hrs ||
 * **Spironolactone** || children || p.o. || 1.5-3.5 mg/kg/day divided q6 - 24 hrs ||
 * adults || p.o. || 25-400 mg/day in 1-2 divided doses ||
 * adults || p.o. || 25-400 mg/day in 1-2 divided doses ||
 * Interactions ||
 * **Interacting Drugs** || **Potential Interactions** ||
 * **ACE Inhibitors** / K+ - Sparing Diuretics || Þ increased hyperkalemia Þ cardiac problems (monitor serum K+ closely) ||
 * **Aminoglycosides** / Loop Diuretics || ÞOtotoxicity and nephrotoxicity. (monitor hearing and serum creatinine closely) ||
 * **Digoxin** / Thiazide & Loop D. || Þ Hypokalemia Þ increased digoxin binding & toxicity. (monitor K+ and cardiac function) ||
 * **ß- Blockers** / Thiazide Diuretics || Þ Hyperglycemia, hyperlipidemia, hyperuricemia. ||
 * **Steroids** / Thiazide & Loop D. || Þ increased risk of hypokalemia (monitor K+ closely) ||
 * **Carbamazepine or Chlorpropamide** / Thiazide Diuretics || Þ increased risk of hyponatremia (monitor Na+) ||

Diuretic ResistanceThe magnitude of diuretic response is dependent not only on the type of diuretic agent used but more importantly on the circulatory, renal, and fluid status of the patient. Edematous patients may exhibit apparent resistance to oral diuretics due to reduced intestinal drug absorption. Patients with renal insufficiency often exhibit "//diuretic resistance//", i.e., a markedly reduced diuretic response. At GFR < 30 mL/min little of the filtered salt and fluid reach the distal segments of the nephron. Hence, in these patients, the use of a thiazide diuretic alone is practically useless. In addition, these patients are often more or less refractory to loop diuretic for several reasons: Occasionally, a poor response to loop diuretics is the results of a poor dosing strategy such as increasing the dosing frequency instead of the individual dose size. For an adult patient, an initial furosemide dose of 40 mg may be doubled every hour until an adequate response is achieved (single dose should not exceed 260 mg). Continuous furosemide infusion (0.10 - 1.0 mg/kg/hr) has recently re-emerged in the critical care setting as an alternative strategy to overcome diuretic resistance. If the patient remains diuretic resistant, the combination of a loop diuretic plus a thiazide diuretic could be useful particularly in patients with moderate to severe renal impairment (CLcr < 35 mL/min). In these patients the choice of diuretics may be important. Torsemide is dependent primarily on hepatic metabolism for its elimination with only 25% of the dose reaching the urine unchanged. Metolazone is a thiazide-like diuretic whose primary site of action is the distal tubule. However, it also appears to have a significant proximal diuretic effect which is highly desirable in patients with markedly reduced GFR. Metolazone would increase the fraction of the filtered Na+ that reaches the loop of Henle and, at the same time, it prevents any compensatory increase in distal Na+ reabsorption. In patients with acute tubular necrosis (ATN), a more powerful proximal diuretic such as mannitol may be required to dislodge and clear cellular debris from the tubule lumen. Mannitol may have the added advantage of a glomerular vasodilator action which results in increased glomerular hydrostatic pressure and GFR. However, mannitol should be used carefully in patients with severe renal impairment because of the potential for mannitol accumulation and the development of pulmonary edema (see next page).  Mannitol Mannitol is an osmotic agent that is freely filterable at the glomerular level but it is not reabsorbed by the renal tubules. By virtue of its primary site and mechanism of action, mannitol has a high diuretic potential and can markedly increase fluid flow rate in all nephron segments including the proximal tubule. Thus, when administered early in the course of acute renal failure (ARF), mannitol tends to flush out cellular debris and prevent tubular cast formation. This action may be responsible for the conversion of oliguric ARF to non-oliguric ARF. Although there is no evidence that the use of mannitol in critically ill patients improves glomerular filtration rate, it does reduce the need for hemodialysis. More importantly, converting oliguric ARF to non-oliguric ARF facilitates the management of fluid and electrolyte imbalance, drug therapy, and nutritional needs of the patient. In order to prevent a compensatory increase in ion reabsorption in the loop of Henle, mannitol is usually administered in combination with a loop diuretic. Mannitol is contraindicated in anuric patients. Uses of Mannitol
 * 1) Reduced secretion of the diuretic into the tubule lumen where it exerts its effect. This may be the result of a marked drop in renal blood flow (CHF, prerenal failure, liver cirrhosis, etc) or due to competitive inhibition of the transport system by other drugs (probenecid, NSAIDs, cephalosporins, etc) or by accumulated endogenous organic anions (chronic renal failure, tumor lysis, etc).
 * 2) Increased intra-luminal protein binding of the diuretic (e.g., nephrotic syndrome), so that fewer molecules of the diuretic are free to interact with and inhibit the Na+ -2Cl- - K+ co-transport system, which is located in the luminal membrane of the thick ascending loop of Henle. This system is normally responsible for the reabsorption of up to 25% of the filtered load of Na+, hence the high diuretic potential of the loop diuretics.
 * 3) Extracellular fluid (ECF) volume contraction or diminished effective arterial blood volume (EABV) result in renal hypoperfusion (ò RBF), ò GFR, and enhanced Na+ retention. In chronic liver disease, Na+ retention and diminished diuretic response are exacerbated by hyperaldosteronism secondary to the reduction in the EABV. While these patients may be resistant to furosemide due to low secretion, they respond adequately to spironolactone.
 * 4) In addition to inhibiting the secretion of loop diuretics, NSAIDs also significantly reduce net filtration pressure and GFR. Thus, the use of these agents should be avoided whenever maximal diuretic response is considered critical.
 * 5) The development of tolerance in patients receiving long-term loop diuretic therapy. In this case, combination therapy may be indicated. Also changing from furosemide (or bumetanide) to ethacrynic acid has in some cases proven effective.
 * In the **//treatment//** of ARF:
 * 1) Initial "test" Dose: 12.5 - 25 g over 3-5 min. Repeat after 1- 2 hrs if necessary. If response is inadequate, no more mannitol should be given until patient is reevaluated.
 * 2) If an adequate diuretic response (urine output ³ 50 mL/hr) to the initial dose is obtained, an infusion of 100 g of mannitol may be given over a period of 3 - 6 hrs (500 mL of a 20% solution or 1000 mL of a 10% solution). Urine flow rate should be monitored and the patient must be observed carefully for signs of peripheral or pulmonary edema. Serum electrolytes and osmolality must also be measured at least twice a day. Osmolality should be measured directly and maintained at < 310 mOsm/L. Mannitol administration must be halted when the osmolality exceeds 310 mOsm/L.
 * For the **//prevention//** of oliguria or ARF
 * A dose of 1 g/kg may be started before or immediately after surgery as an infusion of 5% or 10% solution given over ³ 6 hrs.
 * For pts with refractory edema (nephrotic syndrome, CHF, cirrhosis, ascites):
 * 1 g/kg over 3 - 6 hrs as 10% or 20% solution. These pts have a high risk for the development of pulmonary edema and must be monitored closely.
 * Indications other than renal failure
 * Poisoning: A 5% solution is infused to maintain high urine flow rate to promote the elimination of renally excreted toxins. Dose varies.
 * Mannitol (mostly as a 20% solution) is also used to reduce:
 * intra-ocular pressure
 * CSF pressure
 * Cerebral edema (brain swelling)


 * [[image:http://www.thedrugmonitor.com/blt-sqr44.gif]] || **Further Reading** ||
 * 1) Ellison DH. The physiologic basis of diuretic synergism: its role in treating diuretic resistance. Ann Intern Med 1991; 14:886-894.
 * 2) Dirks JH, Sutton RAL. Diuretics: physiology, pharmacology, and clinical use. WB Saunders; 1986.
 * 3) Martin S. Continuous infusion of loop diuretics: Pharmacodynamic concepts and clinical applications. Clin Trends in pharmacy Practice 1994; 8:10-15.
 * 4) Messerli: Diuretics ... in Cardiovascular Drug Therapy. 2nd ed WB Saunders; 1996.