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Individual classes of Diuretics Carbonic Anhydrase Inhibitors Osmotic Diuretics Loop Diuretics Thiazides and Thiazides like Diuretis Distal Potassium-Sparing Diuretics
Carbonic Anhydrase Inhibitors Acetazolamide (Diamox) Act primarily on proximal tubule cells to inhibit bicarbonate absorption An additional, more modest, effect along the distal nephron, however, is also observed.
Carbonic anhydrase (CA) catalyzes inside the cell theformation of HCO3 from H2O and CO2. This is theresult of the two-step process. Bicarbonate leavesthe cell via the Na-HCO3, cotransporter.464,465 Asecond pool of carbonic anhydrase is located in thebrush border (CA). This participates in disposing ofcarbonic acid, formed from filtered bicarbonate andsecreted H+. Both pools of CA are inhibited byacetazolamide and other CA inhibitors
Pharmacokinetics. Acetazolamide (Diamox) Methazolamide (Neptazane) All of which favor penetration into aqueous humor and cerebrospinal fluid (CSF). It has less renal effect and, therefore, is preferred for treatment of glaucoma.
ADVERSE EFFECTS Patients may complain of weakness, lethargy, abnormal taste, paresthesia, gastrointestinal distress, malaise, and decreased libido. Overall, symptomatic metabolic acidosis develops in half of glaucoma patients treated with CAIs Significant metabolic acidosis induced by acetazolamide. Not a rare complication. Arch Intern Med 1985; 145:1815-1817.
Osmotic Diuretics Omsotic diuretics are substances that are freely filtered but poorly reabsorbed. Mannitol is the prototypic osmotic diuretic Manitol is a hypertonic solute that abstracts water from cells. In the water-permeable nephron segments of the proximal nephron and the thin limbs of the loop of Henle, fluid reabsorption concentrates filtered mannitol sufficiently to diminish tubular fluid reabsorption.
Mannitol is recommended for management of severe head injury. A trial of mannitol therapy for cerebral edema complicating hepatic failure demonstrated a markedly improved survival of 47%, compared with only 6% in the control group. Controlled trial of dexamethasone and mannitol for the cerebral oedema of fulminant hepatic failure. Gut 1982; 23:625-629.
ADVERSE EFFECTS The osmotic abstraction of cell water initially causes hyponatremia and hypochloremia. Later, when the excess ECF is excreted, the decrease in cell water concentrates K+ and H+ within cells, which increases the gradient for their diffusion into the ECF, leading to hyperkalemic acidosis. Later, hypernatremic dehydration may develop if free water is not provided, because urinary concentrating ability is inhibited.
Loop Diuretics The prime action of loop diuretics occurs from the luminal aspect of the TAL . An electroneutral Na+/K+/2Cl− cotransporter, termed NKCC2, is located at the luminal membrane.
Brenner: Brenner and Rectors The Kidney, 8th ed.
Loop diuretics increase the fractional excretion of Ca2+ by up to 30% Loop diuretics can increase fractional Mg2+ excretion by more than 60%Effect of furosemide on calcium and magnesium transport in the rat nephron.Am J Physiol 1981; 241:F340-F347.
The total RBF is maintained or increased and the GFR is little changed during administration of loop diuretics to normal subjects. Furosemide increases the renal generation of prostaglandins (PGs) Loop diuretics, by blocking NaCl entry into macula densa cells, block the TGF completely.This is one reason that loop diuretics tend to preserve GFR, despite ECV depletion. Effects of diuretics on inner medullary hemodynamics in the dog. Circ Res 1982; 51:703-710.
Pharmacokinetic Brenner: Brenner and Rectors The Kidney, 8th ed.
Increase Organic Anion eg Uric acid,NSAID, B-lactam,sulfonamide decrease uptake of furosemide. Metabolic acidosis depolarizes the membrane potential of Proximal tubule cells,with decrease OA- secretion
Both uptake processes are inhibited by probenecid. Plasma albumin concentration facilitates uptake and secretion by PT-S2 but inhibits uptake and metabolism by PT-S1.(Drawn from data in Pichette V, Geadah D, du Souich P: The influence of moderatehypoalbuminemia on the renal metabolism and dynamics of furosemide in the rabbit. Br JPharmacol 119:885, 1996.)
Thaizides and Thiazide-like Diuretics The major site of action of thiazide and thiazide-like diuretics is the distal convoluted tubule (DCT), where they block coupled reabsorption of Na+ and Cl− Thiazides and thiazide-like diuretics are moderately active drugs that increase excretion of sodium, chloride, and potassium while reducing calcium excretion.
Brenner: Brenner and RectorsThe Kidney, 8th ed.
Thiazides increase potassium excretion, their effects on K+ secretion result from their tendency to stimu-late aldosterone secretion, to increase distal flow.
Thiazides reduce Ca2+ excretion. Blockade of luminal NaCl entry— basolateral Na+/Ca2+ exchange Hyperpolarization increases calcium entry via the transient receptor potential channel subfamily V, member 5 (TRPV5) Third, thiazides stimulate proximal reabsorption of Ca2+ owing to ECV depletion Brenner: Brenner and Rectors The Kidney, 8th ed.
Mg excretion Diminishes TRPM6 mRNA expression modestly . Schlingmann KP, Weber S, Peters M, et al: Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 2002; 31:166-170.
Distal Potassium-Sparing Diuretics Act on the cells in the late DCT, connecting tubule, and the cortical collecting duct, where they inhibit luminal Na+ entry via the ENaC . They depolarize the lumen- negative transepithelial voltage, diminishing the electrochemical gradient for K+ and H+ secretion.
Both amiloride and triamterene are organic cations that block ENaC directly from the luminal surface. Spironolactone and eplerenone are competitive antagonists of the mineralocorticoid receptor.
ADVERSE EFFECTS Hyperkalemia is the most common complication of these drugs. The risk is dose-dependent and increases considerably in patients with CKD or in those receiving K+ supplements, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), NSAIDs.
Diuretic Resistance Diuretic resistance implies an inadequate clearance of edema despite a full dose of diuretic.
Common Causes of Diuretic ResistanceCause ExampleIncorrect diagnosis Venous or lymphatic edemaInappropriate NaCl intake Na+ intake > 120 mmol · d−1Inadequate drug reaching tubule lumen in active form: Noncompliance Dose inadequate or too infrequent Poor absorption Uncompensated CHF Decreased renal blood flow CHF, cirrhosis of liver, elderly Decreased functional renal mass AKF, CKD, elderly Proteinuria Nephrotic syndromeInadequate renal response: Low GFR AKI, CKD Decreased effective ECV Edematous conditions Activation of RAA axis Edematous conditions Nephron adaptation Prolonged diuretic therapy NSAIDs Indomethacin, aspirin
Dose –response relationship
ADAPTATION TO DIURETIC THERAPY Short term adaptation or Rebound phenomenon Long term adaptationor Braking phenomenon
Humoral and Neural Modulators of theresponse to Diuretics Renin-Angiotensin-Aldosterone Axis . Catecholamines and Sympathetic Nervous System. Arginine Vasopressin
Braking Phenomenon A reduced NaCl delivery to the site of furosemide action . ( increase Angiotensin II ) An enhanced ability of the distal tubule to reabsorb the extra NaCl load delivered during furosemides upstream action. structural hypertrophy of the DCT, connecting tubule , doubling of NCC expression in the distal tubules of rats adapted to diuretics. A micropuncture study in rats. Clin Sci 1996; 91:299-305.
Nephronal adaptation could underlie the inappropriate renal Na+ retention that can persist for up to 2 weeks after abrupt cessation of diuretic therapy. DeWardener HE: Idiopathic edema: Role of diuretic abuse. Kidney Int 1981; 19:881
Diuretic Combination Diuretics acting on a separate mechanism may be synergistic.Ellison DH: The physiologic basis of diuretic synergism: Its role in treatingdiuretic resistance [see comments]. Ann Intern Med 1991; 114:886-894.
Loop Diuretics and Thiazides. synergistic in normal subjects and in those with edema or renal insufficiency. During prolonged furosemide therapy, the responsiveness to a thiazide is augmented.Patients with advanced CKD (GFR<30 mL/min) who are unresponsive to thiazide alone have a marked natriuresis when a thiazide is added to loop diuretic therapy, probably by blockade of enhanced distal tubular Na+ reabsorption. Coadministration of thiazides increases the efficacy of loop diuretics even inpatients with advanced renal failure. Kidney Int 1994; 46:482-488.
Loop Diuretics or Thiazidesand Distal Potassium-Sparing Diuretics . Amiloride or triamterene increases furosemide natriuresis only modestly but curtails the excretion of K+ and net acid and preserves total body K+. Long-term metabolic effects of spironolactong and thiazides combined with potassium-sparing agents for treatment of essential hypertension. Am J Cardiol 1988; 62:1072-1077.
ADVERSE EFFECTS OF DIURETICS
Hyponatremia Thiazides, which inhibit urinary dilution, whereas loop diuretics inhibit urinary concentration and dilution. Indeed, thiazides are 12-fold more likely than loop diuretics to cause hyponatremia. Spital A: Diuretic-induced hyponatremia. Am J Nephrol 1999; 19:447-452.
Hypomagnesemia Loop diuretics inhibit Mg2+ reabsorption in the TAL by reducing the transepithelial voltage (Tm) that drives Mg2+ and Ca2+ paracellularly Thiazide diminishes TRPM6 mRNA expression
Hypercalcemia Thiazides increase the serum concentrations of total and ionized calcium
Other side effects Hyperglycemia. Thiazides impair glucose uptake into muscle and liver. It has been ascribed to a diuretic-induced reduction in cardiac output with reflex activation of the SNS and catecholamine secretion leading to reductions in hepatic glucose uptake, muscle blood flow, and muscle glucose uptake A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension. N Engl J Med 1989; 321:868-873.
Hyperlipidemia Administration of loop diuretics or thiazides increases the plasma concentrations of total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol but reduces high- density lipoprotein (HDL) cholesterol. These adverse changes average 5% to 20% during initiation of therapy.The mechanism is uncertain Ames RP: The effects of antihypertensive drugs on serum lipids and lipoproteins. II. Non-diuretic drugs. Drugs 1986; 32:335-357.
Hyperuricemia Prolonged thiazide therapy for hypertension increases the serum urate concentration by approximately 35%. Renal urate clearance falls because of competition for secretion between urate and the diuretic and because ECV deplete induced urate reabsorption
Hyponatemia Redrawn from Clark BA, Shannon RP, Rosa RM, Epstein FH: Increased susceptibility to thiazide-induced hyponatremia in the elderly. J Am Soc Nephrol 5:1106, 1994.