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LOOP DIURETICSAt a glance.Classification Mechanism of actionPharmacokineticsUses and indicationsAdverse effectsDiuretic braking Classification of diureticsMECHANISM OF ACTION The diuretics are generally divided into four major classes, which are distinguished by the site at which they impair sodium reabsorption :

LOOP DIURETICS : act in the thick ascending limb of the loop of HenleTHIAZIDE TYPE DIURETICS: in the distal tubule and connecting segment (and perhaps the early cortical collecting tubule)POTASSIUM SPARING DIURETICS: in the aldosterone-sensitive principal cells in the cortical collecting tubuleACETAZOLAMIDE AND MANNITOL: act at least in part in the proximal tubulePRIMARY SITES OF DIURETIC ACTION

To appreciate how diuretics act, it is first necessary to review the general mechanism by which sodium is reabsorbed. Each of the sodium-transporting cells contains Na-K-ATPase pumps in the basolateral membrane. These pumps perform two major functions: they return reabsorbed sodium to the systemic circulation; and they maintain the cell sodium concentration at relatively low levels.

The latter effect is particularly important, since it allows filtered sodium to enter the cells down a favorable concentration gradient via carrier-mediated transport.

Each of the major nephron segments has one or more unique sodium entry mechanisms and the ability to specifically inhibit this step explains the nephron segment at which the different classes of diuretics act.

Loop of Henle Transport

Collecting tubule transport

Distal Tubular transport

The site of action within the nephron is a major determinant of diuretic potency. Most of the filtered sodium is reabsorbed in the proximal tubule (about 60 to 65 percent) and the loop of Henle (20 percent). As a result, it might be expected that a proximally acting diuretic, such as the carbonic anhydrase inhibitor acetazolamide, could induce relatively large losses of sodium and water. However, this does not occur since almost all of the excess fluid delivered out of the proximal tubule can be reabsorbed more distally, particularly in the loop of Henle and to a lesser degree the distal tubule. Transport in these segments is primarily flow-dependent, varying directly with the delivery of chloride .LOOP DIURETICSFurosemideBumetanideTorsemideEthacrynic acid When administered at maximum dosage, the loop diuretics, furosemide, bumetanide, torsemide, and ethacrynic acid, can lead to the excretion of up to 20 to 25 percent of filtered sodium.

They act in the medullary and cortical aspects of the thick ascending limb, including the macula densa cells in the early distal tubule. At each of these sites, sodium entry is primarily mediated by a Na-K-2Cl carrier in the luminal membrane that is activated when all four sites are occupied .

. The loop diuretics appear to compete for the chloride site on this carrier, thereby diminishing net reabsorption.

Inhibition of an isoform of this cotransporter in the inner ear is thought to be responsible for the ototoxicity that is rarely seen with high dose intravenous loop diuretic therapy.Loop diuretics also have important effects on renal calcium handling. The reabsorption of calcium in the loop of Henle is primarily passive, being driven by the electrochemical gradient created by NaCl transport and occurring through the paracellular pathway . As a result, inhibiting the reabsorption of NaCl leads to a parallel reduction in that ofcalcium, thereby increasing calcium excretion.A potential concern is that the calciuric response can lead to kidney stones and/or nephrocalcinosis. PHARMACOKINETICSFUROSEMIDE:Half-life elimination : 30- 120 ,min( normal renal function), 9 hrs ( in ESRD).Absorption: 60-80%(PO)Bioavailability : 47-64% (PO)Protein bound: 91-99%Vd : 0.2 l /KgMetabolism : liver (10%)Duration :iv -2 hr PO- 6-8 hr

Onset : initial effect :30-60 min9PO), 5 min (iv)Max effect: less than 15 min9 iv), 1-2 hr (PO)Clinical uses Edematous conditionsCCF Acute decompensated heart failure and chronic heart failureCirrhosisNephrotic SyndromeIdiopathic EdemaHypertension

Maximum effective dosageADVERSE EFFECTSHyperuricemiaHypokalemia HypomagnesemiaHypocalcemia Glucose intoleranceVertigo ,tinnitusHearing impairmentAnorexia ,nausea, diarrhoeaWeakness ,muscle crampsHypotensionHypersensitivtiy reactions

DIURETIC BRAKING PHENOMENON1st dose of diuretic provides a good diuresisWithin 1 week the body wt stabilises and the excretion no longer exceeds intakeEffect of dietary salt intake on braking phenomenonPost diuresis salt retentionPersist upto 2 weeks of abrupt cessation of loop diuretic therapyContraction alkalosisMechanismIncreased Na Cl Reabsorption at the distal sitesRAAS and Sympathetic nervous system activity increasedReduced Na Cl delivery to frusemide site of actionLimited Inhibition of frusemideHypertrophy of DCT and CD

Cl might be low in AlkalosisGlycosylation of bumetanide sensitive co transporter

Strategies to decrease Diuretic BrakingRestrict dietary salt intakeAnother class of diureticMultiple daily dosing of diuretic with prolonged actionDo not stop diuretic action abruptlyPrevention/ reversal of metabolic alkalosisHUMORAL AND NEURONAL MODULATORS OF THE RESPONSE TO DIURETICSRAASEicasonoids PGE2AVPCatecholamines and symphathetic nervous system

DIURETIC RESISTANCEInadequate clearance of edema despite a full dose of diureticDiuretic dose must be above the natriuretic threshold

Causes of diuretic resistance

Approach to management of Diuretic resistance

DIURETIC COMBINATIONSLoop diuretic and thiazides Syngergistic

Loop Diuretics/ Thiazides + Distal Potassium sparing diureticsCLINICAL USES OF DIURETICSEdematous conditionsCCF Acute decompensated heart failure and chronic heart failureCirrhosisNephrotic SyndromeIdiopathic Edema

Clinical and bichemical characteristics and responses in patients with nephrotic syndrome

Non Edematous cconditions

AKIType IV RTAHypercalcemiaHypercalcemiaNephrolithiasisOsteoporosisDiabetes InsipidusADVERSE EFFECTS OF DIURETICFLUID AND ELECTROLYTE ABNORMALITIESECF Volume depletion and azotemiaHyponatremiaHypokalemiaHyperkalemiaHypomaagnesemiaHypercalcemiaAcid base changes

METABOLIC COMPLICATIONS ASSOCIATED WITH DIURETIC USEHyperglycemiaHyperuricemiaHyperlipidemia

Other Adverse EffectsImpotenceOtotoxicityPregnancy hazardsVitamin DefeciencyDrug allergyMalignancyAdverse drug Interactions

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