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Pharmacology of DiureticsCarmen Chungunco, MD FPCP FPCCAugust 17, 2010
Describe the actions of the major classes of diuretics on the formation of urine and the excretion of sodium, potassium, and other cationsExplain the therapeutic indications, efficacy and side effects of the major classes of diureticsDiscuss the clinical uses of diuretics
Objectives
Nephron Structure
Proximal TubuleMain site of reabsorption: 85% NaHCO3, 40% NaCl, 60% H20, all filtered organic solutesNa+ flows down concentration gradient, water follows passivelyNa/K ATPase maintains gradientOrganic acids secretory system
Loop of HenleTDL permeable to water but not Na+TAL impermeable to water and transports Na, 20-35% reabsorbed Hypertonic medullary interstitiumdifferences in permeabilities creates the countercurrent multiplierLumen-positive electrical potential (K) = driving force for Mg, Ca reabsorption
Distal Convoluted Tubule5-10% of filtered load of Na+ reabsorbedSegment mostly impermeable to waterElectrically neutral Na/Cl transportCa++ actively reabsorbed (regulated by PTH)
Cortical Collecting Duct2-5% of filtered Na+ reabsorbed here via Na+ channels that are regulated by aldosterone, determines final Na concentration of urineWater permeability controlled by antidiuretic hormone (ADH)
Cortical Collecting DuctMajor site of K secretionImpt relation btw Na delivery to CCD and K secretionIncreased HCO3 w/c cannot be reabsorbed like Cl will also enhance K secretion
Diuretics: DefinitionsDiuretic: substance that promotes the excretion of urineNatriuretic: substance that promotes the renal excretion of sodium
Classes of DiureticsCarbonic anhydrase inhibitorsLoop diureticsThiazidesK-sparing diuretics (Aldosterone antagonists) Osmotic diuretics
Classes of Diuretics: Site of Action
Carbonic Anhydrase InhibitorsPrototype: AcetazolamideBlocks carbonic anhydrase activity in the proximal tubuleBlocks NaHCO3 reabsorptionCauses NaHCO3 diuresisSulfonamide group = essential for activity
Carbonic Anhydrase InhibitorsWell absorbed orallyEffects seen within 30 mins, peaks at 2 hours and lasts 12 hoursRenal excretionActions:Inhibits 85% of HCO3 reabsorptive capacity at the proximal tubule (45% of whole body HCO3 reabsorption)
Acetazolamide: Clinical UsesGlaucoma most common indicationDecreases rate of aqueous humor production, decreasing intraocular pressureUrinary AlkalinizationEnhanced secretion of uric acid and cystine
Contraindication: Avoided in hepatic cirrhosis (may cause hepatic encephalopathy)
Acetazolamide: ToxicityHyperchloremic Metabolic AcidosisHCO3 wasting limits diuretic effect to 2-3 daysRenal StonesHypercalciuria and phosphaturiaCalcium salts unstable in alkaline urinePotassium WastingNaHCO3 in the collecting tubule increases lumen negative electrical potential thus enhancing K+ excretion
Loop DiureticsFurosemide (prototype)BumetanideTorsemideEthacrynic acid
Loop Diuretics: MOA inhibits Na/K/2Cl transport system in TALH reduces NaCl reabsorption reduces normal lumen-positive potential causing increased Mg++ and Ca++ excretion
Loop Diuretics : Pharmacological EffectsLoss of diluting ability: Increased Na, Cl and K excretion Loss of concentrating ability: reduction in the medullary osmotic gradient Loss of TAL electrostatic driving force: increased excretion of Ca2+, Mg2+ and NH4+Increased electrostatic driving force in CCD: increased K+ and H+ excretion
Loop Diuretics: PharmacokineticsRapid oral absorption, bioavailability ranges from 65-100%Rapid onset of action (within minutes, lasts 2-3 hours) extensively bound to plasma proteinssecreted by proximal tubule organic acid transporters
Loop Diuretics: Clinical UsesEdema of cardiac, hepatic or renal originAcute pulmonary edema (parenteral route)Most important indicationsChronic renal failureIncreases rate of urine flowHyperkalemia Symptomatic hypercalcemia
Loop Diuretics: ToxicityHypokalemiaMagnesium depletionChronic dilutional hyponatremiaMetabolic alkalosisHyperuricemiaHypovolemia-associated enhancement of uric acid reabsorption in proximal tubuleOtotoxicityDose-related
Thiazides Contain sulfonamide groupChlorothiazide Chlorthalidone Indapamide
Thiazides: MOA inhibit NaCl reabsorption in distal convoluted tubule enhance Ca++ reabsorption (modulated by PTH)
ThiazidesOral administration Diuresis within one hourSecreted by organic acid secretory system, competes with uric acid
Thiazides: Clinical Uses
Essential hypertensionCongestive Heart FailureDiabetes insipidusHypercalciuria
Thiazide Use in Hypercalciuria - Recurrent Ca2+ Calculipromote distal tubular Ca2+ reabsorptionprevent excess excretion which could form stones in the ducts of the kidney
Thiazides: ToxicityHypokalemia due to:Increased availability of Na+ for exchange at collecting ductVolume contraction induced aldosterone release HyperuricemiaDirect competition of thiazides for urate transportEnhanced proximal tubular reabsorption efficiencyHyperglycemiaDiminished insulin secretionRelated to the fall in serum K+Elevated plasma lipidsHyponatremia
Potassium-sparing Diuretics
SpironolactoneSynthetic steroidMechanism of action: aldosterone antagonistSpironolactone prevents conversion of the receptor to active form, thereby preventing the action of aldosterone
Spironolactone: Pharmacokinetics70% absorption in GI tractExtensive first pass effect in liver and enterohepatic circulationExtensively bound to plasma proteins100% metabolites in urine
Spironolactone: Clinical UsesMineralocorticoid excess Prevent K loss caused by other diuretics in:HypertensionRefractory edemaHeart failurePrimary aldosteronism
Spironolactone: ToxicityHyperkalemiaMay range from mild to life-threateningAndrogen like effects due to steroid structureGynecomastia GI disturbances
Osmotic DiureticPrototype: MannitolOthers: urea, glycerinFreely filterableLittle or no tubular reabsorptionInert or non-reactiveResistant to degradation by tubules
Osmotic Diuretics: MOA
Free filtration in osmotically active concentrationOsmotic pressure of non-reabsorbable solute prevents water reabsorption and increase urine volumeProximal tubuleThin limb of the loop of Henle
Osmotic Diuretics: Clinical UsesProphylaxis of renal failureMechanism:Drastic reductions in GFR cause dramatically increased proximal tubular water reabsorption and a large drop in urinary excretion
Osmotic diuretics are still filtered under these conditions and retain an equivalent amount of water, maintaining urine flow
Osmotic Diuretics: Clinical UsesReduction of pressure in extravascular fluid compartmentsReduction of CSF pressure and volumeReduction of intraocular pressure
Osmotic Diuretics: ToxicityIncreased extracellular fluid volumeHypersensitivity reactionsHyperglycemia and glycosuriaHeadache, nausea and vomiting
Summary: Sites of Diuretic Action
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