1DiureticsDiuretics are drugs that increase renal excretionof water and salts.Major purposes of diuretic therapy are todecrease fluid volume of the body and to adjustthe water and electrolyte balance.Diuretics are often used to treat conditionsassociated with water and electrolyte imbalancesuch as edema caused by heart failure, renalfailure and hepatic cirrhosis.Different types of diureticsType Example Site of action MechanismCarbonic anhydrase(CA) inhibitorsOsmotic mannitol Loop of Henle (DTL) Osmotic action Proximal tubuleLoop diuretics furosemide Loop of Henle (TAL) Inhibition of Na+-K+-2Cl- symportThiazides hydrochlorothiazide Distal convoluted inhibition of Na+-Cl- tubulePotassium-sparing diuretics (1) Na+ channel triamterene, Cortical collecting inhibition of Na+ inhibitors amiloride (2) aldosterone spironolactone Cortical collecting inhibition of antagonists acetazolamide Proximal tubule Inhibition of CAsymportchanneltubuletubule aldosterone receptorDevelopment of modern diureticsSO2NH2NH2NNSSO2NH2SO2NH2ClClSO2NH2SO2NH2NNSO2ClClSO2NH2NHCH2OCOOHSulfanilamide AcetazolamideDichlorphenamideChlorothiazideFurosemideTubular Transport SystemMDInterstitium[NaCl]=300 mM[Urea]=600 mMDescendingthin limbProximalconvolutedtubuleAscendingthin limbThickascendinglimbDistalconvolutedtubuleCollecting tubuleCollecting ductCortexOut medullaInner medullaGlomerulusNaHCO3NaCl (50%)H2O(60-70%)(85%)Osmotic diureticsH2ONa+K+2Cl-Na+K+2Cl-Ca++, Mg++(35%)NaClLoop diureticsNa+Cl-Ca++(PTH)MDThiazidesK+-sparing diureticsNa+(Aldosterone)K+H+H2O(ADH)(5%)CA inhibitorsLoop of HenleVasopressin Receptor agonists(e.g. DDAVP)Inhibitors of Carbonic AnhydraseAcetazolamideDichlorphenamideMethazolamideInhibitors of CarbonicAnhydraseATPCACAHCO3- + H+H2O + CO2H2O + CO2 H+ + HCO3-Na+Na+K+Cl-base-Proximal convoluted tubuleepithelial cellNaClNa+XCA InhibitorsLumen InterstitiumMechanism of Action2Inhibitors of Carbonic AnhydraseMajor clinical indications:• Glaucoma: reducing intraocular pressure.• Acute mountain sickness.• Metabolic alkalosis.• Cystinuria* Have also been used to treat edema due to congestive heartfailure.Major side effects ofCarbonic Anhydrase Inhibitors• Electrolyte imbalance: metabolic acidosis.• Renal stones.• Central nerve system effects: drowsiness andparesthesias.• Allergic reactions to sulfonamides.Osmotic DiureticsGlycerinIsosorbideMannitolUreaR, renal excretion; M metabolism; ID, insufficient data.Tubular Transport SystemMDInterstitium[NaCl]=300 mM[Urea]=600 mMDescendingthin limbProximalconvolutedtubuleAscendingthin limbThickascendinglimbDistalconvolutedtubuleCollecting tubuleCollecting ductCortexOut medullaInner medullaGlomerulusNaHCO3NaCl (50%)H2O(60-70%)(85%)Osmotic diureticsH2ONa+K+2Cl-Na+K+2Cl-Ca++, Mg++(35%)NaClLoop diureticsNa+Cl-Ca++(PTH)MDThiazidesK+-sparing diureticsNa+(Aldosterone)K+H+H2O(ADH)(5%)CA inhibitorsLoop of HenleOsmotic DiureticsMajor clinical indications:• To increase urine volume in acute renal failurecaused by ischemia, hemoglobinuria, etc.• To reduce intracranial pressure before and afterneurosurgery and in neurological conditions.• To reduce intraocular pressure beforeophthalmologic procedures and during acuteattack of glaucoma.Major side effects and toxicity ofOsmotic Diuretics• Water and electrolyte imbalance: dehydrationand hypernatremia.• Expansion of extracellular fluid volume increaseheart burden, resulting in pulmonary edema inpatients with congestive heart failure.• Central nerve system symptoms: nausea,headache and vomiting.3Tubular Transport SystemMDInterstitium[NaCl]=300 mM[Urea]=600 mMDescendingthin limbProximalconvolutedtubuleAscendingthin limbThickascendinglimbDistalconvolutedtubuleCollecting tubuleCollecting ductCortexOut medullaInner medullaGlomerulusNaHCO3NaCl (50%)H2O(60-70%)(85%)Osmotic diureticsH2ONa+K+2Cl-Na+K+2Cl-Ca++, Mg++(35%)NaClLoop diureticsNa+Cl-Ca++(PTH)MDThiazidesK+-sparing diureticsNa+(Aldosterone)K+H+H2O(ADH)(5%)CA inhibitorsLoop of HenleFurosemideEthacrynic acidInhibitors of Na+-K+-2Cl- Symport (Loop Diuretics)Loop DiureticsATPNa+Na+K+2Cl-K++-Ca2+Mg2+Cl-Na+K+K+Cl-loop diureticsThick ascending limbepithelial cellLumenInterstitiumMechanism of Action:Inhibition of reabsorption of saltsat Thick asending limb.Increase in sytemic venous capacitanceand renal blood flow.Reducing medullary hypertonicityInhibition of TGF.Loop DiureticsMajor clinical indications:• Acute pulmonary edema.• Chronic congestive heart failure• Hypertension• Hypercalcemia• Hyperkalemia.• Acute renal failure• Toxic ingestion of bomides, fluoride and iodineMajor side effects and toxicity ofLoop Diuretics• Water and electrolyte imbalance: Hypokalemicmetabolic alkalosis.• Ototoxicity• Hyperuricemia• Hypomagnesemia• Allergic reactions to sulfonamides.Tubular Transport SystemMDInterstitium[NaCl]=300 mM[Urea]=600 mMDescendingthin limbProximalconvolutedtubuleAscendingthin limbThickascendinglimbDistalconvolutedtubuleCollecting tubuleCollecting ductCortexOut medullaInner medullaGlomerulusNaHCO3NaCl (50%)H2O(60-70%)(85%)Osmotic diureticsH2ONa+K+2Cl-Na+K+2Cl-Ca++, Mg++(35%)NaClLoop diureticsNa+Cl-Ca++(PTH)MDThiazidesK+-sparing diureticsNa+(Aldosterone)K+H+H2O(ADH)(5%)CA inhibitorsLoop of Henle4BendroflumethiazideDrugChlorothiazideHydrohlorothiazideR,renalChlothalidoneIndapamideMetolazoneQuinethazoneInhibitors of Na+-Cl- symportInhibitors of Na+-Cl- Symport (Thiazides)ATPNa+Na+K+Cl-Ca2+Na+Ca2+Cl-K+ThiazidesDistal convoluted tubuleepithelial cellLumen InterstitiumThiazidesMajor clinical indications:• Hypertension• Edema associated with Chronic congestive heartfailure, hepatic cirrhosis and renal diseases• Nephrolithiasis due to hypercalciuria.• Nephrogenic diabetes insipidusMajor side effects and toxicity ofThiazides• Water and electrolyte imbalance:* Hypokalemic metabolic alkalosis* Hypercalcemia* Hypomagnesemia* Extracellular volume depletion* Hyponatremia• Glucose tolerance impairment and hyperglycemia• Hyperlipidemia• Allergic reactionsTubular Transport SystemMDInterstitium[NaCl]=300 mM[Urea]=600 mMDescendingthin limbProximalconvolutedtubuleAscendingthin limbThickascendinglimbDistalconvolutedtubuleCollecting tubuleCollecting ductCortexOut medullaInner medullaGlomerulusNaHCO3NaCl (50%)H2O(60-70%)(85%)Osmotic