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Dr. Kaukab AzimIntroduction to Renal PharmacologyDiuresis. Conceptual image of the effect of diuretics on the kidney. A diurectic is any drug that encourages the excretion of urine. Common diuretics include caffeine and alcohol. Medically, diuretics can be used to treat heart failure, cirrhosis of the liver and hypertension (high blood pressure). The diuretic alleviates the symptoms of these disease by causing sodium and water loss through urine.

1Carbonic Anhydrase InhibitorsThiazide Diuretics and CongenersLoop DiureticsAcetazolamideDorzolamideHydrochlorthiazideIndapamideFurosemideEthcrynic AcidPotassium Sparing DiureticsOsmotic DiureticsADH AntagonistsTriamtereneAmilorideSpironolactoneMannitolConivaptanTolvaptanDrug ListClinical Condition in which Diuretics are usedEdematous StatesHeart FailureHepatic AscitesIncreased portal pressurehypoalbuminemiaSecondary Aldosteronism: Chronic conditions like cirrhosis oftheliver, nephrotic syndrome of the kidney or a tumour that produces the hormone renin (normally renin is produced by the adrenal glands) are responsible for secondary aldosteronism.Nephrotic SyndromePremenstrual edemaNon-edematous StatesHypertensionHypercalcemiaDiabetes insipidusFrom LippincottHeart FailureHepatic AscitesIncreased portal pressure and hypoalbuminemiaSecondary AldosteronismNephrotic SyndromePremenstrual edema3Site and Mechanism of Action of DiureticsNameSite of ActionMechanism of ActionRelative efficacyCarbonic Anhydrase InhibitorProximal tubuleInhibit NaHCO3 reabsorption2Loop DiureticsThick ascending limb of the loop of HenleBlock the Na+K+/2Cl- symporter15Thiazide DiureticsEarly distal tubuleBlock the Na+/Cl- symporter5Potassium Sparing DiureticsLate distal tubule and cortical collecting ductBlock Na+ channels1Osmotic DiureticsThin descending limb of the loop of Henle and proximal tubuleIncrease osmolarity of tubular fluid6

Carbonic Anhydrase InhibitorsChemistry- Acetazolamide, dorzolamide (All compounds are sulfonamides).Mechanism of actionInhibition of membrane-bound carbonic anhydrase (CA) in the cells of proximal tubule which leads to blockade of the reaction H2CO3 = H2O + CO2 that normally occurs in the proximal tubule lumenInhibition of cytoplasmic CA in the cells of proximal tubule which leads to blockade of the reaction: H2 O + CO2 = H2 CO3 that normally occurs in the cytoplasmThe final effect is a nearly complete abolition of NaHCO3 reabsorption in the proximal tubule (but NaHCO3 reabsorption by mechanisms independent from carbonic anhydrase still occur in other parts of the nephron).

Na+ HCO3- K+Volume of UrineIncreasedUrinarysecretionDecreasedUrinarysecretionAcetazolamidePlease see notes belowRenal effects- Increased renal excretion of: Na+, K+, HCO3-- Decreased renal excretion of: NH4+, H+.- Urine pH: alkaline.- Acid-base balance: metabolic acidosis (acidosis is associated withhyperchloremia because Cl tend to exit from cells when H+ is high, inorder to maintain electroneutrality) .- Efficacy of diuretic: low (the maximum increase in Na+ excretionIs about 5% of the filtered Na+ load. Moreover, as metabolic acidosisdevelops, the filtered load of HCO3- decreases, and therefore thediuretic effect undergoes a complete tolerance in 2-3 days)9Renal effects- Increased renal excretion of: Na+, K+, HCO3-- Decreased renal excretion of: NH4+, H+.- Urine pH: alkaline.- Acid-base balance: metabolic acidosis (acidosis is associated with hyperchloremia because Cl tend to exit from cells when H+ is high, in order to maintain electroneutrality) .- Efficacy of diuretic: low (the maximum increase in Na+ excretion is about 5% of the filtered Na+ load. Moreover, as metabolic acidosis develops, the filtered load of HCO3- decreases, and therefore the diuretic effect undergoes a complete tolerance in 2-3 days)PharmacokineticsOral bioavailability: .100%.Urinary excretion: .90% by tubular secretion.Administration: acetazolamide PO, dorzolamide topical (eye drops)Adverse effectsParesthesias (frequent), drowsinessNephrolithiasis (due to precipitation of calcium phosphate salts in alkaline urine)Hyperchloremic metabolic acidosisHyperuricemiaHypokalemia (the main mechanism is the same as that of thiazides, loop diuretics and osmotic diuretics. In addition, the increased delivery of bicarbonate to the collecting duct increases the lumen negative potential which favors K+ excretion).Sulfa-type allergic reactionsEdemaGlaucoma (50-60% reduction in aqueous humor production)Epilepsy (direct inhibition of carbonic anhydrase in the CNS, which increases carbon dioxide tension and inhibits neuronal transmission) High altitude sicknessMetabolic alkalosisTherapeutic UsesPlease see notes belowMechanism of Action: Carbonic anhydrase is an enzyme responsible for forming hydrogen and bicarbonate ions from carbon dioxide and water. By inhibiting this enzyme, acetazolamide reduces the availability of these ions for active transport. Hydrogen ion concentrations in the renal tubule lumen are reduced by acetazolamide, leading to an alkaline urine and an increased excretion of bicarbonate, sodium, potassium, and water. A reduction in plasma bicarbonate results in metabolic acidosis, which rapidly reverses the diuretic effect. Reduced intraocular pressure (IOP) is the result of a 5060% reduction in aqueous humor production by acetazolamide and is likely due to decreased bicarbonate ion concentrations in ocular fluid.

The anticonvulsant activity of acetazolamide may depend on a direct inhibition of carbonic anhydrase in the CNS, which increases carbon dioxide tension and inhibits neuronal transmission. The successful treatment of altitude sickness involves production of respiratory and metabolic acidosis, which increases ventilation and binding of oxygen to hemoglobin. This occurs because the drug decreases carbon dioxide tension in the pulmonary alveoli, thus increasing arterial oxygen tension.

Other effects- The blockade of CA on the ciliary body epithelium decreases theproduction of the aqueous humor, which is rich in HCO3-.- The blockade of CA in the choroid plexus decreases the production ofcerebrospinal fluid.13Contraindications and PrecautionsHepatic cirrhosis (alkalinization of urine decreases urinary trapping of NH 4+)Chronic obstructive pulmonary disease (the risk of metabolic acidosis is increased)Hypersensitivity to sulfa drugs.Hypokalemic states

Loop DiureticsChemistryFurosemide, bumetanide, and torsemide are sulfonamides. Ethacrynic acid is not a sulfonamideMechanism of actionInhibition of electroneutral Na+/K+/2Cl- cotransport located on the luminal surface of the thick ascending limb of Henle's loop, which leads to:a decreased lumen-positive potential which normally drives divalent cation reabsorption.a decreased hypertonicity of the medulla and therefore a decreased ability of the kidney to concentrate the urine.an inhibition of macula densa sensitivity (by inhibiting Na+ and Cl- transport into macula densa, the macula densa is no longer able to sense salt concentration in the tubular fluid. Therefore it initiates two responses that can increase GFR:It inhibits the tubuloglomerular feed backIt stimulates renin release from the adjacent juxtaglomerular cells.Loop diuretics that are sulfonamide compounds also cause a slight inhibition of carbonic anhydrase.

Pharmacology of Loop DiureticsRenal effectsIncreased renal excretion of: Na+,Cl-, K+, H+, Ca++, (sulfonamides also increase the excretion of HCO3).Acid-base balance: metabolic alkalosis.The diluting and concentrating capacity of the kidney are decreased.Efficacy of diuretic effect: high (the maximum increase in Na+ excretion is 20-25% of the filtered Na+ load. Moreover the diuretic effect remains even when the GFR is less than 30 mL/min).Duration of diuretic effect: 2-6 hours.Vascular effectsVasodilation, mainly in the venous bed.Redistribution of blood flow within the renal cortex. (these effects are due, at least in part, to drug induced induction of prostaglandin synthesis and stimulation of prostaglandin release)PharmacokineticsAbsorption, and biotransformation are drug-related.Kidney excretion occurs by active secretion by the proximal tubule.Administration: PO, IM, IV.Therapeutic uses of Loop DiureticsAcute pulmonary edema (given IV).Heart failure.Edema (associated with chronic renal failure or nephrotic syndrome).Ascites (associated with hepatic cirrhosis or right-sided heart failure).Hypertension (when associated with renal insufficiency or heart failure).Hypercalcemia.(Addition of a thiazide can cause a dramatic synergistic effect when a patient become refractory to a loop diuretic alone ) Na+ Ca2+ K+Volume of UrineIncreasedUrinarysecretionDecreasedUrinarysecretionFurosemideOtotoxicityHyperuricemiaHypotensionHypokalemiaHypomagnesemiaAdverse Effects

Remember the ones in the red boxThiazide DiureticsThe most commonly used diureticsPharmacology of Thiazide(and congeners)ChemistryThiazides are benzothiadiazine derivativesOther compounds (congeners) are not thiazides but are pharmacologically similar to thiazides.All compounds are sulfonamides.Mechanism of actionInhibition of electroneutral Na+/Cl- cotransport located on the luminal surface of early distal convolute tubuleSlight inhibition of carbonic anhydrase.

Renal effectsIncreased renal excretion of: Na+, K+, H+, Cl-, HCO3-,.Decreased renal excretion of: Ca++, NH4+, urates.Urine pH: alkaline (due to inhibition of carbonic anhydrase).Acid-base balance: metabolic alkalosis.Kidney diluting capacity: decreased.Efficacy of diuretic effect: moderate (the maximum increase in Na+ excretion is 5-10% of the filtered Na+ load. Moreover, with the exception of indapamide and metolazone, the diuretic effect disappears if the glomerular filtration rate is less than 30 mL/min).Duration of diuretic effect: variable (6-48 hours). Na+ Ca2+ K+Volume of UrineIncreasedUrinarysecretionDecreasedUrinarysecretionHydrochlorothiazideOther effectsVascular effectsArteriolar vasodilation (after chronic administration) that occurs at lower dosages than are required for diuresisPharmacokineticsAbsorption, distribution and biotransformation are drug-related.Kidney excretion occurs by glomerular filtration and active secretion by the proximal tubule.Administration: PO, IM, IV.Hypertension (first choice diuretics).- Edema associated with diseases of:a) the heart (i.e. heart failure)b) the liver (i.e. hepatic cirrhosis)c) the kidney (i.e. nephrotic syndrome).- Ascites (due to venous occlusion, cirrhosis, endometriosis, etc.)- Calcium nephrolithiasis, idiopathic hypercalciuria.- Menieres disease (they can prevent the endolymphatic fluid buildup)- Nephrogenic diabetes insipidus (this seemingly paradoxical effect is likely mediated through the extracellular volume contraction which promotes proximal tubular reabsorption of Na+ and water. Therefore a reduced volume is delivered to the distal tubule)Therapeutic UsesGoodman and GilmansTHERAPEUTIC USES Thiazide diuretics are used to treat edema associated with heart(congestive heart failure), liver (cirrhosis), and renal (nephrotic syndrome, chronic renal failure,and acute glomerulonephritis) disease. With the possible exceptions of metolazone and indapamide,most thiazide diuretics are ineffective when the GFR is