Diuretic agents

Diuretics are drugs that •increase the rate of urine flow •increase rate of excretion of Na+ (natriuresis), and an accompanying anion, usually Cl•may also modify renal handling of other cations (K+, H+, Ca++, Mg++), anions (Cl-, HCO3-, H2PO4-), and uric acid Mechanism of action •primarily by depleting body sodium stores •sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity, possibly related to increased sodium-calcium exchange with a resultant increase in intracellular calcium •initially •reduced blood volume and cardiac output •increased peripheral vascular resistance •after 6-8 weeks •cardiac output returns to normal •peripheral resistance declines Types of diuretics •carbonic anhydrase inhibitors •blocks sodium bicarbonate reabsorption at proximal tubules •osmotic diuretics •inhibit water reabsorption at proximal tubule and descending loop of Henle •loop diuretics •inhibit NaCl reabsorption at thick ascending loop of Henle, enhance the excretion of K+ •thiazides •inhibit NaCl reabsorption in the distal convoluted tubules •potassium-sparing diuretics •reduce Na+ reabsorption in collecting tubules and ducts

Carbonic anhydrase inhibitors •located predominantly in luminal membrane of proximal tubules •catalyses the dehydration of carbonic acid, H2CO3, leading to systemic reabsorption of bicarbonate •mechanism of action •blocks enzyme action at proximal tubules and collecting duct system •at proximal tubule, blocks sodium bicarbonate reabsorption, causing sodium bicarbonate diuresis, and reduction in body bicarbonate stores •65% bicarbonate can still be reabsorbed at other nephron sites by carbonic anhydraseindependent mechanisms •at collecting duct system, inhibit secretion of titratable acids and ammonia •Acetozolamide •sulphonamide derivative, possible cross-allergenicity with other sulphonamide derivatives •sulphonamide derivative –SO2NH2 essential for activity •used as a diuretic only if oedema is accompanied by metabolic alkalosis •pharmacokinetics •well absorbed after oral administration •increase in urine pH from bicarbonate diuresis apparent within 30 minutes, maximal at 2 hours, and persists for 12 hours after a single dose •t½β 6-9 hours •excretion by S2 proximal tubular secretion •dosage reduction in renal insufficiency •pharmacodynamic effects •hyperchloraemic metabolic acidosis •enhanced NaCl reabsorption, due to the effect of acidosis and HCO3- depletion •alter the pH and the quantity of aqueous humour and cerebospinal fluid secretion •due to interference with carbonic anhydrase in red blood cells, increased CO2 in peripheral tissues, decreased CO2 in expired gas •reduced gastric secretion

•indications •inhibit formation of aqueous humour in glaucoma •oedema due to heart failure •metabolic alkalosis •acute mountain sickness •hypokalaemia periodic paralyis •epilepsy •urine alkalisation •increase urinary phosphate excretion during severe hyperphosphataemia •adverse effects •hyperchloraemic metabolic acidosis •alkalinization of urine with precipitation of calcium phosphate in alkaline urine and stone formation •renal potassium wasting •negative intraluminal electric potential in the collecting tubules caused by sodium bicarbonate load enhances potassium excretion •increased ammonium reabsorption (with hepatic impairment may develop hepatic encephalopathy) •drowsiness •paresthesia •hypersensitivity •bone marrow depression •hypersensitivity •skin toxicity •contraindications •hepatic cirrhosis •alkalinisation of urine decrease excretion of NH4+ •diversion of ammonium of renal origin from renal into systemic circulation may induce hepatic encephalopathy •hyperchloraemic metabolic acidosis •leading to worsening of respiratory or metabolis acidosis •severe chronic obstructive pulmonary disease •conditions with Na+ or K+ depletion Osmotic diuretics •these agents are freely filtered at the glomerulus, undergo limited reabsorption by renal tubule •glycerin, isosorbide, mannitol, urea •mechanisms of action •extraction of water from intracellular compartments and expansion of extracellular fluid volume, decrease blood viscosity, inhibit renin release, and increase renal blood flow •increase renal (medullary) blood flow, removes NaCl and urea from medulla thus reducing renal medullary tonicity •a reduction in renal medullar tonicity decrease extraction of water from distal thin loop, which in turn limits the concentration of NaCl in the tubular fluid entering the ascending thin loop •reduced passive reabsorption of NaCl in ascending thin loop •proximal tubule and descending limb of Henle’s loop are freely permeable to water, an osmotic agent that is not transported cause water to be retained in these segments and promotes diuresis

•Mannitol •not metabolised, filtered at the glomerulus, not secreted at the tubules •poorly absorbed by oral route, must be given parenterally •by oral route, cause osmotic diarrhoea •by parenteral route, excreted by glomerular filtration in 30-60 minutes OH OH OH OH •t½β 0.25-1.7 hours •pharmacodynamic effects OH OH •increase renal blood flow by afferent arteriole dilatation •urine volume increase in conjunction with mannitol excretion •concomitant increase in urine flow rates decreases the contact time between fluid and tubular epithelium, thus reducing Na+ reabsorption •natriuresis is of lesser magnitude than water diuresis, eventually leads to hypernatraemia •increase urinary excretion of K+, Mg++, Ca++, Cl-, HCO3-, and PO43•adverse effects •extracellular volume expansion •dehydration •hypernatraemia •indications •acute renal failure •maintains urine flow during cardiopulmonary bypass •dialysis disequilibrium syndrome (due to sudden reduction in osmolality of extracellular fluid) •control of intraocular pressure during acute attack of glaucoma •reduce cerebral oedema Loop diuretics •frusemide, bumetanide, torsemide are sulphonamide derivatives, potential sulphonamide allergy •ethacrynic acid is a phenoxyxacetic acid derivative •mechanism of action •selective inhibition of Na+/K+/2Cl- transport system (symport) in the luminal membrane of the thick ascending limb of loop of Henle •increasing urinary excretion of Na+ and Cl-, up to 25% of filtered load of Na+ •effects •reduction in the reasorption of NaCl, blocking the ability to produce a hypertonic medullary interstitium •reduction of the normal lumen-positive potential derived from K+ recycling results in marked increase in the excretion of Ca++ and Mg++ •increased urinary excretion of K+ and titratable acid due to increase delivery of Na+ to distal tubule •increased excretion of HCO3- and phosphate •weak carbonic anhydrase activity •the diuretic response correlates positively with their excretion in the urine •increased renal blood flow within renal cortex

•stimulation of renin secretion •due to inhibition of NaCl transport into macula densa •increase systemic venous capacitance, reducing left ventricular filling pressures •pharmacokinetics •rapidly absorbed via oral route •bioavailability, frusemide 60%, bumetanide 80% •99% bound to plasma protein (frusemide, bumetanide) •diuretic response is rapid following intravenous injection •Vd 0.1 L/kg (frusemide, bumetanide) •metabolism and elimination •frusemide 40%; bumetanide 35%; torsemide 70% •remainder excreted via kidneys unchanged •renal secretion dependent on organic acid transport system •t½β dependent on renal function, elimination by glomerular filtration and tubular secretion •sulphonamides are organic acids and are secreted by the organic acid secretory system •secretion is inhibited by indomethacin, probenecid •t½β frusemide 0.3-3 hours •t½β bumetanide 0.3-1.5 hours •t½β torsemide 0.5-6 hours •indications •acute pulmonary oedema •rapid increase in venous capacitance, brisk natriuresis •oedematous conditions such as nephrotic syndrome, chronic renal failure, cirrhosis •hypertension •acute renal failure •acute hypercalcaemia •hyperkalaemia •acute renal failure •anion overdose •induce forced diuresis •adverse effects •hyponatraemia with or without severe dehydration •hypokalaemia metabolic alkalosis •risk of cardiac arrhythmias, especially with digoxin •hypomagnesaemia •hypocalcaemia •hypercalcaemia may occur with severe dehydration •hyperuricaemia •from hypovolaemic enhancement of uric acid reabsorption in proximal tubule •hyperglycaemia •ototoxicity •due to alterations in the electrolyte composition of endolymph, frequently with rapid intravenous administration, higher incidence with ethacrynic acid •increase plasma concentration of LDL cholesterol and triglycerides, while decreasing HDL cholesterol •hypersensitivity, probably to the sulphonamide moiety •bone marrow depression •photosensitivity •paresthesia •gastrointestinal disturbances

•contraindications •severe Na+ and volume depletion •cross-sensitivity may occur if patients are sensitive to other sulphonamides for sulphonamide-based diuretics •hepatic cirrhosis •decreased secretion of the drug into the tubular fluid •in part because of the high serum aldosterone concentrations leading to enhanced salt reabsorption at the collecting ducts •drug interactions •aminoglycosides (augmentation of ototoxicity) •oral anticoagulant (displacement from albumin) •digoxin (potentiate digoxin-induced arrhythmias) •increase plasma concentrations of lithium, propranolol •sulphonylureas (hyperglycaemia) •cisplatin (increased risk of diuretic-induced ototoxicity) •probenecid (reduce transport into tubular lumen and hence diuretic response) •thiazide diuretics (synergism of diuretic activity) Thiazide diuretics •chemistry •benzothiadiazine derivatives •inhibitors of Na+-Cl- symport •have an unsubstituted sulphonamide group (SO2NH2)

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•mechanism of action •distal convoluted tubule (primary site of action) •inhibit NaCl reabsorption from the luminal side of the epithelial cells in the distal convoluted tubule •proximal convoluted tubule (secondary site of action) •small effect on NaCl reabsorption in the late proximal tubule •effects •increase Na+ and Cl- excretion •some are weak inhibitors of carbonic anhydrase •increase excretion of HCO3- and phosphate •excretion of uric acid •increased with acute administration •decreased with chronic administration, from hypovolaemic enhancement of uric acid reabsorption in proximal tubule •increase excretion of K+ and titratable acid •due to increased delivery of Na+ to distal tubule •increase excretion of magnesium and calcium •enhanced Ca++ reabsorption in the distal convoluted tubule •from enhanced Na+/Ca++ exchange in the basolateral membrane as a result of lowering of intracellular Na+ (due to blockade of Na+ entry by thiazides) •attenuate the ability to excrete dilute urine during water diuresis •due to inhibition of Na+ and Cl+ transport in the cortical diluting segment •minimal reduction in GFR due to increase in tubular pressure

•pharmacokinetics •absorption •all absorbed when given orally •chlorothiazide 10-21% •hydrochlorothiazide 65-75% •chlorothiazides, less lipid soluble, must be given in large doses •chlorthalidone is slowly absorbed and has a longer duration of action •elimination •degree of protein binding determines the contribution that filtration makes to tubular delivery of thiazides •sulphonamides are organic acids and are secreted by the organic acid secretory system •secretion is inhibited by probenecid •compete with the secretion of uric acid, uric acid secretory rate may be reduced with initial hyperuricaemia •indapamide is excreted primarily via biliary system •t½β •chlorothiazide, 1.5 hours •hydrochlorothiazide, 2.5 hours •indapamide, 10-22 hours •indications •hypertension •oedema associated with congestive heart failure, liver and renal disease, corticosteroid therapy •nephrolithiasis due to idiopathic hypercalciuria •reduced urinary excretion of Ca++ •nephrogenic diabetes insipidus •reducing urine volume by 50% due to volume contraction leading to increased proximal tubule reabsorption •management of Br- toxicity •similar excretion pathway as Cl•adverse effects •extracellular volume depletion •hypotension •hyponatraemia •hypochloraemia •hypokalaemia metabolic alkalosis •increased delivery of salt and water to collecting duct, thus enhancing renal secretion of K+ and H+ •hypomagnesaemia •hypercalcaemia •hyperuricaemia •from hypovolaemic enhancement of uric acid reabsorption in proximal tubule •impaired glucose tolerance •by reducing insulin secretion, or by acting as potassium channel opener, counteracts the insulinotropic effect of sulphonylurea hypoglycaemic agents •may be related to hypokalaemia as hyperglycaemia is partially reversible with correction of hypokalaemia •hyperlipidaemia •causes 5-15% increase in total serum cholesterol, low density lipoproteins (LDL) cholesterol, and triglyceride concentrations, may return to baseline after prolonged use

•hypersensitivity reactions •cross-sensitivity with patients hypersensitive to sulphonamide •weakness, fatiguability, paresthesia (similar to carbonic anhydrase inhibitors) •drug interactions •quinidine (prolongation of QT interval leading to polymorphic ventricular tachycardia or torsade de pointes, due to hypokalaemia) •diminish the effects of •anticoagulants, uricosuric agents, sulphonylureas, insulin •increase the effects of •anaesthetics, digoxin, lithium, loop diuretics, vitamin D •effect of thiazide diuretics decreased by •NSAIDs (in treatment of hypertension), bile acid sequestrants (reduce reabsorption of thiazides), methanamines (alkalinization of urine) •risk of hypokalaemia increased by •amphotericin B and corticosteroids Potassium sparing diuretics •Aldosterone •Na+ absorption and K+ secretion at collecting tubules and ducts is regulated by aldosterone •at any given rate of Na+ delivery the rate of K+ secretion is positively correlated with the serum aldosterone concentration •aldosterone enhances K+ secretion by increasing NA+/K+ ATPase activity and Na+ and K+ channel activities •Na+ absorption in the collecting tubules generates a lumen-negative electrical potential, which enhances K+ secretion •aldosterone antagonists interfere with this process •similar effects on H+ handling by the collecting tubule •metabolic acidosis seen with aldosterone antagonists •inhibitors of Na+ channel •amiloride, triamterene •blocks Na+ channels X in the luminal membrane of the collecting tubule •produce hyperkalaemia

•effects of inhibiting Na+ channel •since K+ secretion is coupled with Na+ entry in this segment, they are effective potassium-sparing diuretics •small increase in NaCl excretion, as the late distal tubule and collecting duct have a limited capacity to reabsorb solutes normally •reduced excretion of K+, H+, Ca++, Mg++ •due to reduction of lumen-negative voltage •volume contraction increase reabsorption of uric acid •at high concentrations block Na+-H+ and Na+-Ca++ antiporters

•pharmacokinetics •oral absorption •amiloride, 15-25% •triamterene, 30-70% •elimination •amiloride (t½β 21 hours), predominantly urinary excretion of intact drug •triamterene (t½β 4 hours) metabolized to active metabolite, 4-OHtriamterene sulphate which is then excreted in the urine, toxicity enhanced in liver and renal failure •adverse effects •hyperkalaemia •nausea, vomiting, •amiloride •diarrhoea •triamterene •megaloblastosis from folic acid antagonism •glucose intolerance •photosensitivity •interstitial nephritis •renal stones from precipitation of drug •leg cramps •dizziness •contraindications •hyperkalaemia or increased risk of hyperkalaemia (renal failure, concurrent therapy with other K+-sparing diuretics, or aldosterone receptor antagonists, or K+ supplements, or ACEi, or NSAIDs) •liver disease •impaired metabolism of triamterene •folic acid antagonism by triamterene may increase the likelihood of megaloblastosis •Spironolactone •synthetic steroid that competes with aldosterone for binding to X the cytoplasmic mineralocorticoid receptor, and prevents translocation of the receptor complex to the nucleus, reducing expression of gene controlling synthesis of Na+ channels and Na+/K+ ATPase •also reduces the intracellular formation of active metabolites of aldosterone by inhibition of 5α-reductase activity •pharmacokinetics •60-70% absorbed after oral administration •slow onset of action, before full therapeutic effect is achieved •substantially inactivated in the liver •active metabolite, canrenone with t½β of 16.5 hours •t½β 1.6 hours

•adverse effects •hyperkalaemia •hyperchloraemic metabolic acidosis •inhibition of H+ secretion in parallel with K+ secretion •gynecomastia, decreased libido, hirsuitism, menstrual irregularities (synthetic steroid) •acute renal failure with combination of triamterene and indomethacin •diarrhoea, gastritis, gastric bleeding, peptic ulceration •skin rashes •blood dyscrasias •breast cancer •contraindications •chronic renal insufficiency •concomitant use of potassium-sparing drugs •liver disease •impaired metabolism of spironolactone •peptic ulcer disease •indication •states of mineralocorticoid excess, •primary hypersecretion (Conn’s syndrome, ectopic ACTH production) or •secondary aldosteronism where renal K+ wasting occurs •secondary aldosteronism results from congestive heart failure, hepatic cirrhosis, nephrotic syndrome, conditions associated with renal salt retention and diminished intravascular volume

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