Diuretics From Diuresis to Clinical Use Prof Dr Mahmoud Khattab

DIURETICS What are Diuretics? How & Where they work? Osmotic Diuretics Carbonic Anhydrase Inhibitors Thiazide Diuretics Loop Diuretics K+-sparing Diuretics M Khattab 2008

DIURETICS Diuretics work to effectively increase sodium and water excretion (increasing urine volume) In turn they decrease extra-cellular fluid (ECF) and effective circulating volume Diuretics interfere with the normal sodium handling by the kidney. How is Na+ handled by kidneys? Target molecules for diuretics are specific renal tubular membrane transport proteins Adequate quantities of the diuretic drug must be delivered to its site of action. HOW? M Khattab 2008

Sodium Excretion Regulation Nephron Segment Filtered Na+ reabsorbed Na+ Transporter Hormone Proximal CT 60-70% Na+- H+ antiporter Angiotensin II Loop of Henle 20-30% Na+-K+-2Cl- symporter Distal CT 5-10% Na+-Cl- symporter Cortical Collecting T 1-3% Epithelial Na+ channel Aldosterone Medullary Collecting ANP M Khattab 2008

Osmotic Diuretics They do not inhibit a specific transport protein They are pharmacologically inert & filtered by GF NOT reabsorbed creating an increased intra-luminal osmotic pressure inhibiting water/solute re-absorption The main tubular sites of action are the PCT and the thick descending limb of Henle loop (freely permeable to water) Osmotic diuretics produce only mild natriuresis M Khattab 2008

Mannitol/Urea (IV), Isosorbide/Glycerin (Local & Oral) Osmotic Diuretics Therapeutic Uses Mannitol/Urea (IV), Isosorbide/Glycerin (Local & Oral) Acutely raised intracranial pressure, e.g. after head trauma Acute attacks of glaucoma Plasma osmolarity is increased by solutes that does not penetrate into the brain or the eye This results in extraction of water from the two sites but implies no diuretic effect M Khattab 2008

Osmotic Diuretics Acute renal failure to restore glomerular filtration rate that is aggressively diminished Drug overdose or poisoning Adverse Effects Hypokalemia Acute increase in intravascular volume M Khattab 2008

Carbonic Anhydrase Inhibitors Acetazolamise & Dichlorphenamide Site of action? Mechanism of action? CA inhibition→ ↑luminal PCT H+→↓ bicarbonate reabsrobtion → ↓ Na+ /H+ transporter activity Only mild natriuresis (1-3%) Increased bicarbonate in urine M Khattab 2008

Carbonic Anhydrase Inhibitors Therapeutic Uses Glaucoma: CA transports Na+/bicarbonate with water (osmosis) to anterior chamber CA inhibition lowers aqueous humor formation Urine alkalinization to trap acidic substances dissolved in urine (e.g., uric acid, Hb, cysteine) Acute mountain sickness Enhancing bicarbonate excretion in chronic respiratory acidosis (chronic respiratory obstructive diseases with CO2 retention) Epilepsy M Khattab 2008

Carbonic Anhydrase Inhibitors Adverse Effects Hypokalemia Metabolic acidosis Allergic effects Acute renal failure caused by nephrolithiasis, where acetazolamide may crystallize during chronic use (does not occur with methazolamide) M Khattab 2008

Thiazide Diuretics Site & mechanism of action: Early distal renal tubule Block Na+/Cl- symporter Efficacy: Moderate 5% natriuresis Limits the excretion of electrolyte-free water (urine dilution) Reduction of Ca2+ excretion: ↑ Ca2+ reabsrobtn by DCT ↓ECF→ enhance passive Na+/ Ca2+ re-absrobtion by PCT Luminal membrane Basolateral membrane Hydrochlorthiazide, chlorthalidone, metolazone, indapamide M Khattab 2008

Thiazide Diuretics Therapeutic Uses Treatment of hypertension Treatment of mild heart failure Mild edema Diabetes inspidus Calcium nephrolithisis Idiopathic recurrent nephrolithisis with or without hypercalciuria can be prevented by thiazide diuretics M Khattab 2008

Thiazide Diuretics Side Effects Hypokalemia & Metabolic alkalosis Hyperuricemia Hyperglycemia & glucose intolerance related to: Hypokalemia-induced decrease of insulin release Intravascular V↓→ sympathetic stimulation Increased plasma cholesterol, VLDL cholesterol, and TG (high doses) Hyponatremia in elderly HTN patients, mild renal failure (Intravascular V↓→ increased ADH→ water moves to ECF → decreased Na+ concentration Occasionally sustained hypercalcemia, GIT intolerance, pancreatitis, allergic manifestations M Khattab 2008

LOOP DIURETICS (HIGH-CEILING DIURETICS) Frusemide, Bumetanide, Ethacrynic acid, Torasemide Site of action: thick ascending limb of Hele’s loop Loop diuretics inhibit Na+-K+-2C1- symporter at the apical membrane M Khattab 2008

LOOP DIURETICS Pharmacological Actions They decrease the re-absorption of Na+, K+ & Cl- → increases their urinary elimination Increased urinary elimination of Ca2+ /Mg2+, the ascending loop is important site for Ca2+ handling They may enhance glomerular blood flow & filtration (prostaglandins–dependent) Loop diuretics are the most potent diuretics “high ceiling” increasing sodium excretion up to 25-30% of the filtered load. Why? They impair free water clearance (ability to dilute urine) M Khattab 2008

LOOP DIURETICS Pharmacokinetics They reach the lumen by glomerular filtration & tubular secretion They have good bioavailability, peak plasma level after 30 min of oral intake Loop diuretics have fast onset of few minutes They have short duration - <6 hours after oral administration & < two hours after parenteral administration Torasemide has the longest duration M Khattab 2008

LOOP DIURETICS Therapeutic Uses Treatment of CHF: lower peripheral edema (↓preload) ameliorating pulmonary edema (dyspnea, orthopnea, cough) especially acute cases standard formulation (not SR), are preferred because of potency & fast onset Treatment of arterial hypertension Sustained release preparations of longer duration of action & gradual BP lowering effect can be used M Khattab 2008

LOOP DIURETICS Therapeutic Uses Acute pulmonary edema Renal failure Hepatic cirrhosis with ascites Treatment of hypercalcemia as those occuring with hyperparathyroidism & malignancy M Khattab 2008

LOOP DIURETICS Side Effects Hypokalemia, that might be associated with muscle weakness & cardiac dysrhythmias Increased Na+ to collecting tubules increases its exchange with K+ ↑Na+ loss & ↓ECF→ renin- aldosterone release Metabolic alkalosis, related to hypokalemia Occasional glucose intolerance in pred-diabetic patients Hyperuricemia (gout attacks) is frequent because of increased PCT solute re-absorption M Khattab 2008

LOOP DIURETICS Side Effects Ototoxicity: Rapid IV injection of large doses of loop diuretics produced transient deafness Ethacrynic permanent deafness was reported Loop diuretic ototoxicity is magnified by concurrent administration of other ototoxic drugs Hyponatremia is much less frequent than is with thiazide diuretics NSAIDs blunt natriuresis Large doses, in low GFR patients, increase serum creatinine (↓ BP & ↓ GFR) M Khattab 2008

Loop versus Thiazide Diuretics D-R Relationship Thiazide diuretics have almost flat D-R curve Loop diuretics have steep D-R curve with higher efficacy How does this affect drug selection in HTN & CHF? M Khattab 2008

Potassium-Sparing Diuretics Aldosterane Antagonists Spironolactone is a competitive antagonist for aldosterone on its intracellular receptors Binding of aldosterone with the receptors initiates DNA transcription, initiating transcription of specific proteins resulting in: early increase in the number of sodium channels late increase in the number of Na+-K+-ATPase molecules Mild diuresis 1-3% -- -- Spironolactone (Aldosterane Antagonist) M Khattab 2008

Potassium-Sparing Diuretics Triametrene & Amiloride (Na+-channel Blockers) They inhibit Na+ re-absorption & K+ secretion They block the entry of sodium via the Na+ selective channels in the apical membrane of the principal cells With decreased Na+ entry, there is decreased Na+ extrusion across the basolateral membrane by the Na+-K+-ATPase M Khattab 2008

Potassium-Sparing Diuretics Pharmacokinetics & Adverse Effects They have good oral bioavailability Spironlactone is metabolized into the active metabolite canrenone with t1/2 of 18 hours Traimetrene & amiloride durations are 9 & 24 hours respectively Adverse Effects: Hypokalemia, especially when combined with ACEIs, ARBs, NSAIDs Spironolactone caused peppermint unpleasant after-taste & nausea/vomiting Spironolactone steroidal structure is related to gynecomastia in men Impotence & menstrual irregularities M Khattab 2008

Hemodynamic Mechanism of Antihypertensive Effect of Diuretics M Khattab 2008

Molecular Mechanism of Antihypertensive Effect of Diuretics M Khattab 2008

Therapeutic Applications of Diuretics Treatment of hypertension: Thiazide diuretic proved to be equivalent safety & efficacy to new agents (ALLHAT study), Can be used in combination with new agents & beta-blockers at low-dose (fewer side effects) In presence of renal failure, loop diuretic is used Edema States (↑ECF Na+/water retention): Thiazide diuretic is used in mild edema with normal renal function Loop diuretics are used in cases with impaired renal function M Khattab 2008

Therapeutic Applications of Diuretics Congestive Heart failure Diuretics lower peripheral & pulmonary edema Thiazides may be used in only mild cases with well-preserved renal function Loop diuretics are much preferred in more severe cases especially when GF is lowered In cases of life-threatening acute pulmonary edema, high-dose furosemide is given IV It promptly & powerfully decreasing edema + venodilation (↓preload) High-dose furosemide may be life-saving M Khattab 2008

Therapeutic Applications of Diuretics Congestive Heart failure (Continue): Diuretic therapy may cause ↓GFR (↑serum creatinine) in cases of severe fall in preload & CO Spironolactone, aldosterone R antagonist, proved to improve survival in severe CHF It is added to ACEI+diuretic+β-bloker Risk of hyperkalemia must be avoided Aldosterone is implicated in myocardial fibrosis M Khattab 2008

Therapeutic Applications of Diuretics Renal Diseases 1ry Na+/fluid retention as glomerulonephritis, acute/chronic renal failure & diabetic nephropathy 2ry Na+/fluid retention in nephrotic syndrome Thiazides are used till GFR ≥ 40-50 mL/min Loop diuretic are used below given values, with increasing the dose with as GFR goes down Hepatic Cirrhosis with Ascites Spironolactone is of choice, loop diuretic may be added if diuresis was insufficient Rapid powerful diuresis→ ↓plasma volume & renal hypo-perfusion → irreversible renal failure (hepatorenal syndrome) M Khattab 2008

Therapeutic Applications of Diuretics Diabetes Inspidus Rarely occuring metabolic (lack of ADH) or nephrogenic (ADH-insensitive collecting ducts) Large volume(>10 L/day) of dilute urine Thiazide diuretics effectively reduce urine volume They cause both natriuresis & water diuresis → intra-vscular volume decreases → PCT & DCT re-absorptive capacity increases M Khattab 2008

Diuretic Resistance Failure of usual doses of loop diuretics in CHF, nephrotic syndrome, & chronic renal disease Reduced delivery of diuretic molecules to the site of action Chronic suppression of Na+ rebsorption in ascending Henle’s loop → structrural/functional changes in DCT & collecting ducts →↑ absorptive capacity of late segment of the nephron The combination of a loop & a thiazide diuretic is usually very effective in resistant edema cases M Khattab 2008