Diuretics From Diuresis to Clinical Use

1. DiureticsFrom Diuresis to Clinical Use Prof Dr Mahmoud Khattab

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

3. 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

4. Sodium Excretion Regulation M Khattab 2008

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. Thiazide DiureticsSide 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

14. 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- symporterat the apical membrane M Khattab 2008

15. LOOP DIURETICSPharmacological 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 forCa2+ 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

16. LOOP DIURETICSPharmacokinetics • 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

17. LOOP DIURETICSTherapeutic 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

18. LOOP DIURETICSTherapeutic Uses • Acute pulmonary edema • Renal failure • Hepatic cirrhosis with ascites • Treatment of hypercalcemia as those occuring with hyperparathyroidism & malignancy M Khattab 2008

19. LOOP DIURETICSSide Effects • Hypokalemia,that might be associated withmuscle 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

20. LOOP DIURETICSSide 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

21. 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

22. Potassium-Sparing DiureticsAldosterane 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

23. Potassium-Sparing DiureticsTriametrene & 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

24. 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 Potassium-Sparing DiureticsPharmacokinetics& Adverse Effects M Khattab 2008

25. Hemodynamic Mechanism of Antihypertensive Effect of Diuretics M Khattab 2008

26. Molecular Mechanism of Antihypertensive Effect of Diuretics M Khattab 2008

27. 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

28. 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

29. 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

30. Therapeutic Applications of DiureticsRenal Diseases • 1ryNa+/fluid retention as glomerulonephritis, acute/chronic renal failure & diabetic nephropathy • 2ryNa+/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

31. 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

32. 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