Diuretics From Diuresis to Clinical Use Prof Dr

Diuretics From Diuresis to Clinical Use Prof Dr Mahmoud Khattab M Khattab 2009

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

DIURETICS Ø Diuretics work to effectively increase sodium and water excretion (increasing urine volume) Ø In turn they decrease extra-cellular fluid (ECF) and effective circulating volume Ø Diuretics interfere with the normal sodium handling by the kidney. How is Na+ handled by kidneys? Ø Target molecules for diuretics are specific renal tubular membrane transport proteins Ø Adequate quantities of the diuretic drug must be delivered to its site of action. HOW? M Khattab 2008 3

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+-2 Clsymporter Distal CT 5 -10% Na+-Clsymporter Cortical Collecting T 1 -3% Epithelial Na+ channel Medullary Collecting 1 -3% Epithelial Na+ M Khattab 2008 channel Aldosterone ANP 4

Osmotic Diuretics n They do not inhibit a specific transport protein n They are pharmacologically inert & filtered by GF n NOT reabsorbed creating an increased intra- luminal osmotic pressure inhibiting water/solute re -absorption n The main tubular sites of action are the PCT and the thick descending limb of Henle loop (freely permeable to water) n Osmotic diuretics produce only mild natriuresis M Khattab 2008 5

Osmotic Diuretics Therapeutic Uses Mannitol/Urea (IV), Isosorbide/Glycerin (Local & Oral) n Acutely raised intracranial pressure, e. g. after head trauma n Acute attacks of glaucoma o Plasma osmolarity is increased by solutes that does not penetrate into the brain or the eye o This results in extraction of water from the two sites but implies no diuretic effect M Khattab 2008 6

Osmotic Diuretics n Acute renal failure to restore glomerular filtration rate that is aggressively diminished n Drug overdose or poisoning Adverse Effects ü Hypokalemia ü Acute increase in intravascular volume M Khattab 2008 7

Carbonic Anhydrase Inhibitors n Acetazolamise & n n Ø q q Dichlorphenamide Site of action? Mechanism of action? CA inhibition→ ↑luminal PCT H+→↓ bicarbonate reabsrobtion → ↓ Na+ /H+ transporter activity Only mild natriuresis (13%) Increased bicarbonate in urine M Khattab 2008 8

Carbonic Anhydrase Inhibitors n Therapeutic Uses q Glaucoma: CA transports Na+/bicarbonate with water (osmosis) to anterior chamber Ø CA inhibition lowers aqueous humor formation q Urine alkalinization to trap acidic substances dissolved in urine (e. g. , uric acid, Hb, cysteine) q Acute mountain sickness q Enhancing bicarbonate excretion in chronic respiratory acidosis (chronic respiratory obstructive diseases with CO 2 retention) q Epilepsy M Khattab 2008 9

Carbonic Anhydrase Inhibitors Adverse Effects n Hypokalemia n Metabolic acidosis n Allergic effects n Acute renal failure caused by nephrolithiasis, where acetazolamide may crystallize during chronic use (does not occur with methazolamide) M Khattab 2008 10

Thiazide Diuretics q Site & mechanism of action: q Early distal renal tubule q Block Na+/Cl- symporter q Efficacy: Moderate 5% q q ü ü natriuresis Limits the excretion of electrolyte-free water (urine dilution) Reduction of Ca 2+ excretion: ↑ Ca 2+ reabsrobtn by DCT ↓ECF→ enhance passive Na+/ Ca 2+ re-absrobtion by PCT M Khattab 2008 Luminal membrane Basolateral membrane Hydrochlorthiazide, chlorthalidone, metolazone, indapamide 11

Thiazide Diuretics Therapeutic Uses q Treatment of hypertension q Treatment of mild heart failure q Mild edema q Diabetes inspidus q Calcium nephrolithisis o Idiopathic recurrent nephrolithisis with or without hypercalciuria can be prevented by thiazide diuretics M Khattab 2008 12

Thiazide Diuretics Side Effects q Hypokalemia & Metabolic alkalosis q Hyperuricemia q Hyperglycemia & glucose intolerance related to: ü Hypokalemia-induced decrease of insulin release ü Intravascular V↓→ sympathetic stimulation q Increased plasma cholesterol, VLDL cholesterol, and TG (high doses) q Hyponatremia in elderly HTN patients, mild renal failure (Intravascular V↓→ increased ADH→ water moves to ECF → decreased Na+ concentration q Occasionally sustained hypercalcemia, GIT intolerance, M Khattab 2008 pancreatitis, allergic manifestations 13

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+ -2 C 1 - symporter at the apical membrane M Khattab 2008 14

LOOP DIURETICS Pharmacological Actions q They decrease the re-absorption of Na+, K+ & Cl- → increases their urinary elimination q Increased urinary elimination of Ca 2+ /Mg 2+, the ascending loop is important site for Ca 2+ handling q They may enhance glomerular blood flow & filtration (prostaglandins–dependent) q Loop diuretics are the most potent diuretics “high ceiling” increasing sodium excretion up to 25 -30% of the filtered load. Why? q They impair free water clearance (ability to dilute urine) M Khattab 2008 15

LOOP DIURETICS Pharmacokinetics q They reach the lumen by glomerular filtration & tubular secretion q They have good bioavailability, peak plasma level after 30 min of oral intake q Loop diuretics have fast onset of few minutes q They have short duration 6> -hours after oral administration & < two hours after parenteral administration q Torasemide has the longest duration M Khattab 2008 16

LOOP DIURETICS Therapeutic Uses n Treatment of CHF: Ø lower peripheral edema (↓preload) Ø ameliorating pulmonary edema (dyspnea, orthopnea, cough) especially acute cases Ø standard formulation (not SR), are preferred because of potency & fast onset n Treatment of arterial hypertension Ø Sustained release preparations of longer duration of action & gradual BP lowering effect can be used M Khattab 2008 17

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

LOOP DIURETICS Side Effects q Hypokalemia, that might be associated with muscle weakness & cardiac dysrhythmias ü Increased Na+ to collecting tubules increases its exchange with K+ ü ↑Na+ loss & ↓ECF→ renin- aldosterone release q Metabolic alkalosis, related to hypokalemia q Occasional glucose intolerance in preddiabetic patients q Hyperuricemia (gout attacks) is frequent because of increased PCT solute re-absorption M Khattab 2008 19

LOOP DIURETICS Side Effects q Ototoxicity: Rapid IV injection of large doses of loop diuretics produced transient deafness ü Ethacrynic permanent deafness was reported ü Loop diuretic ototoxicity is magnified by concurrent administration of other ototoxic drugs q Hyponatremia is much less frequent than is with thiazide diuretics q NSAIDs blunt natriuresis q Large doses, in low GFR patients, increase serum creatinine (↓ BP & ↓ GFR) M Khattab 2008 20

Loop versus Thiazide Diuretics D-R Relationship n Thiazide diuretics have almost flat D-R curve n Loop diuretics have steep D-R curve with higher efficacy How does this affect drug selection in HTN & CHF? M Khattab 2008 21

Potassium-Sparing Diuretics Aldosterane Antagonists q Spironolactone is a competitive antagonist for aldosterone on its intracellular receptors q Binding of aldosterone with the receptors initiates DNA transcription, initiating transcription of specific proteins resulting in: Ø early increase in the number of sodium channels Ø late increase in the number of Na+-K+-ATPase molecules q Mild diuresis 1 -3% M Khattab 2008 -- -- Spironolactone 22 (Aldosterane Antagonist)

Potassium-Sparing Diuretics Triametrene & Amiloride (Na+-channel Blockers) q They inhibit Na+ re-absorption & K+ secretion q They block the entry of sodium via the Na+ selective channels in the apical membrane of the principal cells q With decreased Na+ entry, there is decreased Na+ extrusion across the basolateral membrane by the Na+-K+-ATPase M Khattab 2008 23

Potassium-Sparing Diuretics Pharmacokinetics & Adverse Effects q They have good oral bioavailability n q Spironlactone is metabolized into the active metabolite n canrenone with t 1/2 of 18 hours q Traimetrene & amiloride n durations are 9 & 24 hours respectively n Adverse Effects: Hypokalemia, especially when combined with ACEIs, ARBs, NSAIDs Spironolactone caused peppermint unpleasant aftertaste & nausea/vomiting Spironolactone steroidal structure is related to gynecomastia in men Impotence & menstrual irregularities M Khattab 2008 24

Hemodynamic Mechanism of Antihypertensive Effect of Diuretics M Khattab 2008 25

Molecular Mechanism of Antihypertensive Effect of Diuretics M Khattab 2008 26

Therapeutic Applications of Diuretics q Treatment of hypertension: o Thiazide diuretic proved to be equivalent safety & efficacy to new agents (ALLHAT study), o Can be used in combination with new agents & beta-blockers at low-dose (fewer side effects) o In presence of renal failure, loop diuretic is used q Edema States (↑ECF Na+/water retention): o Thiazide diuretic is used in mild edema with normal renal function o Loop diuretics are used in cases with impaired renal function M Khattab 2008 27

Therapeutic Applications of Diuretics q Congestive Heart failure Ø Diuretics lower peripheral & pulmonary edema Ø Thiazides may be used in only mild cases with well -preserved renal function Ø Loop diuretics are much preferred in more severe cases especially when GF is lowered Ø 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 28

Therapeutic Applications of Diuretics q Congestive Heart failure (Continue): ü Diuretic therapy may cause ↓GFR (↑serum creatinine) in cases of severe fall in preload & CO ü 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 29

Therapeutic Applications of Diuretics Renal Diseases o 1 ry Na+/fluid retention as glomerulonephritis, acute/chronic renal failure & diabetic nephropathy o 2 ry Na+/fluid retention in nephrotic syndrome Ø Thiazides are used till GFR ≥ 40 -50 m. L/min Ø Loop diuretic are used below given values, with increasing the dose with as GFR goes down q Hepatic Cirrhosis with Ascites Ø Spironolactone is of choice, loop diuretic may be added if diuresis was insufficient Ø Rapid powerful diuresis→ ↓plasma volume & renal hypo-perfusion → irreversible renal failure (hepatorenal syndrome) M Khattab 2008 30

Therapeutic Applications of Diuretics Diabetes Inspidus n Rarely occuring metabolic (lack of ADH) or nephrogenic (ADH-insensitive collecting ducts) n Large volume(>10 L/day) of dilute urine n Thiazide diuretics effectively reduce urine volume n They cause both natriuresis & water diuresis → intra-vscular volume decreases → PCT & DCT reabsorptive capacity increases M Khattab 2008 31

Diuretic Resistance n Failure of usual doses of loop diuretics in CHF, nephrotic syndrome, & chronic renal disease Ø Reduced delivery of diuretic molecules to the site of action Ø 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 Ø The combination of a loop & a thiazide diuretic is usually very effective in resistant edema cases M Khattab 2008 32