Pharmacology - Diuretics (PDF)

 Transudative edema is usually generalized and is associated with renal Na+ retention. The three most common clinical causes are: – Congestive heart failure (CHF): the decreased COP causes renal ischemia which stimulates the renin-angiotensin-aldosterone system (RAAS) → Na+ and...

 Transudative edema is usually generalized and is associated with renal Na+ retention. The three most common clinical causes are: – Congestive heart failure (CHF): the decreased COP causes renal ischemia which stimulates the renin-angiotensin-aldosterone system (RAAS) → Na+ and water retention → edema. – Liver cirrhosis: the cirrhotic liver cannot synthesize sufficient albumin and other plasma proteins → ↓ plasma oncotic pressure. Hypoalbuminemia together with portal hypertension and 2ry stimulation of RAAS cause fluid retention (edema) and accumulation of fluid in the peritoneal cavity (ascites). – Nephrotic syndrome: glomerular dysfunction causes excessive loss of plasma proteins in urine → ↓ plasma oncotic pressure → edema. Part 2: Diuretic classes and agents Diuretics are drugs that increase urine volume and Na+ excretion. Natriuretic: a drug that increase Na+ excretion by the kidney. Classification of diuretics: Renal diuretics E x t r a - r e n a l di u r e t i c s They act directly on the kidney: They act indirectly on the kidney: Thiazide diuretics: act on the Water diuresis: ↑ water intake → ↓ proximal part of the DCT e.g. ADH release → diuresis. hydrochlorothiazide. Digitalis in CHF: ↑ the COP Loop diuretics: act on the leading to ↑ RBF → diuresis. ascending limb of loop of Henle e.g. i.v. albumin in ascites or furosemide. nephrotic edema: to increase K+ sparing diuretics: act on the plasma osmotic pressure → distal part of the DCT e.g. mobilization of edema fluid toward spironolactone. the vascular compartment → ↑ RBF Osmotic diuretics: substances that → diuresis. ↑ the osmotic pressure of tubular fluid → ↓ water reabsorption by renal tubules e.g. mannitol. N.B. Carbonic anhydrase inhibitors e.g acetazolamide: they are weak diuretics that ↓ NaHCO3 reabsorption from the PCT and may cause metabolic acidosis. They also ↓ aqueous humor secretion and can be used in the treatment of glaucoma (see pharmacology of the eye). 89  █ Loop diuretics (Furosemide, torsemide, bumetanide , and ethacrynic acid) Pharmacokinetics  They are absorbed from the GIT and secreted into the lumen of the PCT by an organic acid excretory system.  The absorption of furosemide is erratic but bumetanide is complete.  Diuresis occurs within 5 minutes after i.v. administration and within 30 minutes of oral administration. Mechanism and pharmacological effects  Loop diuretics inhibit Na+/K+/2Cl― co-transport system in the thick ascending limb of LOH leading to inhibition of the active reabsorption Na+, Cl―, and K+. These ions are excreted with equiosmotic amount of water. – They also increase excretion of Ca2+, Mg2+, halides and H+. – Na+ and water loss at this segment is high, so they are potent (or high ceiling) diuretics (i.e., up to 25% of the filtered Na+ load).  They ↑ renal PGE2 and PGI2 production leading to VD and ↑ RBF and GFR. – Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit PG synthesis and antagonize this effect of loop diuretics. – VD of pulmonary vascular bed also occurs due to ↑ PG formation. Therapeutic uses Edematous conditions: e.g. CHF, nephrotic syndrome, etc. – Many patients require fluid and sodium restriction to have the best results. – Diuretics are not used to treat edema due to lymphatic obstruction (lymphedema) or inflammatory edema (localized edema with high protein content is difficult to be resolved by diuretics). Acute pulmonary edema: loop diuretic ↓ pulmonary congestion by: – They cause venodilatation → ↓ venous return. – They cause VD of pulmonary vascular bed even before diuresis occurs. Acute renal failure: to maintain adequate GFR and enhance K+ excretion. Acute hypercalcemia and acute hyperkalemia: saline should be given to compensate for Na+ and water loss. Hypertensive emergencies: i.v. furosemide is usually given in emergencies: – Loop diuretics ↓ plasma volume. – They cause peripheral VD due to ↑ PGs production in many vascular beds. – Hyponatremia ↓↓ sensitivity of the vascular smooth muscles to circulating catecholamines. 90 Adverse effects – Hypovolemia and hypotension. – Electrolyte disturbances: Hyponatremia, hypokalemia, hypomagnesemia, and hypocalcemia (all need to be properly replaced). – Hypokalemic metabolic alkalosis: due to ↑ tubular secretion of K+ and H+. – Hyperuricemia and precipitation of acute gout: This is caused by: – Increased uric acid reabsorption in the PCT as a result of hypovolemia (It may be prevented by using lower doses to avoid hypovolemia). – Competition with uric acid excretion at the organic acid excretory system in the PCT. – Ototoxicity: – It is reversible hearing loss. It occurs with very high doses. – It may be due impairment of ion transport in the stria vascularis (inner ear). – Occurs more frequent with:  Patients with impaired renal function.  Ethacrynic acid.  Concomitant use of other ototoxic drugs e.g. aminoglycosides. – Allergic reactions: all loop diuretics (except ethacrynic acid) are derivatives of sulfonamides; they cause occasional skin rash, eosinophilia, and less often, interstitial nephritis. █ Thiazide diuretics Classification  True thiazides (they are derivatives of sulfonamides): hydrochlorothiazide, bendroflumethiazide.  Thiazide-like diuretics: metalozone, indapamide, chlorthalidone. Pharmacokinetics  Thiazide diuretics are absorbed from the GIT. They are secreted into the lumen of the PCT by an organic acid excretory system.  They produce diuresis within 1–2 hours. Mechanism and pharmacological effects  Thiazides inhibit Na+/Cl― co-transport system in the proximal part of DCT leading to inhibition of the active reabsorption Na+, Cl―. These ions are excreted with equiosmotic amount of water. – Excess Na+ reaching the DCT is reabsorbed in exchange with K+ (→ K+ loss). 91  – They also increase excretion of halides and H+. – They ↓ Ca2+ excretion and enhance its reabsorption. – Thiazides have moderate efficacy (i.e., maximum excretion of filtered Na+ load is only 5-7%). – Most thiazides are ineffective if the GFR is < 30-40 ml/min (so it is not useful, or even harmful, in presence of renal failure).  The action of thiazides also depends on renal PGs like loop diuretics but to much less extent. Therapeutic uses Mild edematous states: cardiac, hepatic, or renal (same as loop diuretics). Essential hypertension (mild to moderate): – They have the same mechanisms like loop diuretics (mention them). – They are often combined with other antihypertensive drugs to enhance their blood pressure-lowering effects. Hypercalcuria and renal Ca2+ stones: to ↓ urinary Ca2+ excretion. Nephrogenic diabetes inspipidus (DI): – Thiazides can reduce urine volume in some cases of DI. This is called “paradoxical antidiuretic action” and it is not clearly understood. It may be due to improvement of ADH receptor sensitivity in the renal collecting tubules. Adverse effects – Hypovolemia and hypotension. – Electrolyte disturbances: Hyponatremia and hypokalemia. – Hypokalemic metabolic alkalosis: due to ↑ tubular secretion of K+ and H+. – Hyperuricemia the same as with loop diuretics. – Hyperglycemia: due to both ↓ pancreatic release of insulin and ↓ tissue utilization of glucose. – Hyperlipidemia: due to ↑ cholesterol and LDL (by 5-15%). – Allergic reactions: thiazides are derivatives of sulfonamides; they cause occasional skin rash, dermatitis, and less often, thrombocytopenia. █ Potassium-sparing diuretics (Spironolactone – triameterine – amiloride)  Spironolactone is a steroid congener of aldosterone.  Triamterene and amiloride are synthetic drugs but not steroids. Pharmacokinetics 92