DIURETICS I Dr Laith M Abbas AlHuseini M

DIURETICS (I) Dr Laith M Abbas Al-Huseini M. B. Ch. B. , M. Sc. , M. Res. , Ph. D.

Diuretics v Drugs increase the volume of urine excreted. v Inhibitors of renal ion transporters that decrease the reabsorption of Na+ at different sites in the nephron. v As a result, Na+ and other ions, such as Cl−, enter the urine in greater than normal amounts along with water, which is carried passively to maintain osmotic equilibrium. v They increase the volume of urine and often change its p. H, as well as the ionic composition of the urine and blood. v In addition to the ion transport inhibitors, other types of diuretics include osmotic diuretics, aldosterone antagonists, and carbonic anhydrase inhibitors. v Most commonly used for management of abnormal fluid retention (edema) or treatment of hypertension.

LOOP OF HENLE (DESCENDING LOOP OF HENLE) v. The filtrate entering here is isotonic due to water reabsorption in this area. v. Tubular fluid becomes concentrated (Hypertonic) (Three fold increase in salt concentration). LOOP OF HENLE (ASCENDING LOOP OF HENLE) 1. ASCENDING LOOP OF HENLE (Medullary part lined by cuboidal cells). v Unique. Impermeable to water.

v Active reabsorption of Na+, K+ & Cl- is mediated by a Na+/K+/2 Cl- Co-transporter. v Mg++ and Ca++ enter the interstitial fluid. v 25% to 30% of tubular Na. Cl returns to the interstitial fluid (blood). So, Loop of Henle is called diluting region. A major site for salt reabsorption. 2. ASCENDING LOOP OF HENLE: Thick Ascending Loop (TAL) (Cortical part lined by flattened cells). v Impermeable to water. v Salt reabsorption continues but through Na+-Clsymporters. v Tubular fluid gets further diluted.

DISTAL CONVULATED TUBULE v Impermeable to water. v 10% of filtered Na. Cl is reabsorbed via Na+/Cl- transporter that is sensitive to Thiazide diuretics. v Calcium reabsorption mediated by Na+/Ca++ exchanger into the interstitial fluid. v Ca++ excretion is regulated by parathyroid hormone in this portion of the tubule.

COLLECTING TUBULE & DUCT v. Na+, K+, water reabsorption. v. Na+ enters through channels to tubular cells but absorption in blood relies on Na+/K+-ATPase. v. Aldosterone receptors in tubular cells influence Na+ reabsorption & K+ secretion. v. Absorption of Na+ at this site occurs through a specific amiloride sensitive Na+ channel & controlled by aldosterone. v. ADH promotes reabsorption of water from the collecting tubule mediated by c. AMP.

v GFR is dependant on pumping action of heart, magnitude of renal blood flow and relative dimensions of afferent & efferent glomerular vessels. v RAS with distal tubular reabsorption: → Angiotensin II produced in kidney has direct effect on intrarenal vascular beds as well as salt & water reabsorption. → Sympathetic stimulation→ ↑es renin release→ Tubular transport. →Directly enhance reabsorption of salt & water. v PGs→ modulates renal circulation & renin release. v PGE 2→inhibits ADH & has direct effect on tubular reabsorption.

Classification of Diuretics A. Very Potent Diuretics (Loop Diuretics): Furosemide, Ethacrynic acid, Torsemide, Bumetamide, Peretanide, Indacrinone. B. Moderately Potent Diuretics: Thiazide Diuretics : Bendrofluazide, Clopamide, Hydrochlorthiazide, Chlorthalidone, Chloroxolone, Indapamide, Polythiazide, Cyclopenthiazide. C. Potassium Sparing Diuretics: Triamterene, Spironolactone, Amiloride.

Classification of Diuretics D. Weak Diuretics: i. Osmotic Diuretics: Electrolytes: Sodium Chloride, Potassium citrate, Potassium carbonate, Potassium acetate, Potassium chloride. Nonelectrolytes: Mannitol, Isosorbide, Sucrose, Urea, Glycerol. ii. Acidifying salts: Ammonium chloride, Arginine hydrochloride. iii. Xanthine derivatives: Aminophylline, Theophylline iv. Carbonic anhydrase inhibitors: Acetazolamide, Dichlorphenamide, Ethozolamide, Methazolamide

Loop Diuretics (High ceiling diuretics) v Inhibitors of Na+ K+ 2 Cl- Co-transporter. v Inhibit Na+ & Cl- re-absorption. v Produce venodilator action, directly or indirectly by releasing renal factor. v Increased H+ & K+ loss. Thus may produce metabolic alkalosis. v Increase in Ca++ & Mg++ concentration & decreased excretion of uric acid. v They also potentiate the action of Thiazides. v The excretion of Na+ continues even if ECF is less & hence may result into dehydration & hypotension.

Therapeutic Uses: Diuretic actions of Loop Diuretics: 1. Oedema due to cardiac failure, hepatic disease, nephrotic syndrome. 2. Acute pulmonary edema & cerebral edema. 3. Acute chronic renal failure. 4. Barbiturate poisoning & salicylate poisoning. Nondiuretic action of Loop Diuretics: 1. As an antihypertensive. 2. Idiopathic calcium urolithiasis. 3. In Hypocalcaemia. 4. Diabetes insipidus. 5. Hyponatremic states due to water retention. 6. Glaucoma

Adverse effects: 1. Hypokalemia, so used with potassium sparing diuretics. 2. Hyponatremia, dehydration & metabolic acidosis. 3. Hyperglycemia & hyperuricemia. 4. Weakness, fatigue, dizziness, cramps & myalgia. 5. Prostatic hypertrophy, ototoxicity, cardiac arrest after IV injection. 6. Hepatic insufficiency & gastric upset. 7. Orthostatic hypotension.

1) Furosemide v Potent, oral, diuretic, possessing halogenated salfamoyl benzene ring common to Thiazide diuretics. v Thick ascending loop of Henle. Blocks Na+-K+-2 Clsymport. v IV administration increases the renal blood flow. It increases PGE 2 synthesis in the kidneys, which has a locally protective, vasodilator effect. v In physiological or pharmacological stress, it counters the intrarenal vasoconstriction. v Furosemide attaches to the Cl- binding site of protein (Na+ K+ 2 Cl-) to inhibit its transport function.

Pharmacological actions: v. Kidneys: - Excretion of Na+, K+, Cl-, PO 4 -. v Excessive chloride loss →hypochloremic alkalosis. v K+ loss→ Hypokalemia. ( Less marked with Furosemide than Thiazides). v Little change in Urine p. H. Potent renin releasers. v. Blood vessels & BP: - IV furosemide dilates peripheral vasculature, Lowers the arterial BP, rapid venous pooling of blood, reducing cardiac preload & afterload. v. Metabolic actions: - ↑sed blood uric acid & disturbances of glucose tolerance, ↑sed blood urea. Ca++ & Mg++ excretion also ↑ses.

Pharmacokinetics: v Absorbed orally, Bioavailability 60 -100%. v Lipid solubility is low, Food reduces bioavailability. v Onset of action is quick & short. v. Excreted within 4 hours. v 50% excreted unchanged, rest conjugated with glucuronide in kidney.

2) Torsemide v. Three times more potent than furosemide. v. Oral absorption more rapid and complete. v 80% metabolized in liver. v t 1/2= 3. 5 hrs. v Duration of action= 4 -8 hrs. v. Used in hypertension & edema.

3) Bumetanide v 40 times more potent than furosemide. v Onset & duration and its effect on electrolyte excretion are similar to furosemide. v 80% absorption. v It is metabolized in liver & its half life is not prolonged in renal insufficiency. v. Axosemide, Tripamide, Piretanide are other diuretics belonging to the furosemide group.

Ethacrynic acid v An unsaturated ketone derivatives of Phenoxyacetic acid, is a potent oral diuretic like furosemide. v Chemically unrelated to diuretic drugs but same effects as of furosemide. v Max. diuresis within 2 -3 hrs after giving orally. v It can be used in edematous states, especially in patients allergic to sulphonamides. v Less used because prone to cause adverse effects which are similar to those of furosemide.

Interactions 1. Potentiate all other antihypertensives. This interaction is intentionally employed in therapeutics. 2. Hypokalaemia induced by these diuretics: v. Enhances digitalis toxicity. v. Produces polymorphic ventricular tachycardia with quinidine and other antiarrhythmics. v. Potentiates competitive neuromuscular blockers and reduces sulfonylurea action. 3. Loop diuretics + aminoglycoside antibiotics – both ototoxic and nephrotoxic → additive toxicity. 4. Cotrimoxazole + loop diuretics- thrombocytopenia.

5. Indomethacin/ NSAIDs + Loop diuretics- diminishes diuretic and antihypertensive effect of loop diuretics. 6. Probenecid + furosemide and thiazides-competitively inhibits tubular secretion of furosemide and thiazides, decreases their action by reducing the concentration in the tubular fluid, while diuretics diminish uricosuric action of probenecid. 7. Serum lithium level rises when diuretic therapy is instituted. This is due to enhanced reabsorption of Li+ (and Na+) in PT. 8. Furosemide and warfarin/ Clofibrates: Displacement of plasma protein binding of warfarin

Resistance to Loop Diuretics 1. Renal insufficiency. v Decreased access of diuretics to its site of action due to low GFR and low proximal tubular secretion. 2. Nephrotic syndrome. v Binding of diuretic to urinary protein, other pharmacodynamic causes. 3. Cirrhosis of liver. v Abnormal pharmacodynamic hyperaldosteronism 4. CHF. v lmpaired oral absorption due to intestinal congestion, decreased renal blood flow and glomerular filtration, lncreased salt reabsorption in PT.