Renal Module L1 Diuretics and Antidiuretics PDF

Al-Azhar University Faculty of Medicine for Girls Renal Module ▪ Module Code :IMP-07-20318 ▪ Phase : 1 ▪ Year : 2nd year ▪ Semester : 3 ▪ Credit hours : 5 hours Pharmacology Department Diuretics and Antidi...

Al-Azhar University Faculty of Medicine for Girls Renal Module ▪ Module Code :IMP-07-20318 ▪ Phase : 1 ▪ Year : 2nd year ▪ Semester : 3 ▪ Credit hours : 5 hours Pharmacology Department Diuretics and Antidiuretics Prof. Dr. Faten Ahmed Youssef Diuretics Lecture 1 : Thiazide Diuretics On completion of this lecture, the student will be able to : - Classify diuretic drugs. - Explain the site of action and mechanism of action of thiazide diuretics. - Summarize the therapeutic uses of thiazide diuretics. - Explain the systemic effects and adverse effects of thiazide diuretics. - Describe the conditions and/or drug interactions that interfere with or contraindicate thiazide diuretics use. -1-  DIURETICS Sites of reabsorption of sodium (Na+) in the nephrone Diuretics are agents that increase the volume of urine. They can be classified into extra-renal (pre-renal) and renal. A) Extra-renal (pre-renal): 1. Water and ethyl alcohol by ↓ release of ADH →↓ facultative water reabsorption. 2. Digitalis only in cases of heart failure : produce positive inotropic →↑ COP →↑ RBF 3. Albumin only in hypoalbuminemia by restoring blood volume →↑ RBF →↑ GFR. 4. Dobutamine (↑ COP) and Dopamine (↑ COP and Renal VD) →↑ RBF. 5. Methylxanthines e.g. theophylline (↑ COP & Renal V.D) →↑ RBF. -2- B) Renal : I. Natriuretics (Saluretics) : They ↓ Na+ reabsorption from nephrone →↑ Na+ excretion in urine with its iso-osmotic (obligatory) water →↑ volume of urine. A. High Efficacy (high ceiling or loop) diuretics: They act mainly on the medullary part of the thick ascending loop of Henle →↓ counter - current multiplier system (CCMS). e.g : Frusemide, ethacrynic acid and bumetanide. B. Moderate efficacy diuretics : They act mainly on the cortical diluting segment. Thiazides and thiazide analogues. C. Low efficacy diuretics: 1. Carbonic anhydrase inhibitors e.g. acetazolamide : They act mainly on proximal convoluted tubules (PCT) and also on distal convoluted tubules (DCT). 2. Potassium retaining (sparing or conserving) diuretics: They act on DCTand collecting tubules. a. Aldosterone antagonists e.g. spironlactone b. Non-aldosterone antagonists e.g. triamterene & amiloride. II. Osmotic diuretics: “PCT, descending loop of Henle and collecting tubules”. e.g : mannitol. -3- III. Acidifying diuretics: e.g : ammonium chloride. N.B.: 1. Diuretics in common use : Thiazides and their analogues, loop diuretics,K+ retaining diuretics and mannitol. 2. Self-limiting diuretics: - Acetazolamide and ammonium chloride due to acidosis. Sites of action of diuretics. -4-  Thiazide Diuretics This group of drugs has a moderately powerful diuretic action. The most widely used member of this group is hydrochlorothiazide. Pharmacodynamics: 1. Kidney (diuretic effect) 1. Thiazide diuretics must be secreted in PCT to act from the luminal side of tubular epithelial cells. This secretion is decreased by probenecid →↓ their diuretic effect. 2. They act mainly on the early part of DCT (cortical diluting segment) → inhibition of NaCl reabsorption (about 10%). 3. Some thiazides → weak inhibition of carbonic anhydrase enzyme (acetazolamide like action) by their free sulphonamide radical. This property is most marked with chlorothiazide in large doses and least marked with hydrochlorothiazide. This effect, however, is not primarily related to their diuretic action. 4. Excess NaCl will reach the late DCT and collecting tubules where part of Na+ is reabsorbed in exchange for K+ mainly and some H+ (K+ secretion ↑ as a consequence of ↑ load of Na+ ions at the distal sites). The remaining Na+ will be excreted in urine with its iso-osmotic water. -5- 5. Decreased renal excretion of calcium and increased excretion ofmagnesium. 6. Thiazides ↓ GFR so not indicated in renal insufficiency. Most Thiazides are not effective as diuretics when GFR < 30 ml/min. The urine will contain : a. Excess H2O → diuresis “moderate efficacy” b. Excess Na+ → Natriuretic effect → hyponatremia - c. Excess Cl → chloruresis → hypochloremia. d. Excess K+ → kaluretic effect → hypokalemia e. Some H+ → acid urine → mild metabolic alkalosis. f. Excess Mg++ → hypomagnesemia g. ↓ Ca++ in urine → hypercalcemia 2. Antidiuretic effect : Thiazides exert an antidiuretic effect in patients with diabetes insipidus of the “nephrogenic type” (insensitivity to ADH). The mechanism of action in such cases is poorly understood, but is has been suggested that it could be due to a decrease in GFR. 3. Antihypertensive effect : The antihypertensive effect may be initially related to a reduced blood volume as a result of the diuretic effect. But after prolonged use, it is mainly due to direct arteriolar VD. This latter effect is due to : -6-  a. K+ channel opener → hyperpolarization → inhibition of Ca++ influx intothe wall of blood vessels. b. They deplet Na+ and H2O from arterial wall →↓ edema and ↓ pressoreffect of noradrenaline and angiotensin. c. Prostaglandins (PGs) may play a role. NSAID may ↓ VD effect ofthiazide diuretics. N.B. : Thiazides are effective antihypertensives even in subdiuretic does. 4. Hyperglycemia: Thiazides may cause hyperglycemia possibly by : 1. Inhibiting pancreatic release of insulin (Open K+ channel ofpancreatic islet cells → hyperpolarization →↓ insulin release). 2. Decreasing peripheral glucose utilization. This action is unimportant in patients with normal carbohydrate tolerance, but the hyperglycemia of overt diabetes mellitus may be intensified. Moreover, glycosuria may occur in some patient with latent diabetes mellitus when given a thiazide diuretic. 5. Hyperuricemia Thiazides increase the uric acid level in the plasma by reducing uric acid secretion via competition in PCT. Acute attacks of gout may, therefore, be precipitated in susceptible patients. -7- 6. Hyperlipidemia: ↑ blood cholesterol. Thiazide cause a 5-15% ↑ in serum cholesterol and ↑ LDL. Therapeutic uses : 1. Hypertesion: a. Thiazides can be used as an initial drug therapy in mild to moderate essential hypertension unless there are compelling reasons to choose another agent. b. The diuretic (initially) and vasodilator effect (mainly) of thiazides are useful in reducing blood pressure. c. Thiazides antagonize edema induced by other direct vasodilators e.g hydralazine. 2. Heart failure: Loop diuretics (not thiazides) are the diuretics of choice in reducing extracellular volume in heart failure. However, thiazide diuretics may be added if additional diuresis is needed. When given in combination, thiazides should be administered 30 minutes prior to loop diuretics in order to allow the thiazides time to reach the site of action and produce effect. The role of thiazides in heart failure is due to : a. Diuresis →↓ blood volume →↓ VR →↓ EDV →↓ pre-load. b. Arterial VD →↓ TPR →↓ after toad. -8- 3. Idiopathic hypercalciuria and renal calcium calculi, because thiazidesinhibit Ca2+ excretion. - Useful in hypocalcemia and osteoporosis. 4. Nephrogenic diabetes insipidus. 5. Premenstrual syndrome and premenstrual migraine. Adverse effects : 1. Hypokalemia → a. Digitalis toxicity may be precipitated in patients under digitalis therapy. b. Worsen liver and kidney insufficiency. Hypokalemia can be avoided by : a. KCl supplement. However, KCl has an irritant effect, so should be avoided in gastritis and peptic ulcer. Oral solution is less irritant than tablets. b. Increasing the consumption of citrus fruits, banana and prunes. c. Thiazides are often prescribed with K+ retaining diuretics e.g spironolactone. d. Intermittent use of least effective dose of the diuretic. 2. Hyponatremia and hypovolemia3- Mild hypochloremic alkalosis. 4- Hypercalcemia, rarly. -9- 5. Hypomagnesemia with chronic uses. 6. Hyperglycemia → worsen diabetes mellitus. 7. Hyperlipidemia : Thiazides cause increase in total serum cholesterol and LDL. 8. Hyperuricemia → worsen gout. 9. Allergic reactions : Cross-sensitivity with other sulfonamides. Rare reactions include; photosensitivity, dermatitis, hemolytic anemia, thrombocytopenia, and pancreatitis. 10. G.I.T disturbances e.g nausea, vomiting. 11. Weakness, fatigability, paraesthesia and impotence.12- Fetotoxic. Contraindications: 1. Advanced renal disease. Most thiazide diuretics are ineffective whenGFR is < 30 ml/min. They also ↓ GFR. 2. Digitals toxicity : (hypokalemia, hypomagnesemia and hypercalcemia). 3. Advanced liver disease : Thiazides may precipitate hepatic coma whichmay result from hypokalemia and alkalosis induced by thiazides. 4. Gout: Thiazides may precipitate attacks of acute gout. 5. Diabetes mellitus: Thiazides may aggravate preexisting diabetesmellitus. 6. With adrenocorticosteroids may aggravate hypokalemia. 7. Pregnancy → fetotoxic. -10- Preparations of thiazide diuretics: All are taken orally and are secreted in PCT. 1. Chlorothiazide 500-1000 mg/day - Water soluble 2. Hydrochlorothiazide 25-100 mg/day - Onset 1 hour 3. Hydroflumethiazide 25-100 mg/day - Rapid excretion 4. Bendroflumethiazide 2.5-15 mg/day - Short duration 6-12 hours 5. Trichlormethiazide 1-4 mg/day - Lipid soluble 6. Polythiazide 1-4 mg/day - Onset 1 hour 7. Cyclothiazide 1-2 mg/day (slow excretion) Long duration 24 hours Thiazide Analogues These diuretics are chemically different from thiazides, but like the latter they contain a sulphonamide group. Their pharmacological properties are similar to those of hydrochlorothiazide. The duration of action is longer than that of thiazides. 1. Chlorthalidone : 50 mg/day. Long duration. 2. Indapamide : 2.5-5 mg single oral dose/day: a. Used in subdiuretic dose in treatment of hypertension. b. Slow calcium channel blocker → direct VD. -11-  c. Minimal effect on glucose, uric acid and electrolytes. d. Its fate depends upon biliary excretion. Safe in renal patients. e. Long duration. 3. Metolazone (2.5-10 mg). It is effective even when GFR < 20 ml/min. The combination with frusemide potentiate the diuretic effect of frusemide and can be effective in renal edema. 4. Clopamide. 5. Xipamide. 6. Quinethazone. -12-