Diuretics Lecture Notes PDF

Diuretics Diuretics are drugs that increase the volume of urine excreted. There are three basic renal processes performed by the nephron: 1. Filtration 2. Reabsorption 3. Secretion Sodium reabsorption in kidney Na...

Diuretics Diuretics are drugs that increase the volume of urine excreted. There are three basic renal processes performed by the nephron: 1. Filtration 2. Reabsorption 3. Secretion Sodium reabsorption in kidney Na+ reabsorption (65% Na+) Thiazide diuretics (5% Na+) K+ Sparing diuretics (1-2 % Na+) (25% Na+) Loop diuretics Diuretics are drugs that increase the volume of urine by increasing salt excretion (mainly Na+). Most diuretic agents are inhibitors of renal ion transporters →↓↓ of Na+ reabsorption at different sites in the nephron. As a result, Na+ and other ions, such as Cl−, enter the urine in greater than normal amounts along with water. Diuretics, thus, increase the volume of urine, change its pH, and the ionic composition of the urine and blood. Diuretics are most commonly used for management of: 1- Abnormal fluid retention (edema) 2- Treatment of hypertension.  Diuretics may act either extrarenal or renal A- Extrarenal diuretics 1. Water and alcohol (↓↓↓ ADH) 2. Digitalis ONLY in heart failure (+ve inotropic→↑ CO →↑ renal blood flow) 3. Dobutamine (↑ CO →↑ renal blood flow) 4. Methylxanthines (inc CO, renal VD, Inc renal blood flow). 5. Albumin only in hypoalbuminemia (restore osmotic pressure, inc blood volume)  B- Renal diuretics i- Natriuretics or Saluretics→ facilitate urinary excretion of salts esp. sodium) High efficacy (loop diuretics) → e.g. Furosemide Moderate efficacy (Thiazides) → e.g. Hydrochlorothiazide Low efficacy : -Carbonic anhydrase inhibitors → e.g. Acetazolamide -Potassium sparing diuretics → e.g. Spironolactone and Triamterene). ii- Osmotic diuretics: e.g. Mannitol, Glucose, Urea.  i- Natriuretics or Saluretics Thiazide diuretics Loop diuretics Moderate efficacy High efficacy Act mainly on proximal part of distal Act mainly on thick ascending loop of Henle convoluted tubule and inhibit Na+/Cl- and inhibit Na+/K+/2Cl- symport. transport →↓↓ NaCl reabsorption. ↑↑ PGs production→ V.D Preparations 1-Sulfa-containing 1. Short-acting e.g. Furosemide e.g. chlorthiazide, hydrochlorothiazide. e.g. Bumetanide (more potent) 2-Long-acting (once daily) e.g. Torsemide e.g: Chlorthalidone 3- long-acting thiazide like- diuretic : 2-Non-sulfa containing e.g. Indapamide (Natrilex): Depends on e.g. Ethacrynic acid (highly ototoxic, used only biliary excretion so safe in renal failure. when the patient is allergic to sulfa compounds)  Bumetanide Torsemide Furosemide Why loop diuretics are more potent than thiazide diuretics ?  Thiazide diuretics Loop diuretics Content of urine: Content of urine: 1. Excess H2O (Diuresis) 1. Excess H2O (Diuresis) 2. Excess Na+ (hyponatremia) 2. Excess Na+ (hyponatremia) 3. Excess Cl- (hypochloremia) 3. Excess Cl- (hypochloremia) 4. Excess K+ (hypokalemia) 4. Excess K+ (hypokalemia) 5. Excess Mg++ (hypomagnesemia) 5. Excess Mg++ (hypomagnesemia) 6. Excess H+ (alkalosis) 6. Excess H+ (alkalosis) 7- ↑↑ Ca++ reabsorption (hypercalcemia) 7- Excess Ca++ in urine (hypocalcemia) (↓ Ca++ in urine) Side effects Side effects 1. Hyponatremia, Hypochloremia 2. Hypokalemia , Hypomagnesemia,Alkalosis 3- Hyperuricemia (↓↓ tubular secretion of The same + 6,7 uric acid) 4- Hyperglycemia (decrease insulin release) 6- Deafness (ototoxicity) (reversible) 5-Hyperlipidemia (increases blood cholesterol 7-Dehydration and triglycerides)  Thiazide diuretics Loop diuretics Uses 1. Edema (cardiac, hepatic, renal) (Mild). 1. Edema (cardiac, hepatic, renal) (severe). 2. Mild and moderate congestive heart failure. 2. Severe congestive heart failure. 3. Hypertension (mild and moderate) 3. Hypertension (severe/emeregency) (20- 80mg/day) 4- Hypocalcemia, osteoporosis. 4. Hypercalcemia 5- In Nephrogenic diabetes insipidus ONLY 5. Acute renal failure –induced oliguria (inability of kidney to respond to ADH). (at high dose 500 mg) →↑ GFR Empirical therapy example Synergistic effect results if thiazide are combined with loop diuretics Drug interactions: 1-warfarin via displacement from plasma protein binding sites. 2-Lithium via decreased renal excretion. 3-Digitalis due to hypokalemia.(inc digitalis toxicity) 4-increases ototoxicity and nephrotoxicity of aminoglycosides.(loop) 5-NSAIDs (inhibit its diuretic effect)→ PGs may play a role VD (NSAID may decrease VD effect of loop diuretic) Contraindications: 1-Digitalis toxicity (due to hypokalemia) 2-Gout 3-with steroids 4-Diabetes mellitus 5-Liver diseases 6-Pregnancy 7-Renal diseases (thiazides) N.B. Hpokalemia worsens digitalis toxicity, liver diseases, and kidney diseases. It is avoided by : 1-Taking K+-rich food e.g. bananas, potatoes, avocados. 2- supplementation with KCl, and adding K+-sparing diuretics.  Potassium sparing diuretics They may be called potassium retaining or potassium conserving diuretics. Mechanism of action: They inhibit Na+/K+ exchange in the late distal convoluted tubule. They are weak diuretics and have low efficacy. They produce hyperkalemia so they are: Never taken with KCl supplement. Not combined with ACE inhibitors or losartan (AT1 blocker)→↑K+ level) Never used in renal insufficiency since they may cause fatal.  Classification A-Aldosterone antagonists: e.g. spironolactone and eplerenone. B-Non-aldosterone antagonists: e.g. Triamterene and Amiloride.  A-Aldosterone antagonists (spironolactone and eplerenone) Pharmacodynamics: They compete with aldosterone for its specific mineralocorticoid receptors (aldosterone causes Na and water retention) in late Distal convoluted tubules and collecting tubules. They cause inhibition of Na+/K+ and Na+/H+ exchanges, leading to: Enhanced excretion of Na+ in urine with water (weak diuretic effect). Retention of K+ in blood (hyperkalemia). Retention of H+ excretion in blood (metabolic acidosis). H+ H+ Spironolactone increases Ca++ excretion in urine by a direct effect….. hypocalcemia Uses 1- Hyperaldosteronism either primary type (Conn’s syndrome) which is due to tumour of adrenal cortex, or secondary due to stimulation of renin- angiotensin system as in CHF (congestive heart failure), liver cirrhosis, nephrotic syndrome. 2- Edema: Liver cirrhosis and CHF with ascites. 3- Essential hypertension. In combination with thiazide and loop diuretics to : 1- synergize their diuretic effect 2-correct their induced hypokalemia. e.g. aldoctazide (spironolactone + hydrochlorothiazide). e.g. Lasilactone (spironolactone plus furosemide). 4- If thiazides and loop diuretics are contraindicated, e.g. in hypokalemia, hyperuricemia, hyperglycemia, and hypersensitivity. 5-antiandrogen (hairsutism) Side effects: Weak diuretics so usually not used alone but combined with other diuretics. Have delayed onset (2-3 days). 1-Cause GIT disturbances. 2-Hypersensitivity and skin rash. 3-Hyperkalemia especially in patients with renal disease. 4-Metabolic acidosis. 5-Hormonal effects include antiandrogenic effects (block androgenic receptors) resulting in gynecomastia and impotence in males, and menstrual disturbances in females. Eplerenone has less side effects and used mainly in treatment of hypertension and CHF. Drug interactions Antagonize the action of Digitalis Excessive hyperkalemia if taken with ACEI, beta blockers, and NSAIDs.  Non-aldosterone antagonists Triamterene and Amiloride They have rapid onset than spironolactone. Pharmacodynamics: Their action does not depend on the presence of aldosterone. They directly block the Na+ channels in distal convoluted tubules leading to direct inhibition of Na+/K+ exchange in the late distal convoluted tubules. In addition, they inhibit excretion of of H+ and Ca++ in urine. Uses: Usually used with thiazides or loop diuretics to synergize their action and correct hypokalemia. Side effects: 1-Hyperkalemia 2- Metabolic acidosis 3- GIT disturbances 4- Hypersensitivity. Note that Diuretics that cause hypocalcemia …….loop diuretics and spironolactone. Diuretics that induce hypercalcemia …….`thiazide diuretics and non-aldosterone antagonists.  Carbonic anhydrase inhibitors Acetazolamide Acetazolamide is a reversible non-competitive inhibitor of carbonic anhydrase enzyme. Carbonic anhydrase catalyzes the reaction of CO2 and H2O, leading to H2CO3 Thus decrease reabsorption of NaHCO3→ diuresis. Uses: 1- weak diuretic 2- Acetazolamide →↓↓ synthesis of aqueous humour →↓↓ intraocular pressure (can be used in glaucoma). 3- Acetazolamide has antiepileptic effect in petit-mal epilepsy (absence seizures). 4- Mountain sickness: Acetazolamide can be used in the prophylaxis of acute mountain sickness as Acetazolamide increases brain ventilation. 5- As urine alkalinizer to dissolve uric acid crystals  Osmotic diuretics Mechanism of action: They are simple, inert, small molecular weight hydrophilic chemical substances that are freely filtered through the glomerulus with little or no reabsorption. The presence of these substances results in a higher osmolarity of the tubular fluid and prevents further water reabsorption from proximal convoluted tubules and descending loop of Henle. Because osmotic diuretics are used to increase water excretion rather than Na+ excretion: they are not useful for treating conditions in which Na+ retention occurs. Examples 1-Mannitol: used as IV infusion because it is not absorbed when given orally (osmotic diarrhea if taken oral) and should be given intravenously to decrease IOP, and treat acute renal failure. 2-Glucose and urea (IV)