Diuretics PDF

DIURETICS Professor (Dr.) Badruddeen Faculty of Pharmacy, Integral University, Lucknow.  DIURETICS Diuretics are the drugs which increase the rate of urine formation by acting directly on the kidney causing a net loss of solut...

DIURETICS Professor (Dr.) Badruddeen Faculty of Pharmacy, Integral University, Lucknow.  DIURETICS Diuretics are the drugs which increase the rate of urine formation by acting directly on the kidney causing a net loss of solute (mainly NaCl) along with equivalent volume of water, by interfering with transport mechanism responsible for the reabsorption of solutes from various parts of the nephron. NORMAL REGULATION OF FLUIDS & ELECTROLYTES BY THE KIDNEYS  Renal transport mechanisms  Proximal tubule  NaHCO3 , NaCl, glucose, amino acids and other organic solutes are reabsorbed (specific transport systems)  Water is reabsorbed passively luminal fluid osmolality remain constant  Organic acid secretory system in middle third of proximal tubule. uric acid, NSAIDs  Loop of Henle  Thin descending limb of Henle’s loop  Water is extracted ------ hypertonic medullary interstitium  Thin ascending limb is water impermeable but is permeable to solutes  Na+ /K+ , 2Cl- co transport  Driving force for re absorption of Mg+ and Ca2+  Distal Convoluted tubule  Na+ and Cl- co transport  Calcium reabsorption under parathyroid hormone control  Collecting tubule system  2-5% of NaCl reabsorption  Mineralocorticoids exert significant influence  Important site of K+ sedretion  Principal cells major site of Na+, K+ and water transport  Intercalated cells are sites of H+ and HCO3 secretion  Site of action of ADH  CLASSIFICATION OF DIURETICS ACCORDING TO ACCORDING TO MECHANISM OF ACTION SITE OF ACTION  CLASSIFICATION (ACCORDING TO MECHANISM OF ACTION) A. DRUGS INTERFERING WITH IONIC TRANSPORT: I. Carbonic Anhydrase inhibitors Acetazolamide Dichlorphenamide Methazolamide II. INHIBITORS OF ACTIVE TRANSPORT OF CHLORIDE: a. THIAZIDES: Hydrochlorothiazide Hydroflum Chlorothia Bendrofluazide Methylchlothiazide Thiazide –related compounds Chlorthali Indapamid Metolazone b. LOOP DIURETICS: i. Carboxylic acid derivative: Furosemide ( Lasix ) Bumetanide Torsemide ii. Phenoxyacetic acid derivative: Ethacrynic a III. POTASSIUM SPARING DIURETICS: a. Aldosterone antagonist: (Aldosterone receptor blockers) Spironolactone Potassium canreonate b. Non-aldosterone antagonist: Amiloride Triamterene B. OSMOTIC DIURETICS: Mannitol Urea Glycerine Isosorbide C. DRUGS INCREASING GFR / SECONDARY DIURETIC: Xanthines Aminophyllin Theophylline Caffeine  CLASSIFICATION OF DIURETICS ACCORDING TO SITE OF ACTION A. Drugs Acting on Proximal Tubule: Osmotic Diuretics Carbonic Anhydrase Inhibitors Acidifying Salt Xanthine Diuretics B. Drugs Acting on Ascending Limb of Loop of Henle: Loop Diureti C. Drugs Acting on Distal Tubule: Thiazide Diuretics D. Drugs Acting on Collecting Tubule: 1. K+ - Sparing Diuretics: Aldosterone Antagonists Non – Aldosterone Antagonists 2. ADH Antagonists.  CARBONIC ANHYDRASE INHIBITORS  CARBONIC ANHYDRASE INHIBITORS Systemic Local Acetazolamide Dorzolamide Dichlorphenamide Brinzolamide Methazolamide  CHEMISTRY Un-substituted sulfonamide derivatives. SO2NH2 (sulfonamide group) is essential for activity. PHARMACOKINETICS  Oral absorption is good  Half life is 6-9 hrs  Route of elimination is mainly renal MECHANISM OF ACTION:  MECHANISM OF SODIUM BICARBONATE REABSORPTION IN THE PROXIMAL TUBULE CELL  Proximal tubular epithelial cells are rich in carbonic anhydrase  Membrane bound and cytoplasmic both are inhibited  Counter transport of Na+ and H+ is inhibited  Net excretion of Na+ occur  Carbonic anhydrase is present in other sites  Eye  Gastric mucosa  Pancreas  CNS (choroid plexus cause HCO3 secretion)  CLINICAL USES: 1. Rarely used as diuretic (limited efficacy) 2. Glaucoma (reduce aqueous humor formation) most common dorzolamide, brinzolamide 3. Prevention and treatment of Mountain sickness (decrease CSF production) 4. Urinary alkalinization (uric acid and cystine) 4. Metabolic alkalosis 5. Severe hyperphosphatemia. 6. Epilepsy (metabolic acidosis and direct actions) 7. Familial periodic paralysis (metabolic acidosis)  TOXICITY: 1. Drowsiness and parasthesias. 2. Metabolic acidosis. 3. Encephalopathy in cirrhosis. 4. Reduction of urinary excretion rate of weak organic bases. 5. Renal stones (calcium phosphate salts in alkaline urine 5. Renal K + wasting. 6. Side effects attributed to sulfonamide moiety: Allergic reactions Bone marrow dep Renal Lesions  CONTRAINDICATIONS  Hepatic cirrhosis  Hyperchloremic acidosis  Severe COPD  OSMOTIC DIURETICS  Glycerin  Isosorbide  Mannitol  Urea  PHARMACOKINETICS  Mannitol poorly absorbed by GI tract produce osmotic diarrhea  Must be given I/V  Route of excretion is mainly renal MECHANISM OF ACTION:  Major effect on proximal tubule and descending limb of Henle’s loop.  Oppose the action of ADH in the collecting tubule  Urine volume increases  Urine flow rate increases which decrease contact time between fluid and tubular epithelium  Increase renal blood flow  Extract water from intracellular compartments and expand extracellular volume  CLINICAL INDICATIONS: To increase urine volume. (acute sodium retention). Large pigment load to the Kidney. Reduction of Intra-cranial pressure. Reduction of Intra-ocular pressure.  TOXICITY Extra-Cellular Volume Expansion. Headache Nausea Vomiting Dehydration Hypernatremia Hyperkalemia  Contraindications  Severe renal impairment  Dehydration  Hyperkalemia  LOOP DIURETICS high-ceiling diuretics  CLASSIFICATION I. Carboxylic Acid Derivatives Furosemide Bumetanide Torsemide Piretanide II. Phenoxyacetic Acid Derivatives Ethacrynic acid Indacrinone I. Carboxylic Acid Derivatives They possess carboxyl + sulfamyl group. Some C.A. inhibiting activity May inhibit HCO3 excretion to small extent. II. Phenoxyacetic acid Derivative. Do not possess sulfonamide group. Contains a ketone & Methyene group. No carbonic anhydrase inhibitory activity.  CHEMISTRY FUROSEMIDE BUMETANIDE ETHACRYNIC ACID  PHARMACOKINETICS  Rapidly absorbed  Eliminated in kidney through Glomerular filtration and tubular secretion  MECHANISM OF ACTION: As Diuretic:- 1. Main Mechanism: Inhibition of Na+/K+ / 2Cl- transporter by acting at the thick ascending limb of loop of Henle. NaCl, K+ REABSORBTION & SECONDARY REABSORBTION OF Ca2+ , Mg2+ IN THICK ASCENDING LOOP OF HENLE. 2. Contributory Mechanisms: a. Interference with counter current multiplier exchange system. b. Change in the renal haemodynamic state. c. Increase synthesis of prostaglandins  Increase calcium and magnesium excretion  Reduce pulmonary congestion and left ventricular filling pressure  THERAPEUTIC USES: 1. Acute pulmonary edema with LVF 2. Acute renal failure (increase rate of urine flow) 3. Refractory edema of nephritic syndrome. 4. Refractory cases of Hypertension. 5. Hyperkalemia. 6. Hypercalcemic States 7. Acute Drug Poisoning – Forced Diuresis 8. Anion over dosage (Bromide, fluoride, Iodide)  ADVERSE EFFECTS: I. Due to Disturbance in fluid and electrolytes balance:- Hypokalemia Hypochloremia Hyponatremia Hypocalcemia Hypophosphatemia  Hypomagnesemia  Halide level Depletion of fluid volume Hypotension II. Metabolic Adverse Effects Hyperuricemia- worsens gout Hyperlipidemia- LDL & cholesterol III. Miscellaneous Adverse Effects Ototoxicity Hepatotoxicity IV. Allergic Reactions: Related to sulfonamide moiety. Skin rashes Dermatitis Photosensitivity Eosinophilia Interstitial Nephritis  DRUG INTERACTIONS  Aminoglycosides, carboplatin and other agents (aggravation of ototoxicity)  Anticoagulants---- increase activity  Digitalis ---- increase arrhythmias  Lithium ---- increase plasma levels  NSAIDs blunt diuretic response  CONTRAINDICATIONS  Severe Na+ and volume depletion  Hypersensitivity to sulfonamides  Anuria THIAZIDE DIURETICS  CHEMISTRY Sulfonamides derivatives Structural analog of 1,2,4 – benzothiadiazine- 1,1- dioxide  CLASSIFICATION OF THIAZIDES DURATION OT ACTION BASED I. Short Acting Chlorothiazide 6-12 hrs Hydrochlorothiazide 6-12 hrs Hydroflumethiazide 6-12 hrs Bendrofluzide 6-12 hrs Cyclopenthiazide 6-12 hrs Metolazone 6-12 hrs II. Intermediate Acting Cyclothiazide 12-24 hrs Quinethazone 18-24 hrs Methylclothiazide 24 hrs Trichlormethiazide 24 hrs III. Long Acting Indapamide 24-36 hrs Polythiazide 24-40 hrs Chlorthalidone 24-74 hrs  Thiazide Related Compounds Phthalimidine Derivatives. Chlorthalidone Quinazoline Derivatives Quinethazone Chlorobenzamide Clopamide Benzene Disulphonamide Mefruside Xipamide  PHARMACOKINETICS  All can be administered orally  Chlorothiazide is the only diuretic for parenteral administration  Chorthalidone has longer duration of action  All thiazides are secreted by organic acid secretory system in PCT ----- compete with secretion of uric acid  MECHANISM OF ACTION: As Diuretic As Anti- Hypertensive MECHANISM OFACTION AS DIURETIC : NaCl REABSORPTION IN DISTAL CONVOLUTED TUBULE & MECHANISM OF DIURETIC ACTION OF Na+ - Cl- SYMPORT INHIBITORS  Mechanism of action  Inhibit Na+ Cl- symport in distal convoluted tubule  Enhance Ca++ reabsorption  Used for treatment of kidney stones caused by hypercalciuria  MECHANISM OF ACTION AS ANTI – HYPERTENSIVE: I) Initially transient fall of B.P. because of diuretic effect: Increased excretion of NaCl and water  Decreased extra cellular fluid volume  Decreased venous return  Decreased Cardiac Output  Decreased B.P. II) NATRIURETIC ACTION AS A MECHANISM FOR ANTI-HYPERTENSIVE EFFECT  Decreased concentration of sodium in the vascular beds loss of response of vascular smooth muscles to circulating catecholamines vasodilatation fall in BP  THERAPEUTIC USES: 1. Mobilisation of edema of Cardiac origin Chronic CCF Hepatic origin Hepatic Cirrhosis Renal Origin Chronic Renal Failure Nephrotic Syndrome Acute Glomerulonephritis 2. Anti-hypertensive 3. Nephrogenic Diabetes insipidus 4. Idiopathetic Hypercalciuric states 5. Osteoporosis 6. Pre-eclampsia of pregnancy 7. Halide poisoning (Br Intoxication)  ADVERSE EFFECTS: I. Due to Abnormalities of fluid and electrolyte balance: Extra-cellular volume depletion Hypotension Hypochloremia Hyponatremia Hypokalemia Hypomagnesemia Hypophosphatemia Hypercalcemia Decreased plasma level of halides Metabolic Alkalosis II. METABOLIC EFFECTS: Hyperglycemia (Impaired carbohydrate tolerance) Hyperuricemia Hyperlipidemia (increase serum cholesterol and LDL) III. Misc Adverse Effect:  CNS (vertigo, headache, paresthesias and weakness) GIT (cramping ,diarrhea, cholecystitis and pancreatitis) Allergic Reactions Hematological Reactions Sexual dysfunction  DRUG INTERACTIONS a. Thiazides diminish effect of anticoagulants, uricosuric agents, sulfonylureas and insulin b. Increase the effects of anesthetics, diazoxide, Cardiac Glycosides, lithium d. Effectiveness of thiazide diuretics is reduced by NSAIDs, bile acid sequestrants e. Amphotericin B and corticosteroids increase risk of hypokalemia f. Hypokalemia increase the risk of quinidine induced arrhythmias  CONTRAINDICATIONS Impaired hepatic functions Impaired renal functions Diabetes mellitus Adrenal diseases Gout  POTASSIUM SPARING DIURETICS (Low efficacy diuretics) CHEMISTRY  PHARMACOKINETICS  Spironalactone is a synthetic steroid.  Inactivation occur in liver  Slow onset of action (several days)  Eplerenone is spironalactone analog with greater effect on mineralocorticoid receptor only MECHANISM OF ACTION: Na+ REABSORBTION COUPLED TO K+ & H+ SECRETION IN COLLECTING TUBULE  Mechanism of action  Antagonize the effects of aldosterone in collecting tubules.  Inhibition of Na influx through ion channels in the luminal membrane (amiloride and triamterene)  H+ ion secretion from intercalated cells is decreased leading to acidosis  The action depend on renal prostaglandin production  CLINICAL INDICATIONS: Primary aldosteronism Secondary aldosteronism Potassium wasting due to excess Sodium delivery to distal nephron sites (Thiazide and Loop diuretics) Used in combination with these drugs Long term treatment for refractory edema as in Cirrhosis  TOXICITY Hyperkalemia Hyperchloremic Metabolic Acidosis Endocrine abnormalities(gynecomastia) Acute Renal Failure (triamterene) Kidney Stones (triamterene precipitate in urine causing stones)  CONTRAINDICATIONS Chronic Renal failure (hyperkalemia) ACE inhibitors. Liver disease Peptic ulcer  DRUG INTERACTIONS Enzyme inhibitors increase blood levels of eplerenone)  Antidiuretic hormone antagonists  ADH level increased in CHF and SIADH (Syndrome of inappropriate antidiuretic hormone ADH release) secretion. eg. of drugs  Demeclocycline and lithium.  Conivaptan, tolvaptan  Mechanism of action  Inhibits the effect of ADH on collecting tubule  Clinical indications  Syndrome of inappropriate ADH secretion  Other causes of elevated antidiuretic hormone (heart failure)  Adverse effects  Nephrogenic Diabetes Insipidus  Renal failure  Other (dry mouth, thirst)  Diuretic combinations  Loop agents and thiazides (block Na + absorption in all segments)  Potassium sparing diuretics and loop diuretics or thiazides (K+ level is maintained)  Renal Autacoids  Locally produced compounds exhibit physiologic effects within kidney  Adenosine  Prostaglandins  Urodilatin: is a hormone that causes natriuresis by increasing renal blood flow  Adenosine A1 – receptor antagonist  Prevent tubuloglomerular feed back  Decrease K+ secretion  Pseudotolerance  Antihypertensive drugs lead to pseudotolerance by salt and water retention  Diuretics do not produce this.