Pharmacology of diuretics with flow charts .pptx
- 2. Learning Objectives After this session, you should be able to • recall the physiology of nephron & renal tubular transport mechanisms • define diuresis & diuretics; and • classify diuretic drugs on basis of site and mechanism of action • Discuss the pharmacology of diuretics
- 3. • A 65-year-old man comes to the emergency department with severe shortness of breath. His wife reports that he has long known that he is hypertensive but never had symptoms, so he refused to take antihypertensive medications. During the last month, he has noted increasing ankle edema, reduced exercise tolerance, and difficulty sleeping lying down, but he reports no episodes of chest pain or discomfort. He now has pitting edema to the knees and is acutely uncomfortable lying down.
- 4. • Vital signs include blood pressure of 190/140 mm Hg, pulse 120/ min, and respirations 20/min. Chest auscultation reveals loud rhonchi, but an electrocardiogram is negative except for evidence of left ventricular hypertrophy. • He is given a diuretic intravenously and admitted to intensive care. What diuretic would be most appropriate for this man’s case of acute pulmonary edema associated with heart failure? What are the possible toxicities of this therapy?
- 5. Anatomy & Physiology of THE Renal System ► The nephron is the most important part of the kidney that regulates fluid and electrolytes. ► Urine formation 1. Glomerular filtration rate = 180L/day 2. Tubular re-absorption (around 98%) 3. Tubular secretion
- 7. The filtrate here is isotonic The filtrate here is hypertonic
- 8. 8 Sodium Reabsorption in the early PCT Na+ H+ Na+ Glucose, Phosphate, Amino acids, Na+ K+ Lumen (urine) Peritubular (Blood)
- 9. 9 Cl- Sodium reabsorption in the late PCT Na+ H+ Na+ H-Anion Lumen (urine) Peritubular (Blood) Cl- HCO3- + + + + + + + + + Na+ K+ H+ Anion
- 12. 12 Sodium Reabsorption in the DCT ATP Na+ Cl- Na+ K+ Lumen (urine) Peritubular (Blood) H2O Ca++ Ca++ Na+ ATP Ca++ H+ PTH
- 14. How can urine output be increased? ↑ Glomerular filtration Vs ↓ Tubular reabsorption (the most important clinically) Increase the glomerular filtration increase tubular reabsorption (so you cant use glomerular filtration)
- 15. Diuresis: increased urine flow Diuretics: substances which elicit diuresis • In the kidney, water reabsorption is dependent primarily on Na+ reabsorption • Thus a diuretic is an agent which inhibits tubular Na+ reabsorption (along with Cl- , HCO3 - ) resulting in increased excretion of these ions.
- 16. Natriuretic effect: enhance secretion of sodium and thus water Mainly act by decreasing tubular reabsorption at one or more sites in nephron Diuretics can have effects on: - Sodium reabsorption - Potassium loss - Body fluids
- 17. Purpose of Using Diuretics 1. To maintain urine volume (renal failure) 2. To mobilize edema fluid (heart failure, liver failure, nephrotic syndrome) 3. To control high blood pressure
- 20. Classification of Diuretics A. Diuretics that inhibit transport in the Proximal Convoluted Tubule (Osmotic diuretics, Carbonic Anhydrase Inhibitors) B. Diuretics that inhibit transport in the Medullary Ascending Limb of the Loop of Henle (Loop diuretics) C. Diuretics that inhibit transport in the Distal Convoluted Tubule (Thiazides) D. Diuretics that inhibit transport in the Cortical Collecting Tubule (Potassium sparing diuretics)
- 22. CLASSIFICATION Chemistry & Site CARBONIC ANHYDRASE INHIBITORS (PCT) Acetazolamide Dorzolamide Brinzolamide Dichlorphenamide Methazolamide
- 23. THIAZIDES & THIAZIDE LIKE COMPOUNDS (PT- Inhibitors of Na+ Cl- symport) Bendroflumethiazide Chlorothiazide Polythiazide THIAZIDE -RELATED COMPOUNDS Phthalimidine derivatives: chlorthalidone Quinazoline derivatives: quinethazone Chlorobenzamide derivatives: clopamide Benzene disulfonamide: mefruside Miscellaneous: indapamide, metolazone
- 24. HIGH-CEILING DIURETICS (LOOP DIURETICS- Inhibitors of Na+ K+ 2Cl- symport) Carboxylic acid derivatives: furosemide, bumetanide, torsemide (sulfonamide moiety) Phenoxyacetic acid derivatives: ethacrynic acid
- 25. POTASSIUM SPARING DIURETICS (CT) Aldosterone antagonist: spironolactone, potassium canrenoate, eplerenone, canrenone Inhibitors of renal epithelial Na+ channels: triamterene, amiloride
- 26. OSMOTIC DIURETICS (PCT) Mannitol Glycerin Isosorbide Urea ADH Antagonist (PCT, DL) Conivaptan
- 27. CARBONIC ANHYDRASE INHIBITORS DRUGS • Acetazolamide • Dorzolamide • Brinzolamide PHARMACOKINETICS • Well absorbed orally secreted in PCT • Urine alkaline within 30 mins, peaks at 2 hrs • Effect lasts for 12 hrs after single dose
- 28. MECHANISM OF ACTION Normal physiology
- 29. MECHANISM OF ACTION What the CAI’s do? It prevents the reabsorption of HCO3 and Na Fluid remains isotonic
- 30. CLINICAL USES • Glaucoma • Urinary alkalinization • Metabolic alkalosis • Acute mountain sickness (HACE, HAPE) • Epilepsy • Hyperphosphatemia • Hypokalemic periodic paralysis • Benign intracranial hyper tension
- 31. ADVERSE EFFECTS • Hyperchloremic metabolic acidosis • Renal stones • Hypokalaemia • Nervous system toxicity in pts with renal failure • Hypersensitivity • Hyperammonemia and hepatic encephalopathy in pts with cirrhosis CONTRAINDICATIONS • Hepatic cirrhosis
- 32. Osmotic Diuretics (Mannitol) Diuretics that inhibit transport in the Convoluted Proximal Tubule DRUGS Mannitol Glycerine Isosorbide Urea CHARACTERISTICS OF AN IDEAL OSMOTIC
- 33. MECHANISM OF ACTION SITE NORMAL PHYSIOLOGY WHAT OSMOTIC DIURETICS DO? hydrophilic compounds that are easily filtered through the glomerulus and little re- absorption increase urinary output via osmosis
- 34. CLINICAL USES Raised intracranial pressure Increased intraocular pressure Renal failure
- 35. ADVERSE EFFECTS - Extracellular water expansion may produce pulmonary edema. -Dehydration, hyperkalemia & hypernatremia - Hyponatremia in pts with diminished renal function CONTRAINDICATION Heart failure
- 36. LOOP DIURETICS Thick Ascending Limb High ceiling DRUGS • Furosemide • Bumetanide • Torsemide • Ethacrynic acid CHEMISTRY • Carboxylic acid derivatives • Phenoxyacetic acid derivative: ethacrynic acid
- 37. MECHANISM OF ACTION :
- 38. WHAT THE LOOP DIURETICS DO? 1. Inhibit the coupled Na/K/2Cl cotransporter in the loop of Henle. 2. They induce the synthesis of prostaglandins in kidney (NSAIDs interfere with this action).
- 39. IONIC CHANGES Decrease Mg++ Ca++ not changed as it is absorbed distally HEMODYNAMIC CHANGES Increase renal blood flow OTHER EFFECTS They have potent pulmonary vasodilating effects (via prostaglandins) – decrease LV filling – beneficial in LV failure & CCF
- 40. CLINICAL USES Acute pulmonary edema Refractory edema (in heart failure, liver cirrhosis, nephrotic syndrome) HTN Acute renal failure Hyperkalemia Hypercalcemia Anion overdose (thalide over dosage)
- 41. ADVERSE EFFECTS Hypokalaemic metabolic alkalosis Hypomagnesaemia Hypovolemia - dehydration Ototoxicity Hyperuricemia Hypersensitivity reactions (sulfonamides)
- 42. CONTRAINDICATIONS • Cross reactivity with sulfonamides • Overzealous use is dangerous in hepatic cirrhosis, & CCF DRUG INTERACTIONS • NSAIDs • Digitalis • Aminoglycosides
- 43. THIAZIDES AND THIAZIDE-LIKE DIURETICS DISTAL CONVOLUTED TUBULE DRUGS Chlorothiazide Hydrochlorothiazide Chlorthalidone Indapamide Metolazone PHARMACOKINETICS Secreted in S2 Long DOA- OD dosing
- 46. WHAT THE THIAZIDE DIURETICS DO? Inhibit NaCl reabsorption via inhibition of Na+ /Cl- cotransporter in DCT
- 47. IONIC CHANGES Natriuretic action Hyponatremia Hypochloremia Hypercalcemia HEMODYNAMIC CHANGES Prostaglandins – vasodilation
- 48. CLINICAL USES Hypertension Refractory Edema together with the Loop diuretics CCF Nephrolithiasis (Renal stone) due to idiopathic hypercalciuria Hypocalcemia Nephrogenic Diabetes Insipidus Bromide intoxication
- 49. ADVERSE EFFECTS Hypokalemic metabolic alkalosis Hyponatremia, hypochloremia Hypomagnesaemia Hyperuricemia Hypercalcemia Hyperglycemia Hyperlipidemia Allergic reactions Weakness, parasthesias, fatigue, impotence
- 50. CONTRAINDICATIONS Cirrhosis CCF Renal disease DRUG INTERACTIONS Synergism with thiazides & K+ sparing diuretics NSAIDs Digoxin
- 51. POTASSIUM SPARING DIURETICS COLLECTING TUBULE CLASSIFICATION A. Direct antagonist of mineralocorticoid receptors (Aldosterone Antagonists e.g. spironolactone) B. Indirect via inhibition of Na+ influx in the luminal membrane (e.g. Amiloride, Triamterene)
- 52. CHEMISTRY • Spironolactone- synthetic steroid • Triamterene & amiloride are weak bases PHARMACOKINETICS • Spironolactone is metabolized in the liver to canrenone • t ½ = 16hrs • Dose adjustment in renal & hepatic disease
- 54. WHAT THE K+ SPARING DIURETICS DO? Aldosterone cause ↑K and H+ secretion and ↑Na reabsorption. Spironolactone bind to mineralcorticoid receptors and blunts aldosterone activity Amiloride and triamterene directly interfere with Na entry through epithelial Na channels (ENaC) in the apical membrane of the collecting tubule
- 55. IONIC CHANGES Excretion of Na+ , Cl- Decrease secretion of K+ and H+ HEMODYNAMIC CHANGES No changes
- 56. CLINICAL USES In states of primary aldosteronism (e.g. Conn’s syndrome, ectopic ACTH production) of secondary aldosteronism (e.g. heart failure, hepatic cirrhosis, nephrotic syndrome) To overcome the hypokalemic action of diuretics Hypertension Refractory edema Hirsutism
- 57. ADVERSE EFFECTS Hyperkalemia Hyperchloremic metabolic acidosis Antiandrognic effects (e.g. gynecomastia: breast enlargement in males, impotence) by spironolactone. Triametrene causes kidney stones. ARF
- 58. ANTIDIURETIC HORMONE (ADH) AGONISTS • Vasopressin and desmopressin - central diabetes insipidus • Renal action mediated primarily via V2 receptors although V1a receptors may also be involved
- 60. ANTIDIURETIC HORMONE (ADH) ANTAGONISTS • Vaptans • Parenteral Conivaptan exhibits activity against both V1a and V2 receptors • The oral agents lixivaptan and tolvaptan are selectively active against the V2 receptor • Two nonselective agents, lithium & demeclocycline have anti-ADH effects, but exhibit many side effects
- 61. Clinical Indications • Syndrome of Inappropriate ADH Secretion (SIADH) • Other Causes of Elevated Antidiuretic Hormone – CCF (Decreased blood volume) Toxicity • Nephrogenic Diabetes Insipidus • Renal failure (Lithium & Demeclocycline)