diuretics.pptx

Diuretics

1. DIURETICS Mrs. Pawar R.V. Assistance Professor SPM’s COP. Akluj .

2. Renal Physiology: Pharmacological Aspect Site I: Movement of Na + is by: Direct Entry of Na + Coupled to active reabsorption of organic anions via specific symporters Exchange with H + ions Diffusion through paracellular pathways (along with Cl - ions) Site II: Medullary Portion: Na + K + 2Cl - and Na + K + ATPase; Na + -Cl - symporter

3. Renal Physiology: Pharmacological Aspect Site III: Na + -Cl - symporter Impermeable to water Dilution of luminal/tubular fluid Site IV: Na + actively reabsorbed (Amiloride sensitive Na + channels) C a tio n- anion balan c e mai n t ained by: Passive Cl - diffusion Secretion of K + ( aldosterone dependent) and H +

4. Diuretics Drugs that cause net loss of Na+ and water in urine. These are the drugs which increase urine flow. All diuretics increase the excretion of water from bodies.

5. Classification High Efficacy Diuretics (Na + K + 2Cl - cotransport inhibitors) Sulphamoyl Derivatives: Furosemide , Bumetanide, Torasemide Medium Efficacy Diuretics (Na + Cl - symport) Thiazides (Benzothiadiazines): Hydrochlorthiazide , Benzthiazide, Hydroflumethiazide, Bendroflumethiazide Thiazide Like (related heterocyclics): Chlorthalidone, Metolazone, Xipamide, Indapamide, Clopamide Weak/ Adjunctive Diuretics Carbonic Anhydrase Inhibitors: Acetazolamide Potassium Sparing Diuretics(Aldosterone antagonist): Spironolactone , Eplerenone Potassium Sparing Diuretics(renal epithelial Na + channel): Triamterene, Amiloride Osmotic Diuretics: Mannitol , Isosorbide, Glycerol

6. High Ceiling Diuretics: Pharmacokinetic Furosemide is rapidly absorbed orally but bioavailability is about 60%. Lipid-solubility is low, and it is highly bound to plasma proteins. It is partly conjugated with glucuronic acid and mainly excreted unchanged by glomerular filtration as well as tubular secretion. Some excretion in bile and directly in intestine also occurs. Plasma t½ averages 1–2 hour but is prolonged in patients with pulmonary edema, renal and hepatic insufficiency. Dose : 20–80 mg once daily in the morning. In renal insufficiency, upto 200 mg 6 hourly has been given by i.m ./ i.v . route.

7. High Ceiling Diuretics: Uses Edema Preferred in CHF Nephrotic syndrome, chronic renal failure, resistant edema Impending acute renal failure Acute pulmonary edema (acute Left Ventricular Failure, following Myocardial Infarction) Hypertension Co-existing renal insufficiency, CHF, resistant cases, hypertensive emergencies Along with Blood Transfusion Hypercalcemia of malignancy Cerebral edema Combined with osmotic diuretics to improve efficacy

8. Medium Efficacy Diuretics: Thiazide and Thiazide like diuretics Mechanism Of Action: Inhibits Na + -Cl - symport in early Distal Tubule  decreased Na+ and Cl- absorption  increased urine passed Additional carbonic anhydrase inhibitory action: generally weak Pharmacokinetic: Well absorbed orally, no injectable preparations . Onset of Action within 1hr, duration 6-48 hrs . More lipid soluble so large volume of distribution and lower renal excretion, longer acting. Metabolism :Liver Excretion :Urine

9. Thiazide and Thiazide like diuretics : Uses Hypertension One of the First line drugs (Chlorthalidone) Edema Diabetes Insipidus (DI) Nephrogenic DI Hypercalciuria with recurrent calcium stones in the kidney

10. Adverse Drug Reaction of Loop Diuretics, Thiazide and Thiazide like Drugs Loop Diuretics Thiazide Hypokalemia Brisk Diuresis Low Dietary K + intake Less common than thiazides More common than Loop Diuretics Acute Saline Depletion Dehydration Fall in BP (erect) Hemoconcentration – venous thrombosis Seen with overuse of Loop Diuretics Not So Common Dilutional Hyponatremia After vigorous use of Loop diuretics in CHF Rare with thiazides GIT and CNS Disturbances Nausea/Vomiting, diarrhoea, headache, giddiness, weakness, paresthesias, impotence Hearing Loss Only with Loop diuretics Allergic manifestation Rahses photosensitivity, blood dyscrasias rare, especially in pts hypersensitive to sulfonamides

11. Loop Diuretics Thiazide Hyperuricemia Avoid probenecid Long term use of high dose thiazides Hyperglycaemia and hyperlipidemia Minimal with low dose thiazides used these days Hypocalcemia Seen on chronic administration Raises serum Ca 2+ levels, may cause hypercalcemia Magnesium depletion Seen after prolonged use Renal insufficiency Can be used in renal insufficiency Aggravated due to decreased GFR Contraindication : Brisk diuresis in cirrhotics may lead to mental disturbances and hepatic coma: may be due to hypokalemia, increased blood NH 3 levels . Avoided in toxaemia of pregnancy Adverse Drug Reaction of Loop Diuretics, Thiazide and Thiazide like Drugs

12. Loop Diuretics and Thiazides: Interactions Potentiates all other Hypertensive's As it induces Hypokalemia : Enhances digitalis toxicity Increased risk of Cardiac arrhythmia Reduces sulfonylurea action (oral hypoglycaemics ) Additive ototoxicity and nephrotoxicity of aminoglycosides Higher incidence of thrombocytopenia when combined with co- trimoxazole Actions reduced when used with indomethacin and other NSAIDs Probenecid and diuretics reduces each other’s actions Serum Lithium level rises.

13. Carbonic Anhydrase (CAse) inhibitors: Acetazolamide Reversibly inhibits CAse (type II) in PT cells  decreased H 2 CO 3 formation  decreased H + concentration  Na + -H + antiport cannot function: Mild alkaline diuresis Secretion of H + in DT and CD also interfered Causes marked kaliuresis

14. Acetazolamide Extrarenal Action: Lowering of intraocular tension due to decreased formation of aqueous humour (aqueous is rich in HCO3 ¯). Decreased gastric HCl and pancreatic NaHCO3 secretion: This action requires very high doses. Raised level of CO2 in brain and lowering of pH, sedation and elevation of seizure threshold. Alteration of CO2 transport in lungs and tissues. Pharmacokinetics : Well absorbed orally and excreted unchanged in urine. Action of a single dose lasts 8–12 hours.

15. Acetazolamide Uses Glaucoma: as an adjuvant Acute Mountain Sickness Other uses: Periodic Paralysis Alkalinise urine Epilepsy: adjuvant Adverse Effects Acidosis Hypokalemia Drowsiness Paresthesias Fatigue Abdominal Discomfort Hypersensitivity reactions Bone marrow depression (rare) Contraindicated in liver disease: potential to induce hepatic coma

16. Potassium Sparing Diuretics Aldosterone Antagonist: Spironolactone , Eplerenone : Mechanism of Action: Blocks aldosterone activity by blocking mineralocorticoid receptor, Aldosterone Induced Protein / Na+ channels not expressed decreased absorption of Na+ and water . Acts from the interstitial side • No aldosterone = no effect Inhibitors of renal epithelial Na+ channels: Triamterene , Amiloride Mechanism of Action: Blocks Amiloride sensitive Na+ channels at DT and CD. entry of Na+ ions blocked, transepithelial potential not generated, excretion of K+ decreased. Due to decreased transepithelial potential, H+ ion secretion (via H+ ATPase pump) is decreased.

17. Mechanism Of Action: Site and mechanism of action of potassium sparing diuretics : On the late distal tubule/collecting duct cell Aldosterone (Aldo) penetrates the cell from the interstitial side and combines with the mineralocorticoid receptor (MR). The complex translocates to the nucleus—promotes gene mediated mRNA synthesis. The mRNA then directs synthesis of aldosterone induced proteins (AIPs). The AIPs include Na+K + ATPase and renal epithelial ( amiloride sensitive) Na+ channels. More of these proteins are synthesized. The AIPs also activate these Na+ channels and, translocate them from cytosolic site to luminal membrane. They also translocate Na+K+ATPase to the basolateral membrane. AIPs also increase ATP production by mitochondria. All these changes promote Na+ reabsorption . More K+ and H+ is secreted indirectly. Spironolactone binds to MR, prevents Aldo action and produces opposite effects. Amiloride approaches the Na+ channel from the luminal side and blocks it—reducing the lumen negative transepithelial potential difference which governs K+ and H+ secretion.

18. Pharmacokinetics : The oral bioavailability of spironolactone from microfine powder tablet is 75%. It is highly bound to plasma proteins and completely metabolized in liver; converted to active metabolites, the most important of which is Canrenone that is responsible for 1/2–2/3 of its action in vivo. The t½ of spironolactone is 1–2 hours, while that canrenone is ~18 hours. Dose: 25–50 mg BD–QID; max 400 mg/day. Uses: Weak diuretic, always used in combination with thiazide and loop diuretics to counteract K+ loss . Hypertension: adjuvant to thiazide Edema (cirrhotic/ nephrotic , refractory) Congestive Heart Failure

19. Drug Interactions : 1. Given together with K+ supplements— dangerous hyperkalaemia can occur. 2. Aspirin blocks spironolactone action by inhibiting tubular secretion of its active metabolite canrenone . 3. More pronounced hyperkalaemia can occur in patients receiving ACE inhibitors/ARBs. 4. Spironolactone increases plasma digoxin concentration. Adverse effects : Drowsiness, mental confusion, ataxia, epigastric discomfort, loose motions. Interacts with progestin and androgen receptors: Gynaecomastia , erectile dysfunction, loss of libido. Breast tenderness, menstrual irregularities. Hyperkalaemia in renal impaired patients Acidosis in cirrhotics . Contraindication : Peptic ulcer

20. Renal epithelial Na+ Channel inhibitors Triamterene , Amiloride : Decreases K+ excretion, accompanied with small increase in Na+ loss. Potassium sparing diuretics, Alkaline urine produced Reduces Ca2+ and Mg2+ excretion.

21. Amiloride : Mechanism of Action: Blocks luminal amiloride sensitive renal epithelial Na+ channels. Decrease reabsorption of Na+ in DT and CD. Luminal negative charge not developed. Less secretion of K+ from principal cells. Less secretion of H+ from intercalated cells Uses : Hypertension As adjuvant • Prevents hypokalaemia • Increase natriuretic response . • Cystic fibrosis

22. Adverse effects : Amiloride : Nausea, diarrhoea , headache. Decreases entry of lithium in CD cells. Lithium induced diabetes insipidus . Triamterene : Impaired glucose tolerance, photosensitivity. Rise in blood urea

23. Osmotic Diuretics: Mannitol Pharmacologically inert Mechanism of Action: Retains water isoosmotically in PT Inhibits transport process in thick Asc LH Expands extracellular fluid volume Increased renal blood flow Increases urinary output, excretion of all cations and anions also enhanced Given as intravenous drip

24. Pharmacokinetics : Mannitol and urea: intravenous. Glycerin and isosorbide : Can be administered orally Metabolism: – glycerin 80% metabolized – mannitol 20% – Urea, isosorbide : not metabolized. Excretion: renal Side Effects Headache, nausea/vomiting, hypersensitive reactions

25. Osmotic Diuretics: Mannitol Uses Increased intracranial and intraocular tension To maintain glomerular filtration rate and urine flow in impending acute renal failure: prognostic benefits not proven Counteract low osmolality of plasma/e.c.f . Contraindications Acute tubular necrosis Anuria Pulmonary Edema, acute left ventricular failure, CHF, cerebral haemorrhage

26. References: Tripathi KD, Essentials of Medical Pharmacology,Seventh Edition:2013, Jaypee Brothers medical Publishers (P) Ltd, Nwe Delhi. Pharmacology and pharmacotherapeutics by R.S Satoskar,21st edition,2012,popular prakashan . Rang H.P, Dale M.M, Ritter.J , Flower.R ,” Rang & Dales Pharmacology, Sixth Edition 2010. Published By : Churchill Livingstone.

27. Spironolacton