DIURETICS & LEVOSOMENDAN............pptx

DIURETICS & LEVOSOMENDAN.

1. DIURETICS & LEVOSOMENDAN Moderator - Dr. Pratima Yadav Presenter - Dr. Deepak Sharma

2. Diuretics Drugs which cause a net loss of Na+ and water in urine. Most diuretics produce their clinical effect by blocking Na reabsorption in different locations of the nephron. The normal driving force for K excretion by distal renal tubules is the transtubular electrical potential difference created by Na reabsorption.

3. Classification

4. Loop Diuretics Most potent diuretics. Dose dependent response. Site of action - medullary portions of thick ascending limb of Loop of Henle. Reabsorption of 20-30% of filtered Na. Impermeable to water. First line therapy in patients with fluid retention due to cardiac causes

5. Furosemide Prototype drug of loop diuretics. Mechanism of action 2 forms of Na-K-2Cl - absorptive and secretary Furosemide attaches to Cl binding site of absorptive isoform to inhibit its transport function. Also has weak CAse inhibitory action Increase Ca and Mg excretion Tends to raise blood uric acid and blood sugar levels

6. Pharmacokinetics Pharmacokinetics Effective when administered orally or iv. Absorption of orally administered furosemide varies between 10 - 100%, with an average of 50%. Protein binding is extensive - 90% bound to albumin. Excretion – a) Glomerular filtration and renal tubular secretion (50 - 60%) b) glucuronide conjugation in kidneys (40 - 50%) Elimination half life - 1 to 2 hrs ( thus short duration of action). Fast onset of action - diuresis within 5 to 10 min, peak effect at 30 min and duration of action of 2 to 6 hrs.

7. Dose 40 mg iv will produce maximal natriuresis in patients with normal renal function. Dosing needs to be increased in chronic renal insufficiency (loading dose followed by continuous infusion). Maximum dose - 200 mg.

8. Bumetanide Oral bioavailability of 80 - 100%. Routes of administration - oral, iv, im . 40x more potent than furosemide. Metabolised in liver. May act in some cases not responding to furosemide, and maybe tolerated by patients allergic to furosemide.

9. Torsemide 3x more potent as furosemide. T1/2 of 3 to 4 hrs , thus allowing for once-a-day dosing regimen. Metabolism by liver. Ethacrynic acid Only non sulfonamide in the group. 70% the relative potency of furosemide. Side effects - a) Ototoxicity b) Nausea

10. Clinical uses of high ceiling diuretics EDEMA - irrespective of etiology - cardiac, hepatic or renal. The high ceiling diuretics are preferred in CHF for rapid mobilization of edema fluid Acute pulmonary edema . To decrease ICP in combination with mannitol. Along with blood transfusion in severe anemia to prevent volume overload Hypercalcaemia of malignancy. Hypertension – high ceiling are indicated in HTN only in renal insufficiency CHF or in renal insuffficiency . Acute exacerbation of heart failure.

11. Side effects of high ceiling diuretics Braking phenomenon and Ceiling effect ; Acute or chronic treatment with diuretics may result in tolerance to the diuretic effect. Acute tolerance - RAAS activation Chronic tolerance - compensatory hypertrophy of those portions of renal tubule responsible for Na retention leading to decreased diuretic effectiveness (Ceiling effect). 2. Hypokalemia 3. Hyperuricemia 4. Hyperglycemia 5. Nephrotoxicity 6. Potentiate NDMR blockade. 7. Lithium toxicity.

12. Thiazide diuretics Mechanism of action Inhibition of Na - Cl cotransporter in the cortical diluting segment or the earty DCT Thiazide tends to reduce GFR so not effective it pts with low GFR Decrease renal Ca excretion and increase Mg excretion Cause reduction in urate excretion than furosemide Elavation of blood sugar level

13. Pharmacokinetics Readily absorbed when administered orally. Extensively protein bound. Eliminated unchanged in the kidney ( except indapamide is metabolized by liver). Long half life of 8 to 12 hrs , thus OD dosing. Ineffective in severe renal insufficiency except metolazone

14. Clinical uses First line therapy for essential hypertension - initially due to decrease in ECF volume and sustained effect is due to peripheral vasodilation. EDEMA : best in cardiac edema but less effectiveness in hepatic or renal edema Diabetes insipidus - decrease positive free water clearance and are the only effective drugs in nephrogenic DI Hypercalciurea with recurrent CA stone in kidney

15. Side effects Hypokalemia - skeletal muscle weakness, GI ileus, digitalis toxicity. Hypomagnesemia Cardiac dysrythmias Hypercalcemia can potentiate NDMR blockade Lithium toxicity

16. Interactions Thiazides and loop diuretics potentiate all other antihypertensives. Hypokalemia Enhances digitalis toxicity Increases risk of polymorphic VT due to drugs prolonging QT interval Reduces sulfonylurea action. Aminoglycoside antibiotics and high ceiling causes ototoxicity and nephrotoxicity NSAIDS diminish action of high ceiling by inhibiting PG synthesis Probenecid competitively inhibits tubular secretion of furosemide and thiazides Lithium toxicity due to enhance reabsorption of Li and Na in PT

17. Carbonic Anhydarse Inhibitors Carbonic anhydrase is an enzyme which catalyzes the reversible reaction H 2 O +CO 2 H 2 CO 3 HCO 3 - + H + Thus, this enzyme functions in CO2 AND HCO3- transport and in H+ secretion. The enzyme is present in specially in PT and ciliary body of eye brain and RBC

18. Acetazolamide Sulfonamide Derivative. Mechanism of action Noncompetitively and reversibly inhibits CAse type II in PT cells resulting in slowing of hydration of CO2 leading to decreased availability of H+ to exchange with luminal Na+ through the Na+ - H+ antiporter. 2. Inhibition of brush border CAse type IV retards dehydration of H2CO3 in the tubular fluid so that less CO2 diffuses back into the cells. The net effect is inhibition of HCO3- (and accompanying Na+) reabsorption in PT and alkaline diuresis occurs. Na and K loss occurs

19. Pharmacokinetics Well absorbed orally Excreted unchanged in urine Action of a single dose lasts 8 to 12 hrs. Dose - 250 mg OD - BD. Extra renal actions of acetazolamide Lowering of IOT. Decreased gastric HCL and pancreatic NAHCO3 secretion Raised level of CO2 in brain and lowering of pH - sedation and elevation of seizure threshold Alteration of CO2 transport in lungs and tissues

20. Uses of Acetazolamide Glaucoma To alkalinise urine - for UTI or to promote excretion of certain acidic drugs Epilepsy Acute mountain sickness Periodic paralysis Adverse effects Acidosis, hypokalemia , drowsiness, paresthesias , fatigue, abdominal discomfort. Hypersensitivity reactions Bone marrow depression - rare but serious Contraindicated in liver disease: may precipitated hepatic coma by interfering with urinary elimination of NH3.

21. Osmotic diuretics Inert substances that do not undergo metabolism and are filtered freely at the glomerulus. Example - mannitol, urea, isosorbide, glycerin, hypertonic saline. Increased plasma and renal tubular fluid osmolality, with resulting osmotic diuresis. Site of action - portions of renal tubules that are highly permeable to water, namely the proximal renal tubules and more importantly, the Loop of Henle

22. Mannitol 6 C sugar Does not undergo metabolism. Mechanism of action By increasing tubular fluid osmolality, it decreases water reabsorption and promotes water diuresis. Inhibits transport processes in the thick AscLH by an unknown mechanism. Quantitatively this appears to be the largest contributor to the diuresis. Also increases plasma osmolarity, thus drawing fluid from intracellular to extracellular spaces resulting in volume expansion which is poorly tolerated in patients with borderline cardiac function. Scavenger of oxygen free radicals, which may prevent cellular injury

23. Pharmacokinetics Not absorbed from git, thus given iv exclusively. Excretion is by glomerular filtration. Begins to exert effect in 10 to 15 min, with a peak effect at 30 to 45 min and a duration of 6 hrs. Uses of mannitol Increased ICT or IOP - acute congestive glaucoma, head injury, stroke, etc. To maintain g.f.r . and urine flow in impending acute renal failure. To prevent perioperative kidney failure in the setting of acute tubular necrosis.

24. Side effects Pulmonary edema in left ventricular dysfunction. Thus, furosemide is the preferred drug in these cases. In patients with renal insufficiency, it is not filtered and causes increased intravascular volume. Prolonged use - hypovolemia, hypotension, electrolyte disturbances, hypokalemic hypochloremic alkalosis, plasma hyperosmolarity MANNITOL is contraindicated in ATN, anuria , pulmo edema , acute LVF ,CHF, and cerebral haemorrhage

25. Hypertonic saline Osmolar agent used at various concentrations to limit edema formation primarily in the treatment of clinically symptomatic hyponatremia. Positive volume expanding effects with less total infused volume helps in fluid resuscitation in critically ill patients. Ideal for use in SIADH where fluid restriction is required. Quicker onset of action, a more robust and durable ICP reduction, and may be advantageous in patients in whom mannitol has failed to decrease ICP. Serum sodium and chloride should be monitored during treatment with HTS. used as an expectorant for cystic fibrosis.

26. Complications of Hypertonic saline therapy Hypernatremia, hyperchloremia, CHF, pulmonary edema , hypokalemia , NAGMA Coagulopathy, phlebitis Renal failure Rebound ICH Seizures Central pontine myelinolysis Subdural and intraparenchymal hemorrhage

27. Potassium sparing diuretics : Aldosterone antagonist and renal epithelial Na channel Despite having a weak diuretic effect, they are rarely used as monotherapy but have been shown to be significantly efficacious in improving the long term prognosis in symptomatic HF patients when combined with loop diuretics. Used in conjunction with Thiazide diuretics to prevent the associated loss of K and Mg. Site of action - collecting duct

28. Pteridine anologues MOA - prevent Na reabsorption in the cortical collecting duct by blocking the epithelial Na channels, independent of aldosterone. Block luminal Na channel and indirectly inhibit K excretion also conserve H ion

29. Clinical uses of K sparing diuretics Used with loop diuretics or thiazides to augment diuresis and limit renal loss of K+ Amiloride given as an aerosol affords symptomatic improvement in cystic fibrosis by increasing fluidity of respiratory secretions. Side effects Hyperkalemia - more with ACE inhibitors, ARBs, Beta blockers, NSAIDs, renal impairement . Both drugs elevate plasma digoxin levels. Triamterene has a structure similar to folic acid, so it can block folic acid, rarely causing megaloblastic anemia

30. Aldosterone antagonists

31. Spironolactone Steroid analogue. Chemically related to the mineralocorticoid aldosterone. Aldosterone penetrates the late DT and CD cells and acts by combining with an intracellular MR which induces the formation of aldosterone induced proteins (AIPs). AIP promotes Na reabsorption and k secretion. Spironolactone acts from the interstitial side of the tubular cell, combines with MR and inhibits the formation of AIPs in a competitive manner. And increase Na and decreases K excretion

32. Pharmacokinetics Oral bioavailability from microfine powder tablet is 75%. Highly bound to plasma proteins. Completely metabolized in liver to active metabolite Canrenone . T1/2 is 1-2 hrs while that of canrenone is 18 hrs. Dose - 25 - 50 mg BD-QID. Uses To counteract K loss due to thiazide and loop diuretics. Edema - more useful in cirrhotic and nephrotic edema in which aldosterone levels are generally high. HTN CHF

33. Adverse effects Drowsiness, ataxia, mental confusion, epigastric distress, loose motions Interacts with progestin and androgen receptors as well. It may enhance testosterone clearance or its peripheral conversion to estradiol . Men - gynecomastia, erectile dysfunction or loss of libido Women - breast tenderness, menstrual irregularities. Contraindicated in ulcer patients as peptic ulcer may be aggravated

34. Eplerenone More selective aldosterone antagonist but lower effinity for steroidal receptors, thus much less likely to cause hormonal disturbances. well absorbed orally. Inactivated in liver by CYP3A4. Uses Moderate to severe CHF. Post infarction left ventricular dysfunction HTN

35. Natriuretic peptides ANP and BNP produced in atria and ventricles respectively, in response to myocardial wall stretch. Site of action - CD MOA - block Na-K-ATPase channel. Nesiritide - a recombinant BNP is available Administered iv as a continuous infusion. T1/2 is 18 min

36. Vasopressin receptor antagonists Vaptans. Eg. Tolvaptan MOA - competitively inhibit the V2 receptor in the renal CD, thus decreased water absorption. Enhanced Aquaretic without loss of electrolytes. Pharmacokinetics - Onset takes 2 to 4 hrs , peak effect within 4 to 8 hrs. T1/2 is about 12 hrs. Highly protein bound. Metablized by CYP3A system Clinical use For the treatment of euvolemic and hypervolemic hyponatremia associated with SIADH, CHF or liver cirrhosis. Side effects Osmotic demyelination - black box warning. Polyuria - dehydration, hypotension, dizziness, pyrexia, thirst, xerostomia

37. Aquaporin modulators Recently described membrane channels that facilitate water movement across cells in response to Osmotic gradient. Site of action - collecting duct. Mutations in these channels

38. Summary

39. Levosimendan Ionodilators are agents with ionotropic effects that also cause vasodilation leading to decreased systemic and/or pulmonary vascular resistane Indicated for the short term treatment of acutely decompensated severe chronic heart failure. Pharmacological effects Increased cardiac contractility by Ca sensitization of troponin C Vasoldilation Cardioprotection

40. Dual mechanism of action Enhances calcium myofilament responsiveness by binding to cardiac troponin C Increases contraction (functions as Ca sensitizer) 2. Opens ATP sensitive K+ channels in myocyte and smooth muscle cells Acts as a vasodilator

41. Pharmacokinetics 98% bound to plasma proteins. Completely metabolized prior to excretion. Because of the long half life of the active metabolite (75-80 hrs ), effects last for upto 7 to 9 days after discontinuation of a 24 h infusion of Levosimendan . Dosage 6-12 microgram/kg loading dose over 10 min followed by 0.05-2 microgram/kg/min as a continuous infusion

42. Side effects Headache Hypotension Prolongation of corrected QT interval Ventricular tachycardia Contraindications Hypersensitivity to levosimendan Severe renal or hepatic impairment Severe hypotension and tachycardia Significant mechanical obstruction affecting ventricular filling and/or outflow. History of Torsades de Pointes

43. THANK YOU