DIURETICS-NEETHU.I.S.pptx FIFTH SEMESTER.B.PHARM KUHS

DIURETICS NOTES BY NEETHU.I.S

1. DIURETICS NEETHU. I.S ASSISTANT PROFESSOR EZHUTHACHAN COLLEGE OF PHARMACEUTICAL SCIENCES TRIVANDRUM

2. DIURETICS Diuretics ( natriuretics ) are drugs which cause a net loss of Na+ and water in urine. Classification 1. High ceiling(Inhibitors of Na+K+2Cl- cotransport) Furosemide Bumetanide Torasemide 2. Medium efficacy( Inhibitors of Na+ Cl- symport) Benzothiadiazines Hydrochlorthiazide Hydroflumethiazide Benzthiazide Thiazide like Chlorthalidone Metolazone Xipamide Indapamide Clopamide

3. 3. Weak/ adjunctive diuretics A. Carbonic anhydrase inhibitors Acetazolamide B. Potassium sparing diuretics 1.Aldosterone antagonist Spironolactone Eplerenone 2. Renal epithelial Na + channel inhibitors Amiloride Triamterene C. Osmotic diuretics Mannitol Isosorbide Glycerol

4. HIGH CEILING DIURETICS Thick ascending limb of loop of Henle (site 2)

5. The major site of action is the thick ascending limb of loop of henle (TAL), therefore, called loop diuretics. Drug binds to the luminal side of Na+-k+-2cl- cotransporter and block its function. Inhibits the reabsorption of Na,K+,Cl - ions by inhibiting Na+-k+-2cl- cotransporter ,also inhibits the reabsorption of Mg2 + & ca2+ There is increased excretion of Na and cl- in urine Loop diuretics called high ceiling diuretics because they are highly efficacious –have maximal Na+ excreting capacity when compared to Thiazide and potassium sparing diuretics.

6. Uses of high ceiling diuretics 1. Edema :edema due to cardiac, hepatic or renal problems can be treated. The high ceiling diuretics are preferred in CHF for rapid mobilization of edema fluid 2. Acute pulmonary edema (acute LVF, following MI): Intravenous administration of furosemide or its congeners produces prompt relief. 3. Cerebral edema Mainly osmotic diuretics are primarily used to lower intracranial pressure by withdrawing water, furosemide may be combined to improve efficacy 4. Hypertension High ceiling diuretics are indicated in hypertension only in the presence of renal insufficiency, heart failure and in hypertensive emergencies . 5. Anaemia : Furosemide may be infused along with blood transfusion, to prevent volume overload in severely anaemic patients. 6. Hypercalcaemia of malignancy : augments Ca2+ excretion and prevents volume overload

7. Bumetanide It is similar to furosemide in all respects, but is 40 times more potent. Effective in some cases not responding to furosemide, and may be tolerated by patients allergic to furosemide Preferred for oral use in CHF Torsemide 2-3 times more potent than frusemide Used in edema and hypertension

8. ADR ELECTROLYTE IMBALANCES Hypokalemia,hyponatremia,hypocalcemia,hypomagnesemia Metabolic disturbances Hyperglycemia,hyperurecemia,hyperlipidemia Hypersensitivity Ototoxicity

9. Thiazide and related diuretics THIAZIDE AND RELATED DIURETICS (Inhibitors of Na+-Cl¯ symport) Thiazides are medium efficacy diuretics Primary site of action is in the early DT (Site III). Inhibit Na+ –Cl¯ symport at the luminal membrane There is net loss of Na,k,cl,Hco3- in urine.unlike loop diuretics thiazide decrease ca2+ excretion Absorbed orally long DOA and excreted in urine ADR Electrolyte disturbances Hypokalemia,hyponatremia,hypomagnesemia,hypocalcemia,metabolic disturbances like Frusemide. Impotence Skin rashes,nausea,vomiting,diarrhoea etc Site 3- drugs acting on cortical diluting segment

10. USES 1. Edema Thiazides may be used for mild to moderate cases. 2. Hypertension Thiazides and related diuretics, especially chlorthalidone and indapamide are one of the first line drugs 3. Diabetes insipidus(increase the concentration of urine) 4. Hypercalciuria

11. Complications of high ceiling and thiazide type diuretic therapy 1. Hypokalaemia This is the most significant problem’. The usual manifestations are weakness, fatigue, muscle cramps; cardiac arrhythmias are the serious complications. Hypokalaemia can be prevented and treated by:(a) High dietary K+ intake or (b) Supplements of KCl (24–72 mEq /day) or (c) Concurrent use of K+ sparing diuretics 2. Acute saline depletion Over use of diuretics, particularly high ceiling ones, may cause dehydration and marked fall in BP, especially on standing up

12. 3 . GIT and CNS disturbances Nausea, vomiting and diarrhoea may occur with any diuretic. Headache, giddiness, weakness, paresthesias , impotence are occasional complaints with thiazides as well as loop diuretics. 4 . Hearing loss This occurs only with high ceiling diuretics but it is infrequent. The risk increases when these drugs are used in the presence of renal insufficiency . 5 . Allergic manifestations Rashes, photosensitivity occur, especially in patients hypersensitive to sulfonamides. Blood dyscrasias are rare; any diuretic may be causative 6 . Hyperuricaemia Long-term use of higher dose thiazides in hypertension cause s rise in the blood urate level. 7 . Hyperglycaemia and dyslipidemia

13. 8.. Magnesium depletion It may develop after prolonged use of thiazides or loop diuretics, and may increase the risk of ventricular arrhythmias 9. . Thiazides have aggravated renal insufficiency, probably by reducing g.f.r .

14. WEAK ADJUNCTIVE DIURETICS 1. CARBONIC ANHYDRASE INHIBITORS Carbonic anhydrase ( CAse ) is an enzyme which catalyses the reversible reaction H2 O + CO2 →← H2 CO3 . Carbonic acid dissociates into H2 CO3 →← H+ + HCO3 ¯ . Carbonic anhydrase thus functions in CO2 and HCO3 ¯ transport and in H+ ion secretion. The enzyme is present in renal tubular cell (especially PT) gastric mucosa, exocrine pancreas, ciliary body of eye, brain and RBC. DRUGS ACTING ON PCT Site 1

15. The main site of action is PCT and in collecting duct Acetazolamide prevent CA enzyme prevent the formation of H+. Thus Na+-H+ Exchange is prevented. Na+ is excreted along with HCO3- in urine. Net effect is loss of Na+,K+,Hco3- Adverse effects Acidosis, hypokalaemia, drowsiness, paresthesias , fatigue, abdominal discomfort. Hypersensitivity reactions—fever, rashes. Bone marrow depression is rare

16. 1. Glaucoma: as adjuvant to other ocular hypotensives . 2. To alkalinise urine: for urinary tract infection or to promote excretion of certain acidic drugs. 3. Epilepsy: as adjuvant in absence seizures 4. Mountain sickness

17. POTASSIUM SPARING DIURETICS Aldosterone antagonists and renal epithelial Na+ channel inhibitors indirectly conserve K+ while inducing mild natriuresis, and are called ‘potassium sparing diuretics’. Normally aldosterone increase sodium reabsorption and potassium excretion Aldosterone antagonist Spironolactone It is a steroid, chemically related to the mineralocorticoid aldosterone Drugs acting on DCT

18. 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. The AIPs activate these Na+ channels and, translocate them from cytosolic site to luminal membrane. They also translocate Na+K+ATPase to the basolateral membrane AIPs increase ATP production by mitochondria as well. All these changes promote Na+ reabsorption . Spironolactone acts from the interstitial side of the tubular cell, combines with MR and inhibits the formation of AIPs to act as a competitive antagonist and opposes aldosterone action ie it inhibit the reabsorption of Na and ex cretion of K ions

19. Use Spironolactone is a weak diuretic and is used mostly in combination with other more efficacious diuretics. 1. To counteract K+ loss due to thiazide and loop diuretics. 2. Edema: Spironolactone is more useful in cirrhotic and nephrotic edema (salt n water retension ) in which aldosterone levels are generally high. It potentiates thiazides and loop diuretics and is frequently added to them in the treatment of ascites (fluid in abdomen) due to cirrhosis of liver. 3. Hypertension: Spironolactone is used to augment a thiazide diuretic in the treatment of resistant hypertension. It also serves to prevent thiazide-induced hypokalaemia . 4. Heart failure: As additional drug to conventional therapy in moderate to severe CHF; it serves to retard disease progression and lower mortality 5. Primary hyperaldosteronism (Conn’s syndrome).

20. Renal epithelial Na+ channel inhibitors Triamterene and amiloride Their most important effect is to decrease K+ excretion. Mechanism of action The luminal membrane of late DT and CD cells expresses a distinct ‘renal epithelial’ or ‘amiloride sensitive’ Na+ channel through which Na+ enters the cell This Na+ entry partially depolarizes the luminal membrane and promotes secretion of K+ through K+ channels. Amiloride and triamterene block the luminal Na+ channels and indirectly inhibit K+ excretion Thus, amiloride conserves both K+ and H+ while marginally increasing Na+ excretion.

21. Both triamterene and amiloride are used with a thiazide type or a high ceiling diuretic to prevent hypokalaemia and slightly augment the natriuretic response Risk of hyperkalaemia is the most important adverse effect of amiloride and triamterene. These drugs should not be given to patients with renal insufficiency or those taking K+ supplements because dangerous hyperkalaemia may develop. Usual side effects are nausea, diarrhoea and headache. Amiloride blocks entry of Li+ through Na+ channels in the CD cells and mitigates diabetes insipidus induced by lithium Uses Edema HRT CHF

22. Drugs acting on entire nephron Osmotic diuretics TUBULAR FLUID Mannitol is freely filtered at the glomerulus

23. ADR Head ache Nausea Vomiting Hyperglycemia

24. Uses Mannitol is never used for the treatment of chronic edema or as a natriuretic. Its indications are: 1. Increased intracranial or intraocular tension (acute congestive glaucoma,head injury, stroke, etc.): by osmotic action it encourages movement of water from brain parenchyma, CSF and aqueous humour . 2. To maintain g.f.r . and urine flow in acute renal failure, e.g. in shock, severe trauma, cardiac surgery, haemolytic reactions. 3. To counteract low osmolality of plasma and e.c.f. due to rapid haemodialysis or peritoneal dialysis

25. Classification based on site of action 1. Drugs acting at PCT (site 1) Carbonic anhydrase inhibitors Acetazolamide, dorzolamide, brinzolamide 2. Drugs acting at thick ascending limb of loop of Henle(site 2) Furosemide Bumetanide Torasemide

26. 3. Drugs acting at cortical diluting segment (site 3) Benzothiadiazines Hydrochlorthiazide Hydroflumethiazide Benzthiazide Thiazide like Chlorthalidone Metolazone Xipamide Indapamide Clopamide

27. 4. Drugs acting at distal convoluted tubule Aldosterone antagonist Spironolactone Eplerenone Renal epithelial Na + channel inhibitors Amiloride Triamterene 5. Drugs acting on entire nephron Osmotic diuretics Mannitol Isosorbide Glycerol