RENAL PHARMACHOLOGY DRUGS LOOP THIAZIDE - moderate powerful (low ceiling) POTASSIUM SPARRING - weak diuretics - excrete only

5% of Na filtrate OSMOTIC (MANNITOL) Powerful diuretic action CARBONIC ANHYDRASE (-) - Act at PCT - CAIs are weak diuretics most fluid & Na lost are reabsorbed at late DCT (-) CAIs responsible for H production (-) Na/H exchange at PCT (-) NaHCO3 reabsobtion loss NaCO3 in urine alkaline urine & blood bicarbonate metabolic acidosis

CHARAC - high ceiling and most TERS effective diuretic

MECHA NISM OF ACTION

INDICA TIONS

1) Block 2 CL/Na/K reabsorbtion pump TALH excretion 20% if filtered Na interference with medullary hypertonicity failure water reabsorbtion by medulla under ADH effect excretion of water of excess Na. 2) Release of vasodilator PGs which the action of loop diuretics VD of aff. glom. Filtration (-) Na reabsorbtion at TALH * NSAIDs (-) PGs 3) venodilator for acute pulm. Oedema 4) RBF for acute renal failure CHOFNAK - hyperCalcemia treated by giving IV saline & add loop diuretic if necessary (-) Ca reabsorbtion at TALH - Hypertensive encephalopathy - acute pulmonary Oedema - refractory Oedema

1) (-) active NaCl reabsorbtion in the early part of DCT excretion of 5-10% of filtered Na 2) VD action antihypertensive effect

(-) Na / K / H exchange at late DCT by 2 mechanism : 1) indirect by SPIRONOLACTONE & EPLERENONE antagonize aldosterone at its receptor synthesis of specific protein that (+) Na pump requires 3-4 days 2) direct by TRIAMTERENE & AMILORIDE rapid onset of action act independent of aldosterone block Na channel directly 1) eodema of hyperaldosteronism caused by liver chirrosis, CHF & nephritic syndrome resistant to the other diuretics because Na lost is reabsorbed again at DCT by the effect of aldosterone direct

Mannitol is freely filtered as it not need carrier limited absorbtion because its MW osmotic pressure retention of water inside renal tubule & urine volume used as dehydrating agent * high osmotic pressure of tubular filtrate > plasma osmotic pr (-) Na reabsorbtion

THERAPUTIC USES : 1) CVS : - hypertension by initially by diuresis blood volume persistent effect due to VD - CHF to overcome refractoriness to loop diuretics

1) dehydrating agent in : - intracranial tension in cerebral oedema caused by head injury - of OCP in acute congestive glaucoma 2) prophylaxis against acute renal failure :

1) emphysema & high altitude sickness produce metabolic acidosis to correct alkalosis 2) epilepsy 3) Eye treatment of glaucoma

(severe CHF) - acute renal Failure - dilutional hypoNatremia increase water excretion > Na - distal renal tubular Acidosis H+ excretion exchange with Na at DCT

2) Renal : - nephrogenic Diabetes Insipidus paradoxically urine output due to PG GFR urine volume -idiopathic hypercalsuria & Ca stones thiazide dose NaCl in MD RBF,GFR reabsorbtion of Ca present in urine Ca stone * preferred for elderly patient as it preserve Ca to prevent osteoporosis 1) Hypokalemia & metabolic alkalosis risk of hepatic encephalopathy in liver impairment 2) hyponatremia 3)glucose intolerance thiazide induced hypokalemia K outflow from prancreas islet cells (-) Ca influx (-) insuline secretion 4) hyperlipidemia LDL HDL coronary stenosis 5) hyperuricemia 6) hypersensitivity 7) impotence

acting K sparring diuretic < effective tha spironolactone K loosing diuretic will cause hepatic encephalopathy in liver chirrosis 2) hypokalemia & hypomagnesia triamterene & amiloride is > preferred as its > rapid & short acting

Surgery, trauma, hemolytic transfusion reactions will produce high concentration of toxic agents cause kidney damage mannitol is given to maintain high rate of urine flow to wash the toxic out

4) excretion of acidic toxin as salicylate & barbiturates by alkalizing the urine

ADVER SE EFFECT

1) Metabolic & electrolyte disturbance - hypovolemia hypotension collapse, hemoconcentration thrombosis - hypokalemia & alkalosis Na delivered to distal tubules excretion of K & H in exchange with Na by aldosterone (-) by spironolactone - hypomagnesimia - hypocalcemia - hyperuricemia by competing with acidic carrier 2) others - ototoxicity

1) hyperkalemia & metabolic acidosis 2) gynecomastia antiendrogenic effect of spironolactone

1) in remal impairment as in acute renal failure mannitol is not filtered persist I plasma intravascular volume HF & dilutional hyponatremia

1) metabolic acidosis drowsiness 2) Ca & PO4 stones due to alkaline urine 3) hypersensitivity due to sulfonamide deritative

DOSES & PREPA RATION

- interstitial nephritis - myalgia ( bumetanide) - hypersensitivity in sulfonamides - GIT upset (ethacrynic acid) - refractoriness 1) frusemide 2) bumetanide 3) torsemide 4) etrachrynic acid * all sulfonamide like

1) hydrochlorthiazide short acting < 24 hours (long acting > 24 hs) 2) chlorthalidone 3) indapamide used in hypertension 4) metolazone used in renal impairment

1) spironolactone 2) eplerenone 3) triamterene 4) amiloride

1) mannitol

1) acetazolamide 2) brinzolamine 3) dorzolamine

Causes of refractoriness to loop diuretics & its management DEFECT pharmacokinetic causes DISEASE intestinal absorbtion in decompensated HF defective plasma protein in hypoalbuminemic states by liver chirrosis & nephritic syndrome extravascular diffusion of diuretics renal excretion Renal impairment defect in acid carrier defective in secretion of diuretic Hyperthrophy of DCT cell due to chronic used Na reabsorbtion blunt the action of diuretics Na lost by loop diuretics reabsorbed in the exchange wih K in DCT by aldosterone TREATMENT Oral Oedema in intestine cant absorb drug Diuretics IV Loop + albumin

pharmachodinami c

Frusemide 5 folds Bumetanide 10 folds Loop + thiazide to (-) Na reabsorbtion in DCT Spironolactone to (-) aldosterone

PHARMACHOKINETIC OF LOOP DIURETICS : ABSORBTION 50% oral of frusemide 100% oral of bumetanide DISTRIBUTION 90% bound to protein METABOLISM

50% IV dose is metabolized frusemide( conjugation) & bumitanide ( CYP450 ) balance 50% act for diuretic effect