Osmotic diuretics Osmotic diuretics are pharmacologically inert substances (e.g. mannitol ) that are filtered in the glomerulus but not reabsorbed by the nephron. Osmotic diuretics are poorly absorbed, which means that they must be given parenterally. If administered orally, mannitol causes osmotic diarrhea. Mannitol is not metabolized and is excreted primarily by glomerular filtration within 30–60 minutes, without any important tubular reabsorption or secretion.

Mecanism of action Osmotic diuretics have their major effect in those segments of the nephron that are freely permeable to water: the proximal tubule and the descending limb of the loop of Henle. They also oppose the action of ADH in the collecting tubule. The presence of a nonreabsorbable solute such as mannitol prevents the normal absorption of water by interposing a countervailing osmotic force. As a result, urine volume increases. The increase in urine flow rate decreases the contact time between fluid and the tubular epithelium, thus reducing Na+ reabsorption. However, the resulting natriuresis is of lesser magnitude than the water diuresis, leading eventually to hypernatremia.

Therefore the main effect of osmotic diuretics is to increase the amount of water excreted, with a smaller increase in Na+ excretion. They are not useful in treating conditions such as heart failure associated with Na+ retention but have much more limited therapeutic indications, including emergency treatment of acutely raised intracranial or intraocular pressure. Such treatment has nothing to do with the kidney, but relies on the increase in plasma osmolarity by solutes that do not enter the brain or eye; this results in extraction of water from these compartments.

. Osmotic Diuretic Increase non absorbable solution in PCT Decrease passive water reabsorbtion Decrease Na+ reabsorbtion Increase excretion of water and Na+ Diuresis

THERAPEUTIC USE It is used as a prophylactic agent in acute cardiac operation (acuterenal failure), severe rheumatic injury, operation in the presence of jaundice Before neuro surgery they are used to reduce cerebral spinal fluid and intraocular pressure. Brain edema. In the management of hemolytic transfusion reaction. Cardio vascular operation . Acutely raised intracranial pressure.

Toxicity Extracellular Volume Expansion Mannitol is rapidly distributed in the extracellular compartment and extracts water from cells. Prior to the diuresis, this leads to expansion of the extracellular volume and hyponatremia. This effect can complicate heart failure and may produce florid pulmonary edema. Headache, nausea, and vomiting are commonly observed in patients treated with osmotic diuretics. Dehydration and Hypernatremia Excessive use of mannitol without adequate water replacement can ultimately lead to severe dehydration, free water losses, and hypernatremia. These complications can be avoided by careful attention to serum ion composition and fluid balance.

CONTRAINDICATION Severe renal diseases Congestive heart failure Pulmonary edema Hyponatremia Anuria ( risk of cardiac failure) Intracranial haemorrhage

Carbonic anhydrase inhibitors Carbonic anhydrase is present in many nephron sites, but the predominant location of this enzyme is the luminal membrane of the proximal tubule cells, where it catalyzes the dehydration of H2CO3, a critical step in the reabsorption of bicarbonate. By blocking carbonic anhydrase, inhibitors block sodium bicarbonate reabsorption and cause diuresis. CA inhibitors are more often used for their other pharmacological action rather than diuretics effect, because they are less effective than loop or high ceiling diuretics. e.g- Acetazolamide, Dichlophenamide, Etazolamide, Methozolamide.

STRUCTURE OF ACETAZOLAMIDE N N SO2 NH2 CH3 CO C C S

Mechanism of action Acetazolamide inhibits the carbonic anhydrase located intracellularly (cytoplasm) & on the apical membrane of the proximal tubular epitheliam. Carbonic anhydrase catalyses the reaction of CO2 & H2O leading to H2CO3, which spontaneously ionizes to H+ & HCO3-. The enzyme thus play an important role in tubular reabsorption of Na+ & HCO3- by providing H2CO3 which makes available H+ for exchange with Na+. But free sulphonamide (SO2-NH2) group of CA inhibitor combine with Zn part of the enzyme carbonic anhydrates & non-competitively inhibit the enzyme. So there is no formation of H+ & HCO3- for Na+ ion reabsorption. Na+ is excreated with large volume of H2O. K+ tries to converse Na+ & NaHCO3 reabsorption. As a result a large volume of Na+ & HCO3- excrete with H2O.

Pharmacokinetics The carbonic anhydrase inhibitors are well absorbed after oral administration. An increase in urine pH from the bicarbonate diuresis is apparent within 30 minutes, maximal at 2 hours, and persists for 12 hours after a single dose. Excretion of the drug is by secretion in the proximal tubule segment. Therefore, dosing must be reduced in renal insufficiency.

THERAPEUTIC USE In reducing the ocular pressure. Prophylaxis & treatment high attitude illness like edema, moutain sickness. In hypertension. Non carcinogenic pulmonary edema. Congestive heart failure. Glaucoma & resistance edema. Prevention of attack of periodic paralysis.

ADVERSE EFFECT: # Metabolic acidosis # Hypokalamia & hyponatramia # Drowsiness # Par aesthesia # Skin rashes # Blood discarriage # Crystalluria # Kidney damage # Renal stone formation.

Carbonic Anhydrase Inhibitors Used Orally in Treatment of Glaucoma. Drug Usual Oral Dose (1–4 Times Daily) Acetazolamide 250 mg Dichlorphenamide 50 mg Methazolamide 50 mg