1. CARBONIC ANHYDRASE INHIBITORS ACETAZOLAMIDE E It is a sulfonamide derivative. It is a sulfonamide derivative. noncompetitively but reversible inhibits CAse in PT cells. noncompetitively but reversible inhibits CAse in PT cells. where it catalyzes the dehydration of H 2 CO 3, a critical step in the proximal re-absorption of bi- carbonate where it catalyzes the dehydration of H 2 CO 3, a critical step in the proximal re-absorption of bi- carbonate

3.  inhibitors of CAse thus block sodium- bicarbonate re-absorption.causing sodium- bicarbonate di-uresis & a reduction in total body bi-carbonate stores.  Inhibition of CAse by the drug occurs in other tissues of the body as well,especially in the kidneys.  The urine produced under acetazolamide action is alkaline and rich in HCO 3.  Continued action of acetazolamide depletes body HCO 3 and causes acidosis ; 

4. extra-renal actions of acetazolamide are: extra-renal actions of acetazolamide are: 1.Lowering of intraocular tension 1.Lowering of intraocular tension 2. decreased gastric HCI and pancreatic NaHCO 3 secretion. 2. decreased gastric HCI and pancreatic NaHCO 3 secretion. 3. Raised level of CO 2 in brain and lowering of 3. Raised level of CO 2 in brain and lowering of pH →raising of seizure threshold, sedation. pH →raising of seizure threshold, sedation.  4.Alteration of CO 2 transport in lungs and tissues: these actions are masked by compensatory mechanisms.

5. Pharmacokinetics 1)acetazolamide is well absorbed orally. Pharmacokinetics 1)acetazolamide is well absorbed orally. 2)excreted unchanged in urine. 3)Action of a single dose lasts 8-12 hours.

6. USES because of self limiting actions, production of acidosis and hypokalemia(Side effect), acetazolamide is no longer used as diuretic. Its current clinical uses are: USES because of self limiting actions, production of acidosis and hypokalemia(Side effect), acetazolamide is no longer used as diuretic. Its current clinical uses are:

7. 1. Glaucoma : as adjuvant to other ocular hypotensives. 1. Glaucoma : as adjuvant to other ocular hypotensives. 2. To alkalinise urine: for urinary tract infection or to promote excretion of certain acidic drugs. 2. To alkalinise urine: for urinary tract infection or to promote excretion of certain acidic drugs. 3. epilepsy: as adjuvant in absence seizures when primary drugs are not fully effective. 4.acutemountain sickness : symptomatic relief as well as prophylaxis. 4.acutemountain sickness : symptomatic relief as well as prophylaxis. 5. periodic paralysis. 5. periodic paralysis.

8. ADVERSE EFFECTS ARE FREQUENT Acidosis Acidosis hypokalemia hypokalemia drowsiness drowsiness paresthesias paresthesias fatigue fatigue abdominal discomfort. abdominal discomfort.

9. Hypersensitivity Hypersensitivity reactions – fever, rashes. reactions – fever, rashes. Bone marrow depression is rare but serious. Bone marrow depression is rare but serious. It is contraindicated in liver disease : may precipitate hepatic coma by interfering with Urinary elimination of NH 3 (due to alkaline urine). Urinary elimination of NH 3 (due to alkaline urine). Acidosis is more likely to occur in patients of COPD. Acidosis is more likely to occur in patients of COPD.

10. OSMOTIC DIURETICS Mannitol is pharma-cologically inert. Mannitol is pharma-cologically inert. can be given in large quantities sufficient to raise osmolarity of plasma and tubular fluid. can be given in large quantities sufficient to raise osmolarity of plasma and tubular fluid. It is not metabolized in the body; It is not metabolized in the body; freely filtered at the glomerulus and undergoes limited reabsorption: freely filtered at the glomerulus and undergoes limited reabsorption: therefore excellently suited to be used as osmotic diuretic. therefore excellently suited to be used as osmotic diuretic.

11. ADMINISTRATION ADMINISTRATION Mannitol is not absorbed orally; Mannitol is not absorbed orally; has to be given i.v as 10-20% solution. has to be given i.v as 10-20% solution. It is excreted It is excreted with a t -1/2 of 0.5-1.5 hour. with a t -1/2 of 0.5-1.5 hour.

12. Uses Uses Cerebral edema (To reduce raised intracranialpressure) Cerebral edema (To reduce raised intracranialpressure) Oliguria in renal failure Oliguria in renal failure Acute attack of Glaucoma Acute attack of Glaucoma Contraindications and Precautions Contraindications and Precautions Absolute Absolute Heart Failure, dehydration, intracranial bleeding Heart Failure, dehydration, intracranial bleeding Precautions Precautions Electrolyte imbalance, hypovolemia, geriatiric, Pregnancy, lactation Electrolyte imbalance, hypovolemia, geriatiric, Pregnancy, lactation

14. HIGH CEILING (LOOP) DIURETICS (INHIBITORS OF NA + -K + -2CI COTRANSPORT) FUROSEMIDE (FRUSEMIDE)

15. MECHANISM OF ACTION Loop diuretics inhibit the cotransport of Na + /K + /2CI - in the luminal membrane in the ascending limb of the loop of henle. Therefore, reabsorption of these ions is decreased. Loop diuretics inhibit the cotransport of Na + /K + /2CI - in the luminal membrane in the ascending limb of the loop of henle. Therefore, reabsorption of these ions is decreased. The loop diuretics are most efficacious of the diuretic drugs, because the ascending limb accounts for the reabsorption of 25 to 30 percent of filtered NaCI and downstream sites are not able to compensate for this increased Na + load. The loop diuretics are most efficacious of the diuretic drugs, because the ascending limb accounts for the reabsorption of 25 to 30 percent of filtered NaCI and downstream sites are not able to compensate for this increased Na + load.

16. Pharmacokinetics Absorption, and biotransformation are drug- related. Kidney excretion occurs by active secretion by the proximal tubule. Administration: PO, IM, IV.

19. Therapeutic uses of Loop Diuretics Acute pulmonary edema (given IV). Acute pulmonary edema (given IV). Heart failure. Heart failure. Edema (associated with chronic renal failure or nephrotic syndrome). Edema (associated with chronic renal failure or nephrotic syndrome). Ascites (associated with hepatic cirrhosis or right- sided heart failure). Ascites (associated with hepatic cirrhosis or right- sided heart failure). Hypertension (when associated with renal insufficiency or heart failure). Hypertension (when associated with renal insufficiency or heart failure). Hypercalcemia. Hypercalcemia. (Addition of a thiazide can cause a dramatic synergistic effect when a patient become refractory to a loop diuretic alone ) (Addition of a thiazide can cause a dramatic synergistic effect when a patient become refractory to a loop diuretic alone )

20. ADVERSE EFFECTS  The adverse effects of the loop diuretics are  Ototoxicity  Hyperuricemia  Hypotension  Hypokalemia  Hypomagnesemia