CARBONIC ANHYDRASE CARBONIC ANHYDRASE INHIBITORSINHIBITORS

ACETAZOLAMIDEACETAZOLAMIDEEE It is a sulfonamide derivative.It is a sulfonamide derivative. noncompetitively but noncompetitively but reversible inhibits CAse in PT reversible inhibits CAse in PT cells.cells.

where it catalyzes the where it catalyzes the dehydrationdehydration of Hof H22COCO33 , a , a critical step in the proximal critical step in the proximal re-absorption of bi-carbonate re-absorption of bi-carbonate

inhibitors of CAse thus block sodium-inhibitors of CAse thus block sodium-bicarbonate re-absorption.causing bicarbonate re-absorption.causing sodium-bicarbonate di-uresis & a sodium-bicarbonate di-uresis & a reduction in total body bi-carbonate reduction in total body bi-carbonate stores.stores.

Inhibition of CAse by the drug occurs in Inhibition of CAse by the drug occurs in other tissues of the body as other tissues of the body as well,especially in the kidneys.well,especially in the kidneys.

The urine produced under acetazolamide The urine produced under acetazolamide action is alkaline and rich in HCOaction is alkaline and rich in HCO33..

Continued action of acetazolamide Continued action of acetazolamide depletes body HCOdepletes body HCO33 and causes acidosis ; and causes acidosis ;

extra-renal actions of extra-renal actions of acetazolamide are:acetazolamide are:

1.Lowering of 1.Lowering of intraocular tensionintraocular tension

2. decreased gastric 2. decreased gastric HCI and pancreatic HCI and pancreatic NaHCONaHCO33 secretion. secretion.

3. Raised level of 3. Raised level of COCO22 in brain and in brain and lowering of lowering of

pH pH →raising of →raising of seizure threshold, seizure threshold, sedation.sedation.

4.Alteration of 4.Alteration of COCO22 transport transport in lungs andin lungs and

tissues: these tissues: these actions are actions are masked by masked by compensatory compensatory mechanisms.mechanisms.

Pharmacokinetics Pharmacokinetics 1)1)acetazolamide is acetazolamide is well absorbed orally.well absorbed orally.

2)excreted 2)excreted unchanged in urine. unchanged in urine.

3)Action of a single 3)Action of a single dose lasts 8-12 hours.dose lasts 8-12 hours.

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

1. Glaucoma : as adjuvant to other 1. Glaucoma : as adjuvant to other ocular hypotensives. ocular hypotensives.

2. To alkalinise urine: for urinary 2. To alkalinise urine: for urinary tract infection or to promote tract infection or to promote excretion of certain acidic drugs.excretion of certain acidic drugs.

3. epilepsy: as adjuvant in absence 3. epilepsy: as adjuvant in absence seizures when primary drugs are seizures when primary drugs are not fully effective .not fully effective .

4.acutemountain sickness : 4.acutemountain sickness : symptomatic relief as well as symptomatic relief as well as prophylaxis.prophylaxis.

5. periodic paralysis.5. periodic paralysis.

ADVERSE EFFECTS ADVERSE EFFECTS ARE FREQUENTARE FREQUENT

AcidosisAcidosis hypokalemiahypokalemia drowsiness drowsiness paresthesiasparesthesias fatigue fatigue abdominal discomfort.abdominal discomfort.

Hypersensitivity Hypersensitivity

reactions – fever, rashes.reactions – fever, rashes. Bone marrow depression is rare Bone marrow depression is rare

but serious.but serious.It is contraindicated in liver It is contraindicated in liver

disease : may precipitate hepatic disease : may precipitate hepatic coma by interfering withcoma by interfering with

Urinary elimination of NHUrinary elimination of NH33 (due (due to alkaline urine).to alkaline urine).

Acidosis is more likely to occur Acidosis is more likely to occur in patients of COPD.in patients of COPD.

OSMOTIC DIURETICSOSMOTIC DIURETICS Mannitol is pharma-cologically inert Mannitol is pharma-cologically inert

.. can be given in large quantities can be given in large quantities

sufficient to raise osmolarity of sufficient to raise osmolarity of plasma and tubular fluid. plasma and tubular fluid.

It is not metabolized in the body;It is not metabolized in the body; freely filtered at the glomerulus freely filtered at the glomerulus

and undergoes limited reabsorption:and undergoes limited reabsorption: therefore excellently suited to be therefore excellently suited to be

used as osmotic diuretic. used as osmotic diuretic.

ADMINISTRATION ADMINISTRATION Mannitol is not absorbed Mannitol is not absorbed orally;orally;

has to be given i.v as 10-has to be given i.v as 10-20% solution. 20% solution.

It is excreted It is excreted

with a t -1/2 of 0.5-1.5 with a t -1/2 of 0.5-1.5 hour. hour.

UsesUses

Cerebral edema (To reduce raised Cerebral edema (To reduce raised

intracranialpressure)intracranialpressure)

Oliguria in renal failureOliguria in renal failure

Acute attack of GlaucomaAcute attack of Glaucoma Contraindications and PrecautionsContraindications and Precautions AbsoluteAbsolute Heart Failure, dehydration, intracranial Heart Failure, dehydration, intracranial

bleedingbleeding PrecautionsPrecautions Electrolyte imbalance, hypovolemia, geriatiric, Electrolyte imbalance, hypovolemia, geriatiric,

Pregnancy, lactationPregnancy, lactation

HIGH CEILING HIGH CEILING (LOOP) DIURETICS(LOOP) DIURETICS(INHIBITORS OF (INHIBITORS OF

NANA++-K-K++-2CI -2CI COTRANSPORT)COTRANSPORT)FUROSEMIDE FUROSEMIDE (FRUSEMIDE)(FRUSEMIDE)

MECHANISM OF MECHANISM OF ACTIONACTION Loop diuretics inhibit the Loop diuretics inhibit the

cotransport of Nacotransport of Na++/K/K++/2CI/2CI-- in the in the luminal membrane in the luminal membrane in the ascending limb of the loop of ascending limb of the loop of henle.henle. Therefore, reabsorption of Therefore, reabsorption of these ions is decreased. these ions is decreased.

The loop diuretics are most The loop diuretics are most efficacious of the diuretic drugs, efficacious of the diuretic drugs, because the ascending limb because the ascending limb accounts for the reabsorption of accounts for the reabsorption of 25 to 30 percent of filtered NaCI 25 to 30 percent of filtered NaCI and downstream sites are not and downstream sites are not able to compensate for this able to compensate for this increased Naincreased Na++ load. load.

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

Therapeutic uses of Loop Therapeutic uses of Loop DiureticsDiuretics Acute pulmonary edema (given IV).Acute pulmonary edema (given IV).

Heart failure.Heart failure. Edema (associated with chronic renal Edema (associated with chronic renal

failure or nephrotic syndrome).failure or nephrotic syndrome). Ascites (associated with hepatic cirrhosis Ascites (associated with hepatic cirrhosis

or right-sided heart failure).or right-sided heart failure). Hypertension (when associated with renal Hypertension (when associated with renal

insufficiency or heart failure).insufficiency or heart failure). Hypercalcemia.Hypercalcemia. (Addition of a thiazide can cause a (Addition of a thiazide can cause a

dramatic synergistic effect when a patient dramatic synergistic effect when a patient become refractory to a loop diuretic alone )become refractory to a loop diuretic alone )

ADVERSE ADVERSE EFFECTSEFFECTS

The adverse effects of the loop The adverse effects of the loop diuretics arediuretics are

OtotoxicityOtotoxicity

HyperuricemiaHyperuricemia

HypotensionHypotension

HypokalemiaHypokalemia

HypomagnesemiaHypomagnesemia