Carbonic Anhydrase Inhibitors - Diuret Cardiovascular Poison

Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors are non-bacteriostatic sulfona-mides that inhibit carbonic anhydrase, thereby reducing the rate of aqueous humour formation in the eye and resulting in decreased intraocular pressure. Acetazolamide is the prototype of this group, which also includes brinzolamide, dichlor-phenamide, dorzolamide, ethoxzolamide, methazolamide, and sulthiame. These drugs act by inhibiting the membrane-bound as well as cytoplasmic forms of carbonic anhydrase, resulting in total abolition of sodium bicarbonate reabsorption in the proximal renal tubule. This results in rapid rise of urinary bicarbonate excretion, raising urinary pH to 8 and causing metabolic acidosis.

Uses

·              Acetazolamide, dichlorphenamide, and methazolamide are primarily used for the treatment of glaucoma.

·              Acetazolamide is used for the treatment of oedema resulting from congestive heart failure, as well as that which is drug-induced. Its main indication however is open angle glaucoma.

·              Brinzolamide and dorzolamide are topical ophthalmic agents that are indicated for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

·              Sulthiame has been used as an antiepileptic in most forms of epilepsy.

Toxicokinetics

Acetazolamide is almost completely absorbed on oral administration and demonstrates a plasma half-life of 6 to 9 hours. Dichlorphenamide acts within 1 hour, with a maximal effect usually observed in 2 to 4 hours. Methazolamide is absorbed from the gastrointestinal tract more slowly than acetazolamide; the duration of action is 10 to 18 hours. These drugs are bound to the carbonic anhydrase II enzyme, and high concentrations are generally found in tissues containing this enzyme, including red blood cells and the renal cortex. Protein binding is to the extent of 94% for acetazolamide, 60% for brinzolamide, 33% for dorzolamide, and 55% for methazolamide. Acetazolamide, brinzolamide, and dorzola-mide are primarily excreted unchanged in the urine.

Adverse Effects and Toxic Features

·      Bone marrow depression (aplastic anaemia, leukopenia, thrombocytopenia, agranulocytosis), skin toxicity, urinary alkalinisation, confusion, lethargy, and metabolic acidosis are common adverse effects.

·      There is increased tendency for renal calculi.

·      Rare adverse effects may include taste disturbances, ataxia, gastritis, cholestatic hepatitis, and renal failure. Impotence has been reported with carbonic anhydrase inhibitors.

·      Overdose causes drowsiness, lethargy, metabolic acidosis, tachycardia, tachypnoea, electrolyte imbalances, and paraes-thesias. Paraesthesias of the extremities, of the tongue, and at the mucocutaneous junction of the lips are common occur-rences following acetazolamide therapy, and will generally resolve upon discontinuation of the medication.

Contraindications

·              Hypersensitivity to sulphonamides

·               Hepatic cirrhosis

·              Addison’s disease

·     Hyperchloraemic acidosis.

Treatment

·      In cases of carbonic anhydrase inhibitor overdose inges-tions, treatment is usually symptomatic and supportive.

·      Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion.

·      Fluid and electrolyte levels should be monitored closely and replaced if needed.

·      Monitor arterial blood gases in symptomatic patients for possible metabolic acidosis. Treat severe acidosis (less than pH 7.1) with IV sodium bicarbonate. Begin with 1 mEq/ kg in adults and children. Repeat doses of no more than one-half the original amount may be given no more often than every 10 minutes if required. Monitor blood gases to adjust dose.

Haemodialysis may be effective, especially in the presence of renal failure.