Carbonic anhydrase inhibitors systemic

Carbonic anhydrase inhibitors decrease aqueous humor production by inhibition of the carbonic anhydrase isoenzyme II located in the ciliary body. In the eye, carbonic anhydrase catalyzes the conversion of water and carbon dioxide to bicarbonate and hydrogen ion, which is a significant step in aqueous humor production. Carbonic anhydrase inhibitors are available in systemic and topical preparations.10,13,14... 

The systemic carbonic anhydrase inhibitors are associated with significant adverse effects which include paresthesias of the hands and feet, nausea, vomiting, and weight loss. Patients... 

Acetazolamide is a carbonic anhydrase inhibitor, which reduces intraocular pressure by reducing aqueous humour production. It is used in the treatment of glaucoma. Acetazolamide is administered systemically. Recently newer carbonic anhydrase inhibitors have been developed, which are available as topical agents (for example, dorzolamide). 

Concomitant oral carbonic anhydrase inhibitors There is a potential for an additive effect of the known systemic effects of carbonic anhydrase (CA) inhibition in patients receiving an oral and ophthalmic CA inhibitor. The concomitant administration of ocular and oral CA inhibitors is not recommended. 

The development of sulfonamide carbonic anhydrase inhibitors was based on the observation that antibacterial sulfanilamides produce alkaline urine. This discovery led to the development of acetazolamide (8.29), a thiadiazole derivative. It is not an ideal drug because it promotes K+ excretion and causes a very high urine pH. Since chloride ions are not excreted simultaneously, systemic acidosis also results. Much more useful are the chlorothiazide (8.30) derivatives, which are widely used as oral diuretic drugs. These compounds differ from one another mainly in the nature of the substituent on C3 ... 

The reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure. This effect is valuable in the management of glaucoma, making it the most common indication for use of carbonic anhydrase inhibitors. Topically active carbonic anhydrase inhibitors (dorzolamide, brinzolamide) are available and reduce intraocular pressure without producing detectable plasma levels. Thus, diuretic and systemic metabolic effects are eliminated for the topical agents. 

Drowsiness and paresthesias are common following large doses of acetazolamide. Carbonic anhydrase inhibitors may accumulate in patients with renal failure, leading to nervous system toxicity. Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) may also occur. 

Dorzolamide (Trusopt) [Carbonic Anhydrase Inhibitor, Sul fonamide/Glaucoma Agent] Uses Glaucoma Action Carbonic anhydrase inhibitor Dose 1 gtt in eye(s) tid Caution [C, ] Contra Component sensitivity Disp Soln SE Irritation, bitter taste, punctate keratitis, ocular allergic Rxn EMS T Effects W/ oral carbonic anhydrase inhibitors, salicylates EMS Drug is absorbed systemically OD May cause electrolyte disturbances (K) and acidosis monitor ECG... 

Along these lines and as a proof of principle, reversible imine formation was implemented in 1997 for the generation of enzyme (carbonic anhydrase) inhibitors from a dynamic covalent library [43] and reversible covalent selection approaches to catalytic systems were presented [44]. 

SAFETY PROFILE Poison by subcutaneous and intravenous routes. Moderately toxic by intraperitoneal route. Human systemic effects by ingestion dyspnea. An experimental teratogen by many routes. Other experimental reproductive effects. When heated to decomposition it emits ver toxic fumes of NOx and SOx. A carbonic anhydrase inhibitor and diuretic used to treat glaucoma. 

Other Medical Conditions. Other systemic disorders can be affected by or contraindicate the use of topically applied medications. Examples include myasthenia gravis, which can be worsened with topical timolol, and erythema multiforme (Stevens-Johnson syndrome), which can be caused or exacerbated by topical ocular sulfonamides and related antiglaucoma drugs such as carbonic anhydrase inhibitors. 

Of the commonly used therapeutic drugs, the greatest risks are encountered when clinicians prescribe topical steroids (for extended periods), systemic steroids, P blockers, miotic antiglaucoma agents, and oral carbonic anhydrase inhibitors (CAIs). Optometrists should be aware of the adverse effects that attend the use of these drugs and should warn patients accordingly. Disclosures should be documented in the patient record. 

Pharmacokinetic Properties of Systemic Carbonic Anhydrase Inhibitors... 

The carbonic anhydrase inhibitors, of which acetazol-amide (rINN), a non-competitive inhibitor, is the prototype, are not suitable for normal diuretic use, because tolerance soon develops. However, they are well suited to brief intermittent use, particularly in the relief of glaucoma and in the prevention of acute mountain sickness. Acetazolamide and methazolamide (rINN) should be used with caution in the long-term control of glaucoma because of its serious systemic adverse effects. However, brinzolamide (rINN) and dorzolamide (rINN) are available for long-term topical administration. 

The safety profile and efficacy of 2% dorzolamide hydrochloride (Trusopt) eye-drops have been evaluated. It was as effective as pilocarpine 2% and its ocular hypotensive efficacy was comparable with that of betaxolol 0.5%. The patients reported less interference with quahty of life with dorzolamide than pilocarpine, particularly in regard to limitations in their ability to drive, read, and perform moderate activities. Long-term use was not associated with important electrolyte disturbances or the systemic effects commonly observed with oral carbonic anhydrase inhibitors (1-3). 

In a 3-month prospective study of the adverse effects and efficacy of topical dorzolamide in 39 patients intolerant of systemic carbonic anhydrase inhibitors, the effect on mean intraocular pressure was similar to that of acetazolamide, and health assessment scores improved significantly in seven of the eight categories of the SF-36 health assessment questionnaire used to evaluate changes in well-being and quahty of life (4). There were no adverse effects with the switch in medication. 

Nesher R, Ticho U. Switching from systemic to the topical carbonic anhydrase inhibitor dorzolamide effect on the quality of life of glaucoma patients with drug-related side effects. Isr Med Assoc J 2003 5(4) 260-3. 

A number of carbonic anhydrase inhibitors have been used topically, including dichlorphenamide (diclofenamide) and methazolamide. These are diuretics used systemically, and the diuretic mannitol is sometimes used in emergencies. 

An even more extreme situation is found with carbonic anhydrase inhibitors such as ac-etazolamide, ethoxyzolamide, and methazol-amide, which are useful for the treatment cf glaucoma. Because of their limited aqueous solubility or unfavorable lipophilicity,they are not active when given topically to the eye and must be given orally or parenterally. Systemic side effects severely limit this mode of therapy and, consequently, numerous investigations are presently under way to find a new carbonic anhydrase inhibitor that readily penetrates the cornea or to prepare a prodrug with adequate water solubility and lipophilicity combined with the ability to be reconverted to the parent sulfonamide after corneal passage (255-257). 

If combined topical therapy fails to achieve the target lOP or fails to halt glaucomatous optic nerve damage, then systemic therapy with carbonic anhydrase inhibitors is a final medication option before resorting to laser or incisional surgical treatment. The best-tolerated oral preparation is acetazolamide in sustained-release capsules, followed by metbazolamide. The least well-tolerated are acetazolamide tablets. 

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