Carbonic anhydrase inhibitor side effects

Epstein DL, Grant WM. Carbonic anhydrase inhibitor side effects. Serum chemical analysis. Arch Ophthalmol 1977 95 1378-1382. 

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. 

Local side effects include burning, stinging, itching, foreign body sensation, dry eyes, and conjunctivitis. Brinzolamide may have a lower incidence of these side effects since the drug is in a neutral pH solution. Dorzolamide has been reported to cause irreversible corneal decompensation. Taste abnormalities have been reported with each agent. Both topical carbonic anhydrase inhibitors are sulfonamides and are contraindicated in patients with history of sulfonamide hypersensitivity.10,13... 

Acetazolamide is a carbonic anhydrase inhibitor, used primarily in glaucoma to reduce aqueous humour production. Acetazolamide may cause blood disorders including agranulocytosis (deficiency of neutrophils) as a side-effect. 

Orally administered carbonic anhydrase inhibitors lower the intraocular pressure of glaucoma patients, however they induce a number of intolerable side effects associated with extraocular inhibition of the enzyme [5,6]. Thus, much research has been directed towards the search for a topically effective agent. Several compounds have been synthesized since the 1980 s in Merck Sharp Dohme Research Laboratories, and have been found to be topically active in man [7]. Unfortunately, many of these compounds were not very soluble. Attempts to obtain an active carbonic anhydrase inhibitor with good solubility resulted in the synthesis of Dorzolamide hydrochloride [8,9], which was first made available for pharmacological evaluation in 1987. Like other carbonic anhydrase inhibitors sulfonamides (such as acetazolamide, ethoxzolaniide, and methazolamide) dorzolamide is an inhibitor of human carbonic anhydrase isoenzymes I, II, and IV. In contrast to the other sulfonamides, dorzolamide is a potent inhibitor of isoenzymes II and IV, and a weak inhibitor of isoenzyme I [ 10]. Isoenzyme II is thought to play a major role in aqueous humor secretion. 

Acetazolamide (a carbonic anhydrase inhibitor) used as diuretic by increasing bicarbonate excretion and thus acidosis occur as side effect which is related to its pharmacological action. 

Alprazolam may also relieve tremor at doses of 0.75 to 3 mg/day (357). Because chronic use can lead to habituation or dependence, alprazolam is best used episodically for patients who require only intermittent tremor reduction to prevent social embarrassment or occupational interference. Methazolamide, a carbonic anhydrase inhibitor, has been reported to reduce hand tremor (at doses of 50 to 300 mg/day) in several open studies ( 358, 359). A controlled trial, however, could not confirm the efficacy of this agent in the treatment of tremor but did report that side effects such as paresthesias, sedation, headache, and gastrointestinal symptoms were common (77, 356). 

Figure 2.5 In addition to its antibacterial activity, sulfanilamide 11 (Figure 2.4) inhibits the enzyme carbonic anhydrase. Acetazolamide 12 is much more potent as a carbonic anhydrase inhibitor but its clinical use as diuretic was impaired by some serious side effects. Hydrochlorothiazide 13 is the prototype of orally active saluretic sulfonamide diuretics. Furosemide (frusemide) 14 and bumetanide 15 are so-called loop diuretics .

SOTALOL DIURETICS-CARBONIC ANHYDRASE INHIBITORS, LOOP DIURETICS, THIAZIDES t risk of ventricular arrhythmias, particularly torsades de pointes ventricular tachycardia, caused by sotalol Hypokalaemia, a side-effect of these diuretics, predisposes to arrhythmias during sotalol therapy Normalize potassium levels before starting sotalol in patients already taking these diuretics. When starting these diuretics in patients already taking sotalol, monitor potassium levels eveiy 4-6 weeks until stable... 

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). 

Brinzolamide is a carbonic anhydrase inhibitor that causes an inhibition of carbonic anhydrase in the cihary processes of the eye deaeases aqueous. It is indicated in the treatment of elevated lOP inpatients with ocular hypertension or open-angle glaucoma. The development of topical carbonic anhydrase inhibitor took many years but was an important event because of the poor side-effect profile of oral carbonic anhydrase inhibitors (CAIs). Dorzolamide (Trusopt) and brinzola-mide both work by inhibiting carbonic anhydrase (isoenzyme n), which is found in the ciliary body epithehum. This reduces the formation of bicarbonate ions, which reduces fluid transport and thus lOP. hi fact, the P-receptor antagonist timolol has been combined with the carbonic anhydrase inhibitor dorzolamide in a single medication (Cosopt). 

When sulfanilamide was introdnced as a chemotherapeutic agent, metabolic acidosis was recognized as a side effect. This observation led to the demonstration that snl-fanilamide is an inhibitor of carbonic anhydrase. Snbse-quently, an enormous number of sulfonamides were synthesized and tested for the ability to inhibit carbonic anhydrase of these componnds, acetazolamide has been studied most extensively. Three carbonic anhydrase inhibitors currently are available in the United States—acetazolamide, dichlorphenamide (Daranide), and methazolamide (GlaucTabs). The common molecnlar motif of available carbonic anhydrase inhibitors is an nnsnbstitnted sulfonamide moiety. 

The development of a topical carbonic anhydrase inhibitor was prompted by the poor side-effect profile of oral CAIs. Dorzolamide (trusopt) and brinzolamide (azopt) both work by inhibiting carbonic anhydrase (isoenzyme II), which is found in the ciliary body epithelium. This reduces the formation of bicarbonate ions, which reduces fluid transport and thus lOP. 

It also was observed that sulfanilamide rendered the urine of dogs alkaline because of the Inhibition of carbonic anhydrase. This Inhibition of carbonic anhydrase resulted In a lesser exchange of hydrogen Ions for sodium Ions In the kidney tubule. Sodium Ions, along with bicarbonate Ions, and associated water molecules were then excreted, and a diuretic effect was noted. The large doses required and the side effects of sulfanilamide prompted a search for more effective carbonic anhydrase Inhibitors as diuretic drugs. 

A list of drugs for carbonic anhydrase inhibitors is provided in the Appendix. Detailed tables show doses, recommendations, expectations, side effects, contraindications, and more available on the book s Web site (see URL in Appendix). 

A -Alkyl and sulfonamide derivatives of the 1,2,3-benzothiazine-l,1-dioxides 40, whose synthesis is shown in Schemes 1 and 2, are inhibitors of carbonic anhydrase <1995USP5464831, 1996USP5510347>. These compounds are used as a treatment for chronic primary angle glaucoma that is associated with a sustained increase in the intraocular pressure of the diseased eye. Topical administration of carbonic anhydrase inhibitors can be used to control intraocular pressure with a reduced risk of side effects such as nausea, dyspepsia, fatigue, and metabolic acidosis. 

Durzolaiiiide is a topically active inhibitor of carbonic anhydrase (CA-2). It can be used alone in patients in whom [3-blockers are con-iraindicated. It is a sulphonainide and systemic side-effects may occur, c.g. skin rashes, bronchospasm. 

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