dorzolamide and Acidosis

Topical carbonic anhydrase inhibitors (CAI), used for treatment of glaucoma, are generally regarded as safe and unconnected with systemic side effects. We report an unusual case of fatigue, metabolic acidosis, and normocytic anaemia associated with ocular administration of the CAI, dorzolamide, in a patient with impaired renal function. In chronic kidney disease, where CAI elimination may be decreased, and patients prone to develop metabolic acidosis, systemic absorption of ocular administered CAI could lead to rare, but potentially serious adverse reaction, that are a consequence of inhibition of extraocular carbonic anhydrase isoenzymes.

Topics: Acidosis; Administration, Ophthalmic; Anemia; Carbonic Anhydrase Inhibitors; Fatigue; Glaucoma; Humans; Male; Middle Aged; Renal Insufficiency; Sulfonamides; Thiophenes

Topics: Acidosis; Administration, Topical; Anesthesia, General; Animals; Carbonic Anhydrase Inhibitors; Dog Diseases; Dogs; Female; Glaucoma; Sulfonamides; Thiophenes

The carbonic anhydrase inhibitor dorzolamide can induce relaxation of retinal arterioles with a consequent increase in blood flow and oxygenation of the retina. It has been shown that the mechanisms underlying this relaxation are independent of extracellular acidosis and CO2. The purpose of the present study was to investigate the possible involvement of nitric oxide (NO) and intracellular acidosis in dorzolamide-induced relaxation of retinal arterioles. Porcine retinal arterioles were mounted in a wire myograph and dorzolamide induced relaxation was studied after 1) the addition of the NO synthase inhibitor l-NAME (3 × 10(-4) M) or the guanylyl cyclase inhibitor ODQ (3 × 10(-6) M), and 2) after loading the smooth muscle cells with the pH sensitive fluorophore SNARF-1-AM and studying changes in vascular tone and intracellular fluorescence after the induction of hypoxia, addition of lactate (10(-2) M), and extracellular acidification (pH = 7.0) alone and in the presence of dorzolamide (10(-3) M). Dorzolamide significantly relaxed retinal arterioles (p < 0.03), and the effect was significantly higher in the presence of perivascular tissue than in isolated vessels at the highest concentration (p < 0.01). In the presence of perivascular tissue dorzolamide-induced relaxation could be reduced by NO inhibition (p < 0.02). Dorzolamide increased intracellular acidification (p < 0.02) during extracellular acidosis, but there was no relation between relaxation and intracellular acidosis. In conclusion, dorzolamide-induced vasorelaxation depends on NO and the perivascular retinal tissue, but is independent of acidification in the extracellular and the intracellular space of retinal vascular smooth muscle cells. Other factors than NO and acidification are involved in dorzolamide-induced relaxation of retinal arterioles.

Topics: Acidosis; Animals; Arterioles; Benzopyrans; Bradykinin; Carbonic Anhydrase Inhibitors; Endothelium, Vascular; Enzyme Inhibitors; Fluorescent Dyes; Hydrogen-Ion Concentration; Lactates; Muscle, Smooth, Vascular; Myography; NG-Nitroarginine Methyl Ester; Nitric Oxide; Oxadiazoles; Quinoxalines; Retinal Artery; Sulfonamides; Swine; Thiophenes; Vasodilation

Carbonic anhydrase inhibitors reduce intraocular pressure, which may protect the optic nerve from ischemia. However, carbonic anhydrase inhibitors have also been shown to dilate the blood vessels in the retina and the optic nerve head. The purpose of the present study was to investigate whether CO(2), H(+), or factors other than carbonic anhydrase inhibition are involved in this vasodilating effect.. Porcine retinal arterioles with preserved perivascular retinal tissue were mounted in a myograph for isometric force measurements. After precontraction with the prostaglandin analogue U46619, concentration-response experiments were performed with acetazolamide and dorzolamide before and after removal of the perivascular retina. The experiments were performed at normal pH and during acidosis, during normocapnia and hypercapnia, as well as in the nominal absence of CO(2) and HCO(3)(-).. The maximum relaxation was significantly lower and the EC(50) significantly higher during normal pH compared with acidosis (P = 0.002 and P < 0.0001, respectively), but neither the maximum relaxation nor EC(50) was changed by hypercapnia (P = 0.054 and P = 0.57, respectively). The findings confirmed that carbonic anhydrase-induced vasodilation depends on the perivascular retinal tissue and that dorzolamide produces significantly more pronounced relaxation than does acetazolamide. EC(50) of carbonic anhydrase inhibitor-induced vasorelaxation and the maximum relaxation of dorzolamide were unchanged in the nominal absence of CO(2) and HCO(3)(-) (P = 0.65 and P < 0.0001, respectively).. The vasodilating effect of carbonic anhydrase inhibitors on porcine retinal arterioles depends on the perivascular retinal tissue and acidosis, but not on hypercapnia. The effect involves mechanisms other than carbonic anhydrase inhibition.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetazolamide; Acidosis; Animals; Arterioles; Carbon Dioxide; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Dose-Response Relationship, Drug; Hydrogen-Ion Concentration; Hypercapnia; Muscle, Smooth, Vascular; Myography; Nifedipine; Retinal Artery; Sulfonamides; Swine; Thiophenes; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Topics: Acidosis; Antihypertensive Agents; Carbonic Anhydrase Inhibitors; Humans; Infant, Newborn; Male; Sulfonamides; Thiophenes