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PubMed1998

Effects of acetazolamide on choroidal blood flow.

BACKGROUND AND PURPOSE: The acetazolamide provocation test is commonly used to study cerebrovascular vasomotor reactivity. On the basis of the effect of a carbonic anhydrase inhibitor in the central nervous system, we hypothesized that acetazolamide may also increase blood flow in the human choroid. METHODS: In a placebo-controlled, randomized, double-blind, three-way crossover design, acetazolamide (500 mg or 1000 mg i.v.) or placebo was administered to nine healthy subjects. The effect of acetazolamide was studied at 15-minute intervals for 90 minutes. Pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation. In addition, mean blood flow velocity and resistive index in the ophthalmic artery were measured with Doppler sonography. In a second study in six healthy subjects, we assessed the effect of acetazolamide (1000 mg i.v.) on intraocular pressure. RESULTS: Acetazolamide increased fundus pulsation amplitude in a dose-dependent manner (1000 mg: +33%; 500 mg: +20%; P<0.001, ANOVA). The effect of acetazolamide on MFV (1000 mg: +18%; 500 mg: +8%; P=0.003, ANOVA) and RI (1000 mg: -4%; 500 mg: -2%; P=0.006, ANOVA) was less pronounced but also significant. Acetazolamide did not induce any changes in systemic hemodynamic parameters but significantly decreased intraocular pressure (1000 mg: -37%; P<0.0001). CONCLUSIONS: The present data show for the first time that intravenously administered acetazolamide increases choroidal blood flow in humans. This phenomenon therefore indicates that the acetazolamide provocation test may qualify as a tool to investigate ocular vasomotor reactivity in a variety of ocular diseases. Moreover, the increase in choroidal blood flow after carbonic anhydrase inhibition can be expected to contribute to the therapeutic efficacy of carbonic anhydrase inhibitors in glaucoma.

Acetazolamide↗
PubMed1989

[Changes in (a-ET) PCO2 produced by acetazolamide in red cells, not in plasma].

The changes in (a-ET) PCO2, concentration of acetazolamide and inhibition rate of carbonic anhydrase in blood were measured for 3 hours after administration of acetazolamide to anesthetized dogs, in order to find whether the changes in (a-ET) PCO2 was in response to the concentration of acetazolamide in red cells or plasma. 1. The increase in (a-ET) PCO2 was stable for 3 hours after administration of acetazolamide (5-30 mg/kg). 2. According to the concentration of acetazolamide measured by HPLC, the concentration in erythrocytes increased quickly but decreased more slowly than in plasma. The concentration of acetazolamide in erythrocytes became higher than in plasma after 3 hours. 3. The change in the inhibition rate of CA activity in red cells and in plasma paralleled to the concentration of acetazolamide in red cells and in plasma. 4. (a-ET) PCO2 levels could be raised by low CA activity inhibited by acetazolamide in red cells, not in plasma. 5. Remaining in higher concentration of acetazolamide in erythrocytes might be occurred by the reason that acetazolamide combines with protein, especially CA, in erythrocytes to be unable to pass through the erythrocytes membrane smoothly.

Acetazolamide↗
PubMed1998

Aqueous humor flow in human eyes treated with dorzolamide and different doses of acetazolamide.

OBJECTIVE: To measure the effect of topically applied 2% dorzolamide hydrochloride (Trusopt, Merck & Co Inc, Whitehouse Station, NJ) and different doses of orally administered acetazolamide (Diamox, Lederle Ophthalmic Pharmaceuticals, Pearl River, NY), alone and in combination, on aqueous humor flow. DESIGN: A randomized, double-masked, placebo-controlled study of 20 human subjects was carried out. Aqueous humor flow was measured by clearance of topically applied fluorescein. Serum standard bicarbonate and serum acetazolamide levels were analyzed. RESULTS: Treatment with dorzolamide reduced aqueous flow by 17%, and a maximum dose of acetazolamide alone reduced flow by 29%. Increasing doses of acetazolamide alone gradually decreased flow, while small doses of acetazolamide did not suppress flow further when dorzolamide was already applied topically. Serum acetazolamide concentrations rose with increasing doses of acetazolamide. Serum standard bicarbonate levels were all in the normal range. CONCLUSIONS: Treatment with dorzolamide reduced aqueous humor flow statistically significantly (2.50 microL/min vs 3.00 microL/min; P=.001) compared with placebo, but less than a maximum dose ofacetazolamide. Small doses of acetazolamide added to dorzolamide treatment did not further enhance the decrease in flow. Since there was no metabolic acidosis as measured by plasma levels of standard bicarbonate, the decrease in aqueous flow could be attributed to the direct action of the carbonic anhydrase inhibitors on the carbonic anhydrase enzymes. It is concluded that the smaller effect of dorzolamide, as compared with acetazolamide, is due to insufficient inhibition of at least 1 of the 2 carbonic anhydrase isozymes involved in aqueous humor production.

Acetazolamide↗
PubMed1997

Comparison of dorzolamide and acetazolamide as suppressors of aqueous humor flow in humans.

OBJECTIVE: To compare the efficacy of topical 2% dorzolamide hydrochloride (Trusopt) as a suppressor of aqueous humor flow in the human eye with the efficacy of systemically administered acetazolamide (Diamox). DESIGN: A randomized, double-masked, placebo-controlled study of 40 human subjects in 2 academic centers. The effect of dorzolamide on aqueous humor flow was compared with that of acetazolamide as measured by the rate of clearance of topically applied fluorescein. RESULTS: Acetazolamide reduced aqueous flow from 3.18 +/- 0.70 (mean +/- SD) to 2.23 +/- 0.48 microL per minute, a reduction of 30% (P < .001), and dorzolamide reduced the flow to 2.65 +/- 0.64 microL per minute, a reduction of 17% (P < .001). The difference between the effect of acetazolamine and dorzolamide was significant (P < .001). When acetazolamide is added to dorzolamide, the aqueous flow was reduced further to 2.21 +/- 0.47 microL per minute, an additional reduction of 16% (P < .001). When dorzolamide was added to acetazolamide, no additional reduction was observed (P = .73). Similar effects were observed for intraocular pressure. Acetazolamide reduced pressure from 12.5 +/- 2.2 (mean +/- SD) to 10.1 +/- 2.2 mm Hg, a decrease of 19% (P < .001) and dorzolamide reduced it to 10.8 +/- 2.1 mm Hg, or a decrease of 13% (P < .001). The greater effect of acetazolamide than dorzolamide was significant (P = .03). CONCLUSIONS: For reasons that are not known, the topically applied carbonic anhydrase inhibitor 2% dorzolamide hydrochloride is not as effective as systemically administered acetazolamide. Clinicians who prescribe dorzolamide should expect less of an ocular hypotensive effect than that experienced from systemically administered acetazolamide.

Acetazolamide↗
PubMed1999

Cerebrocortical microdysgenesis is enhanced in c57BL/6J mice exposed in utero to acetazolamide.

A small percentage of C57BL/6 mice spontaneously develop focal collections of neurons in the molecular layer of the cerebral neocortex. Usually only one "ectopia" is present in each affected brain. Studies in other mouse strains have shown that these ectopias occur before birth, probably because of a breach in the superficial glial membrane during neuronal migration. The ectopias are heritable and are caused by multiple genes. C57BL/6J mice exposed prenatally to acetazolamide, a carbonic anhydrase-specific inhibitor and teratogen, develop an increased frequency of limb malformations, especially in the right forelimb. In the present study, we hypothesized that the prevalence and severity of ectopias would be increased in acetazolamide-exposed mice because carbonic anhydrase plays a key role in brain development. Further, we wanted to determine whether there was a correlation between the side of limb deformity and the hemisphere containing an ectopia. Thus, we injected C57BL/6J time-mated mice intraperitoneally on embryonic day 9 with either sodium acetazolamide (750 mg/kg) or water. Histological analysis of the brains from 105 acetazolamide-exposed offspring and 89 control offspring revealed no difference in the overall prevalence of cerebrocortical ectopias between the acetazolamide and control groups: 34% of the acetazolamide-exposed and 28% of the control mice had ectopias. There was, however, a striking difference in the shape and size of ectopias: 67% of the ectopias were large in the acetazolamide-exposed group in comparison to 32% in controls. The acetazolamide-exposed offspring also were more likely to have multiple ectopias. Thus, there may be a genetic predisposition for developing ectopias in some mouse strains, but epigenetic factors such as prenatal exposure to acetazolamide can influence their severity.

Acetazolamide↗
PubMed1977

Potentiation by the injection vehicle of the teratological action of acetazolamide in rats.

The high alkalinity of the injection vehicle of certain parenteral solutions of acetazolamide produces necrosis of the skin upon sc injection. The possible modification of this effect on the teratogenicity of acetazolamide was examined. Acetazolamide in a vehicle of pH 10.5 produced 36.6% fetal malformations, in a vehicle of pH 8.7, 6.1%, and in neutral suspension, 11.8%. Adrenal medullectomy or phentolamine plus the high pH acetazolamide reduced the frequency to 23.2 and 24.4%, respectively. The teratogenicity of the low pH acetazolamide was increased by epinephrine to 64.2%. The frequency of hemimelia and micromelia, and of bilateral involvement, was greater in litters exposed to the high pH acetazolamide or the epinephrine-acetazolamide combinations, and was reduced by phentolamine or adrenal medullectomy. Neither the high pH vehicle nor epinephrine produced fetal defects in the absence of acetazolamide. The biological disposition of acetazolamide was not altered by any of the treatments. Reduction of uterine blood flow may be responsible for the potentiation of teratogenicity by the high pH vehicle.

Abnormalities, Drug-Induced↗
PubMed1992

Effect of the application of acetazolamide soaked contact lenses on intraocular pressure of rabbits.

Topical application of acetazolamide has no known effect on intraocular pressure (IOP). We tried to detect the hypotensive effect on IOP of acetazolamide soaked onto soft contact lenses (CL). We applied CLs soaked in either 1%, 3%, or 5% acetazolamide solution onto one eye of 29 rabbits while the contralateral eye served as a control. There was an average 32% reduction of IOP amongst all acetazolamide applied eyes, and an average 19% reduction of IOP amongst all control eyes. Amongst the 1% acetazolamide-CL applied eyes there was a mean 37% reduction of IOP, amongst the 3% acetazolamide-CL applied eyes a mean 36% reduction, amongst the 5% acetazolamide-CL applied a mean 30% reduction, and a mean 19% reduction in control eyes. The longest period of IOP reduction followed the application of 1% acetazolamide-CLs, probably owing to improved drug corneal penetration at this concentration. Our results reveal that the application of acetazolamide soaked soft CLs has a significant hypotensive effect on IOP in both the applied and contralateral control eyes of rabbits.

Acetazolamide↗
PubMed1996

Acetazolamide affects performance on the Nagel II anomaloscope.

BACKGROUND: Recent reports have indicated that acetazolamide alters human electroretinograms. We wished to determine the effects of administering acetazolamide on performance on the Nagel II anomaloscope. METHODS: We tested 15 subjects matches of blue-green light to a mixture of blue and green lights (luminance match) on a Nagel type II anomaloscope 2.5 h after ingesting 500 mg of acetazolamide or a placebo. RESULTS: The mean of the luminance settings for the subjects was 54.4 for the placebo condition and 58.5 for the acetazolamide condition. The mean difference of 4.1 was statistically significant, indicating that following ingestion of acetazolamide subjects were less sensitive to a blue-green light. In two supplementary experiments we tested (1) a second group of four normal subjects using the Nagel type II anomaloscope and (2) the previously untreated eyes of four patients with primary open-angle glaucoma before and after placing them on acetazolamide therapy. In both groups, more blue-green light was needed to make the match after ingestion of acetazolamide. CONCLUSIONS: Acetazolamide alters the sensitivity of one or more cone populations, probably the carbonic anhydrase-containing cones. The sensitivity loss is reversible and does not appear to be clinically significant. However, the results suggest that patients administered acetazolamide should be excluded from studies which compare the color vision of glaucomatous patients to that of normals.

Acetazolamide↗
PubMed2002

Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomised placebo-controlled trial.

BACKGROUND: Familial hemiplegic migraine and episodic ataxia type 2 (EA2) are allelic disorders with distinct types of mutations in the CACNA1A gene. EA2 attacks are remarkably sensitive to acetazolamide, a carbonic anhydrase inhibitor. The effectiveness of acetazolamide in migraine prophylaxis is unknown. OBJECTIVES: To evaluate the efficacy and the tolerability of acetazolamide in migraine prophylaxis. METHODS: We compared daily oral 500 mg acetazolamide and placebo in patients with migraine in a multicentre, double-blind, randomised trial of 12 weeks duration after a run-in period of 4 weeks without treatment. Frequency of attacks at the last trial period of 4 weeks was the primary efficacy criterion. Secondary efficacy criteria were the frequency of attacks per 4 weeks, the severity and duration of attacks, the number of hours with migraine as well as the number of responders with more than 50% reduction in attack frequency. RESULTS: 53 patients had been enrolled when the study was prematurely stopped because of a high number of withdrawals (34%), primarily linked to acetazolamide related side effects. Considering the primary and secondary efficacy criteria, among the 53 included patients (27 in the placebo group and 26 in the acetazolamide group), no difference between the 2 study groups could be demonstrated. The most frequent adverse events related to acetazolamide were paresthesias and asthenia. CONCLUSIONS: In this trial, migraine sufferers poorly tolerated acetazolamide given in an oral dose of 500 mg daily. No obvious prophylactic beneficial effect of acetazolamide appeared on migraine attacks.

Acetazolamide↗
PubMed2002

Reduced blood flow response to acetazolamide reflects pre-existing vasodilation and decreased oxygen metabolism in major cerebral arterial occlusive disease.

A decrease in the cerebral blood flow (CBF) response to acetazolamide may indicate an increase in cerebral blood volume (CBV) caused by reduced perfusion pressure in patients with major cerebral artery steno-occlusive lesions. However, a decrease in cerebral metabolic rate of oxygen (CMRO(2)) caused by ischemic changes may also decrease the CBF response to acetazolamide by decreasing the production of carbon dioxide. The purpose of this study was to determine whether the values of CBV and CMRO(2) are independent predictors of the CBF response to acetazolamide in major cerebral arterial occlusive disease. We used positron emission tomography to study 30 patients with major cerebral artery steno-occlusive lesions. The CBF response to acetazolamide was assessed by measuring baseline CBF and CBF 10 min after an intravenous injection of 1 g of acetazolamide. Multivariate analysis was used to test the independent predictive value of the CBV and CMRO(2) at baseline with respect to the percent change in CBF during acetazolamide administration. Both increased CBV and decreased CMRO(2) were significant and independent predictors of the reduced CBF response to acetazolamide. CBV accounted for 25% of the variance in the absolute change in CBF during acetazolamide administration and 42% of the variance in the percent change in CBF, whereas CMRO(2) accounted for 19% and 4% of the variance, respectively. In patients with major cerebral arterial occlusive disease, a decrease in CMRO(2) may contribute to the reduced CBF response to acetazolamide, although an increase in CBV appears to be the major contributing factor.

Acetazolamide↗
PubMed1988

Usual clinical dose of acetazolamide does not alter cerebral blood flow velocity.

Prior reports indicate that acetazolamide, an inhibitor of carbonic anhydrase, in moderate doses reduces symptoms of acute mountain sickness, and in large doses increases cerebral blood flow. The effect on flow is not known for a moderate dose, but were flow to increase, then increased cerebral oxygen delivery would be one mechanism of benefit from acetazolamide at high altitude. We utilized Doppler ultrasound in 8 volunteers to determine whether a usual acetazolamide dose (250 mg three times daily) would increase flow velocities in internal carotid and vertebral arteries. Acetazolamide during normoxia decreased pHa, PaCO2, and PETCO2, but baseline flow velocity remained unchanged. In 2 subjects without acetazolamide, voluntary hyperventilation decreased both PETCO2 and flow velocity. Both hypoxia and hypercapnia caused increases in arterial velocities. The increases were not altered by acetazolamide administration. In one subject, 1 g acetazolamide by acute i.v. injection induced an increase in flow velocity (40%) concomitant with a 5 mm Hg decrease in PETCO2, confirming prior reports using similar intravenous dose. In doses employed for prevention of acute mountain sickness, acetazolamide induced metabolic acidosis and may have prevented the fall in velocity usually associated with hypocapnia, but it neither increased baseline cerebral blood flow velocity nor velocity responses to hypoxia and hypercapnia. Benefit of acetazolamide at high altitude may relate to mechanisms other than increased cerebral blood flow.

Acetazolamide↗
PubMed2001

In vivo evidence for K(Ca) channel opening properties of acetazolamide in the human vasculature.

1. The selective carbonic anhydrase inhibitor acetazolamide is known to increase blood flow in several organs. Acetazolamide directly dilates isolated resistance arteries associated with activation of calcium-activated potassium (K(Ca)) channels. We examined both the presence and mechanism of the direct vascular action of acetazolamide in vivo in humans. 2. Forearm vasodilator responses of 30 healthy volunteers to infusion of placebo and increasing doses of acetazolamide (1-3-10 mg min(-1) dl(-1)) into the brachial artery were recorded by venous occlusion plethysmography, before and after local administration of L-NMMA (0.2 mg min(-1) dl(-1), an inhibitor of NO-synthase, n=6), indomethacin (5.0 microg min(-1) dl(-1), an inhibitor of prostaglandin synthesis, n=6), glibenclamide (10 microg min(-1) dl(-1), an inhibitor of K(ATP) channels, n=6), tetraethylammonium (0.1 mg min(-1) dl(-1), an inhibitor of K(Ca) channels, n=6) or placebo (NaCl 0.9%, n=6). Lower dosages of acetazolamide did not affect vascular tone (n=6). 3. Acetazolamide infusions increased forearm blood flow from 2.41+/-0.17 to 2.99+/-0.18, 4.09+/-0.26 and 6.77+/-0.49 ml min(-1) dl(-1) in the infused forearm (P:<0.001), with no significant changes in the non-infused forearm, blood pressure or heart rate. Acetazolamide-induced vasodilation was not inhibited by L-NMMA, indomethacin, or glibenclamide but was significantly attenuated by TEA (vasodilation: 23+/-6, 82+/-19, 241+/-38% versus 27+/-8, 44+/-22, 42+/-35%). 4. We conclude that acetazolamide exerts a direct vasodilator effect in vivo in humans mediated by vascular K(Ca) channel activation. This makes acetazolamide the first drug known that specifically modulates this channel.

Acetazolamide↗
PubMed1990

Severe metabolic acidosis and disturbances of calcium metabolism induced by acetazolamide in patients on haemodialysis.

1. To investigate mechanisms of extrarenal buffering in uraemic acidosis, we studied the effects of the carbonic anhydrase inhibitor, acetazolamide, in normal subjects and in patients with end-stage kidney disease on maintenance haemodialysis with virtually no urine output. 2. Acetazolamide (500 mg) was administered daily for 7 days, after pretreatment for 1 month with 1,25-dihydroxyvitamin D (n = 12) or placebo (n = 12); only placebo was administered to a third group (n = 12) of haemodialysis patients. In addition, acetazolamide was administered to normal control subjects (n = 12). 3. Treatment with acetazolamide resulted in a more marked metabolic acidosis in haemodialysis patients than in normal control subjects and the effect in haemodialysis patients was attenuated by prior treatment with 1,25-dihydroxyvitamin D. 4. The administration of acetazolamide to haemodialysis patients led to an increase in serum inorganic phosphorus, bone isoenzyme of alkaline phosphatase and parathyroid hormone, and a reduction in serum calcium, whereas acetazolamide had no effect on these variables in normal subjects. In contrast, in the haemodialysis patients previously treated with 1,25-dihydroxyvitamin D, acetazolamide increased serum inorganic phosphorus, bone isoenzyme of alkaline phosphatase, parathyroid hormone and serum calcium. 5. We hypothesize that the metabolic acidosis induced by acetazolamide in haemodialysis patients may result from interference with the mechanisms of extrarenal buffering. 6. As parathyroid hormone, 1,25-dihydroxyvitamin D and carbonic anhydrase are thought to be involved in bone buffering, we suggest that the marked acidosis seen in haemodialysis patients treated with acetazolamide may be due to impaired parathyroid hormone-mediated bone buffering.

Acetazolamide↗
PubMed1993

The effect of acetazolamide on ventilation in panic disorder patients.

OBJECTIVE: Patients with panic disorder are behaviorally hypersensitive to CO2 inhalation and may also be biologically hypersensitive. A report by Mathew et al. showed, however, that administration of the carbonic anhydrase inhibitor acetazolamide, which is believed to increase brain CO2 level, did not cause panic in panic disorder patients. The authors of the present study noted that respiratory frequency did not increase in the earlier experiment and wondered whether respiratory stimulation occurred during acetazolamide administration, as would be expected if CO2 level increases significantly. METHOD: Ten patients with panic disorder and six normal control subjects received injections of acetazolamide, 1 g i.v., as per the Mathew et al. protocol, during breath by breath measurement of both tidal volume and frequency of respiration. RESULTS: Three patients had panic attacks, one before receiving acetazolamide, one during the injection, and one 2 minutes after injection. Only the last of these attacks appeared possibly attributable to acetazolamide. None of the control subjects panicked. Neither patients nor control subjects exhibited meaningful change in tidal volume, respiratory frequency, or minute ventilation, and both groups experienced a trend toward significant decrease in overall levels of anxiety and dyspnea after acetazolamide injection. CONCLUSIONS: The authors replicated the earlier finding that acetazolamide is not panicogenic in patients with panic disorder but also showed that at the dose given, there is no meaningful effect on ventilation. If acetazolamide does affect CO2 levels it does so in a way that does not stimulate ventilation. Therefore, the acetazolamide injection results of Mathew et al. and of the present study do not challenge hypotheses linking panic attacks to hypersensitive respiratory control mechanisms.

Acetazolamide↗
PubMed2004

The effect of deafferentation on cerebral blood flow response to acetazolamide.

BACKGROUND AND PURPOSE: Decreased cerebral blood flow (CBF) response after acetazolamide administration may indicate increased cerebral blood volume (CBV) owing to reduced perfusion pressure from major cerebral artery steno-occlusive disease. However, decreased cerebral metabolic rate of oxygen (CMRO(2)) caused by neuronal damage or deafferentation may also decrease the CBF response to acetazolamide, which adds complexity to the assessment of autoregulatory vasodilatation. The purpose of this study was to investigate the relationship between CBF response to acetazolamide and CBV or CMRO(2) in a pure form of deafferentation, crossed cerebellar diaschisis (CCD). METHODS: We used positron emission tomography to study 17 patients with unilateral supratentorial infarct and contralateral cerebellar hypoperfusion. The CBF response to acetazolamide was assessed by measuring baseline CBF and CBF 10 minutes after an intravenous injection of acetazolamide. Multivariate analysis was used to test the independent predictive value of the CBV and CMRO(2) at baseline with respect to the change of CBF during acetazolamide administration. RESULTS: Multivariate analysis revealed that in CCD CBV was significantly and independently associated with the percent change of CBF during acetazolamide administration (P <.0001), whereas CMRO(2) was not. CONCLUSION: In deafferentation, changes in CBV may account for variations in CBF response to acetazolamide and decreased CMRO(2) may not affect CBF response to acetazolamide expressed as the percent change.

Acetazolamide↗
PubMed1982

Effectiveness of generic acetazolamide.

Comparisons were made between the ocular hypotensive effects and blood levels achieved with the single-dose administration of either generic acetazolamide or brand-name acetazolamide (Diamox). The relative cost of the two products was surveyed. The effect of food on the absorption of acetazolamide was also evaluated. The generic and brand-name acetazolamide were equivalent in their effects on intraocular pressure. Comparable blood levels of acetazolamide were obtained with the two products. The cost of generic acetazolamide was 37% less than brand-name acetazolamide, when available. Food intake did not appear to influence the absorption of acetazolamide.

Acetazolamide↗
PubMed1989

Acetazolamide blood concentrations are excessive in the elderly: propensity for acidosis and relationship to renal function.

Elderly glaucoma patients are often treated with acetazolamide, a carbonic anhydrase inhibitor with clearance dependent on renal function. A high incidence of metabolic acidosis and other adverse effects have been noted among these patients but the reasons for this have not been explained. We hypothesized that commonly used doses of acetazolamide among the elderly result in excessive blood concentrations and that these concentrations are related to acid-base disturbances. We measured steady-state acetazolamide levels in plasma, plasma ultrafiltrate (unbound), and erythrocytes among 12 elderly subjects (79.2 +/- 7.6 years old). Mean plasma (18.9 +/- 10.9 micrograms/mL) and ultrafiltrate concentrations (1.0 +/- 0.7 microgram/mL) exceeded the therapeutic range (plasma 5-10 micrograms/mL; ultrafiltrate 0.25-0.50 microgram/mL) for glaucoma control by two fold and were elevated in 75% of subjects. Plasma and ultrafiltrate acetazolamide levels significantly correlated with the dose adjusted for creatinine clearance (r = 0.91, P less than 0.001; r = 0.89, P less than 0.001, respectively). Acidotic subjects (serum total carbon dioxide less than or equal to 22 mEq/L) tended to have higher plasma, ultrafiltrate, and erythrocyte acetazolamide levels compared with nonacidotic subjects. Serum total carbon dioxide levels were significantly correlated with erythrocyte acetazolamide concentrations (r = -0.75, P = 0.03). The ratio of erythrocyte acetazolamide concentration to creatinine clearance separated acidotic from nonacidotic subjects (P less than 0.01). These findings suggest that some of the adverse effects of acetazolamide can be avoided by reducing the dose to compensate for age-related reductions in renal drug clearance.

Acetazolamide↗
PubMed1998

Pharmacokinetics and pharmacodynamics of acetazolamide in patients with transient intraocular pressure elevation.

OBJECTIVE: To characterize the pharmacokinetics and pharmacodynamics of acetazolamide in patients with transient intraocular pressure (IOP) elevation and to provide individual patients with the optimal dosage regimen for this drug. METHODS: We studied 17 patients with transient IOP elevation, who were given 62.5-500 mg acetazolamide orally as single or repetitive doses. Plasma acetazolamide concentration and IOP were measured at approximately 1, 3, 5, and 9 h after the last acetazolamide administration. Pharmacokinetics and pharmacodynamics were analyzed by nonlinear mixed-effect modeling using the program NONMEM. RESULTS: The plasma concentration profile of acetazolamide was characterized by a one-compartment model with first-order absorption. The apparent oral clearance was related to the creatine clearance (CCR) which was estimated by the Cockcroft and Gault equation, as follows: 0.0468 x CCR1 x h(-1). The estimated apparent oral volume of distribution, first-order absorption rate constant, and absorption lag time were 0.231 l x kg(-1), 0.821 x h(-1), and 0.497 h, respectively. IOP after oral acetazolamide administration was characterized by an Emax model. The maximal effect in lowering the IOP (Emax) was 7.2 mmHg, and the concentration corresponding to 50% of the maximal effect (EC50) was 1.64 microg x ml(-1). As 70% of Emax was achieved at a plasma concentration of 4 microg x ml(-1), this concentration was considered satisfactory for lowering IOP. The recommended dosage was calculated so that the minimum plasma concentration at steady state exceeded this target concentration; 250 mg t.i.d., 125 mg t.i.d., 125 mg b.i.d., and 125 mg once daily for the patients with CCR values of 70, 50, 30, and 10 ml min(-1), respectively. CONCLUSION: Measuring plasma concentrations of acetazolamide and subsequent pharmacokinetic and pharmacodynamic analyses are useful for estimating its concentration-dependent effectiveness in lowering the IOP in individual patients. The dosage regimen presented in this study is expected to improve the benefits of acetazolamide pharmacotherapy in most elderly patients with transient rises in IOP following intraocular surgery.

Acetazolamide↗