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PubMed2006

Dynamic CT perfusion imaging with acetazolamide challenge for evaluation of patients with unilateral cerebrovascular steno-occlusive disease.

BACKGROUND AND PURPOSE: Perfusion CT (PCT) has the ability to measure quantitative values and produce maps of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). We assessed cerebral hemodynamics by using these parameters and acetazolamide challenge in patients with cerebrovascular steno-occlusive disease. METHODS: Fifteen patients underwent PCT with acetazolamide challenge. Comparison of mean CBF, CBV, and MTT was determined between hemispheres and before and after acetazolamide challenge. Hemispheric ratio and percent change due to acetazolamide administration were also calculated. Absolute values and percent changes 2 SDs outside the mean from the nonstenotic hemispheres were defined as abnormal. RESULTS: Significant decreases in CBF (-25.1%, P = .003) and significant increases in MTT (47.1%, P < .001) were found in stenotic hemispheres. After acetazolamide challenge, significant changes in CBF (-39.5%, P < .001) and MTT (92.9%, P < .001) were also seen. The acetazolamide test significantly decreased CBF hemispheric ratio (-20.3%, P < .001) and increased MTT hemispheric ratio (30.8%, P = .002), making both maps more asymmetric. Significance in CBF and MTT percent changes (P < .001 and P = .005, respectively) was found between hemispheres. When CBF percent changes were assumed to represent the true determinant of hemodynamic impairment, normal ranges of baseline MTT value and MTT percent changes demonstrated sensitivities of 66.7% and 100% and specificities of 58.3% and 75%, respectively, for detecting patients with hemodynamic impairment. CONCLUSION: Parameters obtained from PCT with acetazolamide are promising for the evaluation of cerebral hemodynamics in patients with cerebrovascular steno-occlusive disease.

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PubMed1984

Acetazolamide and cerebral oxygenation in dogs.

Acetazolamide could theoretically impair oxygen delivery to cerebral tissue by inhibiting local acidification of capillary blood. There is considerable evidence, however, that acetazolamide improves cerebral oxygen tension. This experiment was designed to demonstrate increased deep cerebral oxygen tension after acetazolamide. Three groups of dogs were anesthetized with pentobarbital and ventilated with a respirator. A Teflon-coated stainless steel catheter was placed through a craniotomy into the parietal lobe and advanced into the corona radiata to monitor cerebral pO2 and pCO2 with a mass spectrometer. Group one dogs were normoxic and eucapneic. Group two dogs were hypoxemic, and Group three dogs were hypocapneic. After control cerebral and arterial gas tensions had been recorded, acetazolamide (30 mg kg-1) was injected intravenously. Cerebral gas tensions were monitored continuously and arterial gases were analyzed at 30, 60, 90 and 120 min. Cerebral oxygen tension was not decreased by acetazolamide in any of the dogs. Cerebral carbon dioxide tension was increased by acetazolamide in all dogs. We conclude that acetazolamide does not deplete cerebral oxygen tension even in the face of hypoxemia or acute hypocapnea.

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PubMed1983

[Acetazolamide in hypercapnic chronic obstructive lung disease--a renaissance?].

The use of acetazolamide, a carbonic anhydrase inhibitor, in chronic obstructive pulmonary disease (COPD) remains controversial. A substantial improvement in blood gas values has been documented, with correction of metabolic alkalosis in COPD, in hypoxemic sleep apnea at high altitudes and in acute mountain sickness. This randomized, double-blind study examined the short and long term effects of acetazolamide (2 X 250 mg) on 14 patients with hypoxemia, hypercapnia and metabolic alkalosis (paO2 49 +/- 5.2 mm Hg, paCO2 50 +/- 3.6 mm Hg, base excess + 5.7 +/- 2.3). A crossover between acetazolamide and placebo occurred on days 3, 6 and 9. On day 12 the patients were again randomized and one group further treated with acetazolamide for 4 1/2 (1-7) months. During the short term phase, a significant rise in paO2 to 58 +/- 6.6 mm Hg with acetazolamide was noted, followed by a drop to 53 +/- 5.7 mm Hg with placebo. The paO2 of the five patients on long-term acetazolamide therapy remained unchanged (59 +/- 2.5 mm Hg) while the untreated patients showed a significant drop in paO2 to 46 +/- 8.2 mm Hg. No side effects and no severe metabolic acidosis were noted during acute or long term treatment. Acetazolamide appears to improve hypoxemic and hypercapnic COPD patients with metabolic alkalosis on short and long term therapy.

Acetazolamide↗
PubMed1981

Effect of acetazolamide on renal function of the newborn piglet.

The effects of renal development on the response of newborns to acetazolamide were determined in an animal model, 5- and 20-day-old piglets. Increasing doses of acetazolamide increased both sodium and potassium excretion in 5-day-old piglets. Sodium excretion increased from 1.89 muEq/min during control periods to 15.7 muEq/min during infusion of acetazolamide (75 mg/kg/h). Potassium excretion increased to 20 muEq/min during acetazolamide infusion and urine pH increased from 5.7 to over 8.0. Sodium excretion by 20-day-old piglets given acetazolamide was similar to that of 5-day-old piglets but potassium excretion was twice as great (40 muEq/min). Changes in urine pH of the two groups were identical. It is concluded that the natriuretic response of 5-day-old piglets to acetazolamide is similar to that of older animals. In newborn piglets, moderate increases in sodium excretion by acetazolamide were accompanied by a marked kaliuresis. These data may identify a role for carbonic anhydrase in potassium excretion by newborn similar to that of adults.

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PubMed1994

The pharmacokinetics of acetazolamide during CAPD.

Acetazolamide is a carbonic anhydrase inhibitor commonly used to reduce intraocular pressure (IOP). We report the first pharmacokinetic study of acetazolamide in a patient undergoing continuous ambulatory peritoneal dialysis (CAPD). The patient was a Type I diabetic with end-stage renal disease (ESRD) undergoing CAPD who received acetazolamide for elevated IOP after surgery for a detached retina. Serum acetazolamide concentrations were measured prior to a 250 mg oral dose and 12 additional times during a 24-h dosing interval. All dialysate effluent was collected and assayed for acetazolamide. Serum concentrations at the beginning and end of the dosing interval were 18 and 17 mcg/mL, respectively, with a maximum concentration of 27 mcg/mL at 6.5 h (therapeutic range = 5-10 mcg/mL). The elimination half-life was prolonged, 28.5 h, compared to that seen in subjects with normal renal function (5-10 h). CAPD did not remove a clinically significant amount of drug (17.1 mg, or 6.8% of dose recovered in dialysate). The patient was very lethargic during therapy, a possible manifestation of acetazolamide toxicity. Marked reduction in acetazolamide dosage (in this case, 125 mg/day) would be required to prevent drug accumulation and toxicity.

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PubMed1977

Effect of acetazolamide and parathyroid hormone on HCO3 and PO4 excretion.

It has been recently demonstrated that parathyroid hormone (PTH) inhibits renal cortical carbonic anhydrase. Based on this in vitro study, it was suggested that PTH depresses proximal reabsorption of phosphate and bicarbonate reabsorption in vivo by inhibiting carbonic anhydrase. To test this hypothesis, we measured bicarbonate and phosphate excretion in four groups of dogs. Group I received PTH for 2 hours; group II received acetazolamide for 2 hours; group III received PTH for 2 hours and acetazolamide in the 2nd hour; and in group IV, acetazolamide was given for 2 hours with PTH ADDED IN THE 2ND HOUR. Acetazolamide administration resulted in maximal bicarbonate excretion in the 1st hour and maximal phosphate excretion in the 2nd hour. Addition of acetazolamide to animals receiving PTH or addition of PTH to animals receiving acetazolamide resulted in additional increases in bicarbonate and phosphate excretion. These data demonstrate that PTH induces bicarbonate and phosphate excretion regardless of whether carbonic anhydrase is intact or nearly 100% inhibited by acetazolamide. These data do not support the hypothesis that PTH inhibits bicarbonate and phosphate reabsorption by inhibiting carbonic anhydrase.

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PubMed1995

Acetazolamide-induced inhibition of carbonic anhydrase influences energy metabolism and respiratory work in healthy subjects.

To assess the usefulness of acetazolamide in weaning a patient from a respirator, we monitored the changes in the respiratory quotient ratio (RQ ratio), the ventilation volume (VE; l/min.), carbon dioxide elimination (VCO2; ml/min.), the oxygen consumption (VO2; ml/min.) and the metabolic energy expenditure (EE; Cal/day) for 6 hours before (baseline) and after the intravenous administration of acetazolamide, 6 mg/kg, in 12 healthy adult volunteers. The RQ ratio decreased significantly from 0.88 to 0.82 after the injection of acetazolamide, 6 mg/kg, and remained below baseline throughout the 6 hours of observation. VCO2 decreased significantly and VE increased significantly after acetazolamide administration. There were no significant changes in VO2 or EE. The RQ ratio increased only slightly, from 0.85 to 0.87, in the control group (no acetazolamide). No significant changes in VCO2 or VE were observed in the control group. Findings suggest that acetazolamide may alter the main pathway of energy metabolism from being carbohydrate-dominant to being fat-dominant, with a resulting fall in CO2 production to maintain the adequate work of ventilation. The inhibition of carbonic anhydrase by acetazolamide may be useful in reducing respiratory work in a patient who is weaned from a respirator.

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PubMed1996

Acetazolamide and CO2: acute effects on cerebral and retrobulbar hemodynamics.

PURPOSE: Acetazolamide and CO2 are cerebral vasodilators whose specific effects in various brain regions have not been carefully defined. We investigated the effects of these agents in both larger cerebral and smaller, retrobulbar arteries, to compare their general cerebral vasodilatory influence with their specific ocular vascular effects. METHODS: Twelve young adults with healthy eyes were studied under normocapnic and hypercapnic (6% CO2, 94% O2 tanked gas) conditions after receiving either placebo or 1,000 mg acetazolamide (3 h before study). Color Doppler imaging was used to measure peak systolic and end-diastolic velocities (PSV and EDV) in the internal carotid, middle cerebral, ophthalmic, and central retinal arteries under each condition. RESULTS: Acetazolamide and CO2 each lowered intraocular pressure; combining the agents provided no additive ocular hypotensive effect. Hypercapnia or acetazolamide per se failed to alter PSV, EDV, or the derived resistance index [RI; (PSV-EDV)/PSV] in the internal carotid or in either orbital artery. However, when hypercapnia was superimposed upon acetazolamide, the resistance index fell in the internal carotid and central retinal arteries (each p < 0.05). In contrast, the middle cerebral artery was responsive to either vasodilator and to their combination: PSV and EDV rose, and RI fell with each experimental treatment. CONCLUSIONS: In the brain, the middle cerebral artery exhibits substantial dependence of flow velocity on the vasodilators CO2 and acetazolamide. In contrast, the ophthalmic and central retinal arteries appear less responsive. Nonetheless, the combination of carbonic anhydrase inhibition (acetazolamide) with CO2 augmentation did lower vascular resistance distal to the central retinal artery, suggesting that this mechanism vasodilates critical ocular tissues.

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PubMed1982

Timolol and acetazolamide. A study of concurrent administration.

A five-week clinical trial of the concurrent administration of topical timolol maleate and oral acetazolamide was conducted to determine the additivity of the ocular hypotensive effects of the two drugs. One drop of 0.5% timolol maleate, every 12 hours, produced a mean reduction in outflow pressure from baseline of 36.0%. When added to an eye pretreated with oral acetazolamide, timolol caused an additional mean decrease in outflow pressure of 27.6%. Acetazolamide, 500 mg orally every 12 hours, produced a mean reduction in outflow pressure from baseline of 48.6%. When added to an eye receiving topical timolol, oral acetazolamide caused an additional mean decrease in outflow pressure of 43.2%. Concurrent administration of oral acetazolamide and topical timolol reduced outflow pressure only slightly less than the predicted reduction assuming full additivity of the drugs. This study supported the clinical usefulness of concurrent administration of acetazolamide and timolol to lower intraocular pressure.

Acetazolamide↗
PubMed1992

Elucidating the relationship between acetazolamide plasma protein binding and renal clearance using an albumin infusion.

The effect of plasma protein binding changes on drug clearance is an important concept in clinical pharmacology. In a hypoalbuminemic patient receiving acetazolamide, albumin infusion (50 g) increased acetazolamide plasma protein binding towards normal as the serum albumin concentration rose (r = 0.91, P < .001). The ratio of acetazolamide renal plasma clearance to creatinine clearance decreased as serum albumin levels increased (r = 0.78, P < .05) and the unbound drug fraction fell (r = 0.88, P < .01), but clearance ratios based on unbound plasma acetazolamide levels did not change. Albumin infusion resulted in a nonparallel decline over time between plasma and unbound plasma acetazolamide concentrations. These data demonstrate that, over the range of observed serum albumin concentrations, acetazolamide renal plasma clearance is sensitive to changes in plasma protein binding. Furthermore, our findings emphasize the importance of measuring unbound drug levels when protein binding changes occur during the course of drug disposition studies. Finally, this methodology allows for the fascile assessment of the effects of plasma protein binding changes on renal drug clearance.

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PubMed2006

Acetazolamide acts directly on the human skeletal muscle chloride channel.

Acetazolamide, a carbonic anhydrase inhibitor, is used empirically in neuromuscular diseases with episodic ataxia, weakness, and myotonia, although not all of the mechanisms responsible for its therapeutic effects are understood. To elucidate whether acetazolamide acts directly on the human skeletal muscle voltage-gated chloride channel (ClC-1), which is associated with myotonia, we evaluated the effects of acetazolamide on ClC-1 expressed in cultured mammalian cells, using whole-cell recording. Acetazolamide significantly shifted the voltage dependency of the open probability (P(o)) toward negative potentials in a dose-dependent manner, resulting in an increase of chloride conductance at voltages near the resting membrane potential. This effect was attenuated when using a pipette solution containing 30 mmol/L Hepes. These results suggest that acetazolamide can influence the voltage-dependent opening gate of ClC-1 through a mechanism related to intracellular acidification by inhibiting carbonic anhydrase, and that the therapeutic effects of acetazolamide in neuromuscular diseases may be mediated by activation of ClC-1.

Acetazolamide↗
PubMed1981

Comparative studies on acetazolamide teratogenesis in pregnant rats, rabbits, and rhesus monkeys.

Acetazolamide produces a characteristic forelimb reduction deformity when administered to pregnant rodents. Past studies indicated that non-rodent species (rabbit and monkey) are resistant to this effect. The present studies confirmed this fact and demonstrated that transport of acetazolamide into the rabbit embryo was similar to that in sensitive rat embryos. In monkeys, however, the concentrations of acetazolamide within maternal plasma and embryo were much lower than in rats. Carbonic anhydrase activity was also measured since inhibition of this enzyme is the primary pharmacologic effect of acetazolamide. Again the rabbit embryo had carbonic anhydrase specific activity levels similar to that of the rat. Monkey embryos, on the other hand, contained negligible levels of enzyme activity during the presumed sensitive period of development. Thus the resistance of monkey embryos to acetazolamide teratogenesis may be due to low carbonic anhydrase activity and/or the small amount of drug reaching the embryo. No basis for the resistance of rabbit embryos to acetazolamide teratogenesis was uncovered.

Acetazolamide↗
PubMed1992

Acetazolamide but not timolol lowers aqueous humor flow in sleeping humans.

The effect of timolol, acetazolamide, and the combination of the two drugs on the rate of aqueous formation in 18 healthy human subjects was measured during the day and at night in a placebo-controlled, double-masked, randomized study. In the absence of any drugs, aqueous flow during the day was 2.61 +/- 0.82 (mean +/- SD) microliters/min and at night, 1.08 +/- 0.59, a 59% lower flow rate when compared with the daytime value (P < 0.0001). When compared with these aforementioned control values, timolol alone reduced the rate of aqueous flow by 39% (P < 0.0001) in awake subjects but had no statistically significant effect on the flow rate in sleeping subjects (P = 0.33). Acetazolamide alone reduced aqueous flow during the day by 21% compared with the control flow rate (P = 0.02) and at night by 24% below the nocturnal flow rate in the sleeping eye (P = 0.04). The combination of the two drugs reduced flow during the day by an additional 13% (P = 0.024) compared with the flow rate achieved by timolol alone, and by an additional 32% (P < 0.0001) compared with the flow rate reduction attained by acetazolamide alone. There was no statistically significant difference in the nocturnal flow rates achieved by acetazolamide alone or in combination with timolol (P = 0.37). These data confirm previous studies demonstrating the effect of timolol, acetazolamide, and sleep on the rate of aqueous humor formation. Unlike a previous study, it was found that acetazolamide lowers the aqueous flow below the already low nocturnal flow rate that occurs spontaneously in the sleeping eye.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetazolamide↗
PubMed1986

Acetazolamide-induced changes of the membrane potentials of the retinal pigment epithelial cell.

Acetazolamide-induced changes of the apical (Vap) and basal (Vba) membrane potentials of the retinal pigment epithelial cell were studied in an in-vitro retinal pigment epithelium (RPE)-choroid of the frog. Both Vap and Vba were hyperpolarized by acetazolamide placed on either the apical or basal side of the RPE. In all cases, acetazolamide on the apical side hyperpolarized Vba more than Vap and decreased the transepithelial potential (TEP) across the RPE. In most cases, acetazolamide on the basal side hyperpolarized both Vap and Vba to almost equal degrees and hardly changed the TEP. We conclude that the Diamox response (a decrease of the ocular standing potential induced by an intravenous sodium acetazolamide) may be triggered by effects of acetazolamide on the apical side of the RPE and generated mainly by a hyperpolarization of the basal membrane of the RPE cell.

Acetazolamide↗
PubMed1996

Cerebellar vascular response to acetazolamide in crossed cerebellar diaschisis: a comparison of 99mTc-HMPAO single-photon emission tomography with 15O-H2O positron emission tomography.

Various observations on the cerebellar vasoreactivity in crossed cerebellar diaschisis (CCD) have previously been reported. The purpose of this study is to clarify the difference between oxygen-15 H2O positron emission tomographic (PET) and technetium-99m hexamethylpropylene amine oxime (HMPAO) single-photon emission tomograph (SPET) findings in CCD and to evaluate the effect of the absolute values of the cerebellar blood flow as measured by 15O-H2O PET on the 99mTc-HMPAO SPET findings. The subjects comprised 15 patients with a supratentorial infarct and CCD. The cerebellar blood flow increased by about 40% at 5 and 20 min after acetazolamide i.v. on both the CCD and the non-CCD side, as measured by 15O-H2O PET. The percentage differences in cerebellar blood flow between the CCD and the non-CCD side were -22.3%+/-5.7% in the resting state, -19. 6%+/-6.4% at 5 min after acetazolamide i.v. and 21.5%+/-6.7% at 20 min after acetazolamide i.v., as measured by 15O-H2O PET, while they were -10.6%+/-5.5% in the resting state and -5.6%+/-5.1% at 5 min after acetazolamide i.v., as measured by 99mTc-HMPAO SPET. After Lassen's linearization correction, the latter two measurements were -16.2%+/-7.7% and -9.6%+/-8.9%, respectively. The effect of acetazolamide did not differ between the CCD and the non-CCD side in 15O-H2O PET, while a greater response on the CCD side was observed in 99mTc-HMPAO SPET, even after Lassen's linearization correction. It is concluded that acetazolamide HMPAO SPET may overestimate the cerebellar vascular response on the CCD side (or underestimate it on the non-CCD side).

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PubMed1991

Oral acetazolamide in the assessment of (urine-blood) PCO2.

Urine-blood (U-B)Pco2 difference in children is usually assessed following urine alkalinization with oral sodium bicarbonate (NaHCO3). Since oral NaHCO3 is often poorly tolerated by children, we compared oral acetazolamide with oral NaHCO3 in a study of (U-B)Pco2. In the first phase of the study 14 children and adolescents aged 11.1 +/- 3.7 years (mean +/- SD) were studied. Eight participants had normal kidney function and 6 had disturbed distal acidification capacity. Each child was studied twice, once with oral NaHCO3 (2.5 mEq/kg) and once with acetazolamide (17 +/- 2 mg/kg). All studies were performed according to the standard protocol. Acetazolamide administration resulted in a lower blood pH than NaHCO3 (7.30 +/- 0.03 vs 7.38 +/- 0.06, P less than 0.001) and a lower serum bicarbonate (HCO3-) concentration (25.1 +/- 2.2 mEq/l vs 27.5 +/- 2.1 mEq/l, P less than 0.025). Acetazolamide also resulted in a higher urine Pco2 (81.9 +/- 26.2 mm Hg vs 71.6 +/- 18.2 mm Hg) than NaHCO3 (P less than 0.025). No significant differences between acetazolamide and NaHCO3 were observed with respect to their effects on urinary pH and HCO3- concentration, plasma Pco2 and (U-B)Pco2. Good linear correlations were found between the effects of acetazolamide and NaHCO3 on urine Pco2 (r = 0.878, P less than 0.001), and on (U-B)Pco2 (r = 0.795, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetazolamide↗
PubMed1986

The role of carbonic anhydrase in gastric mucosal protection with special reference to H+ back diffusion and concomitant metabolic acidosis induced by acetazolamide.

It is suggested that carbonic anhydrase is implicated not only in gastric acid secretion, but in mucosal protection. It was reported that acetazolamide induced gastric mucosal lesions. But acetazolamide also caused concomitant metabolic acidosis by inhibiting H+ secretion from renal tubules. We investigated whether concomitant metabolic acidosis is implicated in gastric mucosal lesions induced by acetazolamide in vivo. We also evaluated the effect of acetazolamide on gastric H+ back diffusion in vivo. Correction of metabolic acidosis with sodium bicarbonate had no effect on the degree of the gastric mucosal lesions. Acetazolamide caused no change in gastric H+ and Na+ flux. These results suggest that metabolic acidosis induced by acetazolamide is not implicated in gastric mucosal lesions. Carbonic anhydrase has no effect on H+ back diffusion but may be implicated in mucosal protection by the disposition of back diffused H+ into the gastric mucosa.

Acetazolamide↗
PubMed2004

Error analysis of measured cerebral vascular response to acetazolamide stress by I-123-IMP autoradiographic method with single photon emission computed tomography: errors due to distribution volume of I-123-IMP.

OBJECTIVES: Iodine-123 (123I)-labeled N-isopropyl-p-iodoamphetamine (IMP) has been used as a cerebral blood flow (CBF) tracer for single-photon emission computed tomography (SPECT), and measurements of the CBF response to acetazolamide stress by SPECT with IMP are widely used to assess cerebral vascular reserve. To quantitate CBF by means of SPECT with IMP, an autoradiographic (ARG) method has been developed and is widely used. In the ARG method, CBF is calculated from the brain counts of the SPECT scan with an assumed distribution volume value of IMP (Vd). However, differences between true Vd and assumed Vd results in errors in calculated CBF. In the present study, errors in the CBF response to acetazolamide stress as calculated by the ARG method were investigated. METHODS: SPECT studies were performed on 12 patients with steno-occlusive lesions of the major cerebral artery. Two studies were performed on separate days. The first study was performed at rest (baseline), and the second during acetazolamide stress. SPECT scans were performed at 40 min (early scan) and 180 min (delayed scan) after intravenous injection of IMP. RESULTS: Although a simulation study showed that errors in calculated changes in CBF in response to acetazolamide stress, which result from differences between the true Vd and the assumed Vd, were larger when the baseline CBF and change in CBF were larger, values calculated by the ARG method with an assumed Vd were in good agreement with those calculated with true Vd obtained from early and delayed scan data. CONCLUSION: These data indicate that errors in the calculated CBF response to acetazolamide stress as calculated by the ARG method are negligible even at high CBF responses. The ARG method is therefore reliable for measurement of CBF response to acetazolamide stress.

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