No abstract

No abstract

The carbonic anhydrase inhibitor acetazolamide stimulates ventilation, resulting in an improvement in arterial oxygen tension (Pa,O 2 ) in patients with chronic obstructive pulmonary disease (COPD) or central sleep apnoea syndrome and in those suffering from acute mountain sickness [1][2][3][4][5][6][7][8][9][10]. The ventilatory effect with the drug is believed to be mediated by a metabolic acidosis, induced by inhibition of renal carbonic anhydrase [11][12][13][14]. However, other local effects of acetazolamide could also contribute to the observed ventilatory effects, since carbonic anhydrase is present in several tissues of the pathways involved in the control of breathing. For example, the enzyme is present in the peripheral and possibly also the central chemoreceptors [15][16][17][18], erythrocytes [16] and muscles [19] and in lung as well as brain capillary endothelium [20][21][22]. Usually, acetazolamide is administered in doses which do not completely inhibit red cell carbonic anhydrase. Complete inhibition of erythrocytic carbonic anhydrase occurs at a fractional inhibition >99.8%, for which doses >10 mg·kg -1 acetazolamide are required [16,23]. In COPD patients, this situation would result in impeded washout of CO 2 from the lungs, leading to CO 2 accumulation in the tissues. Such an undesired complication can be avoided by administering small doses, preventing an increase in the arterial to endtidal carbon dioxide tension (Pa-ET,CO 2 ) gradient.In a previous study in anaesthetized cats, it was found that doses of up to 4 mg·kg -1 acetazolamide (i.v.) did not cause a Pa-ET,CO 2 gradient [24]. In the same study the effect of 4 mg·kg -1 acetazolamide on the ventilatory response to CO 2 during normoxaemia was also investigated: utilizing the technique of dynamic end-tidal forcing (DEF) [25], decreases in the CO 2 sensitivities of the peripheral (Sp) and central (Sc) chemoreflex loops and in the apnoeic threshold (extrapolated carbon dioxide tension (PCO 2 ) at zero ventilation) were found. These effects were attributed to a possible direct action of acetazolamide on the peripheral chemoreceptors and to a change in the relation between brain tissue PCO 2 (Pbt,CO 2 ) and arterial PCO 2 (Pa,CO 2 ), due to a possible effect of the drug on cerebral blood flow regulation.Since this previous study was performed during normoxia, its results may not be directly relevant to a situation of hypoxaemia, such as frequently occurs in patients with COPD.During hypoxaemia, both cerebral blood flow and the relative contribution of the peripheral chemoreceptors to total ventilation are different from that in normoxaemia. Therefore, the aim of this study, in anaesthetized cats, was Effect of low-dose acetazolamide on the ventilatory CO 2 response during hypoxia in the anaesthetized cat. M. Wagenaar, L. Teppema, A. Berkenbosch, C. Olievier, H. Folgering. ©ERS Journals Ltd 1998. ABSTRACT: Acetazolamide, a carbonic anhydrase inhibitor, is used in patients with chronic obstructive pulmonary diseases and central sleep apnoea sy...

1. The effect of inhibition of erythrocyte carbonic anhydrase on the ventilatory response to CO2 was studied by administering benzolamide (70 mg kg- ', i.v.)

Acetazolamide, a carbonic anhydrase (CA) inhibitor used clinically and to prevent acute mountain sickness, worsens skeletal muscle fatigue in animals and humans. In animals, methazolamide, a methylated analog of acetazolamide and an equally potent CA inhibitor, reportedly exacerbates fatigue less than acetazolamide. Accordingly, we sought to determine, in humans, if methazolamide would attenuate diaphragm and dorsiflexor fatigue compared with acetazolamide. Healthy men (dorsiflexor: n = 12; diaphragm: n = 7) performed fatiguing exercise on three occasions, after ingesting acetazolamide (250 mg three times a day) and then in random order, methazolamide (100 mg twice a day) or placebo for 48 h. For both muscles, subjects exercised at a fixed intensity until exhaustion on acetazolamide, with subsequent iso-time and -workload trials. Diaphragm exercise was performed using a threshold-loading device, while dorsiflexor exercise was isometric. Neuromuscular function was determined pre- and postexercise by potentiated transdiaphragmatic twitch pressure and dorsiflexor torque in response to stimulation of the phrenic and fibular nerve, respectively. Diaphragm contractility 3-10 min postexercise was impaired more for acetazolamide than methazolamide or placebo (82 ± 10, 87 ± 9, and 91 ± 8% of pre-exercise value; P < 0.05). Similarly, dorsiflexor fatigue was greater for acetazolamide than methazolamide (mean twitch torque of 61 ± 11 vs. 57 ± 13% of baseline, P < 0.05). In normoxia, methazolamide leads to less neuromuscular fatigue than acetazolamide, indicating a possible benefit for clinical use or in the prophylaxis of acute mountain sickness. NEW & NOTEWORTHY Acetazolamide, a carbonic anhydrase inhibitor, may worsen diaphragm and locomotor muscle fatigue after exercise; whereas, in animals, methazolamide does not impair diaphragm function. Compared with both methazolamide and the placebo, acetazolamide significantly compromised dorsiflexor function at rest and after exhaustive exercise. Similarly, diaphragm function was most compromised on acetazolamide followed by methazolamide and placebo. Methazolamide may be preferable over acetazolamide for clinical use and altitude illness prophylaxis to avoid skeletal muscle dysfunction.