Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression.

Abstract

Inhibitors of carbonic anhydrase (CA) have long been used as respiratory stimulants, most successfully in acute mountain sickness (AMS), but also in chronic obstructive pulmonary disease (COPD) and sleep-disordered breathing syndromes. Although effective, presently available inhibitors have minor annoying side-effects (paraesthesias, mild nausea and gastrointestinal discomfort) that can limit long-term compliance; and in certain cases their use may be hazardous, particularly in those with compromised pulmonary, hepatic and renal function. The overlap in clinical efficacy and side-effects of these drugs is intimately related to the ubiquity of CA in the body, and to the enzyme's many roles in CO2 transport, acid–base regulation, nitrogen metabolism, fluid secretion and absorption, and ventilatory control. It is now known that the effect of CA inhibitors on ventilation and ventilatory responsiveness is a complex and not easily predictable summation of CA inhibition in tissues relevant to the control of breathing, including the kidney, red cells, capillary vascular endothelium, brain, and the central and peripheral chemoreceptors [1]. Depending on the dose of inhibitor, duration of dosing and site of inhibition, there can be both inhibitory and stimulatory effects. A good example of this complexity can be found in the present report by WAGENAAR et al. [2], who studied the effect of acetazolamide on the hypercapnic ventilatory response in hypoxia. The development of the presently available CA inhibitors and their application as respiratory stimulants arose from findings in the late 1930s, that sulphanilamide, the first oral sulphonamide antibiotic (and a weak CA inhibitor), caused metabolic acidosis and a compensatory hyperventilation resulting in a higher arterial oxygen tension (Pa,O2). Only several years earlier, the enzyme had been discovered in erythrocytes and, soon thereafter, in many organs including the kidney, where it was established that renal CA inhibition was responsible for the acidosis. Efforts to produce more potent CA inhibitors yielded acetazolamide (Diamox) and several other less commonly used (but still available) sulphonamides, including methazolamide (Neptazane) and diclorphenamide (Daranide). These and even more powerful sulphonamides (benzolamide and ethoxzolamide) with Ki values 2–4 orders of magnitude less than sulphanilamide permitted the investigation of CA function in other tissues. Interestingly and ironically, further drug development in this field led to the serendipitous discovery of the thiazide and high ceiling loop diuretics, which lost CA-inhibiting activity while yielding even greater natriuresis and diuresis than the earlier sulphonamides [3]. Ventilatory effects of CA inhibitors