Multifaceted clinical effects of acetazolamide: will the underlying mechanisms please stand up?

Luc J. Teppema
2014 Journal of applied physiology  
IN THIS ISSUE, PICKERODT AND colleagues (7) showed for the first time that the acetazolamide (AZ) analog N-methyl acetazolamide (NMA), lacking carbonic anhydrase (CA) inhibiting activity, substantially reduced the acute hypoxia-induced increases in mean pulmonary arterial pressure [hypoxic pulmonary vasoconstriction (HPV)] and pulmonary vascular resistance in conscious dogs in vivo. Previously, they had shown that even the powerful sulfonamide CA inhibitors benzolamide and ethoxzolamide failed
more » ... o reduce HPV (see references in Ref. 7). The study by Pickerodt et al. shows not only that AZ's effect on HPV [note that, in humans, clinical oral doses of the drug substantially reduce HPV in acute hypoxia (see references in Ref . 7) ] does not depend on CA inhibition (CAI), but that it is also a first important effort to identify the pharmacophore(s) that is able or needed to reduce or abolish HPV and thus may contribute to the elucidation of the vasoconstriction mechanism itself. In case of NMA, one hydrogen ion of the sulfonamide moiety is replaced by a methyl group and thereby loses its potency to block CA. In isolated pulmonary smooth muscle cells, AZ and NMA prevented the hypoxia-induced rise in intracellular Ca 2ϩ concentration without influencing the membrane potential, voltage-gated potassium channels, and intracellular pH (see reference in Ref. 7), so the mechanism underlying AZ's and NMA's effects remains obscure. AZ is used in a broad range of clinical settings. Without giving a comprehensive overview, I mention only a few of these. It is used as a mild diuretic, in eye disease (glaucoma), to reduce cerebrospinal fluid production, to treat metabolic alkalosis and sleep apnea, and to prevent and relieve the symptoms of acute mountain sickness. In addition, it is the first-choice pharmacological tool against episodic ataxia type 2 and forms the main treatment of hypokalemic periodic paralysis (6). AZ and other CA inhibitors have anticonvulsive properties and as such are used against epilepsy (5). Known side effects are depression, loss of libido, nausea, anorexia, paresthesias, fatigue, weight loss, and bad taste of carbonated beverages. AZ has several important physiological effects, some of which may have clinical relevance. First, apart from having vasodilatory effects in animals, it causes vasodilation in the human forearm (see references in Ref. 7) and improves the ratio of oxygen supply to demand in the heart in hypoxia (8). Second, at low intravenous dose (but not with usual clinical oral applications), it reduces the ventilatory response to hypoxia (hypoxic ventilatory response; see references in Ref. 11) and thus could be useful in reducing the gain of the ventilatory control system in periodic breathing and apnea syndromes.
doi:10.1152/japplphysiol.00141.2014 pmid:24557795 fatcat:76qwytorxvg2bpwdbhhr3go6me