Prevention of acute mountain sickness by acetazolamide: as yet an unfinished story
2006; American Physiological Society; Volume: 102; Issue: 4 Linguagem: Inglês
10.1152/japplphysiol.01407.2006
ISSN8750-7587
AutoresErik R. Swenson, Luc J. Teppema,
Tópico(s)Hemoglobin structure and function
ResumoINVITED EDITORIALPrevention of acute mountain sickness by acetazolamide: as yet an unfinished storyErik R. Swenson, and Luc J. TeppemaErik R. Swenson, and Luc J. TeppemaPublished Online:01 Apr 2007https://doi.org/10.1152/japplphysiol.01407.2006This is the final version - click for previous versionMoreSectionsPDF (61 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat since the 1970s, over 200 studies with acetazolamide have shown it safe and 60–80% effective in acute mountain sickness (AMS). Despite much investigation, our understanding of its action in AMS remains incomplete and more complicated than generally taught. This should come as no surprise considering the presence of carbonic anhydrase (CA) in many tissues relevant to high-altitude adaptation or maladaptation. In this issue of the Journal of Applied Physiology, Leaf and Goldfarb (10) provide a fine state-of-the-art review that highlights this complexity and updates the field since last reviewed in 1998 (12).A brief history of CA and its inhibitors serves to give some perspective on acetazolamide in AMS prevention. Shortly after the discovery of CA in red blood cells in 1932, sulfanilamide, the first nontoxic oral antibiotic, was introduced and noted to have side effects including mild diuresis, metabolic acidosis, and hyperventilation. These were quickly recognized to be a consequence of renal CA inhibition. Following World War II, synthesis of stronger CA inhibitors yielded the 1,000-fold more potent sulfonamide, acetazolamide. Although first used as a diuretic and gastric acid suppressant, by the mid-1950s it found greater efficacy in glaucoma and hydrocephalus. Pulmonologists explored acetazolamide concurrently as a respiratory stimulant for hypoxemic patients with chronic obstructive pulmonary disease in the expectation of improving arterial oxygenation. Albeit effective, patients could not tolerate the worsened dyspnea when forced to breathe more. Kronenberg and Cain (9), however, realized that such ventilatory stimulation might have a significant impact at high altitude in healthy persons and indeed showed better oxygenation and ventilation in subjects at high altitude. Shortly thereafter, Forwand et al. (4) demonstrated that such ventilatory stimulation by acetazolamide could reduce AMS symptoms, and its use for this purpose was established.How then does acetazolamide work in AMS and what questions remain to be investigated? Leaf and Goldfarb (10) posit that the conventional view by which acetazolamide works is too simplistic. In this model, urinary bicarbonate loss from renal CA inhibition and the resultant mild metabolic acidosis (a ventilatory stimulant) opposes and limits the braking effect of hypocapnia on the full ventilatory response to hypoxia. In essence, acetazolamide simply accelerates the normal bicarbonaturia that would otherwise happen over several days of acclimatization. Although this is clearly not the full story, the renal effect is nonetheless primus inter pares among other possible mechanisms, which include relevant CA inhibition in red blood cells, brain, pulmonary and systemic vasculature, and chemoreceptors.Leaf and Goldfarb (10) explain how tissue enzyme concentrations and drug penetrance into various tissues rule out any significant effect of clinically useful dosing of acetazolamide (3–5 mg/kg) on red blood cell CO2 transport, cerebral blood flow (CBF), and CA inhibition within the central chemoreceptors. The only caveat with respect to CBF is that if regional brain blood flow changes are heterogeneous, measurements of total CBF may not reflect changes in blood flow in critical areas such as the brain stem. Since tissue pH, Pco2, and Po2 are determined by the metabolic rate of the tissue, its blood flow, and arterial values, blood flow changes will alter ventilatory responsiveness. Another effect of CA inhibition in the brain not mentioned, but conceivably relevant to AMS, is cerebrospinal fluid (CSF) formation. Complete choroid plexus CA inhibition reduces this by 50% and in principle could reduce overall intracranial volume and pressure, which are slightly increased with hypoxia and in AMS and have been proposed as pathogenetic in AMS. However, effective doses of acetazolamide that penetrate the blood-brain barrier, reach the choroid plexus, and depress CSF flow and volume are on the order of 20 mg/kg (18).Our present understanding of how acetazolamide works points to critical CA inhibition in the brain vascular endothelium, kidneys, and peripheral chemoreceptors interacting with the primary effect of hypoxia to stimulate ventilation. Luminal brain vascular endothelial CA will be fully and immediately inhibited by even very low drug concentrations in blood, causing a small hindrance to normal "tissue-to-blood" transfer such that tissue Pco2 will be elevated by 1–2 Torr (8). A slight CO2 retention in the vicinity of both the central and peripheral chemoreceptors will be sufficient to stimulate ventilation. Acetazolamide (5–7 mg/kg iv) in normoxic humans induces a small increase in ventilation within minutes consistent with endothelial CA inhibition, well before any significant urinary bicarbonate loss or red blood cell drug uptake reaches a critical inhibitory level (13). Thus, in addition to the metabolic acidosis, slight CO2 retention from vascular CA inhibition will help mitigate the suppressant effect of the primary respiratory alkalosis generated by hypoxic hyperventilation and so allow a more complete hypoxic ventilatory response.Despite the metabolic acidosis, an expected increase in the acute isocapnic hypoxic ventilatory response (HVR) is lacking, indicating that acetazolamide abolishes the H+-O2 interaction in the peripheral chemoreceptors (2, 13, 17). This raises an interesting question as to what could be the advantage of taking a drug at altitude that has inhibitory effects on oxygen-sensing cells. The answer lies in the fact that the ventilatory response to high-altitude hypoxia is essentially poikilocapnic (i.e., hypocapnic). Consequently, any agent abolishing the H+-O2 interaction under these circumstances will blunt the action of a low Pco2 on the hypoxic response and generate more ventilation than would otherwise occur (17). In humans at sea level, acetazolamide has no influence on the peripheral chemoreceptor contribution to the ventilation response on stepwise changes in end-tidal Pco2 (14). It cannot be excluded that, in part, CO2-H+ and O2 follow separate signal-transduction pathways in the carotid bodies. Future studies with acetazolamide are warranted to determine if, despite the absence of a O2-H+ interaction, the carotid bodies may retain their H+ sensitivity.Predictably, acetazolamide's inhibitory effect on the HVR should be due to peripheral chemoreceptor CA inhibition. However, in the cat, even the more lipophilic inhibitor methazolamide does not reduce the HVR, suggesting that acetazolamide may act by a mechanism other than CA inhibition (15) as already established for hypoxic pulmonary vasoconstriction (6). Interestingly, antioxidants reverse the inhibitory effects of low-dose acetazolamide on HVR in humans (16). Further studies are needed to establish if antioxidants interfere with the prophylactic effects of acetazolamide and how possibly acetazolamide, either by CA inhibition or by ligation to some other receptor, alters intracellular redox status of the peripheral chemoreceptors.The contribution of the central chemoreceptors to increased ventilation with acetazolamide is via the stimulatory effect of the metabolic acidosis in raising H+ concentration to counteract the effect of increased ventilation to washout CO2 and raise pH. If a clinically relevant dosing of acetazolamide decreases arterial Pco2 (PaCO2) by ∼7 Torr (14, 17) but does not alter CBF (7, 17) or impair blood CO2 transport, then the brain tissue-to-blood Pco2 gradient should not change very much, implying a considerable fall in brain tissue Pco2. However, as mentioned above, brain vascular endothelial CA inhibition will limit this fall to some extent and so lessen the braking effect of increased ventilation to return H+ in the central chemoreceptors to a less acidic state.Acetazolamide's actions on respiration and the vasculature suggest how it reduces periodic breathing in sleep at high altitude (5). Dempsey (3) proposed that that the "CO2 reserve" (i.e., the difference in PaCO2 between eupnea and the apneic threshold), when combined with "plant gain" (or the ventilatory increase required for a given reduction in PaCO2) and "controller gain" (ventilatory responsiveness to CO2 above eupnea), are the key determinants of breathing stability in sleep. In general, breathing during sleep is made more stable by increases in the CO2 reserve, and reductions in plant and controller gain. Acetazolamide alters all three favorably. First, with elevated arterial Po2 and decreased PaCO2, plant gain will be reduced because larger changes in ventilation are needed to cause equivalent changes in blood gases. Second, a parallel left shift of the CO2 response curve will raise the difference between the prevailing PaCO2 and the apneic threshold (CO2 reserve) and decrease the propensity for apnea. A small rise in brain stem Pco2 with inhibition of vascular CA will have a similar tonic stabilizing influence. Third, due to the higher prevailing Po2, subjects are in a flatter region of the (hyperbolic) hypoxic response curve, resulting in a reduced O2 controller gain. A further reason why acetazolamide reduces ventilatory controller gain in sleep is the abolishment of the CO2-O2 interaction so that responses to hypoventilation-induced combined hypoxia/hypercapnia may be reduced considerably. Finally, it cannot be ruled out that acetazolamide increases the cerebrovascular response to combined hypercapnia/hypoxia (17), leading to a dampening influence on subsequent changes in brain stem Pco2. Note that a lowered cerebrovascular CO2 sensitivity may play a role in the genesis of periodic breathing at high altitude (1). Because acetazolamide does not affect the time constant of the peripheral CO2 response (14) or the time course of the HVR (17), we do not believe slower reaction times within the carotid bodies play a significant role in reducing periodic breathing.Many questions remain to be investigated before we have a complete understanding of acetazolamide protection in AMS. Although not an exhaustive list of experiments and methodological approaches, we believe the following are several key directions to pursue. ) Regional brain blood flow, pH, metabolic rate, and oxygenation (such as with magnetic resonance imaging and spectroscopy) in areas of brain involved in respiratory control need to be performed in humans in conjunction with ventilation, ventilatory responses, and arterial blood gas measurements. Dose-response experiments with acetazolamide in normoxia and hypoxia, combined with plasma measurements of total and free drug levels, are needed to better calculate the degree of red blood cell and tissue CA inhibition. Although not presently available for humans, analogs of acetazolamide, lacking CA inhibiting activity, will be useful in animals to test whether and how much of the effect of acetazolamide is due to CA inhibition or to some other action on O2 and CO2 sensing and responsiveness.) Studies of acetazolamide in conscious and sleeping chemoreceptor-intact animals are needed, both in normoxia and hypoxia, in which central and peripheral chemoreceptor contributions can be gauged by isolating the drug and/or systemic acid-base changes to either the central or peripheral chemoreceptors. This can be done by isolating the circulation to the carotid bodies and perfusing them with appropriately conditioned blood (11).) The contributions of the renal metabolic acidosis and diuresis of acetazolamide to the protection with acetazolamide in AMS need to be explored by using other mild diuretics to achieve the same magnitude of diuresis as acetazolamide and/or using acetazolamide but preventing bicarbonate and sodium losses by carefully calibrated replacement.REFERENCES1 Ainslie PN, Burgess K, Subedi P, Burgess KR. Alterations in cerebral dynamics at high altitude following partial acclimatization in humans: wakefulness and sleep. J Appl Physiol 102: 658–664, 2007.Link | ISI | Google Scholar2 Bashir Y, Kann M, Stradling JR. The effect of acetazolamide on hypercapnic and eucapnic/poikilocapnic hypoxic ventilatory responses in normal subjects. Pulm Pharmacol 3: 151–154, 1990.Crossref | Google Scholar3 Dempsey JA. Crossing the apnoeic threshold: causes and consequences. Exp Physiol 90: 13–24, 2005.Crossref | PubMed | ISI | Google Scholar4 Forwand SA, Landowne M, Follansbee JN, Hansen JE. Effect of acetazolamide on acute mountain sickness. N Engl J Med 279: 839–845, 1968.Crossref | ISI | Google Scholar5 Hackett PH, Roach RC, Harrison GL, Schoene RB, Wills WJ. Respiratory stimulants and sleep periodic breathing at high altitude. Almitrine versus acetazolamide. Am Rev Respir Dis 135: 896–898, 1987.Crossref | PubMed | ISI | Google Scholar6 Hohne C, Pickerodt PA, Francis RC, Boemke W, Swenson ER. Pulmonary vasodilation by acetazolamide during hypoxia is not related to carbonic anhydrase inhibition. Am J Physiol Lung Cell Mol Physiol 292: L178–L184, 2007.PubMed | ISI | Google Scholar7 Huang SY, Mccullough RE, Mccullough RG, Micco AJ, Mancojohnson M, Weil JV, Reeves JT. Usual clinical dose of acetazolamide does not alter cerebral blood-flow velocity. Respir Physiol 72: 315–326, 1988.Crossref | Google Scholar8 Klocke RA. Potential role of endothelial carbonic anhydrase in dehydration of plasma bicarbonate. Trans Am Clin Climatol Assoc 108: 44–57, 1996.Google Scholar9 Kronenberg RS, Cain SM. Effects of acetazolamide on physiologic and subjective responses of men to 14,000 feet. SAM-TR-67–81. School Aviat Med Tech Rep 67: 1–10, 1967.Google Scholar10 Leaf DE, Goldfarb DS. Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness. J Appl Physiol 102: 1313–1322, 2007.Google Scholar11 Smith CA, Rodman JR, Chenuel BJA, Henderson KS, Dempsey JA. Response time and sensitivity of the ventilatory response to CO2 in unanesthetized dogs: central vs. peripheral chemoreceptors. J Appl Physiol 100: 13–19, 2006.Link | ISI | Google Scholar12 Swenson ER. Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression. Eur Respir J 12: 1242–1247, 1998.Crossref | PubMed | ISI | Google Scholar13 Swenson ER, Hughes JMB. Effects of acute and chronic acetazolamide on resting ventilation and ventilatory responses in men. J Appl Physiol 74: 230–237, 1993.Link | ISI | Google Scholar14 Teppema LJ, Dahan A. Acetazolamide and breathing. Does a clinical dose alter peripheral and central CO2 sensitivity? Am J Respir Crit Care Med 160: 1592–1597, 1999.Crossref | PubMed | ISI | Google Scholar15 Teppema LJ, Bijl H, Mousavi-Gourabi B, Dahan A. The carbonic anhydrase inhibitors methazolamide and acetazolamide have different effects on the hypoxic ventilatory response in the anaesthetized cat. J Physiol 574: 565–572, 2006.Crossref | PubMed | ISI | Google Scholar16 Teppema LJ, Bijl H, Romberg R, Dahan A. Antioxidants reverse depression of the hypoxic ventilatory response by acetazolamide in man. J Physiol 572: 849–856, 2006.Crossref | PubMed | ISI | Google Scholar17 Teppema LJ, Balanos GM, Steinback CD, Brown A, Foster G, Duff HJ, Leigh R, Poulin MJ. Effects of acetazolamide on ventilation, cerebrovascular and pulmonary vascular responses to hypoxia. Am J Respir Crit Care Med 175: 277–281, 2007.Crossref | PubMed | ISI | Google Scholar18 Vogh BP. The relation of choroid plexus carbonic anhydrase activity to cerebro-spinal fluid formation: a study of three inhibitors in cat with extrapolation to man. J Pharmacol Exp Ther 213: 321–331, 1980.ISI | Google Scholar Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByHigh-altitude exposures and intestinal barrier dysfunctionZachary J. McKenna, Felipe Gorini Pereira, Trevor L. Gillum, Fabiano T. Amorim, Michael R. Deyhle, and Christine M. Mermier16 February 2022 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 322, No. 3The Neurological Spectrum for Acetazolamide Pharmacotherapy: from Basic Science to Clinical Applications8 November 2021 | SN Comprehensive Clinical Medicine, Vol. 3, No. 12High-altitude illnesses: Old stories and new insights into the pathophysiology, treatment and preventionSports Medicine and Health Science, Vol. 3, No. 2The Carbonic Anhydrases in Health and Disease31 October 2021A Randomized Controlled Trial of the Lowest Effective Dose of Acetazolamide for Acute Mountain Sickness PreventionThe American Journal of Medicine, Vol. 133, No. 12Discovery of New 1,1′-Biphenyl-4-sulfonamides as Selective Subnanomolar Human Carbonic Anhydrase II Inhibitors11 November 2019 | ACS Medicinal Chemistry Letters, Vol. 11, No. 5DFT-Based QSAR Modelling of Inhibitory Activity of Coumarins and Sulfocoumarins on Carbonic Anhydrase (CA) Isoforms (CA I and CA II)Current Computer-Aided Drug Design, Vol. 15, No. 3Reduced Acetazolamide Dosing in Countering Altitude Illness: A Comparison of 62.5 vs 125 mg (the RADICAL Trial)Wilderness & Environmental Medicine, Vol. 30, No. 1Altitude Sickness Prevention with Ibuprofen Relative to AcetazolamideThe American Journal of Medicine, Vol. 132, No. 2Carbonic anhydrase enzymes: Likely targets for inhalational anestheticsMedical Hypotheses, Vol. 123Akute Höhenkrankheitα-Carbonic anhydrasesHuman carbonic anhydrasesInterventions for preventing high altitude illness: Part 1. Commonly-used classes of drugs27 June 2017 | Cochrane Database of Systematic Reviews, Vol. 2018, No. 12Acetazolamide and N -acetylcysteine in the treatment of chronic mountain sickness (Monge's disease)Respiratory Physiology & Neurobiology, Vol. 246Fluorescence-Based Assay for Carbonic Anhydrase InhibitorsChem, Vol. 2, No. 2Benzolamide improves oxygenation and reduces acute mountain sickness during a high-altitude trek and has fewer side effects than acetazolamide at sea level19 May 2016 | Pharmacology Research & Perspectives, Vol. 4, No. 3Acute Mountain Sickness Symptom Severity at the South Pole: The Influence of Self-Selected Prophylaxis with Acetazolamide5 February 2016 | PLOS ONE, Vol. 11, No. 2Acetazolamide during acute hypoxia improves tissue oxygenation in the human brainKang Wang, Zachary M. Smith, Richard B. Buxton, Erik R. Swenson, and David J. Dubowitz15 December 2015 | Journal of Applied Physiology, Vol. 119, No. 12Discovery of 1,1′-Biphenyl-4-sulfonamides as a New Class of Potent and Selective Carbonic Anhydrase XIV Inhibitors4 November 2015 | Journal of Medicinal Chemistry, Vol. 58, No. 21The noncarbonic anhydrase inhibiting acetazolamide analog N -methylacetazolamide reduces the hypercapnic, but not hypoxic, ventilatory response19 August 2015 | Physiological Reports, Vol. 3, No. 8Physiology in Medicine: A physiologic approach to prevention and treatment of acute high-altitude illnessesAndrew M. Luks1 March 2015 | Journal of Applied Physiology, Vol. 118, No. 5Human Carbonic Anhydrases: Catalytic Properties, Structural Features, and Tissue DistributionSex and Acetazolamide Effects on Chemoreflex and Periodic Breathing During Sleep at AltitudeChest, Vol. 147, No. 1Akute Höhenkrankheit (AMS)20 May 2015Serious Altitude Illness in Travelers Who Visited a Pre‐Travel Clinic1 November 2014 | Journal of Travel Medicine, Vol. 21, No. 6The Lungs in Acute Mountain Sickness: Victim, Perpetrator, or Both?The American Journal of Medicine, Vol. 127, No. 10Sleeping in Moderate Hypoxia at Home for Prevention of Acute Mountain Sickness (AMS): A Placebo-Controlled, Randomized Double-Blind StudyWilderness & Environmental Medicine, Vol. 25, No. 3Synthesis and Carbonic Anhydrase Isoenzymes Inhibitory Effects of Brominated Diphenylmethanone and Its Derivatives6 March 2014 | Archiv der Pharmazie, Vol. 347, No. 5Acetazolamide and Inhaled Carbon Dioxide Reduce Periodic Breathing During Exercise in Patients With Chronic Heart FailureJournal of Cardiac Failure, Vol. 20, No. 4Bioavailability, tissue distribution, and excretion characteristics of the novel carbonic anhydrase inhibitor tolsultazolamide in rats16 December 2013 | Acta Pharmacologica Sinica, Vol. 35, No. 2Sleep9 November 2013Carbonic Anhydrase Inhibitors and High Altitude Illnesses17 September 2013Acute high-altitude exposure reduces lung diffusion: Data from the HIGHCARE Alps projectRespiratory Physiology & Neurobiology, Vol. 188, No. 2Effets stimulants respiratoires de l'acétazolamide en réanimation17 January 2013 | Réanimation, Vol. 22, No. 4Acute high-altitude illness: a clinically orientated review30 April 2013 | British Journal of Pain, Vol. 7, No. 2Expedition and Extreme Environmental Medicine11 February 2013Multiple Binding Modes of Inhibitors to Carbonic Anhydrases: How to Design Specific Drugs Targeting 15 Different Isoforms?18 May 2012 | Chemical Reviews, Vol. 112, No. 8Interventions for preventing high altitude illness18 April 2012Patients With Obstructive Sleep Apnea Syndrome Benefit From Acetazolamide During an Altitude SojournChest, Vol. 141, No. 1Carbonic anhydrase inhibitors and activators for novel therapeutic applicationsFuture Medicinal Chemistry, Vol. 3, No. 9Synthesis and evaluation of new carbonic anhydrase inhibitorsBioorganic & Medicinal Chemistry, Vol. 19, No. 10Respiratory PhysiologyAcute Mountain Sickness: Pathophysiology, Prevention, and TreatmentProgress in Cardiovascular Diseases, Vol. 52, No. 6Evaluating the Safety of High-altitude Travel in Patients with Adult Congenital Heart DiseaseCongenital Heart Disease, Vol. 5, No. 3High-Altitude MedicineGeneration of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilationRasmus Aamand, Thomas Dalsgaard, Frank B. Jensen, Ulf Simonsen, Andreas Roepstorff, and Angela Fago1 December 2009 | American Journal of Physiology-Heart and Circulatory Physiology, Vol. 297, No. 6Methazolamide does not impair respiratory work performance in anesthetized rabbitsHeidrun F. Kiwull-Schöne, Yi Li, Peter J. Kiwull, and Luc J. Teppema1 September 2009 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 297, No. 3Acetazolamide suppresses the prevalence of augmented breaths during exposure to hypoxiaHarold J. Bell and Philippe Haouzi1 August 2009 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 297, No. 2Integration of cerebrovascular CO2 reactivity and chemoreflex control of breathing: mechanisms of regulation, measurement, and interpretationPhilip N. Ainslie and James Duffin1 May 2009 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 296, No. 5Prophylactic Low-Dose Acetazolamide Reduces the Incidence and Severity of Acute Mountain SicknessHigh Altitude Medicine & Biology, Vol. 9, No. 4Acetazolamide Fails to Decrease Pulmonary Artery Pressure at High Altitude in Partially Acclimatized HumansHigh Altitude Medicine & Biology, Vol. 9, No. 3Effect of acetazolamide on ventilatory response in subjects with chronic mountain sicknessRespiratory Physiology & Neurobiology, Vol. 162, No. 3Illnesses at High AltitudeChest, Vol. 134, No. 2High hopes at high altitudes: pharmacotherapy for acute mountain sickness and high-altitude cerebral and pulmonary oedema13 December 2007 | Expert Opinion on Pharmacotherapy, Vol. 9, No. 1SightingsHigh Altitude Medicine & Biology, Vol. 8, No. 2 More from this issue > Volume 102Issue 4April 2007Pages 1305-1307 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.01407.2006PubMed17194729History Published online 1 April 2007 Published in print 1 April 2007 Metrics
Referência(s)