Safety of carbonic anhydrase inhibitors.

Review

Safety of carbonic anhydrase inhibitors Erik R Swenson University of Washington -- Medical Service, VA Puget Sound Health Care System, Seattle, WA, USA

1.

Introduction

2.

Drugs with CA-inhibiting action: pharmacology and

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physiology 3.

Adverse reactions

4.

Interactions with other drugs

5.

Mitigation of side effects

6.

Allergic reactions

7.

Conclusion

8.

Expert opinion

Introduction: Carbonic anhydrase (CA) inhibitors have an impressive safety record despite the multiple functions that CA isozymes serve because they are not fully inhibited with most dosing. While reducing the targeted CA-dependent process sufficiently for disease control, residual activity and uncatalyzed rates in combination with compensations are adequate to avoid lethal consequences. Some drugs have in vitro selectivity differences against the 13 active isozymes, but none are convincingly selective in vivo or clinically. Efforts to synthesize selective inhibitors should result in safer drugs with fewer side effects. Areas covered: This review will focus on approved drugs with CA-inhibiting activity, whether used directly for this purpose or others. Side effects are discussed in relation to various organ systems and the disease being treated. Causes of side effects are considered, and strategies for symptom reduction are given. Expert opinion: Common side effects of paresthesias, dyspepsia, lassitude and fatigue in 30 -- 40% of patients are generally tolerable or abate, but if not can be partially relieved by bicarbonate supplementation. The most important safety concerns are severe acidosis, respiratory failure and encephalopathy in patients with renal, pulmonary and hepatic disease where caution is critical, as is also the case in persons with sulfa drug allergies. Keywords: acetazolamide, carbonic anhydrase, side effects, sulfamate, sulfonamide Expert Opin. Drug Saf. (2014) 13(4):459-472

1.

Introduction

Carbonic anhydrase (CA) inhibitors, principally of the sulfonamide class, have been used for over 60 years in a wide variety of clinical conditions. The critical sulfonamide (--SO2--NH2) moiety may be linked to various aliphatic, aromatic or heterocyclic groups, which give rise to their differing pharmacology and inhibition characteristics. They have proven generally safe and well tolerated in use by many millions of people. Although sulfonamides with CA-inhibiting activity predominate, several drugs with a sulfamate (--O--SO2--NH2), rather than a sulfonamide moiety, are clinically available, but are not primarily used as CA inhibitors. CA is a very potent catalyst of the reversible hydration of carbon dioxide and dehydration of carbonic acid, speeding their reaction rates by 5 -- 6 log orders over the slow, but not insignificant or physiologically trivial, uncatalyzed reactions. The catalysis of these reactions by numerous isozymes subserves myriad processes involving ventilation and gas exchange, acid-base regulation, fluid secretion and absorption, nerve transmission, intermediary metabolism of fats, proteins and carbohydrates, reproduction, cardiovascular regulation and musculoskeletal function [1,2]. The indications for CA inhibitor use largely are focused on a single organ system or tissue, where the reduction in a CA-mediated process can be advantageous. However, given the presence of CA in most, if not all, tissues of the body and the fact that largely all clinically available CA inhibitors are relatively nonselective (depending upon dosing) against most of the 13 active isoforms of the enzyme, 10.1517/14740338.2014.897328 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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With > 70 years of use in millions of patients, carbonic anhydrase (CA) inhibiting sulfonamides have a predictable and largely mild side-effect profile. Less is known about newer CA-inhibiting sulfamates, the actions of which, like some of the sulfonamides, especially acetazolamide, may extend beyond CA inhibition to many other targets. The typical side-effect profile of CA-inhibiting sulfonamides, including tingling, nausea, fatigue, weight loss and anorexia, disappears in the majority of cases, but can be mitigated by supplementation of bicarbonate or acetate to correct the metabolic acidosis arising from inhibition of renal CA. These drugs should be prescribed with caution in the elderly and in those with any mild to moderate renal dysfunction in whom otherwise mild metabolic acidosis may be significantly more severe. Patients with diabetes and thyroid disorders should be carefully monitored for control of these conditions when started on a CA inhibitor. CA inhibitors, except the topical ophthalmic agents, should be avoided altogether in patients with severe renal insufficiency, cirrhosis and severe pulmonary disease to avoid renal failure, toxic drug levels, hepatic encephalopathy and respiratory failure. Patients with known mild non-life-threatening sulfa allergies to an antibacterial sulfonamide have a very low likelihood of any cross-reactivity with a CA-inhibiting sulfonamide.

This box summarizes key points contained in the article.

it is not surprising that mild side effects arising from CA inhibition elsewhere are often encountered by many patients, and in rarer circumstances more severe adverse events. Yet, what in one case might be an unwanted side effect may be beneficial under other circumstances; for example, an unwanted diuresis in a patient with normal volume status as opposed to a desirable diuresis in a patient with edema, the undesirable metabolic acidosis as opposed to the correction of a metabolic alkalosis or the unwanted weight loss as opposed to treatment of obesity, to name but a few examples. There has been over the past two decades a concerted effort by many groups to synthesize specific and selective CA isozyme inhibitors for the targeted treatment of disorders in which nonselective clinically available CA inhibitors have shown promise, such as in cancer where malignant rapidly growing cells almost uniquely express CA isozymes IX and XII. These synthetic successes will likely permit higher dosages to be given with reduced side effects and less off-target inhibition in other cells and organs for already established indications. For the interested reader, several recent reviews provide rich detail of this very fertile field [3-5]. In this chapter, I will focus on the safety of these agents in clinical use, describe the wide variety of mild side effects in relation to what tissue CA is being inhibited and which isozymes are involved, discuss the more severe adverse reactions, 460

highlight those clinical conditions in which use of a CA inhibitor is particularly dangerous or life threatening, and discuss strategies to mitigate these problems when a CA inhibitor must be used. It should be noted that owing to the overwhelming predominant use of acetazolamide over other available inhibitors, much of what will be discussed will relate to acetazolamide, but mention will be made of methazolamide and other sulfonamides introduced after acetazolamide for clinical use specifically as CA inhibitors. When there is information specific to other agents not used principally for their CA-inhibiting properties, these data will be identified. For many CA inhibitors there are off-target effects, both at tissue sites of CA not directly related to the disease being treated, and effects completely unrelated to CA inhibition. This applies to even acetazolamide and methazolamide, the prototypical CA inhibitors often used to establish a CAmediated physiologic or pathophysiological contribution [6]. While much of the effect(s) of acetazolamide is the result of CA inhibition, the situation may be more complicated since CA inhibition may not be its only action, nor in some cases do these actions require an unsubstituted sulfonamide moiety, otherwise critical to avid binding of the drugs to the active site of CA isozymes [6]. In a sense, this should be no surprise because in general off-target effects of many drugs are not unusual, and specifically this is the case for the many drugs described in this review used for other purposes and not developed intentionally as CA inhibitors. Table 1 gives a listing of these other known targets of clinically available CA-inhibiting drugs and the specific agents reported. It should be appreciated that in some cases, the doses required for these targetmediated actions, whether inhibitory or stimulating, are often higher than that required for CA inhibition. It is beyond the scope of this paper to go into all particular details, and the reader is referred to the references provided in the table.

Drugs with CA-inhibiting action: pharmacology and physiology

2.

The presently available drugs that are CA inhibitors are listed below and in Tables 2 and 3, although approval for use and indications may differ across countries. These compounds vary considerably in their in vitro inhibition constants against most CA isozymes by many orders of magnitude and have differing inhibitory properties against specific CA isozymes [3,5]. Thus at their properly prescribed dosing (Table 2), only acetazolamide, methazolamide, ethoxzolamide, dichlorphenamide, dorzolamide, brinzolamide, sulthiame and mafenide are unquestionably potent CA inhibitors at their indicated dosing. Except for mefanide (cutaneous bacterial infection), like the first antibacterial sulfanilamide, the others are approved for conditions in which CA inhibition has been shown to be salutary, such as edema, seizure disorders, glaucoma, metabolic alkalosis and acute mountain sickness (AMS). The CA inhibitors listed in Table 3 do not as a general rule act principally as CA inhibitors at their proper dosing,

Expert Opin. Drug Saf. (2014) 13(4)

Safety of carbonic anhydrase inhibitors

Table 1. Other reported targets of clinically used CA inhibitors*.


Target

Drug(s)

Ref.

Anion exchanger-1 (Cl-/HCO3- antiporter)z

Celecoxib Chlorothiazide Hydrochlorothiazide Furosemide Chlorthalidone Hydroflumethazide

[124,125]

Aquaporins

Acetazolamide

[126]

Heat shock protein

Dorzolamide

[127]

Nuclear-related factor 2 (Nrf-2)

Methazolamide, Acetazolamide

[128]

Ca++ activated K+ channel

Acetazolamide

[129]

Voltage-dependent Na+ channel

Topiramate, Zonisamide

[15,112]

GABAA receptor

Topiramate

[15]

AMPA/kinate receptor

Topiramate

[15]

Voltage-sensitive (T) Ca++ channel

Zonisamide

[112]

*In the studies of aquaporins, heat shock protein and Nrf-2, it is not clear whether these targets are directly affected by the listed CA inhibitors or the changes are secondary to changes in the cellular milieu arising from CA inhibition such as acidosis. z These agents can directly inhibit the exchanger for all univalent anion exchange, or slow its HCO3-/Cl- exchange rate by decreasing the rate of CA-mediated HCO3- formation for entry into the antiporter site. Considerable evidence supports either direct non-covalent linking of CA with AE-1 and other anion exchangers or membrane-structured close association of these two proteins. CA: Carbonic anhydrase.

but against other molecular targets for reasons including lesser activity against CA and dosing at lower amounts on a mg to mg basis to bind to their non-CA target receptors or channels. That many drugs have a free unsubstituted sulfonamide group relates historically to the discovery of the early sulfonamide antibiotics, general chemical stability and the facility of this group for multiple bonding interactions and to be anionic at physiological pH [7]. Thus, many of these drugs were found only after the fact to be moderate to good CA inhibitors; and more will likely appear as drug synthetic efforts continue. Most of these drugs, however, have not been or will be studied sufficiently to determine whether CA inhibition (of any or all isozymes) contributes as well to their efficacy. The compounds listed in Table 3, the high ceiling loop diuretics and thiazides, were developed with the initial strategy of synthesizing even more potent CA inhibitors than acetazolamide. They were found subsequently in general to be weaker CA inhibitors, but serendipitously stronger diuretics that did not cause metabolic acidosis or significant bicarbonate loss in the urine [8,9]. The dosing of loop and thiazide diuretics (< 0.5 mg/kg) acting at the loop of Henle to inhibit the

Na--Cl--2K co-transporter and at the distal tubule to inhibit the Na-Cl co-transporter, respectively, to achieve diuresis, natriuresis and other clinical actions such as blood pressure reduction is far less than the minimal 1 -- 2 mg/kg dosing required of the potent CA inhibitors to cause renal CA inhibition and effect [8]. Studies with furosemide, the prototypical loop diuretic with intermediate nanomolar activity (50 -- 500 nM) against all of the renal isozymes (CA II, IV, XII and XIV) [3], fail to show any effects on proximal tubular bicarbonate absorption related to CA inhibition even at inhibitory concentrations [10-12] that may be achieved in kidney due to concentration by active renal organic acid and base secretion [8]. These data remain unexplained, but point to the hazard of extrapolating from in vitro inhibition constants to complex biology. If any of the agents in Table 3 are taken in accidental or purposeful overdosing, however, blood and tissue concentrations may rise sufficiently to cause many of the expected side effects and safety issues related to CA inhibition discussed in this review. Given that most of the thiazides and loop diuretics are concentrated in urine, their failure to cause any of the hallmarks of renal CA inhibition strongly suggests their very weak in vivo CA inhibitory action. What emerges from the data of Tables 2 and 3 in general is the impression that what predicts which drug will act in the kidney typical of a CA inhibitor are KIs versus CA II and CA XII of < 50 nM and perhaps KI versus CA XIV < 100 nM if the KIs against CA II and XII are nominally > 50 nM. Inhibition against CA IV alone does not seem predictive, although the in vitro data may not necessarily reflect the activity of a membrane-bound protein tested outside of its complex membrane environment. Whether any of the drugs listed in Table 3 and several from Table 1 have clinically important actions related to CA inhibition beyond the kidney has not been rigorously studied. At issue is whether very small concentrations of CA in some tissues, such as in blood vessels [13], combined with uptake of the drug into tissues and concentration could lead to sufficient CA inhibition to add clinically to that of the prime target of these drugs. Such studies will require accurate measurements of CA activity and free drug concentrations in these tissues, and ideally should study structural manipulations of the molecule that still retain CA inhibition activity but prevent the drug from binding to or affecting the principal target. Prime examples of this question are whether the antihypertensive drugs, hydrochlorothiazide or chlorthalidone act on vascular or platelet CA in addition to their main target, the NaCl co-transporter in the renal cortical collecting duct and blood vessels [14], and whether CA inhibition in neuronal tissue is central to the effects of topiramate and zonisamide, which have numerous other more compelling targets underlying their efficacy [15-17]. The fact that some CA inhibitors in Table 3 with high nanomolar in vitro inhibition constants for some of the isozymes [3], many of which were not developed as CA inhibitors, do not always cause evidence of CA inhibition in all patients has not been adequately addressed. Inhibition in vivo and isozyme selectivity are likely to be diminished


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E. R. Swenson

Table 2. Drugs used clinically as CA inhibitors or with predictable in vivo CA inhibition. KI (nM)*


CA isozyme

II

IV

Renal acid--base effect XII

XIV

CA inhibitors used principally as such Acetazolamide 12 Methazolamide 14 Ethoxzolamide 8 Dichlorphenamide 38 Dorzolamide 9 Brinzolamide 3

74 6200 93 15,000 8500 3960

6 3 22 50 35 3

41 43 25 345 27 24

Bicarbonaturia, metabolic acidosis Bicarbonaturia, metabolic acidosis Bicarbonaturia, metabolic acidosis Bicarbonaturia, metabolic acidosis None, when given topically to cornea None, when given topically to cornea

Antibiotic Mafenidez

17

ND

ND

ND

Bicarbonaturia, metabolic acidosis

Anti-epileptics Sulthiame Topiramate Zonisamide

7 10 35

95 4900 8590

56 3.8 11,000

1540 1460 5250

Bicarbonaturia, metabolic acidosis Variable metabolic acidosis Metabolic acidosis infrequent

290

ND

ND

Metabolic acidosis extremely rare

Nonsteroidal anti-inflammatory agent Celecoxib 21

*Data -- Supuran and colleagues [3,130]- (composite: either CO2 hydration and esterase reaction). z Unpublished data (Swenson laboratory: 37 C, CO2 hydration reaction). CA: Carbonic anhydrase; ND: No data.

and altered by many complex pharmacological factors that determine the free drug level including differing drug metabolism rates, metabolite formation, plasma protein binding, and sites of metabolism and excretion. Physiological factors that further complicate analysis include tissue CA isozyme concentration(s) and locations (plasma membrane bound with extracellular orientation of its catalytic activity vs cytosolic expression), water and lipid solubility that determine diffusibility into cells and organelles, what the uncatalyzed rate in relation to the rate of the process to be inhibited, and the complex nature of tissues having more than one isozyme. Thus, what makes a drug a CA inhibitor in vivo and clinically relevant is far more than just an inhibition constant determined in solution with the enzyme perhaps not even in its in vivo native state and lacking its natural biochemical milieu. For a more detailed discussion of these issues, the classic review by TH Maren, on the use of CA inhibitors as probes for CA function [10] is highly recommended. Conclusive studies of the role of various CA isozymes in diseases and their inhibition will require a combination of sophisticated pharmacological and physiological investigation, and corroborated with genetic studies done using tissue-specific conditional gene knockout or gene knockdown by small interfering RNA.

two-thirds of those with glaucoma [18] or migraine [19] successfully controlled by acetazolamide choose to remain on the drug despite clinical efficacy. The intensity of side effects in individuals has not been rigorously quantitated, but anecdotally when severe some patients claim that the therapy is worse than the disease. The gastrointestinal (GI) symptom complex of nausea, anorexia and weight loss figures prominently in the intolerance to these drugs. The basis of these symptoms remains poorly defined, but metabolic acidosis, and/or local gastrointestinal and neuronal CA inhibition are most likely given the nature of these subjective complaints. It should be noted that in the following sections, the side effects discussed for CA inhibitors refer to those occurring with either oral or intravenous dosing that lead to systemic inhibition. Except for local irritation, the two topical ocular CA inhibitors used for glaucoma (dorzolamide and brinzolamide) do not cause any side effects related to systemic absorption. The doses applied are extremely small on a weight basis (~ 0.05 mg/kg) such that any systemic absorption across the conjunctivae, sclerae and from the interior of the eye never causes critical inhibitory plasma-free drug concentrations [20]. Renal With the advent of sulfanilamide in the 1930s as the first appreciably nontoxic antibiotic, it was quickly recognized that animals and patients develop a mild metabolic acidosis and an alkaline diuresis. The magnitude of the diuresis is on the order of a 7% contraction of extracellular volume and serum bicarbonate falls roughly about 4 -- 6 mM, with a typical fall in arterial pH of about 0.05 -- 0.1, depending upon the degree of the subject to increase ventilation and 3.1

3.

Adverse reactions

Many patients taking CA inhibitors, for both short term and chronic use, experience a typical set of subjective symptoms including general malaise, fatigue, weight loss, nausea, anorexia, depression and loss of libido. Upwards of 50% of patients complain of this symptom complex, and only 462



Table 3. CA-inhibiting drugs with other targets of action and not used clinically as CA inhibitors. KI (nM)* CA isozyme


High ceiling loop diuretics Furosemide Bumetanide Piretanidez Torsemidez Mefrusidez Thiazide diuretics{ Hydrochlorothiazide Chlorothiazide Chlorthalidone Metolazone Hydroflumethiazide Bendroflumethiazidez Trichlormethazide Polythiazide Quinethazonez Xipamide Indapamide

Renal acid--base effect

II

IV

XII

XIV

65 6980 > 1000 > 1000 650

564 303 ND ND ND

261 21 ND ND ND

52 250 ND ND ND

No No No No No

290 920 138 2000 435 650 91 ND 1260 11000 2520

427 ND 196 216 4780 ND 449 ND ND ND 213

335 ND 5 5 305 ND 312 ND ND ND 10

4105 ND 4130 5432 360 ND 3480 ND ND ND 4959

No bicarbonaturia, metabolic alkalosis No bicarbonaturia, metabolic alkalosis No bicarbonaturia, metabolic alkalosis no bicarbonaturia, metabolic alkalosis No bicarbonaturia, metabolic alkalosis No bicarbonaturia, metabolic alkalosis No bicarbonaturia, metabolic alkalosis No bicarbonaturia, metabolic alkalosis No bicarbonaturia, metabolic alkalosis No bicarbonaturia, metabolic alkalosis No bicarbonaturia, metabolic alkalosis

§

bicarbonaturia, bicarbonaturia, bicarbonaturia, bicarbonaturia, bicarbonaturia,

metabolic metabolic metabolic metabolic metabolic

alkalosis alkalosis alkalosis alkalosis alkalosis

*Data of Supuran and colleagues [3,130] composite: either CO2 hydration and esterase reaction. z Unpublished data (Swenson laboratory: 37 C, CO2 hydration reaction). § Metabolic alkalosis due to volume depletion, hypokalemia and stimulated distal tubular H+ secretion. { Metabolic alkalosis much less than with loop diuretics due to their lesser diuretic effect. ND: No data.

lower arterial PCO2 [6,8]. These effects develop over the first 1 -- 2 days in the initiation of any potent CA inhibitor, but the diuresis and fall in bicarbonate are limited, owing to action of other portions of the nephron beyond the proximal tubule that are capable of fully reabsorbing the lower filtered bicarbonate load and associated fluid and salts [9]. Importantly in the elderly, those with diabetes or other forms of early kidney disease there sometimes is much greater metabolic acidosis with the serum bicarbonate falling further to 12 -- 15 mM [21-23], as a result of the remaining fewer hyperfiltrating nephrons only being able to fully reabsorb filtered bicarbonate when the serum concentration falls to a lower level. Thus, CA inhibitors should be used cautiously in these patients, with the exception of topically applied dorzolamide and brinzolamide that have trivial systemic absorption. Because most CA inhibitors are concentrated in the urine, these renal effects occur at doses as low as 1 -- 2 mg/kg [8]. Thus by virtue of concentration in the urine by tubular fluid reabsorption and secretion by renal organic base and acid transporters, these low doses are virtually selective for the kidney; the one exception being vascular endothelial cell membrane-bound isozymes of CA that have their active site in direct contact with plasma [6]. All of the drugs in Table 2 with the exception of topiramate and celecoxib when given systemically have the signature effect of a mild metabolic acidosis secondary to renal CA inhibition. With regard to renal CA inhibition by celecoxib and topiramate, both of which have high nanomolar in vitro inhibition constants against CA II and other renal isozymes, it is

surprising that metabolic acidosis is not invariably encountered in their use except in the case of intentional or accidental overdosing. In the example of celecoxib at dosing of 200 -- 400 mg twice daily, several studies show no metabolic acidosis [24-26] and only in the very elderly (> 70 years) with higher dosing (400 mg twice daily) does serum bicarbonate fall even slightly (~ 2 mM) [27]. It is likely that this agent is metabolized extensively, such that only a small fraction of the drug is excreted unchanged in the urine and thus not enough may be present to achieve full renal tubular CA inhibition [24]. Regarding topiramate, which is renally excreted, the fact that many patients do not develop a metabolic acidosis [28,29] remains an enigma, but a genetic basis for this heterogeneity based upon a single nucleotide polymorphism (SNP) has been identified for CA XII [30], which is expressed in multiple areas of the nephron. Nothing is known about the protein expression and activity of this SNP that might explain this finding. The acid-base and diuretic effects of CA inhibitor use may also lead to other problems. Nephrolithiasis or kidney stones are a common clinical occurrence [31]. Many of the CA inhibitors reduce citrate concentration in tubular urine [32] as a result of the systemic acidosis caused by renal CA inhibition. The lower pH of the glomerular filtrate shifts the balance of citrate from its trivalent state to divalent state, a form that is more easily taken up by the brush-border proximal tubular Na-citrate co-transporter [33]. Citrate is a powerful inhibitor of the crystallization of calcium salts in tubular fluid and urine [33]. If a CA inhibitor must be continued in the face of concerns for nephrolithiasis, citrate can be administered to minimize


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hypercalciuria [34] even at doses that do not correct the metabolic acidosis if the efficacy of the CA inhibitor requires a state of metabolic acidosis. Additionally, mild potassium losses in the urine occur as a result of both the metabolic acidosis they generate, but more importantly by the activation of distal nephron sodium reabsorption with concurrent excretion of potassium generated by renin-angiotensin-aldosterone activation evoked with volume depletion. The magnitude of hypokalemia will be determined by total body stores of potassium, potassium intake, volume status and whether other drugs with action on renal potassium metabolism are used. If there is a degree of renal insufficiency and diminished potassium excretory capacity, then the metabolic acidosis may cause hyperkalemia by a transcellular movement of K+ out of cells [35]. Although renal CA inhibition reduces phosphate reabsorption [36], hypophosphatemia has only been rarely reported. Perhaps this is because the losses of phosphate are more attributable to urinary alkalization that occurs only on the first day after beginning acetazolamide or due to the slight increase in bone release of phosphate with metabolic acidosis that balances the loss of phosphate [37]. Respiratory As noted above, the initial experience with sulfanilamideinduced metabolic acidosis included the recognition of a compensatory increase in ventilation to help minimize the degree of acidosis [6]. This respiratory stimulation may have utility in many conditions if oxygenation is decreased because breathing is depressed or reduced, but only if pulmonary function and respiratory muscle strength are adequate; for example, periodic breathing, sleep-disordered breathing or at high altitude for prevention of AMS [6]. However, in any patient with advanced lung disease in whom pulmonary function falls below 25% predicted values (e.g., forced expiratory volume in the first second [FEV1] < 1.0 l), the use of acetazolamide or other CA inhibitors to stimulate breathing or to treat some other condition, such as glaucoma, is usually not only ineffectual, but may itself cause more distressing dyspnea [38] and respiratory failure [39]. Thus, these patients should avoid any CA inhibitor unless closely monitored, with the exception of topically applied dorzolamide and brinzolamide that have trivial systemic absorption. Exercise capacity is not generally reduced at normal dosing, but the added breathing may be appreciated as unexpected dyspnea with heavy exertion in healthy subjects or in patients with less than severe pulmonary dysfunction at formerly tolerated levels of exertion. Although rarely given in high enough doses (> 6 mg/kg intravenously and > 12 mg/kg orally), ultimately any potent CA inhibitor, such as acetazolamide and those in Table 2, can lead to sufficient erythrocyte CA inhibition to impair the normal efficiency of blood CO2 transport and excretion by the lung [9]. This might occur with intentional or accidental overdosing, or with normal dosing in the face of renal insufficiency with failure to excrete the drug, or with severe 3.2

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anemia. As the fractional inhibition of red cell CA increases beyond 0.99, then even in the face of increased ventilation, retention of CO2 in the tissues occurs and severe respiratory acidosis develops. In these circumstances, patients with lung disease will develop respiratory failure and die without rescue noninvasive assisted ventilation or intubation with mechanical ventilation. Lastly, acetazolamide reduces diaphragmatic muscle strength in exercise in healthy persons [40]. This is only a small reduction, but in patients with lung disease whose respiratory muscles are often overloaded and fatigued, this may be another reason to avoid a CA inhibitor in such persons. Surprisingly, acetazolamide inhibits diaphragmatic strength in rabbits, but methazolamide does not [41]. The reason for such a dichotomous response between two very similar sulfonamides, differing in only that fact that methazolamide has a methyl group added to the thiadiazole ring of acetazolamide, adds further to the evidence that CA inhibition cannot always be assumed to be the cause of side effects of CA-inhibiting sulfonamides. Gastrointestinal and hepatic CA is present throughout the length of the gastrointestinal tract, where it subserves salivary secretion, esophageal acid sensing, digestive gastric acid secretion, protective gastric and duodenal mucosal bicarbonate secretion, biliary and pancreatic bicarbonate secretion, and intestinal salt, water and fatty acid reabsorption [42]. Given this myriad of roles, it is surprising what little impact the use of CA inhibitors has on GI function. Most patients on CA inhibitors do not have peptic ulcer disease, diarrhea, cholelithiasis or malabsorption. The reasons for this may be related to the adequacy of the uncatalyzed reactions for digestive purposes, particularly with the metabolic acidosis from renal CA inhibition [42,43], which as in the kidney enhances the magnitude of the uncatalyzed reaction, and to other mechanisms that may be evoked in compensation. In the case of peptic ulcers, it may be that the simultaneous suppression of gastric acid secretion counters the adverse effect of loss of protective mucosal bicarbonate secretion [42]. Nonetheless, nausea and appetite suppression occur in about 20 -- 30% of patients taking CA inhibitors suggesting some poorly explained effects of this class of drugs. Whether nausea and anorexia are expressions of central and peripheral nervous system CA inhibition, loss of protective mucosal HCO3- secretion or of the metabolic acidosis remains unsolved and little studied. In two studies, partial correction of the metabolic acidosis by administration of sufficient oral sodium acetate or sodium bicarbonate did help to relieve nausea and other GI-related symptoms in about 50% of patients with glaucoma, especially those with greater hypobicarbonatemia [18,44]. In contrast to the relatively benign effects of CA inhibitors elsewhere in the GI tract, patients with hepatic insufficiency and cirrhosis are at considerable risk for aggravation of hepatic encephalopathy [45,46]. Two factors are involved. The first is that any CO2 retention that might arise with high dosing itself reduces cerebral function in these patients [45]. Second, 3.3




hepatic CA plays a key role in ammonia homeostasis by catalyzing the formation of bicarbonate for use in urea formation, the principal pathway of ammonia detoxification [47]. Additionally, renal CA also is important in renal ammoniagenesis and its inhibition leads to impaired nitrogenous waste excretion [48,49]. Ammonia levels rise minimally in those with normal liver function, but with any significant hepatic dysfunction, the remaining hepatocytes are unable to handle the normal demands of protein catabolism. Thus, CA inhibitor use in patients with any evidence of cirrhosis or history of hepatic encephalopathy is absolutely contraindicated, with the exception of topically applied dorzolamide and brinzolamide that have trivial systemic absorption. Endocrine The question of whether the CA-inhibiting sulfonamides alter glucose metabolism and affect diabetes has been the subject of considerable study. The literature in this area, which is cited below, is complex and conflicting, but in general it appears that acetazolamide use over many decades has not resulted in significant problems for most diabetics [50-56]. This relative safety may stem from competing effects of acetazolamide or other CA inhibitors at multiple points in glucose homeostasis. The metabolic acidosis and mild diuretic effect and volume depletion of acetazolamide may evoke a slight activation of the sympathetic nervous system and thus act to reduce insulin sensitivity and lead to hyperglycemia [50]. Because hepatic and renal gluconeogenesis from pyruvate and other 3 -- 4 carbon intermediates depends upon mitochondrial CA V and other isozymes, inhibition would thus lead to reduced glucose production and hypoglycemia [51,52]. The effects of acetazolamide on pancreatic b-cell insulin release are variable, but in most of these studies acetazolamide was used far in excess of concentrations ever achieved in human therapeutic administration. Recently, it was found that methazolamide, but not acetazolamide, ethoxzolamide, dichlorphenamide, furosemide and chlorthalidone, has hepatic insulin-sensitizing activity in mice, again pointing out that not all CA-inhibiting sulfonamides act by a CA-dependent mechanism [53]. In studies of normal and well-controlled diabetics, blood glucose concentrations either in the fasting or in the fed state are not different with acetazolamide administration [54,55]. Nonetheless, single case reports have highlighted the possible worsening of diabetes control or development of diabetic hypertonic hyperglycemia [56] and severe non-ketotic acidosis [23]. Thus, CA inhibitors should be used with caution in any diabetic patient. Although acetazolamide reduces thyroidal uptake of iodine in healthy persons and patients with hyperthyroidism [57], it does not appear to do so by a CA-dependent mechanism since much weaker sulfonamide CA inhibitors such as sulfanilamide are also effective in blocking iodide uptake [58]. In contrast, very high doses of acetazolamide in mice appear to increase thyroidal iodide uptake [59], but this was not further explored as to whether the severe respiratory acidosis of such high doses might be causal. It is likely that other structural 3.4

aspects of any CA-inhibiting sulfonamides are involved in antithyroid activity [60], because the most potent of the sulfonamides are, in fact, either poor CA inhibitors or lack CA-inhibiting activity at all [8]. While the potential might exist, there have been no published reports of acetazolamide or other CA inhibitors causing hypothyroidism. In fact, the only adverse effect of acetazolamide related to thyroid status is a case report of thyrotoxicosis induced in a patient with familial periodic paralysis [61]. Nonetheless, CA inhibitors should be used carefully in patients with thyroid disease. Hematologic As is the case with many drugs, various sulfonamides have been incriminated in causing myelosuppression, thrombocytopenia and aplastic anemia [62]. Thus, acetazolamide and methazolamide are associated with blood dyscrasias [63-65]. The pathophysiology is idiosyncratic, entirely unpredictable and unrelated to CA inhibition. Although leukocytes contain CA and its inhibition suppresses superoxide generation, migration and cytokine release [66-68], there have been no reports of increased infection risk with CA inhibitors in the absence of idiosyncratic myelosuppression. 3.5

Neurologic Drugs causing CA inhibition in the nervous system are useful in a number of neurological and neuromuscular diseases, but many of the nonspecific complaints of patients taking these drugs are either indirectly or directly related to CNS intolerance. For instance, while acetazolamide, methazolamide and benzolamide reduce AMS, a constellation of symptoms (malaise, nausea, lassitude, headache) that develops in the first few days at high altitude, not all people are helped. However, what is often taken to be a lack of prevention of AMS may simply be the onset of intolerance to CA inhibitors, since the symptoms are largely the same as those of AMS [6]. Metabolic acidosis can cause lethargy and malaise, but these remain in many patients even with bicarbonate or acetate supplementation [18,44]. As mentioned earlier, nausea may be related to GI tract CA inhibition or actions of these drugs in regions of brain involved in taste, smell and reception of gastrointestinal nervous afferent signaling [69,70]. Dysguesia and loss of taste appreciation for carbonated beverages appear to be related to both inhibition of salivary CA isozymes [71] and membranebound isozymes in taste/smell receptors [72]. Impaired memory has been reported in humans on acetazolamide [73,74] and more definitively shown in animals [75]. Although acetazolamide causes short-lived cerebral vasodilation with acute intravenous dosing at > 12 mg/kg often with significant side effects [76], when used conventionally at lower doses and taken orally this does not occur [77,78]. Acetazolamide does cause numerous neuropsychiatric subjective and objective sensations, including its very typical perioral and distal extremity paresthesias, as well as loss of concentration and even balance. In a recent study, we explored these side effects in a group of healthy students and found that benzolamide, a 3.6


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very hydrophilic and poorly permeant CA inhibitor given at doses to cause equal metabolic acidosis, reduced by roughly 50% the side effects perceived by subjects and objective neuropsychological deficits (concentration, balance and memory recall) perceived with acetazolamide 125 mg b.i.d. [74]. These findings suggest that intracellular neuronal CA inhibition is largely responsible for this side-effect profile. Reproductive Although CA is present in many portions of the female and male genital tract, there have been no reports of infertility or reduced fertility associated with CA inhibitor therapy. However, studies in rodents have established that acetazolamide is teratogenic. This and other sulfonamide inhibitors cause a typical forelimb ectrodactyly [79-81] thought to be mediated by reduced intracellular pH in the limb bud [79,82]. Potentiation of the teratogenic effect is also observed with drugs that reduce intrauterine blood flow and so cause acidosis in those vasoconstricted vascular beds [83]. Whether or not these drugs cause human teratogenesis is unknown [84], but all national medicine regulatory bodies, such as the US FDA, list CA inhibitors as contraindicated in pregnancy or in women planning to become pregnant.


3.7

Ophthalmologic Color vision changes have been reported with methazolamide [85] as well as bilateral transient myopia, angle closure glaucoma and choroidal detachment [86], but only as single case reports. With the introduction of two topically active CA inhibitors applied to the cornea, dorzolamide and brinzolamide, the use of acetazolamide and methazolamide for glaucoma has fallen off by > 95% [87]. Although both drugs can be absorbed systemically across the conjunctivae and sclera, the amounts do not lead to any non-ocular CA inhibition. The only observed common side effects are local hyperemia [88], perhaps as a result of local vasodilation, a possible vascular effect of local vessel CA inhibition (see below) and contact dermatitis [89]. Rarely, they may cause blurred vision and corneal, lacrimal and periorbital irritation [90]. 3.8

Cardiovascular CA inhibitors are generally not considered to have important cardiac and vascular effects, either disadvantageous or therapeutically useful. Many of the CA-inhibiting sulfonamides have a diuretic effect, so that hypotension is a concern particularly if they are used in conjunction with other antihypertensive medication. The combination of a CA inhibitor with renal action with a diuretic of a different class may be synergistic, so that salt and water losses may be much greater than the sum of each alone. In addition to volume depletion as a cause for blood pressure lowering, there is considerable evidence emerging that acetazolamide and other sulfonamides may have direct effect on vascular smooth muscle and tone. Whether this is by inhibition of vascular smooth muscle CA per se or by other 3.9

466

actions remains unclear and it may be that both CA and other receptors are involved; with the vasculature of different organs having varying properties in this regard. In the pulmonary vasculature [6,91], it appears that a CA inhibition effect is not responsible for pulmonary artery pressure reduction, particularly against the hypertensive effect of hypoxia, because acetazolamide methylated at the sulfonamide nitrogen to form the substituted inactive n-methyl acetazolamide remains fully active as a hypotensive agent, whereas other equally or more potent CA inhibitors such as benzolamide and ethoxzolamide are ineffective [91-94]. In the systemic circulation, it would appear that vascular CA inhibition may be a contributor along with other possible mechanisms. Mesenteric artery vasoconstriction to norepinephrine is prevented by acetazolamide, benzolamide and ethoxzolamide in a rank order consistent their inhibition constants against membrane-bound CAs [95] and like hydrochlorothiazide this may be related to their action in elevating intracellular pH causing activation of calcium-sensitive potassium channels [96]. Other vascular beds in which CA inhibitors such as acetazolamide and dorzolamide may have vasodilatory capacity include the eye [97], brain [76], kidney [98,99], liver [99], but not elsewhere in the GI tract or skeletal muscle [99]. Very recently, it has been shown, somewhat paradoxically, that CA catalyzes nitrite reduction to nitric oxide, a potent endogenous vasodilator, and that acetazolamide and dorzolamide amplify this activity [100]. It remains to be explained how drugs, which bind to the active site of CA, catalyze this potential vasodilating capacity of CA, but binding of the inhibitor may alter the tertiary structure of the enzyme in a subtle way to facilitate this other catalytic activity elsewhere in or on the surface of the enzyme. Lastly, renal tubular reabsorption of nitrite appears to be dependent on CA [101], which might oppose any possible benefit of direct CA-mediated nitrite reduction by virtue of increased drug-induced urinary losses of the critical substrate. These disparate and opposing findings of varying vasodilation and the lack of demonstrable vasodilation in the skeletal muscle, which constitutes over 60% of body mass, and a possible link to nitrite are likely why CA inhibitors have not found any use in treatment of hypertension. While the vast majority of patients with coronary artery disease and heart failure tolerate CA inhibitors and in some ways may be benefited by the diuretic and ventilatory effects, and correction of loop diuretic-mediated metabolic alkalosis [102], it has been reported that those with severe disease may develop myocardial ischemia [103]. Thus in these patients risks and benefits must be carefully considered. 4.

Interactions with other drugs

Several commonly used medications have known interactions with acetazolamide and other CA inhibitors. First among these are aspirin and likely all salicylates [104]. Because aspirin and many of the CA inhibitors compete for the same excretory pathway in the kidney, concurrent CA inhibitor use has




been reported to cause salicylate overdosing [104-106]. Not only are total blood levels higher, but displacement of plasma-protein-bound aspirin by the metabolic acidosis or any respiratory acidosis (CO2 retention with red cell CA inhibition) increases the free plasma drug concentration. The metabolic and respiratory acidoses arising from CA inhibition favor aspirin concentration within neuronal cells [107,108] and the acidotic state retards its excretion in urine by ionic trapping, which is enhanced in alkaline urine. Aspirin also displaces acetazolamide from plasma proteins and so raises the effective free drug concentration [108,109]. If a nonsteroidal anti-inflammatory drug needs to be taken with acetazolamide, then flurbiprofen is a safer alternative [110]. Acetazolamide and other CA inhibitors have no known cytochrome P450 enzyme-induction or suppression effects [111]. However, other drugs such as zonisamide, which is metabolized by cytochrome P450, may need dose adjustments when other drugs that induce cytochrome P450 are used [112]. Acetazolamide should be used with caution in patients taking carbamazepine since toxic levels of the drug may occur by inhibition of its metabolism [113]. The mild diuretic and kaliuretic action of acetazolamide and other CA inhibitors requires caution in their use if other antihypertensive or drugs causing hypokalemia are given concurrently. The same applies to addition of these drugs to regimens containing drugs used as respiratory stimulants, such as progesterone or theophylline, due to the known respiratory stimulation of CA inhibitors [6]. 5.

Mitigation of side effects

Efforts have been made to reduce CA inhibitor side effects by means of lower dosing, choosing methazolamide over acetazolamide [113,114] and correcting the metabolic acidosis by bicarbonate supplementation [18,44]. Bicarbonate or acetate supplementation was about 50% effective in decreasing the spectrum of side effects in patients taking acetazolamide for glaucoma [3,19]. As alluded to above, more hydrophilic CA inhibitors, whose action is directed at isozymes of CA with extracellular facing activity, might be helpful such as benzolamide (an orphan drug, not presently available). On the horizon are synthetic efforts to develop specific CA IX and CA XII (membrane-bound outwardly facing isozymes expressed largely by malignant cells) inhibitors for treatment of cancer [4]. These drugs will necessarily be very hydrophilic to enhance their activity against cancer cells and to avoid uptake into normal tissues. When and if these become available, there may be situations where their use beyond cancer might help to reduce the side effects of acetazolamide, as has already been demonstrated with benzolamide [74]. 6.

Allergic reactions

The matter of any sulfonamide use in patients with prior exposure to and allergic reaction to a sulfonamide has

generated considerable concern for both patients and physicians. Given their widespread use, it is usually to an antibacterial sulfonamide that most people have developed an allergic reaction. The chemical structures of sulfonamides are complex and while CA-inhibiting sulfonamides have some structural similarity to all sulfonamides in having either an unsubstituted or a substituted --SO2--NH2 moiety, beyond this there is considerable heterogeneity in the aliphatic and ring structures of this large group of compounds [60]. With regard to antibacterial antibiotics such as sulfamethoxazole, it appears that the arylamine (an amine linked to a benzene ring) moiety is most problematic [115-117] and not the sulfonamide moiety. The nonantibiotic sulfonamides do not contain an arylamine group or a substituted aromatic ring. In one study, about 10% of patients with an allergic reaction after a sulfonamide antibiotic also had subsequent reaction to a nonantibiotic sulfonamide [118]; however, the risk was even greater in patients who had a penicillin allergy. Thus, the association initially seen in the primary analysis with the sulfonamide nonantibiotics might represent a general predisposition to allergic reactions among certain patients rather than a specific cross-reactivity with drugs containing the sulfa moiety. With respect to CA-inhibiting sulfonamides, the safest approach is avoidance of the entire sulfonamide drug class, especially in individuals whose previous reaction included a serious and/or life-threatening condition such as anaphylaxis, Stevens-Johnson syndrome (SJS) or toxic epidermal necrosis (TEN) and possibly those with severe allergies to penicillin. Recently, it was found that methazolamide-induced SJS/ TEN is strongly associated with several alleles of the HLA class genes [119]. Any form of re-exposure to the precipitating drug or a sulfonamide in the same group should be absolutely contraindicated. This applies even to the topical inhibitors, because although systemic absorption is insufficient to cause CA inhibition elsewhere, the even very small degree of absorption may present enough antigen to elicit a full allergic/ anaphylactic response. If the reaction to a past sulfonamide, particularly not of a CA-inhibiting subclass, was minor, for example, itching, rhinitis, then it is unlikely that a serious cross-reaction would occur [118,120,121]. However, whether or not a CA inhibitor should be used, the real small risk ought to be discussed with the patient with respect to the benefits or critical need. Other less life-threatening atopic reactions and dermatitis to CA inhibitors of skin and underlying cartilaginous tissue had been reported for the topical agents, mafenide [122], brinzolamide and dorzolamide [90]. 7.

Conclusion

The available CA inhibitors for clinical use have had an impressive safety record over the past half century. In part, this is a consequence of the fact that not all CA activity is fully inhibited over most of the dose ranges employed, except perhaps for the kidney. Residual enzymic activity and the


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uncatalyzed rates, along with physiological compensations, are often sufficient for adequate function of the system being inhibited, and these compensations are often salutary and sought for the purpose of disease control or prevention. The most important safety concerns are those of use in patients with decreased renal, pulmonary and hepatic function, where lower dosing or avoidance is critical.


8.

Expert opinion

The many decades use of sulfonamide CA inhibitors for a variety of diseases has been one of exceptionally favorable risk to benefit ratio. The typical side effects do diminish over time in many people or can be partially mitigated by supplementation of small amounts of bicarbonate or other alkaline salts when these medications are necessary for chronic conditions. With the eventual introduction of newer sulfonamides and sulfamates, and even other compounds that alter CA activity without binding to its catalytic site, we cannot expect to know everything about their safety, despite putative isozyme selectivity, until they come into wide use. It is expected that much of what we know about the sulfonamides will also apply, but unique problems may emerge in clinical trials or later with widespread use. As has been demonstrated amply for many drugs, the number of patients needed to treat for full safety assessment often requires 10 -- 100 times more patients than needed for efficacy determination. Thus, this mandates ongoing Phase IV (post approval) studies for all new compounds. Several issues remain for further work. At both a basic science and clinical level, more needs to be done to determine in vivo isoenzyme selectivity of present and future compounds claimed to be isozyme specific based upon simple in vitro measurements. This is critical not only in establishing the Bibliography

Chegwidden WR, Carter ND, Edwards YN. The carbonic anhydrases: new horizons. EXS Birkhauser, Basel; 2000

2.

Frost SC, McKenna R. Carbonic anhydrases: mechanism, regulation, links to disease, and industrial applications. Springer, Heidelberg; 2014

3.

Carta F, Supuran CT. Diuretics with carbonic anhydrase inhibitory action: a patent and literature review (2005 2013). Expert Opin Ther Pat 2013;23:681-91

4.

468

McKenna R, Supuran CT. Carbonic anhydrase inhibitors drugs design. Carbonic anhyrases: mechanism,

Declaration of interest The author has no competing interests to declare and has received no funding in preparation of the manuscript.

regulation, links to disease, and industrial applications. Springer, Heidelberg; 2014. p. 291-323

Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

mechanism of action of these drugs, but also in avoiding assumptions about the drug that might blind us to other actions and targets. In order to achieve this, researchers must combine convincing physiological assessments with precise pharmacological measurements of free drug concentrations in plasma, and in the cytosol or organelle as appropriate. Ideally any pharmacological data should be corroborated and found consistent with the effects of manipulations, such as conditional tissue-specific gene deletion or overexpression. Discovery of true isozyme-selective CA inhibitors in vivo should be a major goal in the drug discovery field. Any such drugs will surely be more useful than the presently available largely nonselective inhibitors, because compliance with therapy will be enhanced as side effects are reduced. For instance, although it will be likely very difficult to achieve, any selective inhibitor that does not inhibit CA in the kidney will avoid the many complications of metabolic acidosis. Chronic metabolic acidosis leads to osteopenia and muscle loss, not only in adults but more importantly in growing children as well. Whether this is true for CA inhibitor-mediated metabolic acidosis use has not been adequately assessed and whether base supplementation should be always be co-administered is not certain, but these issues ought to be considered particularly with any new CA inhibitor that requires chronic administration. Given the reduction of side effects with hydrophilic and poorly permeant CA inhibitors such as benzolamide, newer agents are needed. As mentioned above, specific CA IX and XII inhibitors, if approved for human use in cancer treatment [123], might serve well in this capacity.

5.

..

6.

7.

Carta F, Scozzafava A, Supuran CT. Sulfonamides: a patent review (2008 - 2012). Expert Opin Ther Pat 2012;22:747-58 Includes a very comprehensive review of present and pending sulfonamides with a discussion of in vitro inhibition constants against the active CA isoforms. Swenson ER. Carbonic anhydrase inhibitors and high altitude illnesses. In: Frost SC, McKenna R, editors, Carbonic anhydrase: mechanism, regulation, links to disease, and industrial applications. Springer, Heidelberg; 2014. p. 361-86 Smith DA, Jones RM. The sulfonamide groups as a structural alert: a distorted


story. Curr Opin Drug Discov Devel 2008;11:72-9 8.

Maren TH. Carbonic anhydrase: chemistry, physiology and inhibition. Physiol Rev 1967;47:595-781

9.

Swenson ER. Respiratory and renal roles of carbonic anhydrase. In: Chegwidden WR, Carter ND, Edwards YN, editors, The carbonic anhydrases: new horizons. EXS Birkhauser, Basel; 2000. p. 281-341

10.

Maren TH. Use of inhibitors in physiological studies of carbonic anhydrase. Am J Physiol 1977;2324:F291-7 An extremely useful and definitive discussion of the complexities of probing CA function in vivo with sulfonamide CA inhibitors. It provides a detailed set of rules that should be

..


followed to ascertain a critical CA role in the function or process under study. This was written before the era of genetic approaches, but the principle of using more than one probe or approach and all giving concordant results remains highly relevant. 11.


12.

13.

14.

Bennett CM, Brenner BM, Berline RW. Micropuncture study of nephron function in the rhesus monkey. J Clin Invest 1968;47:203-16 Tucker BJ, Blantz RC. Effect of furosemide administration on glomerular and tubular dynamics in the rat. Kidney Int 1984;26:112-21 Berg JT, Ramanathan S, Gabrielli MG, Swenson ER. Carbonic anhydrase in mammalian vascular smooth muscle. J Histochem Cytochem 2004;52:1101-6 Roush GC, Buddharaju V, Ernst ME, Holford TR. Chlorthalidone: mechanisms of action and effect on cardiovascular events. Curr Hypertens Rep 2013;15:514-21

15.

Guerrini R, Parmeggiani L. Topiramate and its clinical applications in epilepsy. Expert Opin Pharmacother 2006;7:811-23

16.

Biton V. Clinical pharmacology and mechanism of action of zonisamide. Clin Neuropharmacol 2007;30:230-40

17.

18.

.

19.

20.

21.

Thone J, Leniger T, Splettstosser F, Wiemann M. Antiepileptic activity of zonisamide on hippocampal CA3 neurons does not depend on carbonic anhydrase inhibition. Epilepsy Res 2008;79:105-11 Epstein DL, Grant WM. Carbonic anhydrase inhibitor side effects. Arch Ophthalmol 1977;95:1378-82 A single best reference on the scope, severity and frequency of side effects arising from use of oral sulfonamides. Vahedi K, Taupin P, Djomby R, et al. Efficacy and tolerability of acetazolamide in migraine prophylaxis: randomized placebo-controlled study. J Neurol 2002;249:206-11 Maren TH, Conroy CW, Wynns GC, Levy NS. Ocular absorption, blood levels, and excretion of dorzolamide, a topically active carbonic anhydrase inhibitor. J Ocul Pharmacol Ther 1997;13(1):23-30 Heller I, Halevy J, Cohen S, Theodor E. Significant metabolic acidosis induced by

acetazolamide. Not a rare complication. Arch Intern Med 1985;145:1815-17 22.

.

23.

24.

25.

26.

27.

28.

Chapron DJ, Gomolin IH, Sweeney KR. Acetazolamide blood concentrationsare excessive in the elderly; propensity for acidosis and relationship to renal function. J Clin Pharmacol 1989;29:348-53 A good discussion of the hazards of CA inhibitor use in the elderly on renal function. Many of same issues apply to others, such as those with diabetes or mild renal dysfunction of any cause. Siklos P, Henderson RG. Severe acidosis from acetazolamide in a diabetic patient. Curr Med Res Opin 1979;6:284-6 Alper AB, Tomlin H, Sadhwani U, et al. Effects of the selective cyclooxygenase-2 inhibitor analgesic celecoxib on renal carbonic anhydrase inhibition activity: a randomized controlled trial. Am J Ther 2006;13:229-35 Schwartz JI, Vandormael K, Malice MP, et al. Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal salt diet. Clin Pharmacol Ther 2002;72:50-61 Whelton A, Lefkowith JL, West CR, Verburg KM. Cardiorenal effects of celecoxib as compared with the nonsteroidal anti-inflammatory drugs diclofenac and ibuprofen. Kidney Int 2006;70:1495-502 Benson P, Yudd M, Sims D, et al. Renal effects of high-dose celecoxib in elderly men with stage D2 prostate carcinoma. Clin Nephrol 2012;78:376-81 Welch BJ, Graybead D, Moe OW, et al. Biochemical and stone-risk profiles with topiramate therapy. Am J Kidney Dis 2006;48:555-63

29.

Mirza N, Marson AG, Pirmohamed M. Effect of topiramate on acid-base balance: extent, mechanism and effects. Br J Clin Pharmacol 2009;68:655-61

30.

Mizra NS, Alfirevic A, Jorgensen A, et al. Metabolic acidosis with topiramate and zonisamide: an assessment of it severity and predictors. Pharmacogenet Genomics 2011;21:297-302

31.

Go T. Effect of antiepileptic drug polypharmacy on crystalluria. Pediatr Neurol 2005;32:113-15


32.

Simpson DP. Effect of acetazolamide on citrate excretion in the dog. Am J Physiol 1964;206:883-6

33.

Unwin RJ, Capasso G, Shirley DG. An overview of divalent cation and citrate handling by the kidney. Nephron Physiol 2004;98:15-20

34.

Higashihara E, Nutahara K, Takeuchi T, et al. Calcium metabolism in acidotic patients induced by carbonic anhydrase inhibitors: responses to citrate. J Urol 1991;145:942-8

35.

Wakabayashi Y. Hyperkalemia induced by a carbonic anhydrase inhibitor. Br J Ophthalmol 1991;75:176-7

36.

Fulop M, Brazeau P. The phosphaturic effect of sodium bicarbonate and acetazolamide in the dog. J Clin Invest 1968;47:983-91

37.

Krieger NS, Frick KK, Bushinsky DA. Mechanisms of acid induced bone loss. Curr Opin Nephrol Hypertens 2004;13:423-36

38.

Swenson ER. Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and depression. Eur Respir J 1998;12:1242-7 A comprehensive review of CA inhibitors on ventilation and respiratory function with attention given to problems in those with lung disease.

.

39.

Coudon WL, Block AJ. Acute respiratory failure precipitated by a carbonic anhydrase inhibitor. Chest 1976;69:112-13

40.

Gonzalez JU, Scheuermann BW. Effect of acetazolamide on respiratory muscle fatigue in humans. Respir Physiol Neurobiol 2013;185:386-92

41.

Kiwull-Schone HF, LI Y, Kiwull PJ, Teppema LJ. Methazolamide does not impair respiratory work performance in anesthetized rabbits. Am J Physiol 2009;297:R648-54

42.

Parkkila S, Parkilla AK. Carbonic anhydrase in the alimentary tract. Scand J Gastroenterol 1996;31:305-17

43.

Charney AN, Feldman GM. Systemic acid-base disorders and intestinal electrolyte transport. Am J Physiol 1984;247:G1-12

44.

Arrigg CA, Epstein DL, Giovanni R, Grant WM. The influence of supplemental sodium acetate on carbonic

469

E. R. Swenson

anhydrase inhibitor-induced side effects. Arch Ophthalmol 1981;99:1969-72 45.

..


46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

470

Plum JB, Plum F. The toxic effects of carbon dioxide and acetazolamide in hepatic encephalopathy. J Clin Invest 1960;39:1246-58 A classic and first reference to the danger of CA inhibitor use in those with severe liver disease. Warren KS, Schenker S. Drugs related to the exacerbation or amelioration of hepatic coma and their effects on ammonia toxicity. Clin Sci 1963;25:11-15 Haussinger D, Gerok W. Hepatic urea synthesis and pH regulation. Role of CO2, HCO3-, pH and the activity of carbonic anhydrase. Eur J Biochem 1985;152:381-6 Tannen RL, Ross BD. The impact of acetazolamide on renal ammoniagenesis and gluconeogenesis. J Lab Clin Med 1983;102:536-40 Kim JM, Ryu WS, Hwang YH, Kim JS. Aggravation of ataxia due to acetazolamide induced hyperammonaemia in episodic ataxia. J Neurol Neurosurg Psychiatry 2007;78:771-2 Das SN, Sadhu DP. Effect of acetazolamide on insulin sensitivity in dogs with alloxan diabetes. Indian J Physiol Pharmacol 1978;22:301-4 Dodgson SJ, Forster RE. Inhibition of CA V decreases glucose synthesis from pyruvate. Arch Biochem Biophys 1986;251:198-204 Dodgson SJ, Cherian K. Rat renal proximal tubular gluconeogenesis: possible involvement or nonmitochondrial carbonic anhydrase isozymes. Arch Biochem Biophys 1990;282:1-7

56.

57.

Zaidi FH, Kinnear PE. Acetazolamide, alternate carbonic anhydrase inhibitors and hypoglycemic agents; comparing enzymic with diuresis induced metabolic acidosis following intraocular surgery in diabetes. Br J Ophthalmol 2004;88:714-15 Gabrilove JL, Alvarez AA, Soffer LJ. Effect of acetazolamide (Diamox) on thyroid function. J Appl Physiol 1958;13:491-2

68.

Coakley RJ, Taggart C, Greene C, et al. Ambient pCO2 modulates intracellular pH, intracellular oxidant generation, and interleukin-8 secretion in human neutrophils. J Leukoc Biol 2002;71(4):603-10

69.

Bryant BP. The roles of carbonic anhydrase in gustation, olfaction and chemical irritation. EXS 2000;90:365-74

58.

Krieger DT, Moses A, Ziffer H, et al. Effect of acetazolamide on thyroid metabolism. Am J Physiol 1959;196:291-4

70.

Ferris KE, Clark RD, Coates EL. Topical inhibition of nasal carbonic anhydrase affects the CO2 detection threshold in rats. Chem Senses 2007;32:263-71

59.

Chow SY, Kemp JW, Woodbury DM. Effects of acetazolamide on iodide transport, electrolyte distribution and activities of carbonic anhydrase, Na-K ATPase and HCO3 ATPase in mouse, rat and turtle thyroid glands. J Endocrinol 1983;97:167-74

71.

Kivela J, Parkkila S, Parklia AK, et al. Salivary carbonic anhydrase isoenzyme VI. J Physiol 1999;520:315-20

72.

Chandrashekar J, Yartmolinsky D, von Bucholz L, et al. The taste of carbonation. Science 2009;326:443-5

73.

Wang J, Ke T, Zhang X, et al. Effects of acetazolamide on cognitive performance during high-altitude exposure. Neurotoxicol Teratol 2013;35:28-33

74.

Shulkin D, Olson BR, Levey GS. Thyrotoxic periodic paralysis in a LatinAmerican taking acetazolamide. Am J Med Sci 1989;297:337-8

Collier D, Swenson ER, Hedges AM, et al. Benzolamide improves oxygenation and reduces acute mountain sickness during a high altitude trek and has fewer side effects than acetazolamide. Pharmacol Res Perspect 2014; In press

75.

Wiholm BE, Emanuelsson S. Drug-induced blood dyscrasias in a Swedish reporting system. Eur J Haematol Suppl 1996;60:42-6

Yang MT, Chien WL, Lu DH, et al. Acetazolamide impairs fear memory consolidation in rodents. Neuropharmacology 2013;67:412-18

76.

Saito H, Ogaswwara K, Suzuki T, et al. Adverse effects of intravenous acetazolamide administration for evaluation of cerebrovascular reactivity. Neurol Med Chir (Tokyo) 2011;51:479-83

77.

Huang SY, McCullough RE, McCullough RG, et al. Usual clinical dose of acetazolamide does not alter cerebral blood flow velocity. Respir Physiol 1988;72:315-26

78.

Grossman WM, Koeberle B. The dose-response relationship of acetazolamide on the cerebral blood flow in normal subjects. Cardiovasc Dis 2000;10:65-9

79.

Maren TH, Ellison AC. The teratological effect of benzolamide, a new carbonic anhydrase. Johns Hopkins Med J 1972;130:116-23

60.

..

61.

62.

Maren TH. Relations between structure and biological activity of sulfonamides. Annu Rev Pharmacol Toxicol 1976;16:309-27 A comprehensive review of structure--function relationships in drugs of the sulfonamide class and their use in a variety of diseases.

63.

Mogk LG, Cyrlin MN. Blood dyscrasias and carbonic anhydrase inhibitors. Ophthalmology 1988;95:768-71

64.

Konstantopoulos N, Molero JC, McGee SL, et al. Methazolamide is a new hepatic insulin sensitizer that lowers blood glucose in vivo. Diabetes 2012;61:2146-54

Kodjikian L, Durant B, Burillon C, et al. Acetazolamide-induced thrombocytopenia. Arch Ophthalmol 2004;122:1543-4

65.

Rames I, Kristufek V. Effect of different saluretics on carbohydrate metabolism and blood pressure behavior in diabetics. Dtsch Z Verdau Stoffwechselkr 1984;44:89-94

Martin XD, Danese M. Dorzolamide-induced immune thrombocytopenia: as case report and literature review. J Glaucoma 2001;10:133-5

66.

Grossman AJ, Batterman RC. Effects of acetazolamide (Diamox) upon blood sugar of normal and diabetic patients. Proc Soc Exp Biol Med 1956;93:255-6

during carbonic anhydrase activity inhibition. Burns 2009;35:397-404

67.

Campbell AR, Andress DL, Swenson ER. Identification and characterization of human neutrophil carbonic anhydrase. J Leukoc Biol 1994;55:343-8 Kawaai H, Seino H, Yamazaki S, Taki K. Changes in leukocyte migration




80.

Landauer W, Wakasugi N. Teratological studies with sulphonamides and their implications. J Embryol Exp Morphol 1968;20:261-84

81.

Halladay DW, Layton WM. Forelimb deformity of offspring of rats given dichlorphenamide. Riv Patol Nevr Ment 1966;87:6-8

82.

Bell SM, Schreiner CM, Resnick E, et al. Exacerbation of acetazolamide teratogenesis by amiloride and its analogs active against Na+/H+ exchangers and Na+ channels. Reprod Toxicol 1997;11:823-31

83.

Ugen KE, Scott WJ. Reduction of uterine blood flow by phenylephrine, an alpha-adrenergic agonist, in the day 11 pregnant rat: relationship to potentiation of acetazolamide teratogenesis. Teratology 1987;36:133-41

84.

85.

Merlob P, Litwin A, Mor N. Possible association between acetazolamide administration during pregnancy and metabolic disorders in the newborn. Eur J Obstet Gynecol Reprod Biol 1990;35:85-8

cerebrovascular, and pulmonary vascular responses to hypoxia. Am J Respir Crit Care Med 2007;175:277-81 92.

.

93.

Widengard I, Mandahl A, Tornquist P, Wistrand PJ. Colour vision and sideeffects during treatment with methazolamide. Eye (Lond) 1995;9:130-5

86.

Kwon SJ, Park DH, Shin JP. Bilateral transient mypopia, angle closure glaucoma, and choroidal detachment induced by methazolamide. Jpn J Ophthalmol 2012;56:515-17

87.

Katz LJ, Simmons ST, Craven ER. Efficacy and safety of brinzolamide and dorzolamide in the intraocular pressure lowering in glaucoma and ocular hypertension. Curr Med Res Opin 2007;23:2971-83

94.

H€ohne C, Pickerodt PA, Francis RC, Swenson ER. Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition. Am J Physiol 2007;292:L178-84 This study finds a strong vasodilator influence in the pulmonary circulation of acetazolamide, but not other potent CA inhibitors. Interestingly, this vascular effect of acetazolamide is not lost when acetazolamide is methylated at the sulfonamide group to abolish its binding to and inhibition of carbonic anhydrase. This is to be contrasted with acetazolamide and other CA inhibitor-dependent vasodilation in the systemic circulation (ref. [92]) in which other potent inhibitors, such as benzolamide and ethoxzolamide, act in a dose-response manner consistent with their CA inhibiting potency. Shimoda LA, Luke T, Sylvester JT, Swenson ER. Inhibition of hypoxiainduced calcium responses in pulmonary arterial smooth muscle by acetazolamide is independent of carbonic anhydrase inhibition. Am J Physiol 2007;292:L1002-12 Pickerodt P, Swenson ER. Pulmonary vasodilation by acetazolamide during hypoxia: impact of methyl-group substitutions and administration route in conscious, spontaneously breathing dogs. J Appl Physiol 2014; In press

95.

Pickkers P, Garcha RS, Schachter M, et al. Inhibition of carbonic anhydrase accounts for the direct vascular effects of hydrochlorthiazide. Hypertension 1999;33:1043-8

88.

Cvetkovic RS, Perry CM. Brinzolamide: a review of its use in the management of primary open angle glaucoma and ocular hypertension. Drugs Aging 2003;20:919-47

96.

Pickkers P, Hughes AD, Russel FGM, et al. In vivo evidence of KCa channel opening properties of acetazolamide in the human vasculature. Br J Pharmacol 2001;132:443-50

89.

Holdiness MR. Contact dermatitis to topical drugs for glaucoma. Am J Contact Dermat 2001;12:217-19

97.

90.

Servat JJ, Bernadino CR. Effects of common topical antiglaucoma medications on the ocular surface. Drugs Aging 2011;28:267-82

Haustein M, Spoerl E, Boehm AG. The effect of acetazolamide on different ocular vascular beds. Graedfes Arch Clin Exp Ophthalmol 2013;251:1389-98

98.

Teppema LJ, Balanos GM, Steinbeck CD, et al. Effects of acetazolamide on ventilatory,

Horita Y, Yakabe K, Tadokoro M, et al. Renal circulatory effects of acetazolamide in patients with essential hypertension. Am J Hypertens 2006;19:282-5

99.

Taki K, Oogushi K, Hirahara K, et al. Preferential acetazolamide-induced

91.


vasodilation based upon vessel size and organ. Angiology 2001;52:483-8 100. Aamand R, Dalsgaard T, Jensen FB, et al. Generation of nitric oxide from nitrite by carbonic anhydrase: a possible link between metabolic activity and vasodilation. Am J Physiol 2009;297:H2068-74 101. Chobanyan-Ju¨rgens K, Schwarz A, B€ohmer A, et al. Renal carbonic anhydrases are involved in the reabsorption of endogenous nitrite. Nitric Oxide 2012;26:126-31 102. Swenson ER. Carbonic anhydrase and the heart. Cardiologia 1997;42:453-62 103. Shimotsu Y, Hayashida K, Kume N, et al. Acetazolamide induced myocardial ischemia in patients with severe coronary artery disease. Ann Nucl Med 1998;12:21-7 104. Anderson CJ, Kaufman PL, Strum RJ. Toxicity of combined therapy with carbonic anhydrase inhibitors and aspirin. Am J Ophthalmol 1978;86:516-19 105. Rousseau P, Fuentevilla CA. Acetazolamide and salicylate interaction in the elderly. J Am Geriatr Soc 1993;41:868-9 106. Cowan RA, Haratnell GG, Lowdell CP, et al. Metabolic acidosis induced by carbonic anhydrase inhibitors and salicylates in patients with normal renal function. Br Med J (Clin Res Ed) 1984;289:347-8 107. Hazouard E, Grimbert M, Jonville-Berra A, et al. Salicylism and glaucoma: reciprocal augmentation of the toxicity of acetazolamide and acetylsalicylic acid. J Fr Ophtalmol 1999;22:73-5 108. Lidell NE, Maren TH. CO2 retention as a basis for increased toxicity of salicylate with acetazolamide; avoidance of increased toxicity with benzolamide. J Pharmacol Exp Ther 1975;195:1-7 109. Sweeney KR, Chapron DJ, Brandt JL, et al. Toxic interaction between acetazolamide and salicylate; case reports and a pharmacokinetic explanation. Clin Phramacol Ther 1986;40:518-24 110. Sweeney KR, Chapron DJ, Anatal EJ, Kramer PA. Differential effects of flurbiprofen and aspirin on acetazolamide disposition in humans. Br J Clin Pharmacol 1989;27:866-9

471

E. R. Swenson

111. Pichard L, Fabre I, Fabre G, et al. Cyclosporin A drug interactions. Drug Metab Dispos 1990;18:595-606 112. Leppik IE. Zonisamide: chemistry, mechanism of action, and pharmacokinetics. Seizure 2004;13(Suppl 1):S5-9


113. Lichter PR. Reducing side effects of carbonic anhydrase inhibitors. Ophthamology 1981;88:266-9 . Gives strategies for decreasing side effects in patients who must remain of a CA inhibitor. 114. Lichter PR, Newman LP, Wheeler MS, Beall OP. Patient tolerance to carbonic anhydrase inhibitors. Am J Ophthalmol 1978;85:495-502 115. Tilles SA. Practical issues in the management of hypersensitivity reactions: sulfonamides. South Med J 2001;94:817-24 116. Wulf NR, Matuszewski KA. Sulfonamide cross-reactivity: is there evidence to support broad cross-reactivity? Am J Health Syst Pharm 2013;70:1483-94 117. Smith DA, Jones RM. The sulfonamide group as a structural alert: a distorted story? Curr Opin Drug Discov Devel 2008;11:72-9 118. Strom BL, Schinnar R, Apter AJ, et al. Absence of cross-reactivity between sulfonamide antibiotics and sulfonamide non-antibiotics. N Engl J Med 2003;349:1628-35

472

119. Kim SH, Kim M, Lee KW, et al. HLA-B*5901 is strongly associated with methazolamide-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Pharmcogenomics 2010;11:879-84 120. Kelly TE, Hackett PH. Acetazolamide and sulfonamide allergy: a not so simple story. High Alt Med Biol 2010;11:319-23 .. A very good up-to-date review on the issue of sulfonamide allergy with respect to CA inhibitor use. 121. Lee AG, Andreson R, Kardon RH, Wall M. Presumed “sulfa allergy” in patients with intracranial hypertension treated with acetazolamide or furosemide: cross reactivity, myth or reality? Am J Ophthalmol 2004;138:114-18 122. Firoz EF, Firoz BF, Williams JF, Henning JS. Allergic contact dermatitis to mafenide acetate: a case series and review of the literature. J Drugs Dermatol 2007;6:825-8 123. Monti SM, Supuran CT, De Simone G. Anticancer carbonic anhydrase inhibitors: a patent review (2008 - 2013). Expert Opin Ther Pat 2013;23:737-49 124. Cousin JL, Motais R. The role of carbonic anhydrase inhibitors ion anion permeability into ox red blood cells. J Physiol 1976;256:61-80 125. Morgan PE, Supuran CT, Casey JR. Carbonic anhydrase inhibitors that directly inhibit anion transport by the


human Cl-/HCO3- exchanger, AE1. Mol Membr Biol 2004;21:423-33 126. Tamimura Y, Hiroaki Y, Fujiyoshi Y. Acetazolamide reversibly inhibits waster conduction by aquaporin-4. J Struct Biol 2009;166:16-21 127. Schellenberg M, Prokosch V, Thanos S. Regulation of retinal proteome by topical antiglaucomatous eye drops in an inherited glaucoma rat mode. PLoS One 2012;7:e33593 128. Lisk C, McCord J, Bose S, et al. Nrf2 activation: a potential strategy for the prevention of acute mountain sickness. Free Radic Biol Med 2013;63:264-73 129. Pickkers P, Hughes AD, Russel FG, et al. In vivo evidence for K(Ca) channel opening properties of acetazolamide in the human vasculature. Br J Pharmacol 2001;132:443-50 130. Temperini C, Innocenti A, Mastrolorenzo A, et al. Carbonic anhydrase inhibitors. Interaction of the anti-epileptic drug sulthiame with twelve mammalian isoforms. Bioorg Med Chem Lett 2007;17:4866-72

Affiliation Erik R Swenson University of Washington -- Medical Service, VA Puget Sound Health Care System, 1660 S Columbian Way, S-111-PLUM, Seattle, WA 98108, USA E-mail: [email protected]

Carborane-based carbonic anhydrase inhibitors.

Carbonic anhydrase inhibitors and high altitude illnesses.

Carbonic anhydrase inhibitors in corneal endothelial transport.

Luminal pH in the amphibian distal tubule: effects of carbonic anhydrase and carbonic anhydrase inhibitors.

Azobenzene-based inhibitors of human carbonic anhydrase II.

Recent developments of carbonic anhydrase inhibitors as potential drugs.

X-ray crystallography-promoted drug design of carbonic anhydrase inhibitors.

Toxicity of combined therapy with carbonic anhydrase inhibitors and aspirin.

Glaucoma and the applications of carbonic anhydrase inhibitors.

Carbonic anhydrase.

Sulfonamides and their isosters as carbonic anhydrase inhibitors.

Acetazolamide-like carbonic anhydrase inhibitors with topical ocular hypotensive activity.

Carbonic anhydrase inhibitors are antiarthritic in the rat.

Pyridazinone substituted benzenesulfonamides as potent carbonic anhydrase inhibitors.

Carbonic anhydrase inhibitors: guaiacol and catechol derivatives effectively inhibit certain human carbonic anhydrase isoenzymes (hCA I, II, IX and XII).

Carbonic anhydrase inhibition.

Carbonic anhydrase inhibitors. V: Pyrylium salts in the synthesis of isozyme-specific inhibitors.

Purification of myelin carbonic anhydrase.

Spirobisnaphthalenes effectively inhibit carbonic anhydrase.

Carbonic anhydrase isozymes IV and II in urinary membranes from carbonic anhydrase II-deficient patients.

Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, IX and XII with benzene sulfonamides incorporating 4- and 3-nitrophthalimide moieties.

Discovery and characterization of novel selective inhibitors of carbonic anhydrase IX.

Overexpression of carbonic anhydrase 1 in pterygium.

Sulfamates of methyl triterpenoates are effective and competitive inhibitors of carbonic anhydrase II.