[Comprehensive Monograph: Acetazolamide (DB00819)]

[1.0 Executive Summary]

Acetazolamide is a first-generation, non-competitive inhibitor of the enzyme carbonic anhydrase, a small molecule drug with a remarkably diverse and enduring clinical profile spanning over seven decades.[1] Initially approved by the U.S. Food and Drug Administration (FDA) in the early 1950s, it has long been a cornerstone therapy for a distinct set of conditions, including various forms of glaucoma, certain types of epilepsy (particularly as adjunctive therapy), and the prevention and treatment of acute mountain sickness.[1][ Its therapeutic utility stems from a single, potent mechanism—the inhibition of a fundamental physiological enzyme—which produces a cascade of effects across multiple organ systems, including the kidneys, eyes, and central nervous system.]

Recently, this septuagenarian drug has experienced a significant clinical renaissance, driven by new, high-quality evidence for its use in a major public health challenge: acute decompensated heart failure (ADHF). The landmark ADVOR (Acetazolamide in Decompensated Heart Failure with Volume Overload) trial demonstrated that adding intravenous acetazolamide to standard loop diuretic therapy significantly improves the rate of successful decongestion and shortens hospital stays for patients with ADHF, repositioning the drug from a niche therapeutic to a potentially vital tool in acute cardiology.[5]

The pharmacological profile of acetazolamide is unique. It is not metabolized in the body and is excreted unchanged by the kidneys, a property that simplifies its interaction profile but necessitates caution in patients with renal impairment.[8] It exhibits avid binding to its target enzyme, leading to high concentrations in tissues rich in carbonic anhydrase, such as red blood cells and the renal cortex.[8]

Despite its benefits, acetazolamide possesses a complex safety profile. Common side effects such as paresthesias and dysgeusia are frequent, while the drug’s primary mechanism predictably leads to metabolic acidosis and electrolyte disturbances, including hypokalemia, which require careful monitoring.[10] As a sulfonamide derivative, it carries a risk of rare but severe and potentially fatal hypersensitivity reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which are detailed in a prominent "WARNINGS" section on its FDA label.[12] While some secondary databases have erroneously reported that the drug carries a formal FDA "black box warning," a review of primary regulatory documents confirms this is not the case.[13][ This monograph provides a comprehensive, evidence-based analysis of acetazolamide, synthesizing its foundational pharmacology, established and emerging clinical applications, and detailed safety considerations to guide its effective and safe use in modern clinical practice.]

[2.0 Drug Identification and Physicochemical Properties]

[2.1 Nomenclature and Standard Identifiers]

[Acetazolamide is a well-characterized small molecule drug belonging to the sulfonamide class of compounds. Its precise identification is established through a variety of systematic names and standardized identifiers used across chemical, pharmacological, and regulatory databases.]

• Generic Name: Acetazolamide.[1]
• Systematic (IUPAC) Name: The formal chemical name is N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide.[16] An alternative formal name is N-[5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl]-acetamide.[18]
• Chemical Class: Acetazolamide is classified as a sulfonamide, a member of the thiadiazole chemical family, and a monocarboxylic acid amide.[16] Pharmacologically, it is a first-generation carbonic anhydrase inhibitor and a diuretic.[1]
• Common Brand Names: The most widely recognized brand name is Diamox. The extended-release formulation is known as Diamox Sequels.[1] Over its long history, it has been marketed under numerous other names globally, including Acetamox, Atenezol, Diacarb, Glaupax, Defiltran, Nephramide, Cidamex, and Diluran.[17]
• Synonyms and Code Names: Chemical synonyms include 5-Acetamido-1,3,4-thiadiazole-2-sulfonamide.[23] During its development and investigation, it was also known by code names such as L-579,486 and NSC 145177.[18]

[For unambiguous identification in research and clinical contexts, a comprehensive set of identifiers is crucial. These are consolidated in Table 2.1.]

[2.2 Chemical Structure and Properties]

The chemical structure of acetazolamide is central to its pharmacological activity. It consists of a five-membered 1,3,4-thiadiazole heterocyclic ring, which is substituted at the C2 position with an acetamido group (CH3​CONH−) and at the C5 position with an unsubstituted sulfonamide group (−SO2​NH2​).[16][ It is this sulfonamide moiety that is critical for its ability to bind to and inhibit the zinc-containing active site of the carbonic anhydrase enzyme.]

• Molecular Formula: C4​H6​N4​O3​S2​.[16]
• Molecular Weight: The calculated molecular weight is approximately 222.24 g/mol.[16]
• Physical Description: Acetazolamide is a white to faintly yellowish-white, fine crystalline powder. It is odorless and has no discernible taste.[16]
• Solubility and Stability: It is described as a crystalline solid. It demonstrates solubility in dimethylformamide (DMF) at 15 mg/ml and dimethyl sulfoxide (DMSO) at 15 mg/ml, but it is poorly soluble in a DMSO:PBS (pH 7.2) mixture at 0.25 mg/ml.[18] The compound is chemically stable, with a reported stability of at least 5 years when stored appropriately at room temperature.[18]
• Chemical Representations:[ For use in computational chemistry and cheminformatics, the following standard representations are available:]
• InChI: InChI=1S/C4H6N4O3S2/c1-2(9)6-3-7-8-4(12-3)13(5,10)11/h1H3,(H2,5,10,11)(H,6,7,9).[16]
• InChIKey: BZKPWHYZMXOIDC-UHFFFAOYSA-N.[16]
• SMILES: CC(=O)NC1=NN=C(S1)S(=O)(=O)N.[16]

[Table 2.1: Key Chemical and Database Identifiers for Acetazolamide]

Identifier Type	Value	Source(s)
Chemical Abstracts Service (CAS) Number	59-66-5	16
DrugBank ID	DB00819	1
PubChem Compound ID (CID)	1986	17
ChEMBL ID	CHEMBL20	15
ChEBI ID	CHEBI:27690	16
Molecular Formula	C4​H6​N4​O3​S2​	16
IUPAC Name	N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide	16
SMILES	CC(=O)NC1=NN=C(S1)S(=O)(=O)N	16
InChIKey	BZKPWHYZMXOIDC-UHFFFAOYSA-N	16
UNII (FDA GSRS)	O3FX965V0I	16
KEGG ID	C06805, D00218	16
RxCUI (RxNorm)	167	16
European Community (EC) Number	200-440-5	16

[The consolidation of these identifiers into a single reference table is fundamental for a professional monograph. It ensures unambiguous identification of the active pharmaceutical ingredient, preventing confusion with related compounds (e.g., methazolamide) or its salts. This precision is essential for researchers querying diverse databases—from clinical trial registries to metabolomics platforms—and for regulators and pharmacists verifying formulary information. The availability of multiple chemical representations like SMILES and InChIKey further facilitates cross-disciplinary research in fields such as computational modeling and systems pharmacology.]

[3.0 Comprehensive Pharmacology]

[3.1 Primary Mechanism: Non-competitive Inhibition of Carbonic Anhydrase]

The diverse therapeutic effects of acetazolamide originate from a single, specific pharmacological action: the potent, reversible, and non-competitive inhibition of the carbonic anhydrase (CA) enzyme family.[1][ The CA enzymes are ubiquitous metalloenzymes that play a critical role in maintaining acid-base balance and facilitating ion transport throughout the body. Their primary function is to catalyze the rapid interconversion of carbon dioxide (]

CO2​) and water (H2​O) into carbonic acid (H2​CO3​), which subsequently and spontaneously dissociates into a hydrogen ion (H+) and a bicarbonate ion (HCO3−​).[1][ The reaction is as follows:]

[CO2​+H2​O⇌H2​CO3​⇌H++HCO3−​]

By inhibiting this enzyme, acetazolamide effectively halts this rapid hydration/dehydration cycle. This leads to an accumulation of the substrate, carbonic acid, and a localized or systemic deficit of the products, hydrogen and bicarbonate ions, which are essential for numerous physiological processes.[8][ This singular inhibitory action produces a cascade of predictable physiological consequences that vary depending on the tissue in which the CA isoenzyme is located, thereby explaining the drug's wide range of clinical applications.]

[3.2 System-Specific Pharmacodynamics: A Multi-System Analysis]

[The clinical utility of acetazolamide is a direct result of its targeted action on carbonic anhydrase in specific organ systems.]

[Renal System]

In the kidneys, carbonic anhydrase is abundantly present in the cells of the proximal convoluted tubule.[1][ Here, it plays a crucial role in the reabsorption of filtered bicarbonate from the tubular fluid. By inhibiting CA, acetazolamide prevents the generation of intracellular]

H+ needed for the Na+/H+ antiporter and blocks the dehydration of luminal carbonic acid, thereby preventing the reabsorption of bicarbonate (HCO3−​).[8][ This leads to a significant renal loss of]

HCO3−​, which, due to the need to maintain electrochemical neutrality, carries sodium (Na+), potassium (K+), and water along with it into the urine.[1][ The clinical results are twofold:]

1. Alkaline Diuresis: The increased excretion of bicarbonate raises the urinary pH, making the urine alkaline.[8] This diuretic effect is the basis for its use in treating edema.[1]
2. Metabolic Acidosis: The net loss of bicarbonate (a base) from the body results in a decrease in blood pH, inducing a mild, self-limiting hyperchloremic metabolic acidosis.[1]

[Ocular System]

The ciliary body of the eye contains high concentrations of carbonic anhydrase, which is integral to the production of aqueous humor, the fluid that fills the anterior and posterior chambers of the eye.[8] The secretion of aqueous humor is an active process that depends on the formation of bicarbonate ions within the ciliary epithelial cells. Acetazolamide's inhibition of CA in this tissue reduces the rate of bicarbonate formation, which in turn decreases the secretion of aqueous humor.[1] This reduction in fluid production leads to a decrease in intraocular pressure (IOP), the primary therapeutic goal in the management of glaucoma.[8]

[Central Nervous System (CNS)]

[Acetazolamide exerts multiple effects within the CNS by inhibiting different CA isoenzymes located in various cell types.]

• CSF Production and Intracranial Pressure: The choroid plexus, which is responsible for producing cerebrospinal fluid (CSF), is rich in carbonic anhydrase. Similar to its action in the eye, acetazolamide inhibits CA in the choroid plexus, which reduces the rate of CSF secretion.[8] This leads to a decrease in overall CSF volume and, consequently, a reduction in intracranial pressure (ICP). This mechanism is the rationale for its widespread use in treating idiopathic intracranial hypertension (IIH) and other conditions of elevated ICP.[1]
• Anticonvulsant Activity: The mechanism underlying acetazolamide's anti-epileptic effects is complex and not fully elucidated but is believed to be multifactorial.[19] Inhibition of CA within glial cells and neurons appears to retard abnormal, paroxysmal, and excessive electrical discharges.[8] This may occur through several pathways: the induced systemic metabolic acidosis can directly alter neuronal excitability, or local changes in the equilibrium of CO2​, H+, and HCO3−​ can modulate the activity of ligand-gated ion channels, including GABA-A receptors and various calcium channels, ultimately leading to neuronal stabilization.[8]

[Respiratory System]

The respiratory effects of acetazolamide are an indirect but powerful consequence of its renal action. The drug-induced metabolic acidosis lowers the pH of the blood.[1][ This decrease in pH is detected by central chemoreceptors in the brainstem and peripheral chemoreceptors in the carotid and aortic bodies, which interpret the change as a relative excess of]

CO2​.[1][ In response, the respiratory center stimulates an increase in both the rate and depth of breathing (increased minute ventilation) in a compensatory effort to "blow off" excess]

CO2​ and restore normal blood pH.[1][ This respiratory stimulation leads to an increase in the partial pressure of oxygen in the arterial blood (]

PaO2​). This is the key mechanism that makes acetazolamide effective in the prevention and treatment of acute mountain sickness, as it forces the body to breathe more, accelerating acclimatization to the low-oxygen environment of high altitudes.[1] This same effect is harnessed for the off-label use of acetazolamide as a respiratory stimulant in patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnic respiratory failure.[1]

[The remarkable diversity of acetazolamide's clinical applications is not due to multiple, unrelated pharmacological targets. Instead, it is a clear demonstration of how a single, well-defined molecular action—the inhibition of carbonic anhydrase—can trigger a predictable cascade of physiological events across different organ systems. This "domino effect" begins with the fundamental biochemical blockade of the CO2​ hydration reaction. This first-order effect leads to second-order physiological consequences that are specific to the tissue involved: in the kidney, it causes bicarbonate wasting and diuresis; in the eye and choroid plexus, it reduces fluid secretion; in the CNS, it alters neuronal excitability; and systemically, it induces metabolic acidosis. Each of these physiological effects, in turn, maps directly to a third-order clinical application: treating edema, glaucoma, elevated ICP, epilepsy, and altitude sickness. A thorough understanding of this unified mechanism is paramount for clinicians, as it allows for the logical prediction of both therapeutic benefits and the inevitable side effects, such as metabolic acidosis and hypokalemia, which are direct extensions of the drug's primary action in the kidney.]

[4.0 Clinical Pharmacokinetics]

[4.1 Absorption, Distribution, Metabolism, and Excretion (ADME) Profile]

[The pharmacokinetic profile of acetazolamide is characterized by several unique features that are fundamental to its clinical activity, dosing strategies, and safety considerations.]

• Absorption: Following oral administration, acetazolamide is well absorbed from the gastrointestinal tract.[8] For the extended-release capsule formulation, the presence of food does not significantly impact its bioavailability, allowing for flexible administration with or without meals.[25]
• Distribution: A key feature of acetazolamide's distribution is its avid binding to its target enzyme, carbonic anhydrase.[8] As a result, the drug demonstrates a high affinity for and concentrates in tissues that are rich in this enzyme. The most notable of these tissues are red blood cells (RBCs) and the renal cortex.[8] This extensive sequestration within RBCs acts as a circulating reservoir for the drug. This phenomenon explains the significant difference observed in its plasma half-life depending on the dose administered. At therapeutic doses, where CA binding sites may become saturated, the half-life is relatively short. However, at sub-therapeutic microdoses, the drug remains largely bound within RBCs, leading to a substantially prolonged plasma half-life (e.g., 24.5 hours), a property that has been explored for its potential use as a non-invasive marker of medication adherence.[9]
• Metabolism: Acetazolamide is not subject to metabolic alteration in the body.[8][ This is a significant clinical advantage, as it eliminates the risk of drug-drug interactions mediated by metabolic enzyme systems (such as the cytochrome P450 family) and prevents the formation of potentially active or toxic metabolites.]
• Excretion: The drug is eliminated from the body almost entirely unchanged.[9] Excretion occurs primarily via the kidneys through a combination of active tubular secretion and passive reabsorption.[8] The plasma half-life at standard therapeutic doses is reported to be in the range of 3 to 9 hours.[8]

[4.2 Comparative Analysis of Formulations: Immediate-Release, Extended-Release, and Intravenous]

[Acetazolamide is available in several formulations, each with distinct pharmacokinetic profiles that tailor its use to specific clinical scenarios.]

• Immediate-Release (IR) Tablets: This standard formulation leads to peak plasma concentrations between 1 to 4 hours after oral administration. The duration of its therapeutic effect is approximately 8 to 12 hours, typically requiring multiple daily doses for sustained activity.[25]
• Extended-Release (ER) Capsules (Diamox Sequels): This formulation is designed to provide prolonged action. It achieves peak plasma concentrations more slowly, between 3 to 6 hours post-administration, but its inhibitory effect on aqueous humor secretion is sustained for 18 to 24 hours.[25] This allows for a reduced dosing frequency (typically once or twice daily), which can improve patient convenience and adherence, particularly in the chronic management of conditions like glaucoma.[25]
• Intravenous (IV) Injection: The intravenous formulation provides the most rapid onset of action and is reserved for acute clinical situations or when oral administration is not feasible. It is commonly used for the rapid lowering of IOP in acute angle-closure glaucoma or for initiating therapy in hospitalized patients with conditions like ADHF.[28]

The unique pharmacokinetics of acetazolamide are a primary determinant of its clinical utility and dosing strategies. The absence of metabolism is a notable benefit, simplifying its interaction profile. However, its complete reliance on renal elimination means that its clearance is critically dependent on kidney function. This directly underpins the contraindication of the drug in patients with marked renal disease and the necessity for cautious use and potential dose adjustments in those with any degree of renal impairment.[12] Furthermore, the unusual sequestration of the drug in red blood cells is not merely a pharmacological curiosity; it is the key property that allows it to be explored for the novel application of adherence monitoring. At microdoses, the long apparent half-life created by this RBC reservoir allows for detection in urine for up to 96 hours after a single dose, offering a potential, inexpensive method to verify medication intake in clinical trials.[9][ This represents a clever leveraging of a unique pharmacokinetic property for a purpose entirely distinct from the drug's primary pharmacological effects.]

[5.0 Clinical Applications and Therapeutic Efficacy]

[5.1 FDA-Approved Indications: An Evidence-Based Review]

[Acetazolamide has a long history of FDA approval for several distinct medical conditions, where its efficacy is well-established.]

• Glaucoma: It is indicated as an adjunctive treatment for chronic simple (open-angle) glaucoma, secondary glaucoma, and for the preoperative management of acute congestive (angle-closure) glaucoma to lower intraocular pressure when a delay in surgery is desired.[1] Its mechanism relies on reducing the production of aqueous humor.[8]
• Epilepsy: Acetazolamide is approved as an adjunctive treatment for centrencephalic epilepsies, such as petit mal, and for unlocalized seizures.[1] Its use is particularly noted in the management of menstrual-related (catamenial) epilepsy.[1]
• Edema: It is indicated as an adjunctive therapy for managing edema resulting from congestive heart failure or edema that is drug-induced.[1] Its diuretic effect is achieved through intermittent dosing to allow for renal recovery from the enzyme inhibition.[30]
• Acute Mountain Sickness (AMS): The drug is approved for the prevention and treatment of symptoms associated with rapid ascent to high altitude, including headache, nausea, and dizziness.[1] It works by accelerating physiological acclimatization through the induction of metabolic acidosis, which stimulates an increase in ventilation and improves blood oxygenation.[1]

[5.2 Off-Label and Investigational Uses: Current Status and Future Directions]

[Beyond its approved indications, acetazolamide is widely used off-label for a variety of conditions, with a growing body of evidence supporting some of these applications.]

• Idiopathic Intracranial Hypertension (IIH): This is one of the most common and well-supported off-label uses. Acetazolamide is considered a first-line medical therapy for IIH, where it lowers intracranial pressure by reducing the rate of cerebrospinal fluid production.[1]
• Acute Decompensated Heart Failure (ADHF): This has emerged as a major application, moving from an off-label strategy to an evidence-based recommendation following the ADVOR trial. When added to loop diuretics, acetazolamide enhances diuresis and improves decongestion in hospitalized patients.[5]
• Respiratory Stimulation in COPD: In critical care settings, acetazolamide is used off-label to stimulate the respiratory drive in patients with chronic obstructive pulmonary disease who have developed chronic hypercapnic respiratory failure.[1]
• Urine Alkalinization: It is used to alkalinize the urine to prevent the precipitation of certain substances in the renal tubules. A key application is to prevent methotrexate-induced nephrotoxicity by increasing the solubility and renal excretion of methotrexate.[1]
• Other Investigational and Niche Uses: There is varying evidence for its use in treating Ménière's disease, certain neuromuscular disorders like periodic paralysis, and for the prevention of hemiplegic migraine.[1] Preliminary evidence also suggests it may be beneficial for some patients with visual snow syndrome.[1] Furthermore, it is being investigated for treating conditions like cerebrospinal fluid leaks and symptomatic ruptured arachnoid cysts as a means to potentially avoid more invasive surgical procedures.[26]

The trajectory of acetazolamide in recent years exemplifies a powerful case study in drug repurposing and the renaissance of an old therapeutic agent. For decades, it was a reliable but somewhat "sleepy" drug, confined to a specific set of niche indications.[35][ However, a renewed focus on its fundamental physiology has unlocked its potential to address a major unmet need in modern medicine: diuretic resistance in acute decompensated heart failure. The clinical challenge in ADHF is that loop diuretics, the cornerstone of therapy, often become less effective over time, leading to incomplete decongestion, prolonged and costly hospitalizations, and high rates of readmission.]

Researchers revisited the basic principles of renal physiology and hypothesized that a strategy of "sequential nephron blockade" could overcome this resistance. By using acetazolamide to inhibit sodium reabsorption upstream in the proximal tubule, a greater load of sodium is delivered downstream to the loop of Henle, the site of action for loop diuretics, thereby potentiating their effect. The ADVOR trial was designed to test this elegant physiological rationale in a rigorous, large-scale, randomized, placebo-controlled manner.[5] The trial's unequivocally positive results—demonstrating clinically meaningful improvements in decongestion and shorter hospital stays—provided the high-quality evidence needed to transform this hypothesis into a valid clinical strategy.[7] This success has created a ripple effect, spurring further research into the drug's role in heart failure, as seen with the new ADA-HF trial investigating oral acetazolamide and its chloride-sparing properties, and prompting analyses of its real-world adoption post-ADVOR.[37][ This evolution underscores a critical lesson: even very old, well-understood drugs can find new and impactful roles when a strong physiological rationale is meticulously tested to solve a pressing clinical problem.]

[6.0 Dosing, Administration, and Monitoring]

[6.1 Dosing Regimens by Indication and Formulation]

The dosage of acetazolamide varies significantly depending on the indication, the formulation used, and the patient's age. Dosing must be individualized to achieve the desired therapeutic effect while minimizing adverse reactions. The following table synthesizes dosing information from multiple clinical sources.[27]

[Table 6.1: Comprehensive Dosing Guide for Acetazolamide by Indication and Formulation]

Indication	Formulation	Adult Dose	Pediatric Dose	Dosing Frequency & Key Comments
Glaucoma (Open-Angle)	IR Tablets	250 mg to 1 g total per day	8-30 mg/kg/day total	Doses >250 mg should be given in divided doses (e.g., 2-4 times daily). Doses >1 g/day do not usually increase effect.
	ER Capsules	500 mg	500 mg (≥12 years)	Once or twice daily. Provides 18-24 hours of effect.
Glaucoma (Acute Angle-Closure)	IR Tablets / IV	250 mg every 4 hours. Some regimens start with a 500 mg initial dose.	Not specified, use adult regimen with caution.	Used preoperatively for rapid IOP reduction. IV route preferred for fastest onset. ER capsules are NOT appropriate for acute treatment.
Epilepsy	IR Tablets / IV	8-30 mg/kg/day total (typical range: 375-1000 mg/day)	8-30 mg/kg/day total	Given in divided doses. When adding to other anticonvulsants, start with 250 mg once daily. Doses >1 g/day rarely provide additional benefit. ER capsules are not indicated.
Edema (Heart Failure, Drug-Induced)	IR Tablets / IV	250-375 mg	5 mg/kg	Once daily in the morning. Crucially, dosing is intermittent (e.g., taken for 2 days, followed by 1 day of rest, or taken on alternate days) to allow renal recovery and prevent loss of diuretic effect.
Acute Mountain Sickness (AMS) - Prevention	IR Tablets	125 mg	2.5 mg/kg (Max: 125 mg/dose)	Every 12 hours. Start 24-48 hours before ascent and continue for at least 48 hours at altitude.
	ER Capsules	500 mg	500 mg (≥12 years)	Once or twice daily.
Acute Mountain Sickness (AMS) - Treatment	IR Tablets	250 mg	2.5 mg/kg (Max: 250 mg/dose)	Every 8-12 hours until symptoms resolve.
Idiopathic Intracranial Hypertension (Off-Label)	IR / ER	Titrated based on response, often starting at 250-500 mg BID and increasing up to 4 g/day.	Titrated based on response.	Dosing is highly individualized and guided by symptoms and ophthalmologic findings. The IIHTT study used doses up to 4 g/day, but tolerance can be a limiting factor.27

[6.2 Guidelines for Administration and Therapeutic Monitoring]

[Proper administration and vigilant monitoring are essential for the safe and effective use of acetazolamide.]

• [Administration:]
• Oral formulations can be taken with or without food. If gastric upset occurs, administration with food is recommended.[20]
• For edema, morning administration is preferred to avoid nocturnal diuresis.[27]
• [Intravenous (IV) administration should be used for rapid effect or when the oral route is compromised.]
• Intramuscular (IM) injection is not recommended. The alkaline pH of the solution can cause significant pain at the injection site.[30]
• [Therapeutic Monitoring:]
• Serum Electrolytes: Baseline and periodic monitoring of serum electrolytes—specifically sodium, potassium, and bicarbonate—is crucial. This is especially important in elderly patients, those with any degree of renal impairment, individuals with diabetes, and those on long-term therapy, as acetazolamide can cause hyponatremia, hypokalemia, and metabolic acidosis.[12]
• Complete Blood Count (CBC): A baseline CBC with platelet count should be considered, with periodic monitoring during therapy. This is to screen for the rare but serious risk of blood dyscrasias such as aplastic anemia and agranulocytosis.[12]
• Clinical Monitoring: Patients should be monitored for clinical signs of metabolic acidosis (e.g., confusion, rapid breathing, lethargy) and instructed to report any unusual symptoms.[20] They should also be counseled to report any signs of hypersensitivity, particularly skin rashes, fever, or mouth sores, which could be early indicators of a severe reaction like Stevens-Johnson syndrome.[20]
• Renal and Hepatic Function: The drug is contraindicated in marked renal or hepatic disease. Renal function should be assessed before initiating therapy.[12]

[7.0 In-Depth Safety and Tolerability Profile]

[7.1 Spectrum of Adverse Events: From Common to Life-Threatening]

[The adverse event profile of acetazolamide is extensive, ranging from common, dose-related side effects to rare, life-threatening idiosyncratic reactions.]

• Common and Characteristic Side Effects:[ Many of the most frequent side effects are direct consequences of the drug's pharmacology, particularly the induced metabolic acidosis.]
• Paresthesias: A tingling or "pins and needles" sensation, typically affecting the extremities (fingers, toes) and perioral region, is the most common side effect, affecting up to 50% of patients.[1]
• Dysgeusia: An altered sense of taste, often described as a metallic or bitter taste, is also very common.[10]
• General Malaise: Fatigue, drowsiness, loss of appetite, and general malaise are frequently reported.[1]
• Gastrointestinal and Urinary: Nausea, vomiting, diarrhea, and polyuria (frequent urination) often occur, especially early in therapy.[12]

[A meta-analysis has shown that the risk for paresthesias and dysgeusia increases with higher doses of acetazolamide.11]

• Metabolic and Electrolyte Disturbances:[ These are predictable adverse effects.]
• Metabolic Acidosis: A hyperchloremic metabolic acidosis is an expected consequence of renal bicarbonate wasting.[10] While often mild, it can become severe, especially in patients with underlying respiratory or renal compromise.[31]
• Hypokalemia and Hyponatremia: As a diuretic that promotes sodium and water loss, it can also lead to clinically significant depletion of potassium and sodium.[10]
• Renal Effects: Long-term therapy increases the risk of nephrolithiasis (kidney stones). The alkaline urine produced by acetazolamide reduces the solubility of calcium salts, leading to the formation of calcium phosphate stones.[10] Crystalluria (crystals in the urine) can also occur.[12]
• [Serious and Rare Adverse Events:]
• Severe Sulfonamide Hypersensitivity Reactions: As a sulfonamide derivative, acetazolamide carries a risk of severe, immune-mediated reactions that can be fatal. These include Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which are severe blistering skin conditions; fulminant hepatic necrosis; and anaphylaxis.[12]
• Blood Dyscrasias: Rare but serious hematologic effects have been reported, including aplastic anemia (failure of the bone marrow to produce blood cells), agranulocytosis (a severe lack of neutrophils), leukopenia, and thrombocytopenia.[10] These can manifest suddenly and may be irreversible.[42]
• Hepatic Injury: Abnormal liver function, cholestatic jaundice, and, in rare cases, hepatic insufficiency or failure have been documented.[12]
• Ocular Effects: Transient myopia (nearsightedness) can occur, which is thought to be caused by ciliary body edema and a forward shift of the lens-iris diaphragm. This condition typically resolves upon discontinuation of the medication.[12] Choroidal effusion and detachment have also been reported, particularly in the post-operative setting after ophthalmic surgery.[12]
• Neurologic Effects: In addition to drowsiness, more severe neurologic effects like confusion, depression, and ataxia can occur.[12] Suicidal ideation and behavior have been reported in patients treated with various anti-epileptic agents, including acetazolamide, warranting monitoring for mood changes.[32]

[7.2 Absolute and Relative Contraindications]

[The use of acetazolamide is strictly contraindicated in several clinical situations due to the high risk of severe adverse outcomes.]

• [Absolute Contraindications:]
• Known hypersensitivity to acetazolamide or any other sulfonamide derivative.[12]
• Situations of depressed serum sodium and/or potassium levels (hyponatremia, hypokalemia).[12]
• The presence of hyperchloremic acidosis.[12]
• Marked kidney disease or severe renal dysfunction.[12]
• Severe liver disease or dysfunction, particularly cirrhosis, due to the increased risk of precipitating hepatic encephalopathy.[12]
• Suprarenal (adrenal) gland failure.[12]
• Indication-Specific Contraindication: Long-term administration is contraindicated in patients with chronic non-congestive angle-closure glaucoma. In this condition, acetazolamide can lower the intraocular pressure, thereby masking the underlying progression of the disease as the angle organically and permanently closes.[12]

[7.3 Analysis of Regulatory Warnings: Deconstructing the "Black Box Warning" and Sulfa Cross-Reactivity Debate]

[A careful analysis of regulatory information and clinical literature reveals important nuances regarding two key safety concerns: the existence of a "black box warning" and the risk of sulfa cross-reactivity.]

A critical discrepancy exists in the available data regarding the regulatory status of acetazolamide's warnings. A secondary database, OpenTargets, explicitly states that the drug has a "black box warning from the FDA".[15][ However, a thorough review of primary source documents, including multiple versions of the official FDA-approved prescribing information (drug labels), reveals]

no evidence of a formal boxed warning.[13] Instead, the labels contain an extensive and strongly worded "WARNINGS" section that details the risk of rare but potentially fatal reactions common to sulfonamides, such as SJS, TEN, and aplastic anemia.[14][ The distinction is critical. A formal boxed warning is the highest level of safety alert issued by the FDA and carries significant clinical and legal weight. The discrepancy likely arises from an error in classification by the secondary database, which may have interpreted the severity of the standard warnings as equivalent to a boxed warning. While this does not diminish the seriousness of the potential adverse events, it is crucial for clinicians to understand the correct regulatory context and to avoid propagating misinformation about a non-existent black box warning.]

Similarly, the long-held clinical dogma regarding sulfa cross-reactivity is evolving. Traditional teaching and some drug labels advise strict avoidance of acetazolamide in any patient with a history of "sulfa allergy".[1][ However, modern pharmacological analysis provides a more nuanced perspective. The hypersensitivity reactions associated with sulfonamide antibiotics are largely attributed to a specific chemical structure, the N4 arylamine group, which is present in antibiotics like sulfamethoxazole but is]

absent in the structure of non-antibiotic sulfonamides like acetazolamide.[10] Furthermore, epidemiological studies suggest that the observed increased risk of a reaction to a non-antibiotic sulfonamide in a patient with a prior antibiotic sulfa allergy may be due to a general, underlying predisposition to allergic reactions rather than true chemical cross-reactivity.[10][ While caution is always warranted, especially in cases of a severe prior reaction like anaphylaxis or SJS, a blanket contraindication for a patient with a history of a mild rash to a sulfa antibiotic may be overly restrictive and could deny them a necessary therapy. The decision to use acetazolamide in such patients should be based on a careful risk-benefit analysis that considers the severity of the prior reaction and the availability of alternative treatments.]

[8.0 Clinically Significant Interactions]

[8.1 Critical Drug-Drug Interactions and Management Strategies]

Acetazolamide is involved in numerous drug-drug interactions, with 288 identified in total, of which 23 are classified as major and 247 as moderate.[44][ These interactions stem from its effects on renal function, plasma protein binding, and urinary pH.]

• High-Dose Aspirin: This is the most clinically significant and potentially dangerous interaction. Concurrent administration of acetazolamide and high-dose salicylates can lead to severe metabolic acidosis, anorexia, tachypnea, lethargy, coma, and even death.[12] The mechanism is thought to involve competition for plasma protein binding sites and for renal tubular secretion, leading to the accumulation of both drugs and enhanced CNS toxicity from salicylates.[20][ This combination should be avoided or used only with extreme caution and intensive monitoring.]
• Other Carbonic Anhydrase Inhibitors: Co-administration with other systemic (e.g., methazolamide) or topical (e.g., dorzolamide) carbonic anhydrase inhibitors is not recommended due to the potential for additive pharmacological effects and an increased incidence of systemic side effects.[20]
• Anticonvulsants: Acetazolamide can alter the metabolism and serum levels of other anti-epileptic drugs. It has been shown to increase serum levels of phenytoin, which may enhance the risk of developing osteomalacia with chronic therapy. Conversely, it may decrease the gastrointestinal absorption of primidone, potentially reducing its anticonvulsant effect.[20]
• Drugs Affected by Urinary pH:[ By causing alkalinization of the urine, acetazolamide can alter the renal excretion of other drugs.]
• It decreases the urinary excretion of weak bases, such as amphetamine and quinidine, which can enhance their magnitude and duration of effect.[25]
• It may interfere with the efficacy of methenamine, a urinary antiseptic that requires an acidic urine to be converted to its active form, formaldehyde.[25]
• Lithium: Acetazolamide increases the renal excretion of lithium, which can lead to decreased serum lithium levels and a potential loss of therapeutic effect in patients being treated for bipolar disorder.[20]
• Cyclosporine: There have been reports that acetazolamide may elevate serum levels of the immunosuppressant cyclosporine, increasing the risk of toxicity.[13]
• Sodium Bicarbonate: Concurrent use with sodium bicarbonate supplements increases the risk of renal calculus (kidney stone) formation.[20]

[Table 8.1: Major and Moderate Drug-Drug Interactions with Clinical Management Recommendations]

Interacting Drug/Class	Severity	Mechanism of Interaction	Clinical Consequence	Recommended Management Strategy
High-Dose Aspirin / Salicylates	Major	Competitive renal secretion; displacement from protein binding	Severe metabolic acidosis, CNS toxicity, lethargy, coma, death 12	Avoid combination. If unavoidable, use with extreme caution and monitor acid-base status and for signs of toxicity.
Other Carbonic Anhydrase Inhibitors (e.g., methazolamide)	Major	Additive pharmacodynamic effects	Increased risk and severity of systemic side effects (metabolic acidosis, electrolyte imbalance) 25	Concomitant use is not advisable.
Phenytoin	Moderate	Decreased phenytoin metabolism	Increased serum phenytoin levels; increased risk of osteomalacia with chronic use 25	Monitor phenytoin levels and for signs of toxicity. Consider bone density monitoring with long-term therapy.
Primidone	Moderate	Decreased primidone absorption	Decreased serum primidone levels and potential loss of seizure control 25	Monitor for seizure activity. Dose adjustment of primidone may be necessary.
Amphetamines / Dextroamphetamine	Moderate	Decreased renal excretion due to alkaline urine	Enhanced and prolonged effect of amphetamines 25	Monitor for signs of stimulant over-activity. Dose reduction of the amphetamine may be needed.
Quinidine	Moderate	Decreased renal excretion due to alkaline urine	Enhanced effect and risk of quinidine toxicity (e.g., arrhythmia) 25	Monitor quinidine levels and ECG.
Lithium	Moderate	Increased renal excretion	Decreased serum lithium levels and potential loss of efficacy 25	Monitor serum lithium levels closely, especially upon initiation, discontinuation, or dose change of acetazolamide.
Methenamine	Moderate	Inhibition of conversion to active form due to alkaline urine	Prevention of urinary antiseptic effect 25	Avoid combination. Choose an alternative urinary antiseptic.
Cyclosporine	Moderate	Unknown; may inhibit metabolism	Elevated cyclosporine levels and increased risk of nephrotoxicity 13	Monitor cyclosporine trough levels and renal function.

[8.2 Drug-Disease Interactions and Prescribing Considerations]

Acetazolamide's use must be carefully considered in patients with certain pre-existing conditions, as it can exacerbate them. There are 12 identified disease interactions.[44]

• Renal and Liver Disease: The drug is contraindicated in severe renal or hepatic disease.[12] In patients with mild-to-moderate renal impairment, it should be used with caution as the reduced clearance increases the risk of drug accumulation and severe electrolyte imbalances.[31]
• Respiratory Acidosis and COPD: In patients with severe obstructive lung disease (e.g., COPD, emphysema) and impaired alveolar ventilation, acetazolamide can precipitate or worsen respiratory acidosis and should be used with great caution.[12]
• Diabetes Mellitus: Acetazolamide has been reported to cause both increases and decreases in blood glucose levels. Therefore, diabetic patients require careful monitoring of their blood sugar, as glycemic control may be more difficult to achieve.[13]
• Gout and Metabolic Acidosis: The drug can worsen metabolic acidosis and should be avoided in patients with pre-existing hyperchloremic acidosis.[44]

[8.3 Drug-Food, Alcohol, and Supplement Interactions]

• Food: There are no known clinically significant interactions between acetazolamide and food. It can be administered with or without meals to suit patient preference, although taking it with food may help mitigate potential stomach upset.[20]
• Alcohol: While no specific interaction is documented, alcohol can potentiate the drowsiness and dizziness that are common side effects of acetazolamide. Patients should be counseled to use caution when consuming alcohol while on this medication.[3]
• Supplements: The most notable interaction is with sodium bicarbonate supplements, which can increase the risk of kidney stone formation when taken with acetazolamide.[47] There is also a theoretical risk of additive effects with herbal supplements that have diuretic properties, such as dandelion or uva ursi, which could potentially increase electrolyte loss.[50]

[9.0 Historical Context and Regulatory Journey]

[9.1 From Sulfanilamide to a First-in-Class Diuretic: The Discovery and Development of Acetazolamide]

The discovery of acetazolamide is a classic example of drug development arising from the observation of a side effect of an existing medication. In the 1940s, it was noted that the antibacterial agent sulfanilamide exhibited a diuretic effect, which was later found to be due to its weak inhibitory activity on the enzyme carbonic anhydrase.[35] This observation prompted a dedicated research effort to synthesize related heterocyclic sulfonamide compounds with more potent and specific carbonic anhydrase inhibitory activity, with the goal of creating a new class of diuretics for use in conditions like heart failure.[35]

This research, conducted by scientists at Lederle Laboratories (later part of Wyeth), led to the synthesis of acetazolamide.[51] The method for its synthesis was patented in 1951.[35] In 1940, researchers Mann and Kellin are credited with discovering the compound and first recognizing its anticonvulsant properties, an effect that was distinct from its diuretic action.[36] Acetazolamide subsequently became the first clinically available drug in the class of carbonic anhydrase inhibitor diuretics, a position it has held for approximately 80 years.[2]

[9.2 Key Regulatory Milestones and Post-Marketing Status]

Acetazolamide, under the brand name Diamox, received its initial approval from the U.S. Food and Drug Administration (FDA) in the mid-20th century. The oral tablet formulations (125 mg and 250 mg) were first approved on July 27, 1953, followed by the intravenous formulation (500 mg vial) on June 25, 1954.[52]

The original brand-name Diamox products have since been discontinued by the manufacturer. However, the FDA has formally determined that these products were not withdrawn from the market for reasons of safety or effectiveness.[52] This is a crucial regulatory determination because it allows for the continued approval and marketing of generic versions of acetazolamide under the Abbreviated New Drug Application (ANDA) pathway. As such, acetazolamide remains widely available as a generic medication. The original Diamox products are currently listed in the "Discontinued Drug Product List" section of the FDA's "Approved Drug Products with Therapeutic Equivalence Evaluations," commonly known as the Orange Book.[52]

[10.0 Analysis of Contemporary Clinical Trial Evidence]

[10.1 The ADVOR Trial: A Paradigm Shift in Acute Heart Failure Management?]

[The Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial represents the most significant clinical development for acetazolamide in decades, providing high-quality evidence for its use in a new, high-impact indication.]

• Trial Design: ADVOR was an investigator-initiated, academic, multicenter, randomized, double-blind, placebo-controlled trial conducted across 27 hospitals in Belgium. It enrolled 519 adult patients admitted with a diagnosis of ADHF who had clear clinical signs of volume overload (e.g., edema, pleural effusion, ascites).[5] Key exclusion criteria included a systolic blood pressure <90 mmHg, an estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m², and prior treatment with an SGLT2 inhibitor.[54]
• Intervention: Patients were randomized on a 1:1 basis to receive either intravenous acetazolamide (500 mg once daily) or a matching placebo. This was administered in addition to a standardized regimen of intravenous loop diuretics, given at a dose equivalent to double the patient's oral maintenance dose.[6]
• Primary Outcome: The primary endpoint was successful decongestion, defined as the absence of clinical signs of fluid overload within 3 days of randomization, without the need for escalating diuretic therapy. This outcome was achieved by 42.2% of patients in the acetazolamide group compared to 30.5% in the placebo group (Risk Ratio 1.46; p < 0.001), a statistically significant and clinically meaningful difference.[5]
• Key Secondary Outcomes: The addition of acetazolamide led to a significantly greater diuretic and natriuretic response.[56] This improved decongestion translated into a statistically significant reduction in the length of the index hospital stay, with a geometric mean of 8.8 days in the acetazolamide group versus 9.9 days in the placebo group.[6] There was no significant difference between the groups in the composite endpoint of all-cause mortality or rehospitalization for heart failure at the 3-month follow-up.[6]
• Subgroup Analysis: The beneficial effect of acetazolamide on decongestion was generally consistent across various subgroups, including different strata of left ventricular ejection fraction (LVEF).[5] Interestingly, a post-hoc analysis suggested that the treatment effect was more pronounced in patients with a higher baseline serum bicarbonate level (≥27 mmol/L), indicating that this may be a useful biomarker for identifying patients most likely to respond to therapy.[54]
• Safety Profile: The incidence of adverse events such as hypokalemia and hypotension was similar between the two groups. There was a higher incidence of transient worsening renal function (defined as a rise in serum creatinine) in the acetazolamide group during the treatment phase; however, this difference did not persist at the 3-month follow-up and was not associated with worse long-term outcomes.[7]

[Table 10.1: Summary of the ADVOR Trial Design, Patient Population, and Key Endpoints]

Component	Description
Trial Design	Investigator-initiated, multicenter, randomized, double-blind, placebo-controlled parallel-group trial.5
Patient Population	N=519 patients admitted for acute decompensated heart failure (ADHF) with clinical signs of volume overload (edema, pleural effusion, or ascites). Mean age ~78 years; ~37% female. Key exclusions: SBP <90 mmHg, eGFR <20 mL/min/1.73 m², use of SGLT2 inhibitors.6
Intervention Arms	1. Acetazolamide Group (n=259): IV acetazolamide 500 mg once daily + IV loop diuretic (double oral maintenance dose). 2. Placebo Group (n=260): IV placebo once daily + IV loop diuretic (double oral maintenance dose).5
Primary Endpoint	Successful Decongestion at 3 Days: Absence of clinical fluid overload without need for therapy escalation. - Acetazolamide: 42.2% - Placebo: 30.5% (Risk Ratio: 1.46; 95% CI 1.17-1.82; p<0.001).6
Key Secondary Endpoints	- Length of Hospital Stay: 8.8 days (Acetazolamide) vs. 9.9 days (Placebo).6 -

[10.2 Emerging Research: The ADA-HF Trial and Other Ongoing Investigations]

[The success of the ADVOR trial has catalyzed a new wave of research into acetazolamide's role in heart failure and other conditions.]

• The ADA-HF Trial: The Acetazolamide as a chloride-sparing Diuretic in patients Admitted with Heart Failure (ADA-HF) trial is a key follow-up study. It is designed to assess the safety and diuretic efficacy of oral acetazolamide given alongside high-dose IV loop diuretics in hospitalized HF patients. A primary focus is to determine if acetazolamide acts as a "chloride-sparing" agent, which could help prevent or correct the hypochloremia that can occur with aggressive diuresis.[37][ This trial will complement the findings of ADVOR and further clarify the role of acetazolamide in managing severe congestion.]
• Observational and Real-World Studies: Following the publication of ADVOR, observational studies have begun to emerge evaluating the real-world safety, tolerance, and prescribing trends of acetazolamide in ADHF, providing insights beyond the controlled environment of a clinical trial.[38]
• Systematic Reviews: New systematic reviews and meta-analyses are being conducted to synthesize the growing body of evidence, confirming that the addition of acetazolamide to standard diuretic therapy improves diuretic efficiency, reduces fluid overload, and promotes natriuresis in patients with decompensated heart failure.[58]
• Oncology Research: The National Cancer Institute (NCI) is supporting a clinical trial investigating the safety and efficacy of a novel agent, OBX-115, which involves acetazolamide, in patients with advanced solid tumors, suggesting a potential expansion of its use into oncology.[59]

[11.0 Expert Synthesis and Recommendations for Practice]

[Acetazolamide is a venerable therapeutic agent whose clinical utility is rooted in the elegant and predictable multi-system consequences of its single, targeted mechanism: the inhibition of carbonic anhydrase. For decades, it has been a reliable treatment for a specific set of disorders, but recent, high-quality clinical evidence has propelled it to the forefront of acute heart failure management, demonstrating that even the oldest drugs can be repurposed to meet modern clinical challenges. A comprehensive understanding of its pharmacology, pharmacokinetics, and safety profile is essential for its optimal use.]

[Based on the synthesized evidence, the following recommendations are provided for clinical practice:]

1. Embrace its Role in Acute Decompensated Heart Failure:[ The ADVOR trial provides compelling evidence to support the use of intravenous acetazolamide as an adjunct to loop diuretics in patients hospitalized with ADHF and significant volume overload. This strategy can lead to more effective and rapid decongestion and may shorten the duration of hospitalization. Clinicians should consider this combination early in the management of appropriate patients, particularly those without severe renal impairment (e.g., eGFR >20 mL/min/1.73 m²). Patients with higher baseline serum bicarbonate may derive the greatest benefit.]
2. Prioritize Electrolyte and Acid-Base Monitoring:[ The most predictable adverse effects of acetazolamide are metabolic. Therefore, baseline and periodic monitoring of serum electrolytes (especially potassium and sodium) and bicarbonate is not merely advisable but essential for safe prescribing. This is particularly critical in elderly patients, those with any degree of renal dysfunction, and individuals on long-term therapy.]
3. Adopt a Nuanced Approach to "Sulfa Allergy":[ The traditional contraindication in all patients with a history of sulfa allergy should be reconsidered in light of modern pharmacological evidence. The risk of true cross-reactivity between sulfonamide antibiotics and non-antibiotic sulfonamides like acetazolamide is low. The decision to prescribe should involve a careful risk-benefit analysis, weighing the severity of the patient's prior reaction against the clinical need for acetazolamide. A history of a mild rash to a sulfa antibiotic should not be an absolute contraindication, whereas a history of a severe reaction like SJS or anaphylaxis warrants avoidance.]
4. Heed the Aspirin Interaction Warning:[ The interaction between acetazolamide and high-dose aspirin is severe and potentially fatal. This combination should be avoided. Clinicians must be vigilant in reviewing patient medication lists for salicylates before prescribing acetazolamide.]
5. Respect Formulation Differences:[ The pharmacokinetic differences between immediate-release, extended-release, and intravenous formulations are clinically significant. Extended-release capsules are suitable for chronic management (e.g., glaucoma) but are inappropriate for acute situations where rapid onset is required. Intermittent dosing (e.g., alternate days) is necessary to maintain the diuretic effect in edema management.]

[Directions for Future Research:]

[Despite its long history, key knowledge gaps remain, and the recent resurgence in interest opens new avenues for investigation:]

• Combination Therapy with SGLT2 Inhibitors:[ The ADVOR trial excluded patients on SGLT2 inhibitors. As SGLT2 inhibitors are now a cornerstone of heart failure therapy and also act in the proximal tubule, rigorous trials are urgently needed to evaluate the safety and efficacy of combining acetazolamide with this class of drugs.]
• Robust Trials for Off-Label Uses:[ Many of acetazolamide's long-standing off-label uses, such as for idiopathic intracranial hypertension and periodic paralysis, are supported primarily by observational data and clinical experience. Modern, large-scale, randomized controlled trials are needed to definitively establish their efficacy and optimal dosing.]
• Exploration of Novel Applications:[ Preliminary research into acetazolamide's role in oncology and other areas is intriguing. Further investigation is warranted to explore whether its fundamental mechanism of altering pH and ion transport can be leveraged to treat other diseases.]

[In conclusion, acetazolamide is far more than a historical footnote in pharmacology. It is a dynamic therapeutic agent whose story continues to evolve. By respecting its powerful physiology and adhering to evidence-based principles of use, clinicians can continue to harness its benefits safely and effectively for both its classic indications and its new, promising role in cardiovascular medicine.]

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