Acetazolamide

Synthetic Routes and Reaction Conditions: The synthesis of acetazolamide involves the oxidation of a thiol derivative to form a sulfonyl chloride intermediate. This intermediate then reacts with various amines, hydrazones, and bis-amine precursors to create new sulfonamide derivatives . The oxidation process can be enhanced by substituting chlorine gas with sodium hypochlorite (commercial bleach), which improves safety and environmental conditions .

Industrial Production Methods: In industrial settings, this compound is produced by mixing this compound with lactose, cornstarch, pregelatinized starch, PVP, sucrose, and carboxymethyl starch sodium. The mixture is then pelletized, dried, and tabletted to obtain this compound tablets .

Types of Reactions: Acetazolamide undergoes various chemical reactions, including oxidation, reduction, and substitution. The compound is known for its inhibitory effect on carbonic anhydrase, which leads to a decrease in the formation of hydrogen ions and bicarbonate from carbon dioxide and water .

Common Reagents and Conditions:

Oxidation: Sodium hypochlorite (commercial bleach) is used as an oxidizing agent.

Reduction and Substitution: Various amines, hydrazones, and bis-amine precursors are used in the synthesis of new sulfonamide derivatives.

Major Products Formed: The major products formed from these reactions include novel sulfonamide derivatives with enhanced antibacterial and antioxidant properties .

FDA-Approved Indications

Acetazolamide is approved for several medical conditions:

• Glaucoma : Reduces intraocular pressure by decreasing aqueous humor production.
• Idiopathic Intracranial Hypertension (IIH) : Lowers cerebrospinal fluid (CSF) production, thus reducing intracranial pressure.
• Altitude Sickness : Alleviates symptoms by promoting respiratory compensation and diuresis.
• Congestive Heart Failure : Enhances diuretic efficacy when used in conjunction with loop diuretics.
• Periodic Paralysis : Manages symptoms associated with this condition.
• Epilepsy : Acts as an adjunctive treatment for certain types of seizures.

Non-FDA-Approved Indications

In addition to its approved uses, this compound has been explored for several non-FDA-approved applications:

• Central Sleep Apnea : Investigated for its potential benefits in managing sleep-related breathing disorders.
• Marfan Syndrome : Used in some cases to manage symptoms.
• Prevention of High-Dose Methotrexate Nephrotoxicity : Explored as a protective agent against kidney damage during chemotherapy.
• Prevention of Contrast-Induced Nephropathy : Studied for its role in protecting renal function during imaging procedures.

Idiopathic Intracranial Hypertension

A study reported significant reductions in intracranial pressure among patients treated with this compound. The drug was effective in managing symptoms and preventing complications like vision loss .

Acute Mountain Sickness

In a clinical trial involving patients with acute mountain sickness, this compound demonstrated efficacy in reducing symptoms such as headache and nausea, attributed to its effects on respiration and fluid balance .

Hydrocephalus Management

In pediatric patients with shunt-dependent hydrocephalus, this compound led to a dramatic reduction in CSF output, allowing clinicians to manage shunt function more effectively .

Pharmacokinetics

This compound is well absorbed orally, with a plasma half-life ranging from 6 to 9 hours. It is primarily excreted through the kidneys without undergoing significant metabolic alteration .

Summary Table of Applications

Acetazolamide works by inhibiting the enzyme carbonic anhydrase, which decreases the formation of hydrogen ions and bicarbonate from carbon dioxide and water . This inhibition leads to a reduction in the reabsorption of bicarbonate, sodium, and chloride ions in the proximal tubule of the kidney, resulting in increased excretion of these ions along with excess water . This mechanism helps lower blood pressure, intracranial pressure, and intraocular pressure .

Diuretic Efficacy: Acetazolamide vs. Loop Diuretics and Thiazides

This compound enhances decongestion in HF by targeting proximal tubule sodium reabsorption, complementing loop diuretics like furosemide. A randomized trial demonstrated:

This compound’s proximal action spares distal nephron electrolyte losses (e.g., hypokalemia) but induces metabolic acidosis, unlike furosemide. Compared to thiazides like chlorthalidone, this compound showed superior weight loss and alkalosis correction in the CANDI trial (observational), though larger trials are needed .

Carbonic Anhydrase Inhibition: Selectivity and Potency

This compound’s CA inhibition varies by isoform and compares differently with newer agents:

*Novel indole-based hydrazones (e.g., compound 23) exhibit 10–100x greater potency against tumor-associated hCA IX/XII than this compound, with reduced off-target effects on hCA I/II .

Intracranial Pressure Reduction: this compound vs. Topiramate

Both drugs lower ICP via CA inhibition, but this compound acts faster:

In female rats, this compound achieved maximal ICP reduction at 120 minutes, mirroring human pharmacokinetics .

High-Altitude Sickness: this compound vs. Benzolamide

Benzolamide, a non-penetrating CA inhibitor, avoids central side effects (e.g., paresthesia) but requires higher dosing:

This compound’s efficacy is dose-dependent (125–375 mg/bid), with 250 mg being optimal for AMS prophylaxis .

Glaucoma: this compound vs. Methazolamide

Sublingual methazolamide matches this compound’s IOP reduction with fewer systemic effects:

Methazolamide’s sublingual formulation improves bioavailability, reducing dosing frequency .

Binding Affinity and Structural Insights

This compound’s sulfonamide group interacts with CA-II’s Zn²⁺ and His94/Thr199 residues (docking score: −9.47 kcal/mol). Structurally similar compounds with extended alkyl chains (e.g., compound 19, score: −9.66 kcal/mol) exhibit tighter binding, correlating with higher inhibitory activity .

Acetazolamide is a carbonic anhydrase inhibitor that has garnered attention for its diverse biological activities and therapeutic applications. This article explores the mechanisms of action, pharmacological effects, and clinical implications of this compound, supported by case studies and research findings.

This compound primarily functions by inhibiting carbonic anhydrase, an enzyme that catalyzes the reversible reaction between carbon dioxide (CO2) and bicarbonate (HCO3−), leading to the formation of carbonic acid (H2CO3). This inhibition results in:

• Increased Acidity : The accumulation of carbonic acid lowers blood pH, promoting increased acidity in the bloodstream.
• Altered Electrolyte Excretion : Inhibition of carbonic anhydrase in the proximal tubule of the nephron leads to increased excretion of sodium, bicarbonate, and chloride, resulting in diuresis and natriuresis .
• Neuronal Effects : In epilepsy management, this compound modulates neuronal excitability by affecting GABA-A receptor signaling and calcium ion kinetics, which may help in controlling seizure activity .

Pharmacokinetics

This compound exhibits favorable pharmacokinetic properties:

• Absorption : It is well absorbed when administered orally.
• Distribution : The drug has a high volume of distribution and is found in red blood cells at higher concentrations in elderly patients compared to younger individuals .
• Elimination : this compound is primarily excreted unchanged in urine, with minimal metabolism occurring .

1. Glaucoma Management

This compound is used to lower intraocular pressure in patients with glaucoma. By decreasing aqueous humor production through carbonic anhydrase inhibition, it helps manage this condition effectively .

2. Treatment of Idiopathic Intracranial Hypertension (IIH)

A multicenter study demonstrated that this compound significantly improved visual function and reduced papilledema in patients with IIH. Participants receiving this compound showed greater improvements in perimetric mean deviation compared to placebo .

3. Heart Failure

Recent literature reviews indicate that this compound can enhance diuretic efficacy in heart failure patients experiencing fluid overload. Studies suggest it improves decongestion and natriuresis when used alongside loop diuretics, although limitations such as small sample sizes warrant further investigation .

4. Antibacterial Activity

Emerging research highlights this compound's potential as an antibacterial agent against enterococci. It has shown effectiveness at clinically achievable concentrations, suggesting a new therapeutic avenue for treating infections caused by resistant strains .

Study on Glioblastoma Multiforme (GBM)

A phase I clinical trial evaluated the safety and efficacy of this compound combined with temozolomide in GBM patients. Results indicated that the combination was well tolerated, with median overall survival reaching 30.1 months, suggesting a promising role for this compound in enhancing treatment outcomes for this aggressive cancer .

Research Findings

• Diuretic Efficacy : A systematic review found that this compound significantly improved outcomes related to fluid retention in heart failure patients when combined with standard diuretics .
• Epilepsy Control : this compound's role in managing epilepsy was supported by its ability to modulate neuronal excitability through various pathways, including GABA-A signaling modulation .
• Bone Health : Chronic use of carbonic anhydrase inhibitors like this compound has been studied for their effects on bone mineral density, indicating potential implications for long-term therapy .

Basic Research Questions

Q. What evidence supports the efficacy of different acetazolamide dosages in preventing acute mountain sickness (AMS), and how are optimal doses determined in clinical trials?

• Methodological Answer: Systematic reviews and meta-analyses comparing dosages (e.g., 250 mg vs. 750 mg daily) are critical. For example, a meta-analysis stratified outcomes by dose and used pooled risk ratios to assess AMS incidence reduction. Trials typically employ double-blind, placebo-controlled designs with endpoints like Lake Louise Scores . Dose selection prioritizes balancing efficacy (e.g., 250 mg reduces AMS incidence by 48%) with adverse effects like metabolic acidosis.

Q. How does this compound synergize with dietary sodium restriction in idiopathic intracranial hypertension (IIH), and which outcome metrics best capture therapeutic benefits?

• Methodological Answer: Randomized controlled trials (RCTs) combine this compound with low-sodium diets, using perimetric mean deviation (PMD) to quantify visual field improvements. Secondary outcomes include papilledema grade (Frisén scale) and quality-of-life surveys (e.g., VFQ-25). For instance, this compound + diet improved PMD by 0.71 dB more than diet alone, with statistical significance (95% CI: 0–1.43 dB; P = 0.05) .

Q. What pharmacokinetic properties of this compound are critical for designing bioavailability studies?

• Methodological Answer: Key parameters include renal excretion (90% unchanged), plasma half-life (~6–9 hours), and protein binding (70–90%). Bioavailability studies use LC-MS/MS to quantify urinary concentrations, as this compound is excreted unmetabolized. Protocols often reference validated assays, such as GC-NICI-MS for derivatized sulfonamides in urine .

Advanced Research Questions

Q. How can researchers mitigate confounding from prophylactic this compound use in observational studies of hypoxia-induced gene expression?

• Methodological Answer: Confounding is addressed via sensitivity analyses excluding this compound users or multivariable regression adjusting for drug exposure. For example, in genomic studies of hypoxia-inducible factor (HIF-1), post hoc stratification by this compound use clarifies gene expression patterns . Ethical constraints (e.g., withholding prophylaxis) necessitate transparent reporting of confounding in limitations.

Q. What trial design considerations optimize assessments of this compound’s diuretic efficiency in acute decompensated heart failure (ADHF)?

• Methodological Answer: The ADVOR trial used stratified randomization by ejection fraction and defined "successful decongestion" as absence of edema/ascites within 72 hours. Primary endpoints combined clinical signs and biomarker thresholds (NT-proBNP >1000 pg/mL). Mixed linear models evaluated urine output and natriuresis, showing this compound increased decongestion success (42.2% vs. 30.5%; RR: 1.46) .

Q. What statistical methods handle missing data in this compound trials, such as studies on obstructive sleep apnea (OSA) in high-altitude populations?

• Methodological Answer: Intention-to-treat (ITT) analyses with multiple imputation (e.g., chained equations) preserve randomization integrity. Per-protocol analyses supplement ITT by excluding protocol violators. For example, OSA trials use mixed linear regression to compare treatment effects (this compound vs. placebo) on apnea-hypopnea index (AHI) changes, with sensitivity analyses for missing data .

Q. How does this compound’s thermal instability influence compatibility studies with excipients during formulation development?

• Methodological Answer: Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) identify decomposition temperatures (~260°C for this compound). Compatibility studies with excipients (e.g., chitosan) compare thermograms to detect interactions. For instance, amorphous phase formation post-melting necessitates stability testing under accelerated conditions (40°C/75% RH) .

Q. Data Contradiction & Synthesis

Q. How should conflicting results on this compound’s neuropsychiatric effects (e.g., bipolar disorder) be reconciled in scoping reviews?

• Methodological Answer: PRISMA-guided reviews categorize evidence by study design (RCTs vs. case reports) and outcomes (e.g., affective symptoms vs. cognitive function). For bipolar disorder, data extraction tables highlight dose-response relationships and safety profiles, noting gaps like absent long-term tolerability data .

Q. What explains disparities in this compound’s efficacy across conditions like AMS, IIH, and ADHF?

• Methodological Answer: Mechanistic heterogeneity—carbonic anhydrase inhibition affects distinct pathways (e.g., cerebral blood flow in AMS vs. renal bicarbonate excretion in ADHF). Cross-disciplinary synthesis links pharmacokinetics (e.g., CSF penetration in IIH) to condition-specific outcome measures .