Acetazolamide

合成路线和反应条件： 乙酰唑胺的合成涉及硫醇衍生物的氧化，形成磺酰氯中间体。 该中间体随后与各种胺、腙和双胺前体反应，生成新的磺酰胺衍生物 . 氧化过程可以通过用次氯酸钠（商业漂白剂）替代氯气来增强，从而提高安全性并改善环境条件 .

工业生产方法： 在工业环境中，乙酰唑胺通过将乙酰唑胺与乳糖、玉米淀粉、预糊化淀粉、PVP、蔗糖和羧甲基淀粉钠混合来生产。 然后将混合物制粒、干燥和压片，以获得乙酰唑胺片剂 .

反应类型： 乙酰唑胺会发生多种化学反应，包括氧化、还原和取代。 该化合物以其对碳酸酐酶的抑制作用而闻名，这会导致二氧化碳和水转化为氢离子和碳酸氢根的生成减少 .

常用试剂和条件：

氧化： 次氯酸钠（商业漂白剂）用作氧化剂.

还原和取代： 各种胺、腙和双胺前体用于合成新的磺酰胺衍生物.

主要生成物： 这些反应生成的主要产物包括具有增强抗菌和抗氧化特性的新型磺酰胺衍生物 .

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

乙酰唑胺通过抑制碳酸酐酶起作用，从而减少二氧化碳和水转化为氢离子和碳酸氢根的生成 . 这种抑制导致肾脏近端小管中碳酸氢根、钠和氯离子的重吸收减少，从而导致这些离子和多余的水的排泄增加 . 这种机制有助于降低血压、颅内压和眼压 .

类似化合物：

磺胺酰胺： 早期发现的化合物，具有类似的酶抑制作用，但效力远低于乙酰唑胺.

其他磺酰胺衍生物： 各种利尿剂和抗惊厥药，具有轻度至中度的碳酸酐酶活性.

乙酰唑胺的独特性： 乙酰唑胺以其对碳酸酐酶的强效抑制作用而著称，使其在治疗多种疾病方面非常有效。 它作为利尿剂、抗惊厥药和青光眼药物的能力突出了其在临床和研究环境中的多功能性和重要性 .

Sulfanilamide: An earlier discovered compound with similar enzymatic inhibitory activity but much less potent than acetazolamide.

Other Sulfonamide Derivatives: Various diuretics and anticonvulsants with minor to moderate carbonic anhydrase activity.

Uniqueness of this compound: this compound stands out due to its potent inhibitory effect on carbonic anhydrase, making it highly effective in treating a wide range of medical conditions. Its ability to act as a diuretic, anticonvulsant, and glaucoma medication highlights its versatility and importance in both clinical and research settings .

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 .