Acetazolamide
| 證據等級: L5 | 預測適應症: 10 個 |
目錄
Acetazolamide: From Altitude Sickness and Glaucoma to Cardiomyopathy
Editorial Note: The TxGNN model’s highest-ranked prediction (exercise-induced malignant hyperthermia, rank #1) has no supporting clinical trials or literature. This report focuses on Cardiomyopathy (rank #7 by TxGNN score) because it carries the strongest evidence (L2) and the only actionable recommendation in this candidate set. A full summary of all 10 predictions is provided at the end.
One-Sentence Summary
Acetazolamide is a carbonic anhydrase inhibitor with established global use for altitude sickness (acute mountain sickness), glaucoma, and certain seizure types, though it is not currently registered in Australia. The TxGNN model predicts it may be effective in Cardiomyopathy — specifically as an adjunct diuretic in acute decompensated heart failure — a direction already validated by the landmark 2022 ADVOR Phase 3 RCT (NEJM, n=519) and supported by 3 ongoing Phase 4 trials enrolling over 1,800 participants worldwide.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Altitude sickness, glaucoma, certain epilepsies (established global use; not TGA-registered) |
| Predicted New Indication | Cardiomyopathy (Acute Decompensated Heart Failure) |
| TxGNN Prediction Score | 99.83% |
| Evidence Level | L2 |
| Australia Market Status | Not marketed |
| Number of ARTG Entries | 0 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data was not available in the current evidence pack. Based on established pharmacological knowledge, Acetazolamide inhibits carbonic anhydrase — an enzyme critical to bicarbonate and acid-base regulation — in the proximal renal tubule. This blockade reduces bicarbonate (HCO₃⁻) and sodium reabsorption, producing urinary alkalinisation and a mild diuretic effect.
This mechanism is directly relevant to cardiomyopathy and acute decompensated heart failure (ADHF). Patients with ADHF who are treated with loop diuretics (e.g., furosemide) frequently develop metabolic alkalosis, which in turn causes diuretic resistance — a major obstacle to effective decongestion. Acetazolamide corrects this alkalosis by blocking bicarbonate reclamation, thereby restoring the responsiveness of loop diuretics. This mechanism of diuretic synergy is well-grounded in renal physiology.
This hypothesis was confirmed in the ADVOR trial (2022, New England Journal of Medicine, Phase 3 RCT, n=519): adding intravenous Acetazolamide to standard loop diuretic therapy produced a significantly higher rate of successful decongestion compared to placebo (42.2% vs 30.5%; RR 1.46, 95% CI 1.17–1.82, p < 0.001). The three Phase 4 trials currently recruiting represent direct follow-on work designed to optimise dosing, route of administration, and patient selection criteria across broader heart failure and cardiomyopathy populations.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT06166654 | Phase 4 | Recruiting | 939 | Double-blind RCT comparing loop diuretic + Acetazolamide vs loop diuretic + Metolazone vs loop diuretic alone in AHF with volume overload. Largest ongoing confirmatory trial in this therapeutic space. |
| NCT05802849 | Phase 4 | Recruiting | 400 | Oral vs intravenous Acetazolamide for decompensated heart failure (non-inferiority design). Directly follows on from the ADVOR trial to evaluate a more convenient oral route. |
| NCT06092437 | Phase N/A | Recruiting | 466 | TAILOR-AHF: Urine sodium–guided tailored diuretic algorithm in ADHF. Acetazolamide is a core component of the algorithm under investigation. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 38806171 | 2025 | Annual Review | ESC Heart Failure | 2024 update on heart failure management; contextualises evolving diuretic strategies and new pharmacotherapy recommendations from the 2023 ESC guidelines update. |
| 37169875 | 2023 | Review | Eur Heart J Cardiovasc Pharmacotherapy | Comprehensive 2022 cardiovascular pharmacology review; covers ADVOR trial and first-in-class agents for obstructive HCM (mavacamten), supporting the broader HF pharmacotherapy landscape. |
| 30279861 | 2018 | Case Report | Journal of Cardiology Cases | 87-year-old with advanced HF and hypertrophic cardiomyopathy treated with Acetazolamide for hypochloraemia under loop diuretic therapy; highlights chloride manipulation as a therapeutic target and importance of urinary electrolyte monitoring. |
| 29123889 | 2017 | Adverse Event Report | Acute Medicine & Surgery | Non-cardiogenic pulmonary oedema occurred one hour after IV Acetazolamide in a patient with dilated cardiomyopathy. Important safety signal for IV administration in cardiac patients. |
| 22426904 | 2012 | Preclinical (Animal) | Saudi Medical Journal | Acetazolamide effects in ischaemia-reperfusion isolated rabbit heart models in two age groups; exploratory myocardial protection data. |
| 7324871 | 1981 | Case Series | Acta Neurologica Scandinavica | Hypokalaemic periodic paralysis patients on Acetazolamide 750–1000 mg/day developed exercise angina and ECG ST-segment changes; cardiac involvement documented. |
| 742352 | 1978 | Case Report | Acta Neurologica Scandinavica | Echocardiographic findings in a family with hypokalaemic periodic paralysis associated with permanent muscular weakness; cardiac muscle involvement noted alongside skeletal muscle disease. |
| 23571262 | 2014 | Case Report | Indian Journal of Ophthalmology | Danon disease (LAMP2 mutation; associated with hypertrophic cardiomyopathy) with cystoid macular oedema treated with oral Acetazolamide; demonstrates use adjacent to a cardiomyopathy syndrome. |
| 9627326 | 1998 | Imaging Case Report | Journal of Nuclear Medicine | SPECT imaging in mitochondrial encephalomyopathy; Acetazolamide used as cerebrovascular challenge agent. Peripheral relevance. |
| 35619116 | 2022 | Case Report | Journal of Medical Case Reports | Congenital hydrocephalus in trisomy 9p with coexisting congenital heart disease; Acetazolamide used to manage CSF production in a complex cardiac-neurological comorbidity context. |
Australia Market Information
Acetazolamide is not currently registered on the Australian Register of Therapeutic Goods (ARTG) and has no TGA-approved Product Information (PI) or approved indications in Australia. There are 0 ARTG entries.
Clinicians wishing to prescribe Acetazolamide in Australia would need to access it through one of the following pathways:
| Access Pathway | When Applicable |
|---|---|
| TGA Special Access Scheme (SAS) — Category B | Individual patient access for unapproved therapeutic goods |
| TGA Authorised Prescriber | Ongoing prescribing for a defined patient class |
| Clinical Trial (CTN/CTA) | Participation in one of the 3 registered Phase 4 trials |
In the absence of a TGA PI, prescribers should reference the US FDA Prescribing Information or the EMA Summary of Product Characteristics (SmPC) for safety, dosing, and contraindication information.
All Predicted Indications — Summary
| Rank | Indication | TxGNN Score | Evidence Level | Recommendation |
|---|---|---|---|---|
| 1 | Exercise-induced malignant hyperthermia | 99.95% | L5 | Hold |
| 2 | Hypertrophic cardiomyopathy | 99.93% | L5 | Hold |
| 3 | Congenital myopathy with excess of thin filaments | 99.90% | L5 | Hold |
| 4 | HCM due to intensive athletic training | 99.89% | L5 | Hold |
| 5 | Distal myopathy, Tateyama type | 99.88% | L5 | Hold |
| 6 | Cirrhotic cardiomyopathy | 99.88% | L5 | Hold |
| 7 | Cardiomyopathy ⭐ | 99.83% | L2 | Proceed with Guardrails |
| 8 | Intestinal obstruction ⚠️ | 99.82% | L5 | Hold |
| 9 | Glycogen storage disease — late-onset Pompe | 99.80% | L5 | Hold |
| 10 | Unclassified intestinal pseudoobstruction ⚠️ | 99.79% | L5 | Hold |
⚠️ Reverse safety signal — Ranks 8 and 10: Existing published literature indicates that Acetazolamide may cause adynamic ileus and intestinal motility impairment (via hypokalaemia), rather than treat it. These indications carry a safety concern and must not be pursued as repurposing candidates.
Safety Considerations
Formal safety data (warnings, contraindications, drug interactions) was not available in the current evidence pack. Based on the literature included in this evidence pack, one clinically important adverse event was identified:
- Non-cardiogenic pulmonary oedema has been reported following intravenous Acetazolamide in a patient with dilated cardiomyopathy (PMID 29123889). Caution is warranted with IV administration in patients with pre-existing cardiac dysfunction.
- Cardiac effects under long-term use: Exercise angina and ST-segment changes were documented in patients on Acetazolamide 750–1,000 mg/day (PMID 7324871). Electrolyte monitoring (particularly potassium) is essential.
As Acetazolamide is a sulfonamide derivative, allergy screening should be conducted prior to prescribing.
Please refer to the FDA Prescribing Information or EMA SmPC for the complete safety profile, as no TGA-approved PI is available for Australia.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: The ADVOR trial (2022, NEJM, Phase 3 RCT, n=519) provides high-quality evidence that Acetazolamide meaningfully improves decongestion outcomes in acute decompensated heart failure when added to standard loop diuretic therapy (RR 1.46). Three Phase 4 trials are actively building on this foundation. However, Acetazolamide is not registered in Australia, requiring formal TGA access pathways before clinical use, and a complete safety and drug-interaction review is essential given the absence of a TGA PI.
To proceed, the following is needed:
- TGA access pathway: Initiate an SAS Category B application or Authorised Prescriber arrangement to enable clinical use in Australia
- Complete safety profile: Obtain FDA Prescribing Information or EMA SmPC; formally assess contraindications (sulfonamide hypersensitivity, renal impairment thresholds, hepatic disease, electrolyte requirements)
- Drug interaction review: Conduct a formal DDI assessment — particularly interactions with loop diuretics, digoxin, antiepileptics, and lithium
- MOA documentation: Retrieve full mechanism of action data from DrugBank API (DB00819) to support regulatory submissions
- Patient selection criteria: Define the appropriate Australian patient population based on ADVOR trial inclusion/exclusion criteria (ADHF with loop diuretic resistance, adequate renal function)
- Electrolyte monitoring plan: Develop a protocol for regular FBC, electrolytes (K⁺, Na⁺, Cl⁻), renal function, and acid-base status monitoring
- Australian trial linkage: Explore feasibility of adding Australian sites to NCT06166654 or NCT05802849 to generate local safety and efficacy data
This report is generated from TxGNN model predictions and publicly available evidence. It is intended for research evaluation purposes only and does not constitute medical or clinical advice. All drug repurposing candidates require prospective clinical validation before any therapeutic application.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.