Verapamil
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Verapamil: From Hypertension and Arrhythmia to Malignant Hypertensive Renal Disease
One-Sentence Summary
Verapamil is a calcium channel blocker originally used for hypertension, atrial fibrillation, acute coronary syndrome, Prinzmetal angina and ventricular tachycardia. The TxGNN model's top-ranked prediction is obsolete bundle branch block, and its other high-scoring predictions include malignant hypertensive renal disease, pulmonary hypertension and arrhythmogenic right ventricular cardiomyopathy. Evidence is weak: no clinical trials are registered for any of these predictions, and the available publications are mostly indirect or preclinical.
Note: The top-ranked prediction (obsolete bundle branch block) is an obsolete ontology term and is mechanistically implausible, since slowing conduction could be harmful. This report therefore presents it as the formal rank-1 prediction but also discusses the other leading candidates.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Hypertension, atrial fibrillation, acute coronary syndrome, Prinzmetal angina, ventricular tachycardia (the Singapore license text gives no approved indication) |
| Predicted New Indication | Obsolete bundle branch block (rank 1) |
| TxGNN Prediction Score | 99.62% |
| Evidence Level | L5 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 1 |
| Recommended Decision | Hold |
Other leading predictions:
| Rank | Predicted Indication | TxGNN Score | Evidence Level |
|---|---|---|---|
| 2 | Malignant hypertensive renal disease | 99.27% | L5 |
| 3 | Malignant renovascular hypertension | 99.27% | L5 |
| 4 | Pulmonary hypertension with unclear multifactorial mechanism | 99.26% | L5 |
| 5 | Pulmonary hypertension owing to lung disease and/or hypoxia | 99.26% | L4 |
| 9 | Arrhythmogenic right ventricular cardiomyopathy | 98.40% | L4 |
| 10 | Brain stem infarction | 97.73% | L5 |
Why is This Prediction Reasonable?
Currently, detailed mechanism of action data is not available in the data compiled for this report. Based on known pharmacology, verapamil is an L-type calcium channel blocker. It slows atrioventricular nodal conduction and relaxes vascular smooth muscle, which explains its use in hypertension, angina and supraventricular and ventricular arrhythmias.
Rank 1, obsolete bundle branch block: This prediction is not mechanistically convincing. Slowing conduction is not a plausible way to treat a conduction block and could be harmful. The term is also flagged as obsolete in the ontology, so the score likely reflects a graph artefact rather than a real therapeutic signal.
Rank 2, malignant hypertensive renal disease: This is the most plausible of the predictions. Verapamil is already used for hypertension, and vasodilation through calcium channel blockade is a reasonable mechanism. The prediction probably reflects similarity to the existing antihypertensive indication rather than new evidence. Malignant hypertension with renal involvement is an emergency usually managed with established agents.
Pulmonary hypertension (ranks 4-5): Pulmonary vasodilation through L-type calcium channels is biologically plausible. However, calcium channel blockers are recommended only for the small vasoreactive subset of pulmonary arterial hypertension, and verapamil is generally not favoured because of its negative inotropic effect. In hypoxic lung disease, vasodilators can also worsen ventilation-perfusion matching.
Arrhythmogenic right ventricular cardiomyopathy (rank 9): Verapamil works in verapamil-sensitive fascicular ventricular tachycardia, but that mechanism differs from the scar-related reentry seen in this cardiomyopathy. Its negative inotropy is also a concern in cardiomyopathy.
Clinical Trial Evidence
Currently no related clinical trials are registered for any of the top predictions.
Literature Evidence
Publications were retrieved for four of the predictions. None is a randomised trial of verapamil in the predicted condition. The table lists the most relevant ones.
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 24827485 | 2014 | Case report | Internal Medicine | Verapamil-sensitive fascicular ventricular tachycardia in a patient with left ventricular noncompaction (relevant to the ARVC prediction by analogy only) |
| 18375968 | 2008 | Case report | Europace | Electrical storm in a patient with arrhythmogenic right ventricular cardiomyopathy and an SCN5A mutation |
| 8846953 | 1995 | Review | Harefuah | Overview of arrhythmogenic right ventricular dysplasia, with a case presenting with ventricular arrhythmia |
| 15475817 | 2004 | Review | AACN Clinical Issues | Diagnosis and treatment of idiopathic ventricular tachycardia |
| 9768801 | 1998 | Preclinical/mechanistic | Anesthesia and Analgesia | Ketamine-induced pulmonary vasodilation in isolated rat lung is partly mediated by L-type calcium channels, with verapamil used as a probe |
| 21962069 | 2011 | Preclinical (animal) | High Altitude Medicine & Biology | Calcium influx through L-type channels and serotonin-mediated contractility in pulmonary arteries after long-term hypoxia |
| 24977753 | 2014 | Preclinical (animal) | Journal of Trauma and Acute Care Surgery | Verapamil preserved cytoskeletal function in an in vitro intestinal model after hypoxia-reoxygenation |
| 22147655 | 2012 | Review | Hormone and Metabolic Research | Factors affecting the aldosterone/renin ratio; it does not evaluate verapamil for renovascular hypertension |
| 10224210 | 1999 | Case report | Pediatrics | Solitary renal myofibromatosis as a cause of infantile renovascular hypertension; it does not evaluate verapamil |
| 22356043 | 2011 | Case report | JPMA | Cluster-like headache after lateral medullary infarct; it does not address treatment of the infarct |
Most other retrieved papers were off-topic (for example migraine, retinal neuroprotection and natural products chemistry).
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN00344P | ISOPTIN SR TABLET 240 mg | Tablet, film coated (oral) | Not stated in the data compiled for this report |
Safety Considerations
Package insert warnings and contraindications were not available in the data compiled for this report; please refer to the package insert for authoritative safety information.
- Disease-level contraindication signals (knowledge graph, not label text): The knowledge graph flags conditions including heart failure, atrioventricular block, hypotensive disorder, aortic stenosis, hypertrophic cardiomyopathy, ventricular tachycardia subtypes, kidney and liver disease, myasthenia gravis and neuromuscular junction disease, angioedema, and neutropenia/agranulocytosis. These signals should be verified against the label.
- Drug interactions: The interaction screen returned 100 entries, and 20 are shown in the data compiled for this report. Of these, Loperamide is rated Major. Most others are rated Moderate, including corticosteroids (hydrocortisone, dexamethasone, betamethasone, triamcinolone, budesonide), metformin, bupropion, aprepitant, acetylsalicylic acid, canagliflozin, cimetidine, clarithromycin and several calcium salts. Morphine is rated Minor.
- Indication-specific concerns: Negative inotropy is relevant to cardiomyopathy and pulmonary hypertension. Vasodilation may worsen ventilation-perfusion matching in hypoxic lung disease.
Conclusion and Next Steps
Decision: Hold
Rationale: All predictions rely on model scores alone or on indirect, preclinical or off-topic literature, and no clinical trials exist. The top-ranked prediction is an obsolete, mechanistically implausible term. Several predictions also carry safety concerns, such as negative inotropy and ventilation-perfusion mismatch. Blocking data gaps, notably the package insert safety information, also prevent safety screening from proceeding.
To proceed, the following is needed:
- Package insert warnings and contraindications from the HSA, to enable safety screening
- Mechanism of action data from DrugBank
- A clinical literature review focused on malignant hypertensive renal disease, the most mechanistically plausible candidate, to see whether any direct evidence exists
- Expert review of whether the remaining predictions (pulmonary hypertension, ARVC) are clinically worth pursuing given the safety concerns
- Confirmation of the approved indication text for the Singapore license
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.