Fenfluramine
Fenfluramine is an anticonvulsant medication primarily used to treat seizures associated with Dravet syndrome, a severe form of epilepsy beginning in childhood. Originally developed as an appetite suppressant, fenfluramine has been repurposed for epilepsy due to its ability to reduce seizure frequency in patients with Dravet syndrome. Fenfluramine increases serotonin levels in the brain, which affects neuronal activity and may contribute to its anticonvulsant effects.
Trade Names
Fenfluramine is marketed under the trade name Fintepla for seizure management.
Chemical Properties
Chemical Structure: Fenfluramine is an amphetamine derivative with an additional trifluoromethyl group, which contributes to its unique effects on serotonin.
Molecular Formula: C₁₂H₁₆F₃N
Molecular Weight: 231.26 g/mol
Solubility: Fenfluramine is available as an oral solution for seizure management.
Biochemical Properties
Mechanism of Action: Fenfluramine primarily works by releasing serotonin and inhibiting its reuptake, increasing serotonin availability in the brain. This modulation of serotonin activity has been shown to reduce seizure frequency, particularly in patients with Dravet syndrome. The exact mechanism by which it affects seizures is not fully understood but is likely related to its influence on neuronal excitability.
Pharmacology
Administration: Fenfluramine is administered orally, typically in liquid form, and taken with or without food.
Bioavailability: Fenfluramine is well absorbed after oral administration.
Metabolism: It is primarily metabolized in the liver to active metabolites, including norfenfluramine.
Half-Life: The half-life of fenfluramine is about 20 hours, while the metabolite norfenfluramine has a longer half-life, contributing to its sustained effect.
Clinical Indications
Dravet Syndrome: Approved as an adjunctive treatment to reduce the frequency of seizures in patients with Dravet syndrome who have not achieved adequate control with other antiepileptic medications.
Off-Label: In some cases, fenfluramine may be explored for other treatment-resistant epilepsy syndromes, though further research is needed.
Side Effects
Drowsiness and Fatigue: Fatigue and sedation are common, especially when treatment is first initiated.
Loss of Appetite and Weight Loss: Originally developed as an appetite suppressant, fenfluramine may reduce appetite and lead to weight loss.
Diarrhea and Gastrointestinal Issues: Some patients may experience GI symptoms such as diarrhea and abdominal discomfort.
Behavioral Changes: Mood swings, aggression, and, less commonly, depression may occur.
Cardiovascular Effects: Regular cardiac monitoring is required because fenfluramine has previously been associated with heart valve issues.
Monitoring and Precautions
Cardiac Monitoring: Due to the historical association of fenfluramine with heart valve abnormalities, patients require regular echocardiograms to monitor for potential cardiac side effects.
Behavioral and Mood Changes: Patients should be monitored for mood swings, aggression, or signs of depression, particularly during initial treatment.
Weight Monitoring: Regular weight and nutritional intake monitoring is recommended due to potential appetite suppression.
Discontinuation: To avoid withdrawal effects, fenfluramine should be tapered gradually if discontinued.
Pregnancy and Breastfeeding: Fenfluramine’s safety in pregnancy has not been established, so it is generally recommended only if the benefits outweigh the risks. Breastfeeding is typically discouraged while on fenfluramine.
Use in Dravet Syndrome
Fenfluramine is particularly effective in reducing seizure frequency in patients with Dravet syndrome, especially those who have not achieved adequate control with other medications. It is often used in combination with other antiepileptic drugs and requires ongoing monitoring to minimize side effects.
