Amifampridine, also known as 3,4-diaminopyridine (3,4-DAP), is a potassium channel blocker used primarily to improve neuromuscular transmission in patients with certain rare disorders, such as Lambert-Eaton myasthenic syndrome (LEMS) and congenital myasthenic syndromes (CMS). It works by prolonging the action potential at nerve endings, which increases the release of acetylcholine at the neuromuscular junction, thereby enhancing muscle strength. Amifampridine was first developed in the 1970s and initially investigated for its effects on nerve conduction. Over time, its use became more focused on treating neuromuscular disorders with proven clinical benefits. Today, it is recognized as an orphan drug in several countries due to its role in managing rare conditions and has gained approval in Europe and the United States for specific indications.
BRAND NAMES
Amifampridine is available under the primary brand names Firdapse, Ruzurgi and 3,4-DAP.
MECHANISM OF ACTION
Amifampridine (3,4-diaminopyridine) works by blocking voltage-gated potassium channels at the presynaptic nerve terminals of the neuromuscular junction. By inhibiting these potassium channels, it prolongs the depolarization phase of the action potential, which allows more calcium to enter the nerve endings. The increased calcium influx enhances the release of acetylcholine into the synaptic cleft, improving neuromuscular transmission and increasing muscle strength. This mechanism makes it particularly effective in conditions like Lambert-Eaton myasthenic syndrome (LEMS) and certain congenital myasthenic syndromes (CMS), where acetylcholine release is impaired.
PHARMACOKINETICS
Absorption
Amifampridine is rapidly and nearly completely absorbed when taken orally, with a high bioavailability of about 93–100%. Peak plasma levels are generally achieved within 20 minutes to 1 hour, with an average time to maximum concentration of 0.6 to 1.3 hours.
Distribution
The apparent volume of distribution (V/F) of amifampridine in healthy volunteers is estimated to be around 467 liters, suggesting that the drug is extensively distributed throughout the body.
Metabolism
Amifampridine is largely metabolized in the liver and intestine by N-acetyltransferase 2 (NAT2) into an inactive metabolite called 3-N-acetylamifampridine. This metabolic process is highly polymorphic, resulting in considerable differences in how the drug is processed among individuals.
Excretion
Amifampridine is mainly eliminated through the urine following extensive hepatic metabolism.
PHARMACODYNAMICS
Amifampridine exerts its pharmacodynamic effects by blocking presynaptic voltage-gated potassium channels, thereby enhancing neuromuscular transmission and improving muscle strength in patients with Lambert-Eaton myasthenic syndrome (LEMS).
ADMINISTRATION
Amifampridine is an oral tablet used for the symptomatic treatment of Lambert-Eaton myasthenic syndrome (LEMS) in adults and children aged 6 years and above. It is administered in divided doses throughout the day, with the exact dose tailored to each patient’s response and tolerance.
Administration tips:
Take with or without food.
Avoid sudden dose increases due to risk of neurological or cardiovascular side effects.
Close monitoring is recommended, especially during dose titration.
DOSAGE AND STRENGTH
Adults and children ≥6 years:
Starting dose: Typically 5 mg orally 3–4 times daily
Titration: Gradually increased in 5 mg increments at intervals of several days until optimal effect is achieved.
Maximum total daily dose: Usually 80–100 mg/day, divided into multiple doses.
Formulations/Strengths:
Tablets: Commonly 10 mg per tablet
Oral suspension: Available in some regions for pediatric dosing
DRUG INTERACTIONS
Amifampridine can interact with many drugs, particularly those that may prolong the QT interval, increase the risk of seizures, or enhance cholinergic effects. It is important to consult a doctor or pharmacist before taking any new medications, including over-the-counter drugs and herbal supplements, while on amifampridine.
FOOD INTERACTIONS
Amifampridine may be taken with or without food. Although food can influence its absorption, this effect is generally not clinically significant, and the medication is considered safe to use in either condition.
CONTRAINDICATIONS
Amifampridine is contraindicated in individuals with a known allergy to the drug or its components, in patients with a history of seizure disorders, and in those with pre-existing heart rhythm problems, such as a prolonged QT interval, due to the increased risk of arrhythmias.
SIDE EFFECTS
Paresthesia (tingling or numbness).
Headache.
Nausea.
Abdominal discomfort.
Insomnia.
Dizziness.
Fatigue.
Diarrhea.
Less common but serious side effects:
Seizures.
Heart rhythm disturbances (e.g., QT prolongation).
OVERDOSE
Neurological symptoms: Severe tingling, numbness, dizziness, confusion.
Gastrointestinal symptoms: Nausea, vomiting.
Serious complications: Seizures, heart rhythm disturbances (e.g., QT prolongation).
TOXICITY
Amifampridine toxicity is mainly related to its effects on the nervous and cardiovascular systems and is usually dose‑dependent. Excessive exposure can increase the risk of neurological symptoms, particularly seizures, as well as cardiac effects such as QT interval prolongation and arrhythmias. Other signs may include tingling sensations, dizziness, gastrointestinal discomfort, and confusion. Toxicity is more likely in patients with predisposing conditions or when recommended doses are exceeded. Management is primarily supportive, with careful monitoring and dose adjustment or discontinuation if needed.
