Selected topic: ToxicologySevere Accidental Overdose of 4-Aminopyridine Due to a Compounding Pharmacy Error
Introduction
4-Aminopyridine (4-AP) is an orphan drug used to ameliorate symptoms of multiple sclerosis and spinal cord injury by facilitating neural impulse conduction (1). It is not Food and Drug Administration (FDA) approved, but information about it is disseminated via the Internet, and it is currently available from both brick-and-mortar and Internet compounding pharmacies with a physician's prescription (2, 3). Typical doses are 10–50 mg/day. A slow-release formulation of 4-AP (Fampridine SR 25 mg) has recently undergone phase 3 clinical trials (4). It is also marketed for agricultural use as Avitrol, which is used for repelling and killing bird pests (5). 4-AP selectively blocks voltage-gated potassium channels in nerve and other excitable tissues, prolonging the action potential, increasing presynaptic calcium influx, thus facilitating both interneuronal and neuromuscular transmission (6). Dose-related toxicity is frequent and includes dizziness, insomnia, paresthesia, asthenia, headache, diaphoresis, hypersalivation, tremor, delirium, choreoathetosis, and seizures (7). Despite the fact that 4-AP blocks potassium channels in experimental animal cardiac muscle preparations, it does not prolong the QT interval in therapeutic doses, nor has it yet been reported to produce torsade de pointes in overdose (8, 9). I report here a case of life-threatening accidental overdose of 4-AP resulting from a pharmacy error.
Section snippets
Case Report
A 42-year-old man weighing 132 kg, with a history of C3 spinal cord injury with residual left-sided weakness and anesthesia, presented to the Emergency Department via ambulance in 2001 with the sudden onset of abdominal pain, vertigo, and anxiety. His only medication was “F.A.P.” On arrival, he quickly became agitated, incoherent, and combative. Blood pressure was 200/100 mm Hg, heart rate 47 beats/min, oral temperature 36.2°C (97.2°F), respiratory rate 32 breaths/min, and pulse oximetry was
Discussion
Most emergency physicians are unfamiliar with the clinical effects of 4-AP. Initially, the specific etiology of this patient's symptoms seemed inexplicable despite a full neurological work-up. When the medication history was provided by his wife, it became immediately apparent that he was experiencing typical symptoms of 4-AP overdose. The cerebral hemorrhage was associated with the use of enoxaparin and occurred some 2 weeks after the overdose. All symptoms ultimately resolved with supportive
Conclusions
Emergency physicians should be familiar with the signs of 4-AP toxicity. Additionally, they should be aware that 4-AP and other non-FDA-approved medications may be available to patients from compounding pharmacies. There is a significant risk of compounding pharmacy error, which can result in inadvertent therapeutic overdose.
Addendum
Subsequent to the initial submission of this paper for publication, Burton et al. reported four patients with multiple sclerosis taking compounded 4-AP, who presented in status epilepticus to hospital(s) in Ontario, Canada. One died and the other three were discharged with worsened chronic disability. Their labeled 10 mg tablets were found to contain between 90.1 and 125.6 mg of 4-AP (18).
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