4-aminopyridine (4-AP)

Timothy C. Hain, MD

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4-aminopyridine is an obscure medication that may be useful in treating dizziness associated with cerebellar disorders. It is related to 3,4 Diaminopyridine (3-4 DAP). 3-4 DAP which acts to a greater extent on outside the brain than 4-AP, and for treatment of cerebellar disorders, 4-AP is preferred to 3-4 DAP because it gets into the brain to a greater extent (Kalla et al, 2011).

While the author of this page prescribes 4-AP from time to time, including in patients with EA2, most patients stop taking it after a few weeks, due to lack of effect. We presume that this is because it is somewhat of a "shot in the dark", that rarely hits its target. Thus, the author of this page sees 4-AP as a last resort medication.

Availability

4-AP is a prescription medication. There are several ways of getting 4-AP in the US. If you have multiple sclerosis, or if you are very wealthy, you can get 4-AP under the brand name of "Ampyra". Ampyra is a 10 mg time-release preparation of 4-AP. If you do not have MS, as there is no other FDA approved indication, your insurance company will likely not cover Ampyra, leaving you to pay out of your pocket (and it is very expensive). Think $1000/month.

Otherwise, you can usually obtain 4-AP, for relatively reasonable prices similar to the copay price for many brand name medications, preferably in a time release format, from a compounding pharmacy. This is because the chemical 4-AP is not expensive. As a matter of curiousity, 4AP was very cheap until it became FDA approved in the US for MS. Then it became prohibitively expensive. Thus it seems that the key here to being able to charge insurance companies $1000/month for a cheap drug is to get it FDA approved. It reminds us of how epipens are sold for $800/dose, paid by US health insurance, although the raw materials cost about $1.00.

The usual dose of 4-AP from a compounder is 10 mg ER three times/day.

Rationale for use of 4-AP:

4-AP is a potassium channel blocker that works both on nerves and the central nervous system (Leigh, 2003). 4-AP affects cerebellar metabolism (Bense, 2006). Some authors suggest that it increases the excitability of the cerebellar Purkinje cells (Glasauer et al, 2005). Some authors sugest that it increases the resting discharge and precision ... (Strupp et al, 2017). Although it is a little difficult to say exactly what precision of firing rate means in a biological system, this makes 4AP a unique medication. From the same authors, 4AP also has effects that persist after the drug is stopped, attributed to a "neuroprotective effect". All together, at least in the German literature, 4AP would seem to be almost miraculous.

Reports of the effect of 4-AP on central disorders

As an summary, 4-AP has been reported largely by German researchers to be helpful in an assortment of neurological disorders, as documented in many case reports. This drug is not a "swiss army knife" for cerebellar disorders -- rather it is an occasional magic bullet.

Cerebellar disorders.

4-AP has been reported to improve patients with EA-2 (Lohle et al, 2008; Spacey, 1993;; Strupp 2007; Strupp 2011)

4-AP has also been reported to improve oculomotor and vestibular function in ataxia telangiectasia (Shaikh et al, 2013), including periodic alternating nystagmus (PAN).

There are also other miscellaneous reports of improvement in various cases.

downbeating nystagmus

There have been several studies that report it to be effective for downbeating nystagmus and improves postural stability in persons with downbeating nystagmus (Claassen et al, 2013a,b; Helmchen et al, 2004; Sander et al, 2011; Sprenger et al, 2005, 2006).

4-AP has also been reported in the German literature to improve upbeating nystagmus. (Glasauer et al, 2005). This effect was suggested to be related to improved visual tracking. As the effect was only present in the light, it was suggested that the mechanism was light dependent.

gaze-evoked nystagmus.

Kalla et al (2007) suggested that 4-AP reduces ocular drift leading to nystagmus and that it was a "promising" treatment option for gaze evoked nystagmus.

Positional nystagmus.

Kremmyda (2013) suggested that 4-AP suppressed positional nystagmus associated with a cerebellar vermis lesion.

4-AP does not work in:

Essential tremor (Lorenz et al, 2006).

Side Effects

4-AP can cause dizziness and confusion and stomach upset. It can rarely cause seizures. (Strupp et al, 2017). 4AP should not be administered to patients where the creatine clerance is < 80. Caution is also necessary when administered with drugs that are OCT2 substrates such as carvediolol, propranolol and metformin (Strupp et al, 2017). A prolonged QT interval is a contraindication. The most common reported side effect is urinary tract infection.

It is nearly completely eliminated unchanged in the urine, and thus it has little opportunity to result in drug interactions. In patients with impaired kidney function, levels are higher and it lasts longer (Cornblath et al, 2012).

An overdose of 4-AP ws reported by Schwam (2011). A man developed sudden onset of abdominal pain, vertigo, anxiety, profuse diaphoresis, hypersalivation, hypertension, bradycardia, agitation, and choreoathetosis, followed by status epilepticus. Due to a compounding pharmacy error, he was given pills that contained approximately 10 times the dose indicated on the label.

Suggestions

4-AP is an "emerging" treatment for cerebellar nystagmus and ataxia. We think it is prudent to use relatively low doses -- such as those reported in the literature (10 to 20 mg twice/day), and also to monitor the effects on the eyes and posture. We think a video-recording of downbeating nystagmus (before and after) combined with a posturography study would be a good method of proving that a drug is useful (or not).

Summary:

4-AP has recently been reported to be helpful in treating cerebellar disorders. It is likely that it works by stimulating the cerebellum.

References: