Journal of Clinical Pharmacy and Therapeutics (2007) 32, 655–657
CASE REPORT
4-Aminopyridine (fampridine) effectively treats amlodipine poisoning: a case report B. Wilffert* , PD , R. J. Boskma MS , P. H. J. van der Voort MD PhD , D. R. A. Uges§ , , PhD , E. N. van Roon* PhD and J. R. B. J. Brouwers* PhD *Department of Pharmacotherapy and Pharmaceutical Care, GUIDE, University of Groningen, Groningen, The Netherlands, Department of Clinical Pharmacy of Zorggroep Noorderbreedte and De Tjongerschans, Leeuwarden, The Netherlands, Department of Intensive Care, Onze Lieve Vrouwe Gasthuis (formerly Medical Center Leeuwarden), Amsterdam, The Netherlands and §Department of Pharmacy and Toxicology, University Medical Center Groningen, Groningen, The Netherlands SUMMARY
A case of a serious poisoning with the calcium entry blocker amlodipine is described, which was treated effectively with 4-aminopyridine. Calcium is suggested as general treatment of poisoning with calcium entry blockers in many guidelines. The use of intravenous 4-aminopyridine is theoretically useful to treat poisoning from calcium entry blockers and was demonstrated in this case report. Keywords: 4-aminopyridine, amlodipine, fampridine, poisoning INTRODUCTION
Calcium entry blockers inhibit calcium influx into the cell predominantly via L-type calcium channels. In the cytosol under resting conditions the Ca2+-concentration amounts to approximately 10)7 mol ⁄ L. During the contractile process the cytosolic Ca2+-concentration rises to approximately 10)5 mol ⁄ L. The extracellular Ca2+-concentration amounts to approximately 10)3 mol ⁄ L. Consequently, the concentration-gradient across the cellular membrane under resting conditions amounts to approximately 104. Theoretically, because of this high concentration-gradient, the treatment of a poisoning with calcium entry blockers by increasing the extracellular Ca2+-concentration Received 18 May 2007, Accepted 18 May 2007 Correspondence: B. Wilffert, Zorggroep Noorderbreedte, PO Box 888, 8901 BR Leeuwarden, The Netherlands. Tel.: +31 582867019; fax: +31 582867319; e-mail:
[email protected]
under clinical conditions, to compensate for the reduced Ca2+-current through the blocked calcium channel, cannot be expected to be the most effective way of increasing blood pressure. It has been stated that that calcium salts are frequently ineffective in maintaining perfusion (1). Perfusion can also be maintained by administration of vasopressors. However, in particular the a-adrenoceptor-mediated vasoconstriction of catecholamines is partly elicited by L-type channel-mediated Ca2+-influx. The contribution of this Ca2+-influx varies with the subtype of the a-adrenoceptor involved. This explains the necessity of relatively high doses of catecholamines required to restore blood pressure during calcium entry blocker poisoning, which increases the dysrhythmogenic potential of the catecholamines. This is corroborated by the lack of effect of even a combination of dopamine and noradrenaline infusion in a patient with an overdose of amlodipine also after administration of calcium chloride and calcium gluconate (2). A more appropriate way of increasing the cytosolic Ca2+-concentration during blockade of the L-type calcium channels is enabled by 4-aminopyridine (fampridine). 4-Aminopyridine inhibits different types of potassium channels [G-proteincoupled potassium channels, ATP-sensitive potassium channel, Na+-activated potassium channel (3)]. This blocking action causes a slight depolarization thereby opening Na+ and subsequently calcium channels. In particular, the Na+-influx can elicit a rise in cytosolic Ca2+-concentration by inhibiting the Na+ ⁄ Ca2+-exchanger, which under physiological conditions removes Ca2+ out of the cell driven by the Na+-gradient.
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The 4-aminopyridine-mediated Na+-influx will decrease the Na+-gradient and will thereby decrease the driving force for this Ca2+-extruding Na+ ⁄ Ca2+-exchanger. Therefore in calcium entry blocker overdose 4-aminopyridine can increase the cytosolic Ca2+-concentration very efficiently independent of the calcium channels. This is demonstrated by restoration of decreased blood pressure, heart rate and atrioventricular block under conditions of verapamil intoxication in experimental animals and in humans (4–7). In the cases of verapamil intoxication described by Magdalan et al. (7), the hypotension, circulatory insufficiency and atrioventricular block previously did not respond to calcium therapy, high dose of vasopressor amines and atropine. CASE REPORT
During the night shift the clinical pharmacist on call was asked for assistance in an intentional poisoning with amlodipine. A female patient (47 years) with a history of fibromyalgia, eczema, depression and hypertension became progressively depressive during the preceding weeks prior to hospitalization and attempted to commit suicide by hanging, which failed. Subsequently she swallowed 20 tablets of lorazepam 1 mg and 40 tablets amlodipine 5 mg. The patient was admitted to the emergency unit of our hospital 7 h after swallowing the tablets according to her own statement. At presentation her blood pressure was 124 ⁄ 65 mmHg (Fig. 1), heart rate 75 beats ⁄ min, body temperature 36Æ9 C.
Blood pressure (mm Hg)
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SBP 100 80 60 40 20 0 0
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4-AP infusion 20
Time after intake (h)
Fig. 1. Blood pressure during the amlodipine overdose and its treatment.
To reduce absorption from the intestine magnesium sulphate an activated charcoal (50 g) was administered orally 8 h after intake of the tablets. Because of the slow absorption of amlodipine (tmax = 6–12 h) administration of charcoal was still considered justified. The patient was hospitalized in the Medium Care Unit where she remained awake, oriented and coordinated. Her blood pressure at arrival at the Medium Care Unit was 115 ⁄ 55 mmHg, heart rate 65 beats ⁄ min, respiration rate 18 ⁄ min. Other relevant laboratory values were: glucose 8Æ6 mmol ⁄ L, potassium 3Æ1 mmol ⁄ L, creatinine 96 lmol ⁄ L, pH 7Æ48 and pCO2 4Æ2 kPa. Potassium chloride (40 mmol) was administered orally. The blood pressure decreased to 90 ⁄ 38 mmHg with a heart rate of 58 beats ⁄ min 16 h after intake of the amlodipine and lorazepam tablets. The respiration rate was approximately 22 ⁄ min. The decision was made to administer 4-aminopyridine because of the patient’s deteriorating clinical situation. Over a 3-h period, 4-aminopyridine (50 lg ⁄ kg ⁄ h) was administered intravenously (8) and the patient’s blood pressure increased to 110 ⁄ 50 mmHg, her heart rate increased to 68 beats ⁄ min, her respiration rate remained stable at 22 ⁄ min, and her abnormal laboratory values normalized with the exception of a slightly elevated pH (pCO2 4Æ7 kPa, pO2 11Æ7 kPa, bicarbonate 24 mmol ⁄ L, sodium 140 mmol ⁄ L, potassium 4Æ0 mmol ⁄ L, chloride 103 mmol ⁄ L, pH 7Æ46). DISCUSSION
We have described a case of serious amlodipine poisoning which was successfully treated with intravenous 4-aminopyridine. Our preference for 4-aminopyridine is based on the lack of effectiveness with calcium salts and catecholamines (1, 2) and indeed we observed a good response upon 4-aminopyridine administration, which corroborates earlier observations on verapamil intoxication (4–7). However, being asked for 4-aminopyridine (or for the diamino-derivative) during the night shift at our hospital pharmacy confronted us with the very limited availability of an intravenously administrable preparation. After a thorough nightly search across different hospital pharmacies in the Netherlands, we obtained a suitable preparation (8).
2007 The Authors. Journal compilation 2007 Blackwell Publishing Ltd, Journal of Clinical Pharmacy and Therapeutics, 32, 655–657
Fampridine effectively treats amlodipine poisoning
Calcium entry blocker intoxications are relatively rare, however because of the effectiveness of 4-aminopyridine we strongly recommend that a preparation is readily available from hospitals.
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1. Barrueto F Jr (2005) Management of calcium channel blocker toxicity. Up-to-Date online 14.1. www.utdol. com 2. Harris NS (2006) Case 24-2006: a 40-year-old woman with hypotension after an overdose of amlodipine. New England Journal of Medicine, 355, 602–611. 3. Castle NA, Haylett DG, Jenkinson DH (1989) Toxins in the characterization of potassium channels. TINS, 12, 59–66. 4. Ter Wee PM, Kremer Hovinga TK, Uges DR, Van der Geest S (1985) 4-Aminopyridine and haemodialysis in
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the treatment of verapamil intoxication. Human Toxicology, 4, 327–329. Agoston S, Maestrone E, Van Hezik EJ, Ket JM, Houwertje MC, Uges DRA Jr (1984) Effective treatment of verapamil intoxication with 4-aminopyridine in the cat. Clinical Investigation, 73, 1291–1296. Magdalan J (2003) New treatment methods in verapamil poisoning: experimental studies. Polish Journal of Pharmacology, 55, 425–432. Magdalan J, Kochman K, Antonczyk A, Przewlocki M, Smolarek M (2003) Successful treatment by 4-aminopryridine of three cases of severe verapamil poisoning. Przeglad Lekarski, 60, 271–273. Uges DRA, Huizinga T (1981) 4-Aminopyridine; analysis of the substance and a method for the preparation of a solution for injection in man. Pharmaceutica Acta Helvetia, 56, 158–162.
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