|Internet Journal of Medical Toxicology
A publication of The American College of Medical Toxicology
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Flunarizine Ingestion Without Hemodynamic Consequence
Sztajnkrycer MD, Bond GR
Drug and Poison Information Center
Children's Hospital Medical Center
University of Cincinnati Medical Center
Department of Pharmacy
Int J Med Toxicol 2002; 5(2): 8
This case report is supported by an unrestricted educational grant from Orphan Medical, Inc.
For more information, please call 1-888-8ORPHAN.
Matthew D. Sztajnkrycer, MD, PhD
Department of Emergency Medicine
200 First Street SW
Rochester MN 55905
Phone: (507) 255-9559
Fax: (507) 255-6592
Currently, ten calcium channel antagonists (CCAs) are available in the United States.1 All block the L-Type voltage-operated calcium channels (VOCCs). Disturbances of the cardiovascular system are the hallmark of L-Type CCA overdose.1,2 Manifestations include hypotension, bradycardias, including junctional rhythms and ventricular escape rhythms. Extreme negative inotropy may manifest as cardiogenic shock or electromechanical dissociation, a form of pulseless electrical activity.
Both the number of exposures to these agents and the number of adverse outcomes have increased over recent years. During the year 2000, the American Association of Poison Control Centers, through its TESS database, recorded 8975 calcium channel antagonist exposures, a 94% increase from 1990.3,4 Of these exposures, 986 suffered moderate outcomes, 317 suffered major outcomes, and 44 fatalities were recorded.
In Europe and India a selective inhibitor of T-Type VOCCs, flunarizine (Flunarin ®), has been introduced for both prophylaxis and management of migraine headaches.5,6,7 T-Type VOCC inhibitors differ from L-Type VOCC inhibitors in their effects on myocardial slow calcium channels, effects on atrioventricular nodal conduction, and negative inotropic properties (Table 1). Little is known about effects of T-Type VOCCs in overdose, particularly their effect on the cardiovascular system. No reports exist in the English-language literature. We report a case of flunarizine overdose without apparent hemodynamic consequence.
A 25 year old female, weighing approximately 50 kg, who recently arrived in the United States from India, presented to a community emergency department (ED) with a complaint of headache. She reported being on flunarizine 10 mg daily, for migraine prophylaxis. Her previous headache evaluation consisted of a history and physical examination, complemented with plain radiographs of the skull. During her examination, the patient revealed that two hours previously, she had ingested a total of flunarizine 140 mg in an attempt to relieve a severe headache. Other than headache, she had no complaints.
Vital signs upon presentation included BP 106/54 mmHg, HR 80 beats per minute, respiratory rate 14 breaths per minute. Physical examination was unremarkable. Laboratory evaluation was notable only for a serum calcium concentration of 7.9 mg/dL (1.98 mmol/L). Portable chest radiograph demonstrated no evidence of cardiomegaly or pulmonary edema. Initial electrocardiograph demonstrated normal sinus rhythm with a ventricular rate of 85/minute, PR interval 156 msec, QRS duration 72 msec, and QTc 421 msec. (Figure 1).
The patient was admitted to the intensive care unit for close observation and hemodynamic monitoring. No gastric decontamination was performed. At the direction of the ICU staff, the patient empirically received 2 g calcium gluconate 10% slow IVP upon arrival to the ICU, and 1 g calcium gluconate by mouth, every twelve hours until discharge. With the exception of asymptomatic sinus bradycardia (HR 58, Figure 2) while asleep, which resolved upon wakening, the patient remained hemodynamically stable. The patient was discharged to home the following day without incident.
The patient subsequently returned to the emergency department with a complaint of pleuritic chest pain 5 weeks after her ingestion. At that time, vital signs included BP 105/65 mmHg and HR 68 beats per minute. An electrocardiogram obtained during her emergency department evaluation demonstrated sinus bradycardia but was otherwise unremarkable (Figure 3).
Telephone follow-up at one week, two weeks, and three months demonstrated no sequelae from the ingestion, and abatement of the headaches with celecoxib. Specifically, the patient denied any chest pain with the exception of the ED visit noted above. She further denied palpitations, dyspnea on exertion, orthopnea, dizziness, presyncope or syncope.
A serum flunarizine level on blood obtained 20 hours post ingestion was 191 ng/mL (GC/MS EI mode, full scan, extraction at pH 9.0, no derivatisation). Therapeutic range is considered to be 50 - 100 ng/mL. The level of the metabolite, hydroxyflunarizine, was not able to be determined.
Based upon mechanism of activation, three general classes of calcium channels have been identified:8,9,10
1) Voltage-Operated Calcium Channels (VOCCs)
2) Receptor-Operated Calcium Channels (ROCCs)
3) Second Messenger-Operated Calcium Channels (SOCCs)
The latter two channel types are involved in smooth muscle excitation-contraction coupling (ROCC) and stimulus response in non-motile cells (ROCCs, SOCCs).8 Voltage-Operated Calcium Channels (VOCCs) have been extensively studied, and have been subcategorized into 6 distinct channel subtypes:8
1) L-Type: Excitation-contraction coupling, pacemaker activity, AV node activity, transmitter release from endocrine cells.
2) T-Type: Growth regulation and cardiac pacemaker activity
3) N-Type: Neurotransmitter release
4) P-Type: Endocrine and neurotransmitter release
5) Q-Type: Neurotransmitter release
6) R-Type: Neurotransmitter release
As cardiovascular agents, L-type calcium channel antagonists (CCAs) are commonly prescribed for the management of atrial fibrillation, hypertension, and angina. In the United States, the L-type CCA verapamil is employed in both treatment and prophylaxis of migraine-type headaches.11,12 L-type CCAs may have pronounced effects on both myocardium and vascular smooth muscle. Unlike CCAs approved for use in the United States, flunarizine is a selective T-type calcium channel inhibitor. It has been marketed in Europe and India for treatment and prophylaxis of migraine headache. Additionally, flunarizine has been used in these countries for the treatment of refractory partial seizures and vertigo. Investigational studies in both the United States and Europe have evaluated flunarizine as a neuroprotective agent. As a T-type calcium channel antagonist, flunarizine has advantages over L-type calcium channel antagonists. Flunarizine does not effect AV node function or inotropy at therapeutic doses. (Table 1) Although classified as a selective calcium channel antagonist, it may be more appropriate to consider flunarizine a calcium overload antagonist. Flunarizine appears to function in part by mitigating excessive increases in intracellular calcium, thereby avoiding cerebral vasoconstriction and cerebral hypoxia.13
In addition to effects on T-type VOCCs, flunarizine demonstrates H1 histamine receptor antagonism, possibly explaining the commonly noted side-effects of sedation and somnolence with increasing doses.5 Flunarizine also acts as a post-synaptic striatal dopaminergic D2 receptor antagonist.14 It is speculated that this receptor blockade leads to the extrapyramidal side-effects occasionally noted with flunarizine use.15,16 The mechanism of flunarizine-mediated analgesia appears at least in part due to agonism at the mu1 opioid receptor, and possible antagonism or mixed agonism/antagonism at the delta1 opioid receptor.17,18
Flunarizine is well-absorbed from the gastrointestinal tract, with peak levels occurring 2 to 4 hours after ingestion.17 It has a reported volume of distribution of 43.2 L/kg, and is greater than 90% protein bound at therapeutic doses.13,19 Flunarizine is metabolized to hydroxyflunarizine, and demonstrates a distribution half-life of 5.5 hours and an elimination half-life of 18 days in patients receiving therapy. 13,19 A wide variation in serum steady-state concentrations is noted with therapeutic dosing.13 At oral doses of 10 mg per day, fifty percent of patients would be expected to have serum concentrations between 50 - 100 ng/mL. When employed as an antiepileptic drug, target serum concentrations range from 30 - 60 ng/mL to 60 - 120 ng/mL.20
In an escalating dose study, adverse events increased with increasing doses. The most common adverse events included sedation, somnolence, blurred vision, weight gain, and cognitive impairment. An increased risk of depression above the baseline noted in patients with migraine headaches has been noted in patients taking flunarizine.7 History of depression is considered a contraindication to the administration of flunarizine. Parkinsonism and ocular dystonias were rare adverse events with escalating doses. Post-marketing studies have demonstrated no difference in the risk/benefit ratio of flunarizine and propranolol.22 No significant cardiovascular events have been noted.13,19,22
Previous reports of overdose for flunarizine were not found in the English literature. The current patient was not noted to be somnolent upon admission, nor did she manifest evidence of hemodynamic compromise, despite a serum flunarizine concentration of 191 ng/mL, 20 hours after acute ingestion. While only modestly elevated, this concentration falls between two and six times the presumed therapeutic concentration, and was obtained approximately 16 hours after expected peak serum levels. With L-type calcium channel antagonists, similarly elevated serum levels have been associated with cardiovascular symptoms, suggesting that the lack of significant symptomatology in this case was not due solely to non-toxic serum drug levels.23
Of note, these "low-threshhold" T-type VOCCs are found in the sinoatrial node of the heart, where they are felt to play a role in cardiac pacemaker function. As such, the bradycardia noted during the ICU admission may have reflected mild flunarizine toxicity. However, the fact that it occurred during sleep and resolved upon awakening would suggest physiological bradycardia.
We report a case of acute ingestion of the T-type calcium channel antagonist flunarizine. Despite modestly elevated levels, the patient remained awake, alert, and hemodynamically stable. No previous overdose information for these agents is available in the English literature. However, escalating dose data might suggest that this agent may be well tolerated even at high doses. The empiric administration of calcium to this patient prevents a complete assessment of the toxic potential of her ingestion.
While management strategies should not be based on isolated case reports, flunarizine may be relatively safe in mild to moderate overdoses. At the levels seen in our patient, we speculate that specificity for T-type channels remains intact, and that no cross-over antagonism of L-type calcium channels occurs.
Table 1: Comparison of L-Type and T-Type Voltage-Operated Calcium Channel (VOCC) Antagonists.
|Characteristic||L-Type VOCC||T-Type VOCC
|Inhibition of Myocardial Slow Ca+2 Channels||+||-
|Damping Effects on Sino-Atrial Node Pacemaker||+||+
|Damping Effects on AV Node Conduction||+||-
|Inhibition of Receptor-Operated Ca+2 Channels in Vascular Smooth Muscle||+||+
Figure 1: Admission Electrocardiogram. The ECG obtained upon admission to the emergency department demonstrates normal sinus rhythm at a rate of 85 beats per minute. PR, QRS, and QTc intervals are all within normal limits.
Figure 2: ICU Electrocardiogram: An ECG obtained at 01:28 am during the patient's observation period demonstrates sinus bradycardia at a rate of 58 beats per minute. PR, QRS, and QTc intervals all remain within normal limits. The bradycardia resolved upon fully awakening. The patient reported no symptoms with the bradycardia.
Figure 3: Return Electrocardiogram: The ECG demonstrates sinus bradycardia at a rate of 58 beats per minute. PR, QRS, and QTc intervals are all within normal limits. Evidence of early repolarization is noted.
- Bond GR. Calcium Channel Blocker Overdose. In Harwood-Nuss ALL, Linden CH, Sternbach G, Wolfson AB (eds): The Clinical Practice of Emergency Medicine. JB Lippincott Company. 3rd Edition. 2001. Proano L, Chiang WK, and Wang RY. Calcium Channel Blocker Overdose. Am J Emerg Med. 1995; 13: 444-450.
- Litovitz TL, Klein-Schwartz W, White S, et al. 2000 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2001; 19: 337 - 395.
- Litovitz TL, Bailey KM, Schmitz BF, et al. 1990 Annual Report of the American Association of Poison Control Centers National Data Collection System. Am. J Emerg Med. 1991;9:461-509.
- de Bock GH, Eelhart J, van Marwijk HWJ, et al. A Postmarketing Study of Flunarizine in Migraine and Vertigo. Pharm World Sci 1996; 19: 269-274.
- Lucetti C, Nuti A, Parvese N, et al. Flunarizine in Migraine Prophylaxis: Predictive Factors for a Positive Response. Cephalgia 1998; 18: 349 - 352.
- Verspeelt J, De Locht P, Amery WK. Post-Marketing Cohort Study Comparing the Safety and Efficacy of Flunarizine and Propranolol in the Prophylaxis of Migraine. Cephalgia 1996; 16: 328-336
- Katz AM. Calcium Channel Diversity in the Cardiovascular System. J Am Coll Cardiol 1996; 28: 522-529
- Vanhoutte PM. The Expert Committee of the World Health Organization on Classification of Calcium Antagonists: The Viewpoint of the Raporteur. J Am Coll Cardiol 1987; 59: 3A-8A
- Katz AM, Hager WD, Messineo FC, et al. Cellular Actions and Pharmacology of Calcium Channel Blockers. Am J Emerg Med [Suppl] 1985; 3: 1-9.
- Evans RW, Lipton RB. Topics in Migraine Management: A Survey of Headache Specialists Highlights Some Controversies. Neurol Clin 2001; 19: 1-21.
- Ramadan NM, Schultz LL, Gilkey SJ. Migraine Prophylactic Drugs: Proof of Efficacy, Utilization, and Cost. Cephalgia 1997; 17: 73-80.
- Holmes B, Brogden RN, Heel RC, et al. Flunarizine: A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Uses. Drugs 1984;27: 6-44.
- Moorthy NS, Balsara JJ. Effects of Flunarizine on Dopamine Dependent Behaviors in Rats. Indian J Med Sci 1999; 53: 43-48.
- Brucke T, Wober C, Podrecka I, et al. D2 Receptor Blockade by Flunarizine and Cinnarizine Explains Extrapyramidal Effects. A SPECT Study. J Cereb Blood Flow Metab 1995; 15: 513-518.
- Negrotti A, Calzetti S. A Long-Term Follow-Up Study of Cinnarizine- and Flunarizine-Induced Parkinsonism. Mov Disord 1997; 12: 107-110.
- Weizman R, Pankova IA, Schreiber S, et al. Flunarizine Analgesia is Mediated by Mu-Opioid Receptors. Physiol Behav 1997; 62: 1193-1195.
- Weizman R, Getslev V, Pankova IA, et al. Pharmacological Interaction of the Calcium Channel Blockers Verapamil and Flunarizine with the Opioid System. Brain Res 1999; 818: 187-195.
- Hurlburt KM. Cinnarizine and Related Agents. Poisindex. MICROMEDEX ® Healthcare Series Vol 111, 3/2002.
- Treiman DM, Pledger GW, DeGiorgio C, et al. Increasing Plasma Concentration Tolerability Study of Flunarizine in Comedicated Epileptic Patients. Epilepsia 1993; 34: 944-953.
- Handforth A, Mai T, Treiman DM. Rising Dose Study of Safety and Tolerance of Flunarizine. Eur J Clin Pharmacol 1995; 49: 91-94.
- Edmeads J. Flunarizine versus Propranolol in the Prophylaxis of Migraine. Cephalgia 1996; 16: 288.
- Palmer RB, Kokan L, Hurlburt KM, et al. Calcium Antagonists. Poisindex. MICROMEDEX ® Healthcare Series Vol 111, 3/2002.
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