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Flunarizine

A Reappraisal of its Pharmacological Properties and Therapeutic Use in Neurological Disorders

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Summary

Synopsis

Flunarizine is a class IV calcium antagonist with a pharmacological profile which suggests its therapeutic potential in a number of neurological and cerebrovascular disorders. It is an effective prophylactic treatment for common or classic migraine in children and adults, and it appears at least as effective as a number of other agents which act by different pharmacological mechanisms, including pizotifen (pizotyline), cinnarizine, methysergide, nimodipine, metoprolol, propranolol, aspirin and cyclandelate. Flunarizine is also effective in reducing the frequency of seizures, when used as an ‘add- on’ treatment, in some patients with partial or generalised epilepsy resistant to maximal therapy with a combination of several conventional antiepileptic drugs. Placebo-controlled studies show that flunarizine is effective in the treatment of vertigo and associated symptoms of either peripheral or central origin, and in the treatment of cerebrovascular insufficiency where psychological symptoms, rather than vertigo, are the primary symptoms. In the treatment of vertigo, flunarizine appears at least as effective as cinnarizine and more effective than nicergoline, betahistine dichlorhydrate, pentoxifylline (oxpentifylline) and vincamine.

Flunarizine therefore is useful in the prophylaxis of migraine, an effective treatment for vertigo and a worthwhile alternative as ‘add- on’ therapy in patients with epilepsy resistant to conventional drugs.

Pharmacodynamic Properties

Flunarizine, a difluorinated piperazine derivative, is a ‘selective’ calcium antagonist structurally related to cinnarizinie, with which it shares a qualitatively similar pharmacodynamic profile. It selectively blocks the entry of calcium into cells when calcium is stimulated to enter cells in excels, thereby preventing cell damage caused by ‘calcium overload’ in various tissues. It inhibits the contraction of vascular smooth muscle mediated by the entry of extravascular calcium, and it protects endothelial cells against damage from calcium overload, red blood cells from membrane rigidity induced by calcium ion loading, and brain cells from the effects of hypoxia. Flunarizine also shows vestibular depressive effects, as well as antihistaminic and anticonvulsant properties.

Pharmacokinetic Properties

Peak plasma concentrations of 39 to 115 Mg/L occur 2 to 4 hours after oral administration of repeated once-daily doses of flunarizine 10mg in healthy subjects. The mean volume of distribution is 43.2 L/kg, suggesting extensive tissue distribution. In vitro experiments indicate that 0.8% of flunarizine is present as free drug in blood, 9% is distributed to blood cells, and 90% to plasma proteins. Animal experiments show that flunarizine is extensively metabolised by oxidative 7V-dealkylation, aromatic hydroxylation and glucuronidation, with little unchanged drug excreted in urine or faeces. The main route of metabolite elimination appears to be biliary. A similar pattern of metabolism and excretion is believed to occur in humans. The terminal elimination half-life of flunarizine is about 18 days in healthy subjects.

Age does not appear to affect the bioavailability of flunarizine, but the possible effects of renal or hepatic impairment on disposition have not been reported. In epileptic patients the plasma concentrations of flunarizine may be lower than in healthy subjects receiving the same dosage. This appears related to hepatic enzyme induction by concomitant anti-epileptic drugs increasing the metabolism of flunarizine.

Therapeutic Trials

Flunarizine has been shown to be an effective prophylactic treatment of classic and common migraine in children and adults, significantly reducing the frequency of attacks compared with placebo. Comparative clinical trials have found flunarizine to be at least as effective as usual therapeutic dosages of pizotifen (pizotyline), cinnarizine, methysergide, nimodipine, metoprolol and propranolol in adults, and aspirin and cyclandelate in children.

Clinical studies have evaluated the use of flunarizine as an ‘add-on’ therapy in the treatment of paediatric and adult patients with partial and generalised seizures resistant to maximal therapy with a combination of several conventional antiepileptic drugs. Flunarizine was effective in reducing the rate of seizures in some patients, without any change in concomitant antiepileptic medication or their plasma concentrations. However, hepatic enzyme induction by the concomitant medication necessitated an approximately 2-fold increase of flunarizine dosage to achieve therapeutic plasma flunarizine concentrations comparable to those in non-epileptic patients.

Placebo-controlled trials have shown that flunarizine is effective in the treatment of vertigo and associated symptoms of either peripheral or central origin, and in the treatment of cerebrovascular insufficiency where psychological symptoms, rather than vertigo, are the primary symptoms. Controlled trials in patients with vertigo show that flunarizine is at least as effective as cinnarizine and more effective than nicergoline, betahistine dichlorhydrate, pentoxifylline (oxpentifylline) and vincamine.

Adverse Effects

Flunarizine has been generally well tolerated in clinical trials. The principal adverse effect is drowsiness, which occurs in about 7% of patients. Weight gain has also been related to treatment with flunarizine. More recently, there have been a number of reports of extrapyramidal reactions, including a Parkinsonism-like syndrome, in elderly patients receiving flunarizine long term in clinical practice.

Dosage and Administration

The recommended maximum dosage of flunarizine in the treatment of migraine, cere-brovascular disturbances and vestibular disorders is 10 mg/day in adults and 5 mg/day in children weighing less than 40kg. An optimal therapeutic dosage in epileptic patients receiving other antiepileptic drugs is 15 to 20 mg/day in adults and 5 to 10 mg/day in children.The drug should be administered once daily in the evening to minimise the inconvenience of any drowsiness which may occur. Adverse effects may be relieved by dosage reduction to as low as 5 mg/day.

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  1. ADIS Drug Information Services, Auckland, New Zealand

    Peter A. Todd & Paul Benfield

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  1. Peter A. Todd
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  2. Paul Benfield
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Various sections of the manuscript reviewed by: M. Anthony, Department of Neurology, The Prince Henry Hospital, Little Bay, New South Wales, Australia; M. Eadie, Department of Medicine, University of Queensland, Brisbane, Australia; R.T. Jackson, The Emory Clinic, Atlanta, Georgia, USA: J.S. Meyer, Baylor College of Medicine, VA Medical Center, Houston, Texas, USA; F.C. Rose, Charing Cross Hospital, London, England; J.S. Turner, Emory University School of Medicine, Atlanta, Georgia, USA.

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Todd, P.A., Benfield, P. Flunarizine. Drugs 38, 481–499 (1989). https://doi.org/10.2165/00003495-198938040-00002

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