D₂ Receptor Blockade by Flunarizine and Cinnarizine Explains Extrapyramidal Side Effects. A SPECT Study

Abstract

Twenty-six patients under treatment with the calcium channel blockers flunarizine (Fz) or cinnarizine (Cz) were examined-with single-photon emission computed tomography using [123I]iodobenzamide as a ligand. The striatal dopamine D2 receptor-binding potential was determined and found to be reduced by 14 to 63% (39.5 +/- 15.0%; p < 0.0001) in patients compared with age-matched control values. This reduction was larger in 12 patients with extrapyramidal symptoms and was only slowly reversible after discontinuation of treatment. Patients treated for > 6 months had significantly larger reductions than patients treated for a shorter period. Parkinsonian symptoms were only seen in patients older than 50 years. Our findings prove a neuroleptic-like action of Fz and Cz, which seems to be the major reason for their extrapyramidal side effects. Older age and long-term treatment are predisposing factors for these effects.

Parkinsonism and other movement disorders in outpatients in chronic use of cinnarizine and flunarizine

“…This is similar to the results by Brucke et al with an average onset of the symptoms after 16 months. This time latency is shorter than the results obtained by Gimenez -Roldan, which demonstrated cinnarizine-induced parkinsonism after a mean exposure of 4 (± 4) years 6,19 . The association of both drugs, cz and fz, increased the risk of MD.…”

“…Neuroleptics can induce a variety of MD due to changes in the dopaminergic pathways and it is the second most frequent cause of parkinsonism 7,17,18 . The pathophysiology of these disorders is almost always related to disturbances in the dopamine pathways, mainly by blocking the D2-receptors, like many neuroleptic drugs 1,2,4,5,7,11,19 . Brucke et al demonstrated that studying patients examined with single-photon emission tomography using {123} iodobenzamide as a ligand and it showed the D2 receptor blockade by cz and fz 19 .…”

“…The pathophysiology of these disorders is almost always related to disturbances in the dopamine pathways, mainly by blocking the D2-receptors, like many neuroleptic drugs 1,2,4,5,7,11,19 . Brucke et al demonstrated that studying patients examined with single-photon emission tomography using {123} iodobenzamide as a ligand and it showed the D2 receptor blockade by cz and fz 19 . Both drugs also inhibit the Mg ATP-dependent generation of a transmembrane proton electrochemical gradients in chromaffin granule ghosts, reduce 3H-spiperone binding to bovine striatal membranes and 3H-dopamine uptake.…”

Association between Trimetazidine and Parkinsonism: A Population-Based Study

“…Although the pathophysiology underlying TMZ-induced Parkinsonism remains unclear, a possible mechanism of action, as suggested by previous studies, involves the piperazine component in its chemical structure, similar to flunarizine, thiethylperazine, and perphenazine, that blocks striatal dopamine D2 receptors, thus resulting in an extrapyramidal type of adverse reaction [10,11,24,25]. Some studies have shown that the dopamine D2 receptor activity in the basal ganglia decreases in patients treated with drugs containing the piperazine ring [24,25]. Our results indicated that age could represent an important risk factor in the development of TMZ-associated Parkinsonism, in agreement with other published studies [26].…”

Parkinsonism in Phenylketonuria: A Consequence of Dopamine Depletion?

“…Notably, a substantial part of the PKU patients with an intellectual disability is prescribed DA antagonists that are associated with extrapyramidal symptoms such as parkinsonism. Other agents that negatively influence DA transmission include the calcium channel blockers flunarizine and cinnarizine (Br€ ucke et al 1995) and the antiemetic drug metoclopramide. Although no systematic studies exist, and motor symptoms emerge only after pronounced cerebral DA dysfunction (Cummings et al 2014), prescription of medication that negatively influences DA transmission might carry a risk to cause or aggravate parkinsonian symptoms in PKU patients.…”