Sepan - Pharmacodynamics

Pharmacodynamics

Cinnarizine is classified as a selective antagonist of T-type voltage-operated calcium ion channels, because its binding blocks the channels and keeps them inert. It has a Ki (inhibitory constant) value of 22nM. It is also known to have antihistaminic, antiserotoninergic and antidopaminergic effects, binding to H1 histamine receptors, and dopaminergic (D2) receptors. The IC50 (half-maximal inhibitory concentration) of cinnarizine for smooth muscle contraction inhibition is 60mM and it has been shown that this drug preferentially binds to its target calcium channels when they are in an open, as opposed to closed conformation. In treatment of nausea and motion sickness it was previously hypothesized that cinnarizine exerts its effects by inhibiting the calcium currents in voltage gated channels in type II vestibular hair cells within the inner ear. However, more recent evidence supports the idea that at pharmacologically relevant levels (0.3–0.5 µM), cinnarizine is not lessening vestibular vertigo by blocking calcium channels, but rather by inhibiting potassium (K+) currents that are activated by heightened hydrostatic pressure on the hair cells. It is true that cinnarizine does abolish calcium currents in vestibular hair cells as well; it is just that this only occurs at higher concentrations of drug (3nbsp;µM). The inhibition of these currents works to lessen the vertigo and motion-induced nausea by dampening the over-reactivity of the vestibular hair cells, which send information about balance and motion to the brain.