Betahistine Other names: Betahistine hydrochloride

The mechanism of action of betahistine is only partly understood. There are several plausible hypotheses that are supported by animal studies and human data:

Betahistine affects the histaminergic system: Betahistine acts both as a partial histamine H₁-receptor agonist and histamine H₃-receptor antagonist also in neuronal tissue, and has negligible H₂-receptor activity. Betahistine increases histamine turnover and release by blocking presynaptic H₃-receptors and inducing H₃-receptor downregulation.

Betahistine dihydrochloride is a histamine-like drug in which pharmacological activity can be attributed to a specific effects and/or more direct influences on recovery mechanisms the vestibular nuclei. It has weak agonist activity at histamine H₁ receptors and moderate antagonist activity at H₃; receptors. The antagonist action of betahistine dihydrochloride at the H₃: receptor can be expected to potentiate the release of presynaptic histamine in vivo by blocking the auto-inhibitory feedback at histaminergic terminals, its action on medial vestibular nucleus cells is to significantly reduce their responsiveness to histamine. This action of betahistine dihydrochloride occurs at post-synaptic H₁ receptors, since betahistine dihydrochloride lacks any effect at H₂ receptors. The effects of betahistine dihydrochloride are thus consistent with a partial agonist action at these receptors, with betahistine dihydrochloride having little excitatory action on its own but reducing the excitatory responses to histamine by occupying H₁ receptor sites.

The reduced response of the medial vestibular nucleus cells to histamine in the presence of betahistine dihydrochloride may be the result of the activation of H₂ receptor-coupled second-messenger pathways alone rather than the normal activation of both H₁ and H₂ second-messenger systems together. Thus, simultaneous stimulation of the H₁ and H₂ receptor pathways is known to cause a large amplification of the cellular cAMP response, above that caused by stimulation of the H₂ receptor pathway alone. The reduction in the amplitude and total duration of the histamine-induced excitation in medial vestibular nucleus cells in the presence of betahistine dihydrochloride is suggestive of such a mechanism. This partial agonist action of betahistine dihydrochloride at H₁ receptor may be an important part of its mechanism of action.

Betahistine may increase blood flow to the cochlear region as well as to the whole brain: Pharmacological testing in animals has shown that the blood circulation in the striae vascularis of the inner ear improves, probably by means of a relaxation of the precapillary sphincters of the microcirculation of the inner ear. Betahistine was also shown to increase cerebral blood flow in humans.

Betahistine facilitates vestibular compensation: Betahistine accelerates the vestibular recovery after unilateral neurectomy in animals, by promoting and facilitating central vestibular compensation; this effect characterized by an up-regulation of histamine turnover and release, is mediated via the H₃ Receptor antagonism. In human subjects, recovery time after vestibular neurectomy was also reduced when treated with betahistine.

Betahistine alters neuronal firing in the vestibular nuclei: Betahistine was also found to have a dose dependent inhibiting effect on spike generation of neurons in lateral and medial vestibular nuclei. The pharmacodynamic properties as demonstrated in animals may contribute to the therapeutic benefit of betahistine in the vestibular system.

The efficacy of betahistine was shown in studies in patients with vestibular vertigo and with Ménière’s disease as was demonstrated by improvements in severity and frequency of vertigo attacks.

Absorption

Betahistine dihydrochloride is readily and almost completely absorbed after oral administration from all parts of the gastro-intestinal tract, and peak plasma concentrations of ¹⁴C-labelled betahistine dihydrochloride are attained one hour after oral administration to fasting subjects. After absorption, the drug is rapidly and almost completely metabolized into 2-pyridylacetic acid. Plasma levels of betahistine are very low. Pharmacokinetic analyses are therefore based on 2-PAA measurements in plasma and urine.

Under fed conditions C_max is lower compared to fasted conditions. However, total absorption of betahistine is similar under both conditions, indicating that food intake only slows down the absorption of betahistine.

Distribution

The percentage of betahistine that is bound by blood plasma proteins is less than 5%.

Biotransformation

After absorption, betahistine is rapidly and almost completely metabolized into 2-PAA (which has no pharmacological activity). After oral administration of betahistine the plasma (and urinary) concentration of 2-PAA reaches its maximum 1 hour after intake and declines with a half-life of about 3.5 hours.

Excretion

2-PAA is readily excreted in the urine. In the dose range between 8 and 48 mg, about 85% of the original dose is recovered in the urine. Renal or faecal excretion of betahistine itself is of minor importance.

Betahistine dihydrochloride is eliminated by the kidney with 85-90% of the radioactivity of an 8 mg dose appearing in the urine over 56 hours. Maximum excretion rates are reached within 2 hours of administration. Plasma levels of the parent drug are below the limits of detection of the assay.

Bioavailability has therefore been assessed from urinary excretion of its main metabolite, 2-pyridylacetic acid.

There is no evidence for presystemic metabolism. Biliary excretion is not important as a route of elimination of either the drug or its metabolites in the rat and is unlikely to be so in man.

Linearity

Recovery rates are constant over the oral dose range of 8–48 mg indicating that the pharmacokinetics of betahistine are linear, and suggesting that the involved metabolic pathway is not saturated.

Adverse effects in the nervous system were seen in dogs and baboons after intravenous doses at and above 120 mg/kg.

Chronic oral toxicity testing for 18 months in rats at a dose of 500 mg/kg and 6 months in dogs at a dose of 25mg/kg showed Betahistine to be well tolerated with no definitive toxicities.

Betahistine was not mutagenic in conventional in vitro and in vivo studies of genotoxicity.

Histopathological examination in the 18 months chronic toxicity study indicated no carcinogenic effects. However,specific carcinogenicity studies were not performed with Betahistine.

Effects in reproductive toxicity studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.