Pharmacotherapeutic group: Anti-vertigo preparations. ATC-Code: N07CA01.
Pharmacology: Pharmacodynamics: 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 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.
Pharmacokinetics: Absorption: Orally administered betahistine is readily and almost completely absorbed from all parts of the gastro-intestinal tract. 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 Cmax 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 fecal excretion of betahistine itself is of minor importance.
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.
Toxicology: Preclinical safety data: Chronic toxicity: Adverse effects in the nervous system were seen in dogs and baboons after intravenous doses at and above 120 mg/kg.
Studies on the chronic oral toxicity of betahistine dihydrochloride were performed in rats over a period of 18 months and in dogs over 6 months. Doses of 500 mg/kg in rats and 25 mg/kg in dogs were tolerated without changes in the clinical chemical and hematological parameters. There were no histological findings related to treatment at these dosages. After increasing the dose to 300 mg/kg, the dogs showed vomiting. In an investigational study with betahistine in rats over 6 months at 39 mg/kg and above hyperemia in some tissues was reported in the literature. Data presented in the publication are limited. Therefore, the impact of this finding in this study is not clear.
Mutagenic and carcinogenic potential: Betahistine does not have mutagenic potential.
Special carcinogenicity studies were not performed with betahistine dihydrochloride. However, in the 18 months chronic toxicity studies in rats there was no indication of any tumors, neoplasms or hyperplasia in the histopathological examination. Therefore, betahistine dihydrochloride up to a dose of 500 mg/kg did not show any evidence for carcinogenic potential in this limited 18 months study.
Reproduction toxicity: Betahistine has no effects on fertility in male and female rats and is not teratogenic in rats and rabbits up to and including 1000 mg/kg for rats and 75 mg/kg in rabbits. In a pre- and postnatal development study in rats, lower pup weight, smaller litter size and lower viability in F1 pups and increased post implantation loss in F1 generation were seen at maternally toxic doses of 1000 mg. Lower average force for startle response test was observed in F1 pups of 300 and 1000 mg/kg dose groups. At 100 mg/kg, no effects on pre- and postnatal development were noted. The relevance of changes noticed at higher doses to humans is unknown.