RiteMED Betahistine Mechanism of Action

Pharmacotherapeutic group: Central Nervous System Antiemetic and anti-vertigo.
Pharmacology: Pharmacodynamics: 16 mg: Betahistine Dihydrochloride is an analogue of histamine. Betahistine Dihydrochloride is readily absorbed from the gastrointestinal tract. It is converted to two metabolites and peak concentrations in blood of the two metabolites are achieved within 3 to 5 hours. Most of a dose is excreted in the urine, in the form of the metabolites, in about 3 days. The mechanism of action of Betahistine is not known. 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. In pharmacological studies, Betahistine was found to have weak H₁ receptor agonistic and considerable H₃ antagonistic properties in the central nervous system and autonomic nervous system. Betahistine was also found to have a dose dependent inhibiting effect on spike generation of neurons in lateral and medial vestibular nuclei. The importance of this observation in the action against Ménière's syndrome or vestibular vertigo, however, remains unclear.
24 mg: The mechanism of action of Betahistine is only partially 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 down regulation.
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 is characterised 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.
Mechanism of Action: Betahistine is a histamine analogue with agonist effects on H₁ receptors and antagonist on H₃. The clinical expression of this mechanism is its efficacy as an antivertiginous and to combat ringing in the ear.
At a vestibular peripheric level, Betahistine decreases the level of basal discharge of the receptors of the bulla and increases the vestibular-cochlear organs.
At a central level, Betahistine through the antagonism of H₃ autoreceptors, increases the synthesis of histamine in the tuberomammillary nucleus and release of it through the vestibular nucleus. Due to its partial agonist activity on cerebral H₁ receptors of cortical and subcortical structures, Betahistine does not affect wakefulness and even improves response capacity.
Pharmacokinetics: 16 mg: Absorption: Orally administered Betahistine is readily and almost completely absorbed from all parts of the gastrointestinal tract. After absorption, the drug is rapidly and almost completely metabolised 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 metabolised 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.
24 mg: Absorption: Betahistine is completely absorbed after oral administration, and for fasting subjects, peak plasma concentrations of 14C-labelled betahistine are attained approximately one hour after oral administration.
Distributions: After oral administration of Betahistine, its levels in plasma are very low. Therefore, the pharmacokinetic assessment of this drug is based on plasma concentration data of the only known metabolite, 2-pyridylacetic acid. Little or binding occurs with human plasma proteins.
Metabolism and Elimination: Elimination of Betahistine primarily occurs by metabolism in the liver. Subsequently, the metabolites are mainly eliminated by renal excretion. 85-90% of the radioactivity of an 8 mg dose appears in urine over 56 hours, within 2 hours of administration. There is no evidence of presystemic metabolism, and biliary excretion is not thought to be an important route of elimination for the drug or any of its metabolites.