|Year : 2015 | Volume
| Issue : 2 | Page : 39-42
Pharmacotherapy of vestibular disorders
Hesham Mahmoud Samy
Hearing & Balance Unit, Otolaryngology Department, Minia University Hospitals, Minia, Egypt
|Date of Submission||09-Nov-2015|
|Date of Acceptance||20-Nov-2015|
|Date of Web Publication||10-Dec-2015|
Hesham Mahmoud Samy
4 Botros Ghali St, Roxy, Heliopolis, Cairo 11341
Source of Support: None, Conflict of Interest: None
Dizziness and vertigo are symptoms directly related to dysfunction of the vestibular system. Imbalance is the most common complaint, especially in the elderly population, which results in falls and mobility restriction. There is no common drug for the management of balance disorders. Medications should be prescribed carefully, and according to clear diagnosis. The pharmacotherapy of vertigo can be optimized with detailed knowledge of the drugs effective in vertigo, as well as their side effects. A thorough review of the literature reveals that there is a significant lack of information concerning the real utility of different drugs used in clinical practice. This article discusses the pharmacological options that are available for the treatment of balance disorders, along with some recent advances.
Keywords: inner ear, vertigo, dizziness, pharmacotherapy, meniere′s disease
|How to cite this article:|
Samy HM. Pharmacotherapy of vestibular disorders. Adv Arab Acad Audio-Vestibul J 2015;2:39-42
| Introduction|| |
Vertigo, dizziness, and imbalance are common symptoms of vestibular disorders. These symptoms can have drastic consequences, such as impaired postural control and falls as well as psychological and psychiatric consequences such as depression, anxiety, panic, agoraphobia, and cognitive defects, especially in the elderly  . Balance disorders are mainly due to an imbalance between inputs from the inner ear, which is modulated by the central vestibular system. The main aim of vestibular disorder treatment is to control symptoms, reduce functional disability, and improve the quality of life of the patients. This article reviews the neuropharmacology of balance disorders with an emphasis on the mechanism of action of drugs commonly used in the treatment of such pathologies.
Before prescribing any medication for the treatment of vertigo and dizziness it is essential to reach a correct diagnosis. This can be achieved in most patients through a systematic approach on the basis of the patient's history and clinical examination even without any laboratory examinations. According to the etiology, the various forms of vestibular disorders can be treated with pharmacological therapy, physical therapy, including repositioning maneuvers, psychotherapeutic measures, or, in rare cases, surgery.
Hair cells and efferent neurons release numerous other neuroactive substances including calcitonin gene related peptide (CGRP), substance-P, opioid peptides, endocannabinoids, g-aminobutyric acid (GABA), ATP, nitrous oxide, adenosine, and histamine  . At the level of vestibular end organs, drugs have diverse cellular targets. These targets include homeostasis of electrolytes in the inner ear, regulation of blood flow, cellular homeostasis and survival, and modification of sensory processes, including mechanoelectrical transduction in hair cells and post-transductional processing of sensory information. At the level of the central vestibular system, pharmacological effects are more difficult to understand because of the complexity of the neural systems involved in vestibular information processing.
From a pharmacological point of view, it is important to emphasize that the central vestibular system is isolated from the systemic blood flow by the blood-brain barrier, whereas the vestibular end organs are isolated by the blood-labyrinthine barrier. Because of this, some drugs can affect one region without affecting the other. Some medical procedures have also been designed that allow the local administration of some drugs, thus limiting their systemic effects. The complexity of the synaptic connections governing the activity of the afferent neurons in the vestibular end organs, together with the complexity of the central vestibular system, decides that many drugs acting on synaptic receptors may influence the activity of the whole vestibular system network  .
Excitatory amino acid
Glutamate is the major excitatory neurotransmitter at vestibular afferents as well as with neurons of the vestibular nuclei  . Glutamate interacts with several subreceptors including N-methyl-Daspartic Acid (NMDA), Amino-3-hydroxyl-5-methyl-4- isoxazole-propionic acid (AMPA), and kainic acid (KA), and with metabotropic receptors. Ketamine, a derivative of phencyclidine, is also an NMDA receptor antagonist that is used in anesthesia and neuropathic pain, and has been reported to inhibit the vestibular afferent neuron activity in frogs  . Neramexane, which is an amino-alkylcyclohexane derivate that acts as a nicotinic receptor channel blocker and noncompetitive NMDA receptor antagonist, was found in double-blind randomized trials to have a modest efficacy in moderate to severe tinnitus  .
Acetylcholine is both a peripheral and central agonist affecting muscarinic receptors, including the vestibular nucleus as well as efferent synapses  . Receptors found in the pons and medulla, presumably those involved with dizziness, are almost exclusively of the M2 subtype  . Scopolamine, a nonselective competitive inhibitor of mACh receptors, is a commonly used drug in vestibular disorders. It is effective for the treatment of motion sickness; nevertheless, it has not yet been determined whether its effect takes place at the peripheral or at the central vestibular system  . Among the drugs that modulate cholinergic activity, scopolamine and atropine have the most significant clinical application for the treatment of motion sickness and vestibular diseases. Side effects of anticholinergic drugs include blurred vision and dry mouth; occasionally, confusion also appears. Low doses of scopolamine or atropine may produce a transitory tachycardia  .
Calcium channel blockers
Calcium channels play a major role in the triggering of neurotransmitter release. The subtypes of L, N, and T are reportedly active in the vestibular system. Two hypotheses were postulated on how calcium channel blockers might prevent migraine. The first hypothesis is that there are actions on neurons, and furthermore that the agents enter the brain (to affect the neurons). This likely varies according to the agent. The second theory is that calcium channel blockers block vasoconstriction through their effects on smooth muscle  . Flunarizine, however, is also a dopamine blocker, and cinnarizine an antihistamine. Cinnarizine also blocks pressure-sensitive potassium channels, a property that may provide it with a separate mechanism for treatment of hydrops  . Furthermore, cinnarizine and flunarizine have antihistaminic action (acting on H1 receptor) and potential (although very weak) nicotinic receptor antagonism. Nevertheless, no studies have evaluated the exact role of these actions in the therapeutic effect of these drugs  .
GABA and glycine are inhibitory neurotransmitters found in connections between second-order vestibular neurons and oculomotor neurons. Pathways from the cerebellum and commissural fibers from the contralateral nuclei exert a powerful inhibitory input on the vestibular nuclei, activating both GABA-A (ionotropic) and GABA-B (metabotropic) receptors  . Involvement of commissural GABAergic system in vestibular compensation indicates that early mechanism of compensation is a down regulation of GABA receptor in the ipsilesional nucleus neurons  . It has been found that reactive neurogenesis in the vestibular nuclei after unilateral vestibular neurectomy that lead to GABAergic neurons, along with glial cells, seems to significantly contribute to vestibular compensation process  . Stimulation of the two types of GABA receptors, GABA-A and GABA-B, has similar effects on vestibular pathways  . The inhibitory effect of benzodiazepines on the electrical activity of the vestibular nuclei leads to a therapeutic effect in acute vestibular pathologies. Diazepam, a typical GABA-A receptor agonist, significantly reduces the spontaneous electrical activity of neurons in the medial vestibular nuclei, exerting both presynaptic and postsynaptic actions on diverse groups of neurons  .
Baclofen, a selective agonist of the GABA-B receptor, is commonly used for the treatment of spasticity, and recently it has been found that it probably acts by enhancing inhibition in vestibular nuclei and related networks, consequently reducing nystagmus in patients with vestibular alterations. Baclofen also improves periodic alternating nystagmus  .
Histamine (H1-H3) is found diffusely in central vestibular structures and in the central vestibular system. Both the H1 and H2 subtypes of histamine receptors affect vestibular responses  . The inhibition of the histamine-synthesizing enzyme l-histidine decarboxylase produces a significant inhibitory action on the afferent neurons. Pharmacological evidence indicates that H1, H2, and H3 histamine receptors exist in the vestibular periphery  . A fourth histamine receptor (H4) has been identified. H4 antagonists are reported to suppress rat primary vestibular neuron firing  . H1 and H2 histamine antagonists inhibited ampullar nerve activity. A specific inhibitor of histidine, decarboxylase, the enzyme that catalyzes the synthesis of histamine, reduced ampullar nerve firing in a dose-dependent manner  .
Among the antihistaminics, betahistine, diphenhydramine, meclizine, its derivate cyclizine, and promethazine have been the most commonly used in the medical treatment of vertigo. In Europe, betahistine is more frequently used: 92% of doctors prescribe betahistine  . In contrast, in the USA, the antihistaminics most commonly used in the treatment of vestibular disorders are diphenhydramine, meclizine, its derivate cyclizine, and promethazine. The phenothiazines (promethazine and prochlorperazine) are the most frequently prescribed antiemetic drugs  . All of these drugs are primarily H1 receptor antagonists, but they also have an anticholinergic effect that is more remarkable in the case of promethazine. Their actions are both central and peripheral, although the central action seems essential because antihistaminics that do not cross the blood-brain barrier did not show usefulness in the treatment of vertigo.
All of them cause sedation and, because of its potential anticholinergic effect, these medications must be administered cautiously in patients with bronchial asthma, glaucoma, or prostate hypertrophy.
Betahistine is an analog of histamine that has an antagonistic action on H3 receptors  . It also has a partial, weak agonist effect on H1 and H2 receptors  . In the vestibular end organs of rodents and amphibians, betahistine, as well as its metabolite 2-(2-aminoethyl) pyridine, diminishes the discharge frequency of the vestibular afferent neurons  . Electrophysiological studies have established that the clinical action of betahistine is most probably produced by an inhibitory influence exerted at the vestibular nuclei and at the peripheral end organs; this inhibitory action modulates the afferent sensory input and the release of other neurotransmitters and re-establishes the bilateral balance of activity in the afferent neurons  .
Medications that affect biogenic amine receptors have been widely used in the treatment of different vestibular diseases; there is an agreement that their effects are exerted essentially at the level of the central nervous system, not specifically in the vestibular nuclei, although these have an important noradrenergic, serotonergic, and dopaminergic input  . Serotonergic and dopaminergic innervation of the vestibular nuclei may account for the association that has been observed between vestibular alterations, anxiety disorders, and migraine  . Rizatriptan and zolmitriptan (5-HT1B/1D receptor agonists) have shown to be efficient in preventing motion sickness in patients with migraine-associated vertigo  .
Corticosteroids have been used for the treatment of Meniere's disease and vestibular neuritis in an attempt to reduce the duration of a vertiginous attack. They are also commonly used for sudden hearing loss. Data on its efficacy are highly debated. There are many possible mechanisms of efficacy, modulation of compensation, and reduction of immune responses in the inner ear  . Clinical trials and meta-analysis suggested that dexamethasone might have a beneficial effect in patients with Meniere's disease, especially in the temporary relief from vertigo, without destroying the vestibular function  .
| Conclusion|| |
Although many medications are available for the treatment of balance disorders, the complexity of the vestibular system and the adaptive processes that compensate for vestibular loss leading to the appearance of different complex signs and symptoms make it difficult to evaluate the effectiveness of commonly used drugs in the treatment of vestibular disorders. A careful study of the literature reveals that there is a significant lack of information describing the real efficacy of different drugs used in clinical practice. Basic research on drug actions at the molecular and cellular level, combined with reliable and well-controlled clinical trials, can provide the scientific basis for new strategies for the management of balance and vestibular diseases.
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Conflicts of interest
There are no conflicts of interest.
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