19 Medications Used in Treating Acute and Chronic Vertigo and Various Vestibular Disorders The vestibular system is critical for perception of one’s position in space. It is composed of three building blocks interacting in complex order: the labyrinth within the inner ear, the visual system, and the somatosensory system. If a mismatch occurs between any of these three systems, the brain may perceive a sensation of dizziness or vertigo. Vertigo is the sensation of motion without true motion, and is typically a spinning sensation. True rotatory vertigo is secondary to lesions or dysfunction within the vestibular system. When prescribing medication to relieve dizziness, it is critical to attempt to define what type of dizziness the patient is experiencing, and therefore which of the three systems may be malfunctioning. This chapter focuses on medication used to treat vertigo and other various vestibular disorders. The goals of pharmacotherapy for vertigo include eliminating the vertigo, enhancing vestibular compensation, and decreasing the neurovegetative and psychoaffective symptoms that often accompany vertigo and that may limit the patient’s ability to compensate. The neurovegetative symptoms, such as nausea, vomiting, and prostration, are often more bothersome to the patient than the vertigo itself. Many patients also experience anxiety that may be quite disabling and can limit activity required for compensation. Although the immediate goal is to reduce the vertigo, several medications that reduce vertigo may also reduce the brain’s ability to compensate for the reduction in vestibular function, and therefore may be indicated only for a short time. Sensory feedback is essential for adaptation to occur and treatment must balance immediate relief of symptoms with long-term correction. Therefore, treatment for vertigo commonly combines therapies aimed at both the vertigo itself and the secondary symptoms. Fig. 19.1 shows a schematic of the relationship between the causes and symptoms of vertigo. Fig. 19.1 Interaction between the visual, vestibular, and somatosensory systems leading to vertigo and the failure of compensation leading to adjunctive symptoms. Currently, medical treatment of vertigo is primarily treatment of symptoms. If the vertigo is secondary to a defined etiology, such as infection or vascular insufficiency, the underlying cause must be treated in addition to treating the vertigo itself. If a specific vestibular disorder causing episodic dizziness is suspected, such as Meniere’s disease, particular medications may be given to help prevent future attacks and to treat symptoms as they arise. Lastly, several medications also cause vertigo either due to direct peripheral ototoxic effects or due to effects on the central vestibular pathways. Although the effects may be temporary, multiple medications can cause irreversible damage to the vestibular system. The medial vestibular nucleus contains histamine, glutamate, and muscarinic acetylcholine receptors.1 Glutamate is the primary excitatory neurotransmitter at the vestibular hair cell-vestibular nerve synapse and the vestibular nerve-vestibular nucleus synapse and may work through N-methyl-D-aspartate (NMDA) receptors.2,3 M2 acetylcholine muscarinic receptors involved in vertigo are found in the pons and medulla and in the vestibular nuclei complex.2 The efferent nerves to the vestibular neuroepithelium contain cholinergic receptors.2,4 Gamma-aminobutyric acid (GABA) is one of the inhibitory neurotransmitters in the connection of the vestibular system to the oculomotor neurons. Histamine is found throughout the central vestibular system. A high density of H1 receptors has been found within the medical vestibular nuclei.1 Both H1 and H2 histamine receptors affect the vestibular response.5 Norepinephrine modulates the reaction to vestibular stimuli centrally, and dopamine also modulates the vestibular system centrally. The area postrema, located within the brainstem, contains the chemoreceptor trigger zone. Stimulation of this area causes vomiting. This response is reduced by blockade of the dopaminergic receptors.3 Signaling from the gastrointestinal tract to the brain to induce vomiting is via serotonin, and serotonin blockers (5HT3) block this response. Medications may act on one or multiple neurotransmitter pathways. The complexity of the interactions can make defining the exact location of action difficult. The treatment of acute vertigo consists mainly of controlling the associated symptoms of nausea and vomiting, and allowing the patient to perform the activities of daily living. One must ensure that life-threatening and more serious causes have been ruled out, and the etiology and further recommended treatment may be determined once the patient’s symptoms have improved. Antihistamines are the most common agents used in the treatment of acute vertigo, and multiple medications from this class have shown efficacy: diphenhydramine, dimenhydrinate, cyclizine, meclizine, promethazine, cinnarizine, and astemizole. The most commonly prescribed is meclizine, due to its side effect profile. These drugs are thought to work centrally but it is difficult to pinpoint their exact mechanism, as many of these drugs have multiple sites of action. Many of the antihistamines listed also have anticholinergic activity. The most effective antihistamines are unfortunately those with the most anticholinergic properties as well,4 causing the side effects of sedation and dry mouth.3 These drugs are administered orally, with a duration of action between 4 and 12 hours. Interestingly, although antihistamines are effective against vertigo, histamine itself has also been used as a treatment for vertigo. It has primarily been used to treat vertigo thought to be of vascular origin. Histamine is administered intravenously, subcutaneously, or sublingually. It increases capillary and venous volume and is a regulator of the microcirculation.4 Betahistine, an analogue of L-histidine, is a partial H1 postsynaptic agonist and an H3 presynaptic antagonist3,5 that can be taken orally and has largely replaced histamine in use. It increases inner ear blood flow and may have central effects as well. Adverse effects include headache and nausea, and it is contraindicated in patients with a history of gastroduodenal ulcer or pheochromocytoma. It has been shown to be effective for patients with Meniere’s disease, both in the treatment of acute vertigo and in preventing the attacks.6 Anticholinergics are some of the oldest agents used to control vertigo. This class includes atropine, homatropine, and the more commonly used scopolamine (hyoscine). These drugs are nonselective and block all muscarinic receptor subtypes, both centrally and peripherally. Only anticholinergics that cross the blood–brain barrier are effective in reducing vertigo.3 Effects after oral administration last ~ 4 hours; however, scopolamine has been developed into a transdermal patch for prolonged administration with a decreased side-effect profile and lasts ~ 4 days. In addition to improving symptoms of dizziness, the central blockade of muscarinic receptors also causes some undesired effects, such as sedation, memory problems, and confusion, particularly in the elderly. Side effects from peripheral parasympathetic blockade include mydriasis, cycloplegia, dry mouth, constipation, and urinary retention. Closed-angle glaucoma and prostatic hypertrophy are contraindications to their use. Benzodiazepines are GABA receptor potentiators and are often used for severe acute vertigo. Intravenous administration can be effective in preventing attacks of vertigo, and the area of action may be at the lateral vestibular nucleus.4 Low doses of oral benzodiazepines may be effective both for treatment during an acute attack and in preventing attacks. The anxiolytic property is often useful in reducing the anxiety that often accompanies vertigo.3 Etizolam, a benzodiazepine currently not available in the United States, has been shown in one recent study to help patients with BPPV return to daily life more rapidly and comfortably after a canalith-repositioning maneuver,7 and it may help patients undergo treatment. Typically, diazepam is the agent of choice due to its length of action. However, in addition to being potentially addictive, diazepam can prolong compensation and recovery time if given during an acute vestibular crisis. Other adverse effects include sedation, memory impairment, and an increased risk of falls. Although benzodiazepines are efficacious, some physicians recommend benzodiazepines not be used for treatment of chronic vertigo because of their lack of selectivity for the vestibular system and their addictive potential.2 Calcium channel blockers have been proven effective in the treatment of acute vertigo, as well as in the prevention of vestibular migraine. Recent randomized-controlled trials from Europe and India have shown efficacy for both cinnarizine and flunarizine alone or in combination with an antihistamine.8,9,10 Cinnarizine and flunarizine have been used primarily in Europe for the treatment of acute vertigo. These drugs have not been approved by the U.S. Food and Drug Administration (FDA), and are therefore not available for use in the United States. Cinnarizine is an antagonist of histamine, norepinephrine, nicotine, and angiotensin, as well as a calcium channel blocker. Flunarizine is its derivative and is a potent H1 blocker with antidopaminergic properties. Neither has anticholinergic properties. Although their mechanism is not completely known, they are vestibular suppressants and likely work by blocking the entry of extracellular calcium into cells, including endothelial cells causing vasodilation. Both are administered orally. Flunarizine has a long half-life, and steady-state concentrations are not reached until 2 months. Adverse effects include sedation, weight gain, extrapyramidal reactions, and depression,11 all of which are worsened with prolonged administration or in the elderly. Therefore, these drugs should not be used for more than a month, particularly in the elderly population.3 Steroids have long been advocated for the treatment of acute vertigo, although the evidence often is equivocal. In addition to treatment for autoimmune inner ear disease, steroids are used to treat early vestibular neuritis or Meniere’s attacks.2,12,13 Glucocorticoid receptors have been found in cochlear and vestibular tissue, leading researchers to speculate that steroids themselves may influence inner ear function.14 A Cochrane review from early 2011 on the use of steroids for the treatment of vestibular neuritis found insufficient evidence from these trials to support the administration of corticosteroids to patients with idiopathic acute vestibular dysfunction.15 However, a subsequent study from later that year found glucocorticoids administered within 3 days after onset of vestibular neuronitis improve long-term recovery of vestibular function and reduce length of hospital stay.16 Several studies using intratympanic corticosteroid administration have also been performed, with varying results.14
Introduction
Neuropharmacology of Pathways in the Vestibular System Involved in Vertigo
Medications for Treatment of Acute Vertigo
Antihistamines
Anticholinergics
Benzodiazepines
Calcium Channel Blockers
Corticosteroids
Antidopaminergics
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