PHARMACOTHERAPY OF

VERTIGODr.Anita Bhandari

Consultant Neurotologist

Vertigo and Ear clinic

Jaipur

NO COMMON TREATMENT FOR

ALL PATIENTS.Therapeutic approach requires recognition

of the pathomechanism

Detailed history

Clinical examination

Neurotological tests

Imaging

ETIOLOGY

Central

Otological

Systemic

Unknown

OTOLOGICAL CAUSES

Meniere's disease

Vestibular neuritis

Labyrinthitis

BPPV

Fistula

AUTONOMIC NERVOUS

SYSTEM

•Major role in balance control

•3 major neurotransmitters involved in 3

neuron arc between vestibular hair cells

and oculomotor nuclei - VOR

NEUROTRANSMITTERS

Acetylcholineexcitatory

GABAinhibitory

MAO Dopamine

5-HT Norepinephrine

maintain resting tone of vest nucleus

DRUGS MODIFYING ACTION

OF NEUROTRANSMITTERS

Agonists

Antagonists

TREATMENT MODALITIES OF

VERTIGO

Anticholinergics

Antihistamines

Benzodiazepines

Ca Channel blockers

GABA modulators

Neurotransmitter reuptake

inhibitors[SSRI,tricyclic antidepressants]

Nootropics

Vestibular Suppressants

Rascol O et al, Drugs 1995; 50: 777-91

Lacour M. Curr Med Res Opion 2006; 22: 1651-9

Reduction in the

symptom of vertigo

comes at a price of

reduction in

vestibular function

Vestibular Suppressants

Useful for prevention of nausea and

reduce vomiting (generally to be used for

not more that 1-3 days) post an event

Should be discontinued as soon as

possible after event subsides

They are not to be used chronically or for

prophylaxis against subsequent attacks

Lacour M. Curr Med Res Opion 2006; 22: 1651-9

Goebel J. Otolaryngol Clin N Am 2000; 33: 483-93

Brandt T, Vertigo. Its Multisensory Syndromes, 2nd Ed: Pg 49-61

Treatment with Vestibular

Suppressants

Suppressants reduce activity at intact side and thus hamper recovery by VC

Not recommended for long term use

They should be discontinued as soon as possible

Lacour M. Curr Med Res Opion 2006; 22: 1651-9

Vestibular

Nuclei

INTACT DAMAGED

ANTI-CHOLINERGIC DRUGS

Suppress spontaneous firing of

Vestibular nuclei

2ND & 3RD order neurons

Reticulo-vestibular pathway

TYPES OF

CHOLINORECEPTORS

Muscaranic

Nicotinic

Nerve terminal activated

Influx of Ca ions Release of Ach

ANTIMUSCARANIC DRUGS

Atropine and its analogues 0.4 mg orally or IM

Scopalamine

Most potent 0.6mg orally

Transdermal patch 0.05mg

S/E Dry mouth

Tachycardia

Sedation

Cause of Side Effects

Drugs which act by interfering with the

function of neurotransmitters have the

disadvantage of causing effects wherever the

neurotransmitters work in the CNS.

Anti-cholinergics- sedation, dryness of mouth,

tachycardia

Anti-dopaminergic drugs – sedation,

depression

HISTAMINERGIC

RECEPTORS

H1 receptors

• Smooth muscle

• Endothelial cells

• Brain

H2 receptors

• Gastric mucosa

• Cardiac muscle

• Brain

H3 receptor

• Brain

ROLE OF HISTAMINE

Histamine is not a major neurotransmitter in the vestibular pathway

It exerts effect by acting on H1 and H3 receptors present in the brain

Structure of H1 receptors is similar to Muscaranic receptorsDrug which blocks H1 receptors will also

have an anti-cholinergic effect

DIMENHYDRINATE

Inhibits spread of hyperactive vestibular input into vegetative regulation centers of medulla

Effective anti-vertigo and anti-emetic drug

S/E – drowsiness , dry mouth, constipation

Caution – glaucoma , urinary retention

Dosage: 50mg TID

Gravol, Dramamine

PROMETHAZINE

Useful in motion sickness

Dosage: 25-50mg TID

Avomine,Phenargan

PROCLOPERAZINE

Antimuscaranic and anti-dopaminergiceffect

Effective in acute vertigo and vomiting

S/E – CNS depressantExtrapyramidal reactionsHypotension

Dosage: 5-25mg TID Stemetil, Acuvert

MECLIZINE

1ST line of treatment for vertigo in USA

Less anticholinergic activity than other antihistamines

Safe in pregnancy

Also effective in sea sickness

Diligan,Pregnidoxin

CINNARIZINE : MODE OF ACTION

Antihistaminic effect

Ca channel blocker

• Anticholinergic effect

• Reduced irritability of labyrinth

• Reduced blood viscosity

• Antivasoconstrictive effect

• Stabilizes vascular endothelium

CINNARIZINE –Mode of

Action Anti-histaminic effect

Ca channel blocker

reduces labyrinthine irritability

reduces blood viscosity

anti-vasoconstrictive effect

stabilizes vascular endothelium

CINNARIZINE

Dosage : 25-75mg TID

Contraindications:

Hypersensitivity

Parkinsonism

Children

Hypotension

Side Effects :

Extrapyramidal effect

Drug induced Parkinsonism

BETAHISTINE

Historically seen that histamine relieved

vertigo. However had to be given IV and

had serious side effects.

Betahistine is a histamine analogue having

the advantages of histamine like action

without its side effects.

Peripheral vestibular lesion Activation of vestibulo-hypothalmic-vestibular loop

Release of endogenous histamine in vestibular nuclei

Betahistine competes with histamine for binding to histaminergic receptors in vestibular nuclei

Histamine cannot bind to receptors due to betahistine binding

Free histamine increases alertness and vestibular compensation

BETAHISTINE

Inhibits response of rotatory stimuli in

medial vestibular nucleus

Reduces firing rate in lateral vestibular

nucleus

Enhances cochlear blood flow

Important not to use generalized

vasodilators as they lead to“STEAL

EFFECT”

BETAHISTINE

Contraindications :

Bronchial asthma

Peptic ulcer

Phaeochromocytoma

Porphyria

Concurrent use with antihistaminics

Dosage : 48mg in divided doses

ANTIEMETICS

Antidopaminergic

• Metaclopromide

• Domperidon

Antiserotonergic

• Ondansterone

Antimuscaranic

• Procloperazine

• Cinnarizine

MIGRAINE RELATED VERTIGO

5-HT [Serotonin] – the mediator in the

pathogenesis of migraine.

5-HT 1B & 1D are the selective receptors

implicated in migraine.

5-HT receptors agonists form the

mainstay of treatment .

Avoidance of triggers

Abortive therapy

Preventive therapy

MIGRAINE RELATED VERTIGO

MIGRAINE ABORTIVE THERAPY

Triptans

Selective 5-HT I agonists

Useful only in acute attacks; not for prophylaxis

Contraindications: IHD , CAD, HTN

Side effects: Coronary artery spasm

Transient MI

Arrhythmias

Paraesthesia

Drug reaction with MAO inhibitors

TRIPTANS

Triptans act by binding to serotonin 5-

HT.sub.1B and 5-HT.sub.1D receptors

in cranial blood vessels (causing their

constriction) and subsequent inhibition

of pro-inflammatory neuropeptide

release.

TRIPTANS

Sumatriptan

Oral – 25- 100mg

Nasal spray – 5-25mg

Subcut. – 6mg

Zolmitriptan

Oral- 1.25-2.5mg

Nasal spray

Rizatriptan

5-10 mg

MIGRAINE ABORTIVE THERAPY

Ergot alkaloids

Should be restricted to patients with

frequent moderate headaches or

infrequent severe headaches.

Sublingual Ergotamine tartarate 2mg

[Ergomar]

Ergotamine nasal spray[Migranal]

MIGRAINE PROPHYLAXIS

Beta blockers – Propranolol Adults : 40mg BID-TID; may be increased to

160mg/day

Contraindications :

Bronchial asthma

Congestive cardiac failure

DM

Hypothyroidism

Flunarizine Antihistaminic

Ca channel blocker

5-10mg/day

Tricyclic amines –Antidepressants

Flunarizine Potential mechanism in migraine prophylaxis

Interferes with initiation and propagation of spreading

depression1

Inhibits neurogenic inflammation1

Inhibits neuronal NO-synthase activity2

1. Silberstein SD. Trends in Pharmacological Sciences 2006; 27: 410-415.

2. Frediani F. Neurol Sci 2008; 29:S127–S130.

FLUNARIZINE

Dosage : 5-10mg hs

Contrindications: Pregnancy and lactation

GI & Urinary tract obstruction

Porphyria

Special precautions : Driving

Elderly

CVS disease

BOTULINUM TOXOID

Paracelsus described the duality of a

drug as "only the dose makes a

remedy poisonous" .

Botulinum toxin therapy

Minute quantities - highly selective

and long-lasting therapeutic effect

Large quantities - Botulism

BOTULINUM TOXOID

Botulin toxin or botox -toxin produced

by the Clostridium botulinum.

Interferes with release of acetylcholine

at neuromuscular junction leading

paralysis of muscles.

BOTULINUM TOXOID

Pericranial injection of Botox.RTM. Used as the prophylactic treatment of migraine

Benefit

decreased measures of migraine frequency, maximal severity, associated vomiting and acute medication use over the three month period following the 100U injection.

Disadvantage – very expensive

STEROIDS

Uses

Vestibular neuritisInitial treatment : 60-80mg/day then taper

Auto-immune vestibulopathyPrednisolone : 80-100mg/day for 2-3 weeks then

taper & continue with maintenance dose of

10mg/day

Multiple sclerosis

GINKGO BILOBA

Extract from gingko biloba tree leaves

Contains flavanoids , terpenoids and

organic acids

Used in ischemia, dementia ,tinnitus,

VBI,

SNHL, Meniere’s disease,

Neurological diseases

GINGKO BILOBA : MODE OF

ACTION

↑blood supply to brain & peripheral vascular system

Antagonist of PAF to ↑ microvascular permeability

Thrombolytic & vasoprotective

Inhibition of MAO

↑ glucose uptake in brain

Scavenging of free radicals

ACETAZOLAMIDE

Carbonic anhydrase inhibitor

Inhibition of carbonic anhydrase in dark

cells and stria vascularis decreases the

formation of endolymph

K rich diet

Dose: 250 -500mg /day

Side effects:

Paraethesia

Tingling

Drowsiness

DIURETICS IN MENIERE’S

DISEASE

Triamterene 50mg with

hydrochlorthiazide 50mg

Frusemide – 40mg /day

Spironolactone – 100mg /day

PIRACETAM

Cyclic derivative of GABA

Decreases vertigo of central origin

Decreases frequency and severity of

exacerbations in chronic & recurrent

vertigo

PIRACETAM : MODE OF ACTION

Interaction with polar heads of phospholipidmembrane

Reoganizationof lipid molecules with formation of drug-phospholipidcomplex

Restored membrane fluidity

RESTORED MEMBRANE

FLUIDITY

• Improves

• Neurotransmission,

• Neuroplasticity

• Interhemispheric info transfer

Neuronal effects

• RBC deformability

• adhesion of RBC prevents vasospasm

Vascular effects

PIRACETAM : MODE OF ACTION

Facilitates vestibular

compensation and

adaptability

Improvedneuronal function

Improvedmicrocirculation

INTRATYMPANIC DRUG

DELIVERY

Intratympanic steroids

Indications Suspected auto-immune mediated

vestibulo/cochleopathy

Meniere’s disease

Technique: 1ml of methylprednisolone/dexamethasonewith 0.5 ml hyaluronidase injected in posteroinferior quadrant. Patient to lie with injected ear up for minimum 30 min.

INTRATYMPANIC GENTAMYCIN

Used for vestibular ablation in

Meniere’s disease which is not

controlled by oral medicines when

other ear shows normal hearing

Converts unstable labyrinth to stable

non-functioning labyrinth

GENTAMYCIN : MODE OF

ACTION

Reduces endolymphatic production

Damage to dark cells of secretory epithelium

Death of vestibular cells

Gentamycin passes RW→Perilymph to endolymph

Damage to mitochondria

GENTAMYCIN

Technique

0.7ml gentamycin + 0.3ml of soda

bicarb injected intratympanically . Pt

should lie with injected ear up for

30min.

Repeat audiometry before each

injection to rule out SNHL , check for

spontaneous nystagmus and do Head

Impulse test to look for peripheral

dysfunction

AGOROPHOBIA

SOMATISATION DISORDER

HYPOCHONDRIADEPRESSION

ANXIETY

PANIC

PSYCHOTROPIC DRUGS

ANTIDEPRESSANTS

TRICYCLIC ANTIDEPRESSANTS

SSRI

BENZODIAZAPINESALPRAZOLAM

DIAZEPAM

• Effective in anxiety, panic disorders, agorophobia

• Ineffective in depression

• Addictive, sedative

• Inhibits vestibular compensation

BENZODIAZAPINES

ANTI DEPRESSANTS

Tricyclic antidepressants

Strong anticholinergics

May precipitate orthostatic

hypotension

Imipramine : 25mg TID

Nortryptaline : 25-50mg BD

ANTI DEPRESSANTS

Selective serotonin reuptake inhibitors

Very effective in anxiety, anxiety with

depression and panic disorders

Delayed onset of action – 3-4 weeks.

Hence better to combine

benzodiazepines initially , then

withdraw after 4 weeks.

Fluvoxamine: 25-50mg/day

Sertaline : 50-100mg/day

“Only a dose can make a remedy

poisonous…” PARCELUS

An incorrectly prescribed drug can also

make a remedy poisonous.

Judicious use of medicines remains the

key in vertigo.