1. “Drugs affecting the Balance system”
PHARMACOLOGY
Lecture 1
Neuropsychiatry block
25/9/2018

2. Learning Objectives
At the end of lecture the student should be able to:
Recognize causes and symptoms of balance disorders.
Identify the transmitters involved in vestibular transmission
Segregate classes of drugs used in the management protocols to control or prevent vertigo
Identify drugs that can precipitate vertigo.

3. Human balance system
Is the system that prevent humans and from falling over when standing or moving.
Balance results from number of body systems working together.
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5. The Vestibular System
balance is primarily controlled by structure in our inner ear called the labyrinth filled with fluid (endolymph).
Upon movement, fluid in the semi-circular canals stimulates nerve endings → firing impulses along the vestibular nerve to the brain.
If a disease or injury damages this system, it can lead to a vestibular disorder.
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6. Vestibular System Structure
The internal ear is highly complex. The essential component of the inner ear for hearing is the membranous labyrinth where the fibers of the auditory nerve (the nerve connecting the ear to the brain) end. The membranous labyrinth is a system of communicating sacs and ducts (tubes) filled with fluid (the endolymph). The membranous labyrinth is lodged within a cavity called the bony labyrinth. At some points the membranous labyrinth is attached to the bony labyrinth and at other points the membranous labyrinth is suspended in a fluid (the perilymph) within the bony labyrinth. The bony labyrinth has three parts: a central cavity (the vestibule), semicircular canals (which open into the vestibule) and the cochlea (a snail-shaped spiral tube). The membranous labyrinth also has a vestibule which consists of two sacs (called the utriculus and sacculus) connected by a narrow tube. The utriculus, the larger of the two sacs, is the principal organ of the vestibular system(which informs us about the position and movement of the head). The smaller of the two sacs, the sacculus (literally, the little sac) is connected with a membranous tube in the cochlea containing the organ of Corti. It is in the organ of Corti that are situated the hair cells, the special sensory receptors for hearing.
Two sections of the labyrinth help us accomplish position of our body changes: the semicircular canals and the otolithic organs.
Each semicircular canal has a plump base, which contains a raindrop-shaped structure filled with a gel-like substance. This structure, called the cupula, sits on top of a cluster of sensory cells, called hair cells. The hair cells have long threadlike extensions, called stereocilia, that extend into the gel. When the head moves, fluid inside the semicircular canal moves. This motion causes the cupula to bend and the stereocilia within it to tilt to one side. The tilting action creates a signal that travels to the brain to tell it the movement and position of your head.
Between the semicircular canals and the cochlea lie the otolithic organs, which are two fluid-filled pouches called the utricle and the saccule. These organs tell the brain when our body is moving in a straight line, such as when we stand up or ride in a car or on a bike. They also tell the brain the position of our head with respect to gravity, such as whether we are sitting up, leaning back, or lying down.
Like the semicircular canals, the utricle and the saccule have sensory hair cells. These hair cells line the bottom of each pouch, and their stereocilia extend into an overlying gel-like layer. On top of the gel are tiny grains made of calcium carbonatecalled otoconia. When you tilt your head, gravity pulls on the grains, which then move the stereocilia. As with the semicircular canals, this movement creates a signal that tells the brain the head's position.
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7. Neurotransmitters Involved in Vestibular Transmission
Glutamate: the major excitatory neurotransmitter
Acetylcholine (ACH): acts on M receptors centrally & peripherally, involved in dizziness
Gamma-­‐amino butyric acid(GABA) & glycine are inhibitory neurotransmitters
Histamine: centrally acting histamine affects symptoms of motion sickness
Norepinephrine centrally acting that affects vestibular adaptation
Dopamine & Serotonin (involved with nausea)
Neurotransmitters relevant to dizziness
Major excitatory neurotransmitters in the vestibular system.
Glutamate is the major excitatory neurotransmitter at vestibular afferents (Serafin et al, 1992), V1 above, as well as with neurons of the vestibular nuclei, or V2 above, where they may also release aspartate. Glutamate interacts with several subreceptors including NMDA, AMPA, and KA, and metabotrophic receptors (Soto et al, 2013). The NMDA glutamate receptors determine the basal discharge and tonic response, while the non-NMDA receptors seem to modulate responses to high-frequency mechanical stimulation (Soto et al, 2013). Drugs that affect glutamate tend to affect the entire brain, as glutamate is a major CNS neurotransmitter. In other words, if you shut down glutamate, you shut down everything. Weak glutamate drugs, such as memantine (an antagonist) are generally not useful in treating dizziness. Glutamate drugs can be hallucinogenic (such as phencyclizine -- a NMDA glutamate antagonist), and overdose induces intense nystagmus.
There are other excitatory amino-acids that may be important. Aspartate is also used at the V2 synapse. So far, this has not been used in vestibular medicine.
Acetylcholine (ACH) is mainly a central agonist affecting muscarinic receptors in the vestibular nucleus. In the periphery, it is the mediator of the efferent synapses (Soto et al, 2013). However there are also nicotinic receptors, as well as M1 and M5 expressed in vestibular afferent neurons (Soto et al, 2013). The significance of their efferent action is probably negligable, The situation with respect to the other cholinergic receptors is somewhat uncertain.
Centrally acting ACH drugs are commonly used for treatment of dizziness. Peripherally acting ACH drugs, such as glycopyrrolate, are rarely encountered (i.e. they usually dobn't work). This probably means that the role of peripheral ACH is minor, while central ACH is major.
There are numerous ACH receptor types (Nm, Nn, and M1-5). The Nm and Nn are "nicotinic", and the M1-5 are "muscarinic". Receptors found in the pons and medulla, presumably those involved with dizziness, are almost exclusively of the M2 subtype (Barton et al, 1994), but both muscarinic and nicotinic receptors are found centrally. Although acetylcholine is also a widely distributed neurotransmitter in the brain as a whole, drugs that affect acetylcholine are heavily used in vestibular medicine, as they suppress nystagmus and vertigo. Examples are meclizine and scopolamine. Scopolamine is a nonselective ACH antagonist. There is no reason to believe that any one nonselective ACH antagonist (e.g. scopolamine) is better than any other ACH antagonist (e.g. meclizine, and many other antihistamines), but scopolamine has no central antihistamine component (which is associated with sleepiness and weight gain). Oral versions of scopolamine would seem equally likely to work as patches (e.g. drugs for IBS) for motion sickness.
ACH agonists, such as physiostigmine can induce motion-sickness in experimental models (Soto et al, 2013). Neostigmine, another ACH agonist but one which does not cross the blood brain barrier, does not have any significant vestibular effects. It seems likely that ACH agonists would decrease thresholds for vestibular signals, but to our knowledge, this has not been studied.
Anticholinergics also affect compensation, producing a reversible overcompensation if administered after compensation has been attained to a vestibular imbalance (Zee, 1988).
Major inhibitory neurotransmitters (i.e. GABA)
Gamma-aminobutyric acid (GABA) and glycine are inhibitory neurotransmitters found in connections between second order vestibular neurons and onto oculomotor neurons (Spencer et al, 1992). Stimulation of the two types of GABA receptors, GABA-A and GABA-B, have similar effects on vestibular pathways (Neerven et al, 1989), but specific GABA-B agonists, such as baclofen, decrease the duration of vestibular responses in animal models (Cohen et al, 1987). Baclofen has not proven very useful in vestibular medicine (e.g. Devalck et al, 1989). Drugs that affect GABA, mainly benzodiazepines, are heavily used in vestibular medicine, as they suppress dizziness as well as anxiety.
Minor transmitters of various kinds, roughly in order of importance.
Histamine (H1-H3) is found diffusely in central vestibular structures and centrally acting antihistamines modulate symptoms of motion sickness (Takeda et al, 1989). Both the H1 and H2 subtypes of histamine receptors affect vestibular responses (Serafin et al, 1992). The H3 receptor is an autoreceptor and thus affects H1 and H2. The H4 receptor affects primary vestibular neurons (Desmadryl et al, 2012). A drug that increases histamine, betahistine, is heavily used in vestibular medicine, and it is thought to affect H3 and H4. Antihistamines, generally H1 antagonists, that do not cross the blood brain barrier are not useful for dizziness (such as most allergy medications). Centrally acting antihistamines generally cause sleepiness and increase appetite, resulting in weight gain over time.
Norepinephrine is an excitatory neurotransmitter. It is involved centrally in modulating the intensity of reactions to vestibular stimulation (Wood, 1979) and also affects adaptation. Both alpha (1 and 2) and beta receptors are found in the vestibular nucleus. Drugs that manipulate norepinephrine are generally not used in vestibular medicine, aside from manipulation of alertness, that may be diminished by other drugs. According to Soto et al (2013), the vestibule receives sympathetic innervation.
Dopamine is another excitatory neurotransmitter, and it affects vestibular compensation. Dopamine blockers reduce nausea. While dopamine agonists and antagonists are readily available to treat many medical conditions, think major tranqulizers, it is rare that they are used to treat dizziness. It seems likely that they might reduce compensation.
Glycine is generally an inhibitory neurotransmitter in the CNS. Glycine receptors "colocate" with GABA receptors (Soto et al, 2012). Glycine is a "co-agonist" for glutamate, playing an excitatory role (Trist, 2000). Strychnine, which is a strong antagonist of glycine, can cause death through loss of inhibition of muscle activation and spasms. Because of this mixture of inhibition and excitation, it is difficult to understand what glycine is doing in the vestibular system.
Serotonin receptors are also found in the vestibular nerve and vestibular nucleus (5HT-1, 2 and 7, according to Soto et al, 2013), but the functional significance of this uncertain (Ahn and Balaban, 2010). CGRP co-localizes with 5HT-1F (Soto et al, 2013). Withdrawal from serotonergic drugs, such as SSRI antidepressants, is commonly associated with vertigo, and serotonin depletion can cause severe dizziness (Soto et al, 2013). It has been speculated that this is due to loss of inhibition of glutamate -- in other words, increased vestibular responses as glutamate is excitatory (Smith PF, Darlington CL, 2010). There is some equivocal data suggesting that serotonin agonists such as sumatriptan (a 5-HT1-d and1-b agonist), used for migraine can prevent motion sickness. Serotonin is one of the numerous neurotransmitters involved with nausea, and drugs that block the 5-HT3 receptor such as ondansetron are very effective.
Nitric oxide is also produced in the vestibular nucleus, and may play a role in compensation (Soto, 2013).
Cannabinoid receptors are present in the central vestibular circuitry, but their action is presently unclear (Smith, 2006). It is well known that recreational use of substances that contain THC often reduce nausea.
According to Soto et al (2013), hair cells and efferent neurons release numerous other neuroactive substances including CGRP (which co-localizes with 5HT1-1F), substance-P, opiod peptides, ATP, and adenosine. In the near future, a CGRP antagonist will become commercially available for migraine treatment, and it will be interesting to see if it is useful for vestibular medicine.
Other neurochemical apparatus in the vestibular system
Calcium channels: These are not neurotransmitters but rather are methods that neurotransmitter release is triggered. The subtypes of L, N and T are reportedly active in the vestibular system (Soto et al, 2013). In the CNS, the N or P/Q type are the ones that participate in neurotransmitter release. Because calcium channels are ubiquitous, then may affect both input and output to the vestibular system (Soto et al, 2013). Many of the calcium channel blockers used to treat vertigo are very sloppy drugs with other actions. For example, flunarizine (Rascol et al, 1989). Flunarizine is a powerful dopamine antagonist.
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8. Balance Disorders
The individual will feel unsteady when standing or walking
Ex. Vertigo, Ménière's disease, labyrinthitis, Benign paroxysmal positional vertigo (BPPV), Vestibular neuronitis
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9. Causes of Balance Disorders
CNS
Impact on vestibular nuclei , afferent inputs or efferent outputs
MENIERE’S
Inner ear
Vestibular hair cell stimulation unrelated to head and body motions
Others
Low tolerance for vehicular motion such as cars, boats, cruise ships, and airplanes that cause MOTION SICKNESS.
Fluid / Electrolyte / Ca disturbances; ↑ BP, ↑ cholesterol
diabetes, anemia , calcium disorders …..
↓ equalization of air pressure in middle ear due to blocking or swelling of Eustachian tube → undue pressure on inner ear

10. Symptoms of Balance Disorders
Dizziness or vertigo (a spinning sensation)
Falling or feeling as if you are going to fall.
Lightheadedness, faintness
Blurred vision.
Confusion or disorientation.
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11. Pathophysiology of Meniere's Disease
Inner ear chamber is filled with
perilymph & endolymph.
↑endolymphatic pressure ( hydrolymphatic hydrops )→ microscopic breaks of separating membrane often with vestibular hair loss → depolarization and functional loss
Meniere's disease is a disorder of the inner ear that can affect hearing and balance.
It is characterized by episodes of vertigo, tinnitus and progressive hearing loss .
Ménière's disease; disorder of control of inner ear fluid homeostasis

12. Drugs used to control or prevent vertigo episodes
Vertigo is a type of dizziness that creates the sense that you or your environment is SPINNING
It is associated with Nausea or vomiting, sweating, & abnormal eye movements (nystagmus)
Vestibular suppressants drugs are the mainstay of treatment of vertigo.
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13. Vestibular Suppressants
They intend to reduce brain response to vestibular signals from inner ear.
This will reduce the vertigo symptoms; spinning, nausea and vomiting
There are 2 types:
1. Vestibular suppressants (anti emetics)
2. Vestibular suppressants (drugs that reduce spinning)
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14. 1. Vestibular suppressants (anti emetics)
These include:
1. Drugs that suppress the illusion of motion (anti motion sickness) antihistamines, anticholinergics
2. Drugs that relieve nausea and vomiting accompanying the condition; dopamine antagonists.
Ex.
Anti-histaminergic - Dimenhydrinate , Promethazine
Anti-cholinergics - Scopolamine, Meclizine
Anti-dopaminergic - Droperidol
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15. A. Anti histamines:
Ex. Dimenhydrinate (Dramamine) and Promethazine (Phenergan)
M.O.A:
Inhibition of H1 receptors in vomiting center CTZ
Sedative effect
Week anticholinergic effect
S/E: Sedation, dizziness, anticholinergic s/e.
C/I: Glaucoma, prostatic enlargement
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16. B. Anti cholinergics Ex. Scopolamine, Meclizine
Anticholinergic agents affect muscarinic receptors centrally thus suppressing conduction in the vestibular- cerebellar pathways.
They are useful in symptomatic control of vertigo and motion sickness
Scopolamine transdermal application one of the most effective drugs for motion sickness.
S/E: dry mouth, dilated pupils, and sedation.
C/I: Glaucoma, prostatic enlargement
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17. C. Anti dopaminergics They block dopamine receptors at CTZ
A. Prochlorperazine (a Piprazine Phenothiazine derivative):
has an antipsychotic effects
(Schizophrania+sedation+antiemetics)
is the best antiemetic in vertigo with sedation and vestibular suppression action
B. Metochlopramide
A potent antiemetic action
Has some sedation effect
It has potent gastroprokinetic effect
S/E: Extrapyramidal symtoms (Parkinson like effect)
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18. 2. Vestibular suppressants (drugs that reduce spinning)
(Betahistine) =H1 Agonists+H3 Antagonists=the first choice
Antidepressants (benzodiazepines) promote vestibular compensation through GABA modulation i.e. Lorazepam, Clonazepam, Diazepam
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19. Betahistine
It acts as a histamine H1-agonist,Stimulating the H1- receptors in the inner ear causes a vasodilatory effect and increased permeability in the blood vessels which results in reduced endolymphatic pressure.
Betahistine also acts as a histamine H3-receptor antagonist (those are inhibitory presynaptic receptors that inhibit histamine release) which causes an increased output of histamine from histaminergic nerve endings which can further increase the direct H1-agonist activity
↑levels of neurotransmitters such as 5HT in the brainstem, which inhibits the activity of vestibular nuclei.

20. Betahistine
H 1 +
H 2 +
H 3 +
H 3
-ve presynaptic autoregulation

21. Betahistine Pharmacokinetics:
Tablet form , rapidly & completely absorbed
t½=2-3h
Partially metabolized ( active) & excreted in urine
S/E: Headache, Nausea, ↓ appetite and weight loss
Contraindications:
Peptic ulcer
Pheochromocytoma (tumor of adrenal gland)
Bronchial asthma

22. Prevention of vertigo Intend to suppress acute attacks
Diuretics (decrease fluid retention) (but not loop diuretics=furosemide)
Corticosteroids (decrease inflammation)
L-type Ca Channel Blockers i.e. Verapamil (vasodilation)
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23. Drugs that can precipitate vertigo
 They can produce damaging effects on structure or function of labyrinthine hair cells &/ or their neuronal connections.
VESTIBULOTOXINS
MIXED OTOTOXINS
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24. 1. VESTIBULOTOXINS
They affect the function of labyrinth (Vestibule only)
Induce vertigo (no hearing loss)
They are two types:
1. Drugs altering fluid & electrolytes;
Diuretics
Antihypertensives
2. Drugs altering vestibular firing;
Anticonvulsants
Antidepressants
Sedatives & hypnotics
Alcohol
Cocaine
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25. 2. MIXED OTOTOXINS They affect the function of (Vestibule + Cochlea)
Induce vertigo & impairment of hearing loss.
They cause structural or functional apoptosis in the hair cells.
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26. Structural Apoptosis
Aminoglycoside antibiotics; streptomycin, kanamycin, neomycin, gentamycin, tobramycin, netlimycin
Neomycin → activate caspases → Apoptosis
Gentamycin → induces free radicals → damages Mitochondrial Pathway→ Apoptosis
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27. Functional Apoptosis
↓local blood flow → biochemical changes → alter electromechanical transduction
Ex.
Quinine, chloroquine, quinidine
Loop diuretics (furosemide)
NSAIDs
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28. Good luck 
Mrs.Sandra Hababeh