Drugs in equilibrium disorder

Nurina Hasanatuludhhiyah dr., M.Si

 Learning objectives
Setelah mengikuti kuliah ini, mahasiswa smt 5 FK UNAIR
mampu menjelaskan :
• Mekanisme dasar neurotoksisitas
• Obat yang dapat menyebabkan efek gangguan
keseimbangan
• Mekanisme toksisitas obat/senyawa terhadap sistem
keseimbangan
• Obat yang digunakan untuk terapi gangguan
keseimbangan
 Outlines
• Basic of neurotoxicity
• Mechanism of neurotoxicity
• Drug/substance which may cause equillibrium
disorder
• Mechanism of vestibulotoxic drugs
• Mechanism of drug induced cerebellar disorder
• Mechanism of drug induced sensory ataxia
• Drug treatment for equilibrium disorder
 Anatomical & physiological basis of
neurotoxicity
• The privileged status of nervous
system → protected with blood
brain barrier
• High energy requirements
• Spatial extensions as long
cellular processes
• The transmission of information
across synapse
• The maintenance of an
environment rich in lipids
Comparison between systemic
and brain capillaries
Patterns of
neurotoxic
injuries
Mechanisms of neurotoxicity
Targets of neurotoxic agents:
• Neuron
• Axon
• Myelinating cell
• Neurotransmitter system
 Neuronopathies
• Injury or death of neurons
• Irreversible
• Include degeneration of all of its
cytoplasmic extensions, dendrites, axons,
myelin
• Toxic agents tend to be diffuse in their
action → often diffuse encephalopathy w/
global dysfunction
 Axonopathies
• Axon degenerates
• Cell body intact
• Effect of toxicants – chemical transection
• Peripheral axon can regenerate whereas
central axon cannot
• Sensations and motor strength are first
impaired in the feet & hands → “ glove &
stocking” neuropathy
 Myelinopathies
• Absence of myelin – slowing of
conduction & aberrant conduction of
impulses
• Exposure to toxicants :
separation of the myelin lamellae
(intramyelinic edema)
selective loss of myelin
(demyelination)
• Remyelination : CNS (limited)
 Neurotransmission-associated
neurotoxicity
Mechanisms
• Interrupt transmission of impulses
• Block or accentuate transsynaptic
communication
• Block the reuptake of neurotransmitter
• Interfere with second- messenger systems
Drug/substance induced
equilibrium disorder
 Toxic vestibulopathies
Substances Mechanisms Manifestations
Alcohol Differential distribution between Acute positional vertigo
cupula and endolymph
Aminoglycosides Destroying sensory hair cells Vertigo; nausea vomiting;
Streptomycin gait ataxia; nystagmus
Gentamycin
Tobramycin
Salicylates Cochlear and vestibular end Vertigo, tinnitus,
organ damage sensoryneural hearing
loss
Quinine Impairment of N. VIII; Alteration Cinchonism: vertigo,
of outer hari cells; decrease tinitus, sensoryneural
blood flow hearing loss
Cisplatin ATPase inhibition & increased Tinnitus, vestibular
oxidative stress in labyrinth dysfunction
 Drug/substance induced
cerebellar disorder
Acute
Due to acute intoxication of:
• Ethanol
• Sedative hypnotics
• anti convulsants
• hallucinogens
Chronic
• Alcoholic cerebellar
degeneration
• Toxin induced cerebellar
degeneration
- Phenytoin; Lithium;
Amiodarone; Fluorouracil;
Cytarabine; Toluene;
Lead; Mercury; Thallium
 Drug/substance induced
cerebellar disorder
Substances Mechanisms Manifestations
Phenytoin Degeneration of Nystagmus, ataxia,
Purkinje cells dizziness
Alcohol -Pirkinje cells loss in -ataxia; nystagmus;
superior vermis dysarthria
-Thiamine deficiency -Wernicke
encephalopathy
Cytarabine -Purkinje cells loss -ataxia; dysarthria;
in the depths of nystagmus
cortical sulci
 Drug/substance induced
sensory ataxia
• Sensory neuronopathy- targets dorsal root
ganglia
Ex: Doxorubicin (lack data in human); High dose of
Pyridoxine
• Sensory neuropathy- targets peripheral sensory
nerves
Ex: Isoniazid, Platinum analogs, Podopyllin, Taxol
• Myelopathy – targets posterior columns of spinal
cord
• Combined lesions: Nitrous oxide, Vit B12
deficiency, Vit E deficiency
 Vestibular
vertigo disorder nystagmus

Equilibrium disorder
symptoms

Cerebellar or sensory ataxia

Soto, E., Vega, R., & Seseña, E. (2013). Neuropharmacological basis of vestibular
system disorder treatment. Journal of Vestibular Research, 23(3), 119-137.
 Drug treatment for
vestibular disorder-based on molecular target
Antihistamin Anticholiner Calcium GABA
e gic antagonist

Drugs Betahistin Scopolamine Cinnarizine Benzodiazepines

Dyphenhyra Atropine Flunarizine Baclofen
mine Gabapentin
Dimenhydrin
ate
Meclizine
Cyclizine
Mecha improves the Reduced -antihistaminic inhibitory input on
nism labyrinthine activation of action the
microcirculati vestibular -affect the input and vestibular nuclei
on by acting neurons output
on the of information of the
precapillary vestibular nuclei
sphincters of -blocker of the
the stria pressure sensitive
vascularis potassium channels
 Principles of pharmacotherapy in
vestibular disorders
• acute vestibular symptoms
• specific treatment -for 1. Correct
example, Meniere’s diagnosis
disease, migraine or 4Ds 2. Correct drug
epilepsy 3. Appropriate
• non-specific but empirical dosage
treatment of a chronic 4. Sufficient
vestibular disorder —for duration
example, central vestibular
symptoms.
 Refferences
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Soto, E., Vega, R., & Seseña, E. (2013). Neuropharmacological basis
of vestibular system disorder treatment. Journal of Vestibular
Research, 23(3), 119-137
Yacovino DA, Luis L. 2014. Pharmacologic treatment of vestibular
disorder. Vestibular disorder association. Vestibular.org