Clinical Pharmacology and Therapeutics

MYASTHENIA GRAVIS 129
CHOREA
The γ-aminobutyric acid content in the basal ganglia is reduced
in patients with Huntington’s disease. Dopamine receptor
antagonists (e.g. haloperidol) or tetrabenazine suppress the
choreiform movements in these patients, but dopamine antagonists
are best avoided, as they themselves may induce dyskinesias.
Tetrabenazine is therefore preferred. It depletes neuronal
terminals of dopamine and serotonin. It can cause severe doserelated
depression. Diazepam may be a useful alternative, but
there is no effective treatment for the dementia and other manifestations
of Huntington’s disease.
DRUG-INDUCED DYSKINESIAS
• The most common drug-induced movement disorders are
‘extrapyramidal symptoms’ related to dopamine receptor
blockade.
• The most frequently implicated drugs are the
‘conventional’ antipsychotics (e.g. haloperidol and
fluphenazine). Metoclopramide, an anti-emetic, also
blocks dopamine receptors and causes dystonias.
• Acute dystonias can be effectively treated with parenteral
benzodiazepine (e.g. diazepam) or anticholinergic (e.g.
procyclidine).
• Tardive dyskinesia may be permanent.
• Extrapyramidal symptoms are less common with the newer
‘atypical’ antipsychotics (e.g. olanzapine or aripiprazole).
NON-DOPAMINE-RELATED MOVEMENT
DISORDERS
• ‘Cerebellar’ ataxia – ethanol, phenytoin
• Tremor
• β-Adrenoceptor agonists, e.g. salbutamol;
• caffeine;
• thyroxine;
• SSRls, e.g. fluoxetine;
• valproate;
• withdrawal of alcohol and benzodiazepines.
• vestibular toxicity – aminoglycosides;
• myasthenia – aminoglycosides;
• proximal myopathy – ethanol, corticosteroids;
• myositis – lipid-lowering agents – statins, fibrates;
• tenosynovitis – fluoroquinolones.
TREATMENT OF OTHER MOVEMENT
DISORDERS
TICS AND IDIOPATHIC DYSTONIAS
Botulinum A toxin is one of seven distinct neurotoxins produced
by Clostridium botulinum and it is a glycoprotein. It is
used by neurologists to treat hemifacial spasm, blepharospasm,
cervical dystonia (torticollis), jaw-closing oromandibular dystonia
and adductor laryngeal dysphonia. Botulinum A toxin is
given by local injection into affected muscles, the injection site
being best localized by electromyography. Recently, it has also
proved successful in the treatment of achalasia. Injection of
botulinum A toxin into a muscle weakens it by irreversibly
blocking the release of acetylcholine at the neuromuscular junction.
Muscles injected with botulinum A toxin atrophy and
become weak over a period of 2–20 days and recover over two
to four months as new axon terminals sprout and restore transmission.
Repeated injections can then be given. The best longterm
treatment plan has not yet been established. Symptoms
are seldom abolished and adjuvant conventional therapy
should be given. Adverse effects due to toxin spread causing
weakness of nearby muscles and local autonomic dysfunction
can occur. In the neck, this may cause dysphagia and aspiration
into the lungs. Electromyography has detected evidence of
systemic spread of the toxin, but generalized weakness does
not occur with standard doses. Occasionally, a flu-like reaction
with brachial neuritis has been reported, suggesting an acute
immune response to the toxin. Neutralizing antibodies to botulinum
toxin A cause loss of efficacy in up to 10% of patients.
Botulinum B toxin does not cross-react with neutralizing antibodies
to botulinum toxin A, and is effective in patients with
torticollis who have botulinum toxin A-neutralizing antibodies.
The most common use of botulinum is now cosmetic.
AMYOTROPHIC LATERAL SCLEROSIS (MOTOR
NEURONE DISEASE)
Riluzole is used to extend life or time to mechanical ventilation
in patients with the amyotrophic lateral sclerosis (ALS)
form of motor neurone disease (MND). It acts by inhibiting
the presynaptic release of glutamate. Side effects include nausea,
vomiting, dizziness, vertigo, tachycardia, paraesthesia
and liver toxicity.
MYASTHENIA GRAVIS
PATHOPHYSIOLOGY
Myasthenia gravis is a syndrome of increased fatiguability and
weakness of striated muscle, and it results from an autoimmune
process with antibodies to nicotinic acetylcholine receptors.
These interact with postsynaptic nicotinic cholinoceptors at the
neuromuscular junction. (Such antibodies may be passively
transferred via purified immunoglobulin or across the placenta
to produce a myasthenic neonate.) Antibodies vary from one
patient to another, and are often directed against receptor-protein
domains distinct from the acetylcholine-binding site.
Nonetheless, they interfere with neuromuscular transmission
by reducing available receptors, by increasing receptor turnover
by activating complement and/or cross-linking adjacent receptors.
Endplate potentials are reduced in amplitude, and in some
fibres may be below the threshold for initiating a muscle action