A Textbook of Clinical Pharmacology and Therapeutics

cervical dystonia (torticollis), jaw-closing oromandibular dysto-

nia 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 junc-

tion. 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 trans-

mission. Repeated injections can then be given. The best long-

term 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 botu-

linum toxin A cause loss of efficacy in up to 10% of patients.

Botulinum B toxin does not cross-react with neutralizing anti-

bodies 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)

Riluzoleis used to extend life or time to mechanical ventila-

tion 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 nau-

sea, 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-pro-

tein 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 recep-

tors. Endplate potentials are reduced in amplitude, and in some

fibres may be below the threshold for initiating a muscle action

CHOREA

Theγ-aminobutyric acid content in the basal ganglia is reduced
in patients with Huntington’s disease. Dopamine receptor
antagonists (e.g. haloperidol) or tetrabenazinesuppress the
choreiform movements in these patients, but dopamine antag-
onists are best avoided, as they themselves may induce dyski-
nesias.Tetrabenazineis therefore preferred. It depletes neuronal
terminals of dopamine and serotonin. It can cause severe dose-
related depression. Diazepammay be a useful alternative, but
there is no effective treatment for the dementia and other mani-
festations 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. haloperidoland
  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. olanzapineoraripiprazole).

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 pro-
duced by Clostridium botulinumand it is a glycoprotein. It is
used by neurologists to treat hemifacial spasm, blepharospasm,

MYASTHENIAGRAVIS 129