A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

128 MOVEMENT DISORDERS AND DEGENERATIVE CNS DISEASE
potentiated. Hypertensive reactions to tyramine-containing
products (e.g. cheese or yeast extract) have been described,
but are rare. Amantadine and centrally active antimuscarinic
agents potenti-ate the anti-parkinsonian effects of selegiline.
Levodopa-induced postural hypotension may be potentiated.
DRUGS AFFECTING THE CHOLINERGIC SYSTEM
MUSCARINIC RECEPTOR ANTAGONISTS
Use
Muscarinic antagonists (e.g. trihexyphenidyl, benzatropine,
orphenadrine, procyclidine) are effective in the treatment of
parkinsonian tremor and – to a lesser extent – rigidity, but produce
only a slight improvement in bradykinesia. They are
usually given in divided doses, which are increased every two
to five days until optimum benefit is achieved or until adverse
effects occur. Their main use is in patients with parkinsonism
caused by antipsychotic agents.
Mechanism of action
Non-selective muscarinic receptor antagonism is believed to
restore, in part, the balance between dopaminergic/cholinergic
pathways in the striatum.
Key points
Treatment of Parkinson’s disease
• A combination of levodopa and a dopa-decarboxylase
inhibitor (carbidopa or benserazide) or a dopamine
agonist (e.g. ropinirole) are standard first-line therapies.
• Dopamine agonists and COMT inhibitors (e.g.
entacapone) are helpful as adjuvant drugs for patients
with loss of effect at the end of the dose interval, and
to reduce ‘on–off’ motor fluctuations.
• The benefit of early treatment with an MAO-B
inhibitor, selegiline, to retard disease progression is
unproven, and it may even increase mortality.
• Polypharmacy is almost inevitable in patients with
longstanding disease.
• Ultimately, disease progression requires increasing drug
doses with a regrettable but inevitable increased
incidence of side effects, especially involuntary
movements and psychosis.
• Anticholinergic drugs reduce tremor, but dose-limiting
CNS side effects are common, especially in the elderly.
These drugs are first-line treatment for parkinsonism
caused by indicated (essential) antipsychotic drugs.
Adverse effects
These include the following:
• dry mouth, blurred vision, constipation;
• precipitation of glaucoma or urinary retention – they are
therefore contraindicated in narrow angle glaucoma and
in men with prostatic hypertrophy;
• cognitive impairment, confusion, excitement or psychosis,
especially in the elderly.
Pharmacokinetics
Table 21.1 lists some drugs of this type that are in common
use, together with their major pharmacokinetic properties.
SPASTICITY
Spasticity is an increase in muscle tone, for example, due to
damage to upper motor neurone pathways following stroke or
in demyelinating disease. It can be painful and disabling.
Treatment is seldom very effective. Physiotherapy, limited surgical
release procedures or local injection of botulinum toxin
(see below) all have a role to play. Drugs that reduce spasticity
include diazepam, baclofen, tizanidine and dantrolene, but
they have considerable limitations.
Diazepam (see Chapter 18, Hypnotics and anxiolytics)
facili-tates γ-aminobutyric acid (GABA) action. Although spasticity
and flexor spasms may be diminished, sedating doses are
often needed to produce this effect.
Baclofen facilitates GABA-B receptors and also reduces
spasticity. Less sedation is produced than by equi-effective
doses of diazepam, but baclofen can cause vertigo, nausea and
hypotension. Abrupt withdrawal may precipitate hyperactivity,
convulsions and autonomic dysfunction. There is specialist
interest in chronic administration of low doses of baclofen
intrathecally via implanted intrathecal cannulae in selected
patients in order to maximize efficacy without causing side
effects.
Dantrolene (a ryanodine receptor antagonist) is generally
less useful for symptoms of spasticity than baclofen because
muscle power is reduced as spasticity is relieved. It is used
intravenously to treat malignant hyperthermia and the neuroleptic
malignant syndrome, for both of which it is uniquely
effective (see Chapter 24). Its adverse effects include:
• drowsiness, vertigo, malaise, weakness and fatigue;
• diarrhoea;
• increased serum potassium levels.
Table 21.1: Common muscarinic receptor antagonists, dosing and pharmacokinetics
Drug Route of Half-life (hours) Metabolism and Special features
administration
excretion
Trihexyphenidyl Oral 3–7 Hepatic
Orphenadrine Oral 13.7–16.1 Hepatic-active Central
metabolite stimulation
Procyclidine Oral 12.6 Hepatic