A Textbook of Clinical Pharmacology and Therapeutics

128 MOVEMENT DISORDERS AND DEGENERATIVE CNS DISEASE

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 sur-

gical release procedures or local injection of botulinum toxin

(see below) all have a role to play. Drugs that reduce spasticity

includediazepam,baclofen,tizanidineanddantrolene, but

they have considerable limitations.

Diazepam (see Chapter 18, Hypnotics and anxiolytics)

facili-tatesγ-aminobutyric acid (GABA) action. Although spas-

ticity and flexor spasms may be diminished, sedating doses are

often needed to produce this effect.

Baclofenfacilitates GABA-B receptors and also reduces

spasticity. Less sedation is produced than by equi-effective

doses of diazepam, but baclofencan cause vertigo, nausea and

hypotension. Abrupt withdrawal may precipitate hyperactiv-

ity, 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 baclofenbecause

muscle power is reduced as spasticity is relieved. It is used

intravenously to treat malignant hyperthermia and the neu-

roleptic 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.

potentiated. Hypertensive reactions to tyramine-containing
products (e.g. cheese or yeast extract) have been described,
but are rare. Amantadineand 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 pro-
duce 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.

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

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.