A Textbook of Clinical Pharmacology and Therapeutics

126 MOVEMENT DISORDERS AND DEGENERATIVE CNS DISEASE

• involuntary movements (dystonic reactions) – these
  include akathisia (abnormal restlessness and inability to
  keep still), chorea and jerking of the limbs (myoclonus).
  Involuntary movements may become worse as treatment
  is continued, and may necessitate drug withdrawal;


• psychological disturbance, including vivid dreams,
  agitation, paranoia, confusion and hallucinations;


• cardiac dysrhythmias;


• endocrine effects of levodopa, including stimulation of
  growth hormone and suppression of prolactin.


• sedation and sudden onset of sleep (avoid driving at onset
  of treatment and if these symptoms recur).

Pharmacokinetics

Levodopais absorbed from the proximal small intestine and is
metabolized both by decarboxylases in the intestinal wall and
by the gut flora. Oral absorption is variable. Absorption/
bioavailability are improved by co-administration of decar-
boxylase inhibitors. Addition of a COMT inhibitor further
increases t1/2and AUC.

Drug interactions

Monoamine oxidase inhibitors can produce hypertension if
given concurrently with levodopa. The hypotensive actions of
other drugs are potentiated by levodopa.

INCREASED RELEASE OF ENDOGENOUS

DOPAMINE

AMANTADINE

Use

Amantadinehas limited efficacy, but approximately 60% of
patients experience some benefit. Severe toxicity is rare.

Mechanism of action

Endogenous dopamine release is stimulated by amantadine,
which also inhibits reuptake of dopamine into nerve terminals.

Adverse effects

These include the following:

• peripheral oedema;


• gastro-intestinal upset and dry mouth;


• livedo reticularis;


• CNS toxicity – nightmares, insomnia, dizziness,
  hallucinations, convulsions;


• leukopenia (uncommon).

Pharmacokinetics

Thet1/2ofamantadinevaries from 10 to 30 hours, so steady-

state concentrations are reached after four to seven days of treat-

ment. About 95% is eliminated by the kidneys and it should not

be used in patients with renal failure.

DOPAMINE RECEPTOR AGONISTS

Uses

Dopamine receptor agonists are used as initial therapy or as

adjuncts to levodopa–dopa decarboxylase inhibitor combin-

ations in patients with severe motor fluctuations (on–off

phenomena). Dopamine agonists share many of their adverse

effects with levodopa, particularly nausea due to stimulation of

dopamine receptors in the chemoreceptor trigger zone. This

brain region is unusual in that it is accessible to drugs in the sys-

temic circulation, so domperidone(a dopamine antagonist that

does not cross the blood–brain barrier) prevents this symptom

without blocking dopamine receptors in the striatum, and hence

worsening the movement disorder. Neuropsychiatric disorders

are more frequent than with levodopamonotherapy. (See also

Chapter 42 for use in pituitary disorders, and Chapter 41 for use

in suppression of lactation). Pulmonary, retroperitoneal and

pericardial fibrotic reactions have been associated with some

ergot-derived dopamine agonists. Dopamine receptor agonists

are started at a low dose that is gradually titrated upwards

depending on efficacy and tolerance. If added to levodopa, the

dose of the latter may be reduced.

Ergot derivatives include bromocriptine,lisuride,pergolide

andcabergoline. Other licensed dopamine agonists include

pramipexole,ropiniroleandrotigotine.

There is great individual variation in the efficacy of

dopamine receptor agonists. The initial dose is gradually

titrated upwards depending on response and adverse effects.

Adverse effects

These are primarily due to D 2 agonist activity, although 5HT 1

and 5HT 2 effects are also relevant.

• gastro-intestinal – nausea and vomiting, constipation or
  diarrhoea;


• central nervous system – headache, drowsiness,
  confusion, psychomotor excitation, hallucination;


• orthostatic hypotension (particularly in the elderly),
  syncope;


• cardiac dysrhythmias – bradycardia;

L-dopa (100 mg)  MK 485

L-dopa (1000 mg)

L-dopa (100 mg)

0

0.2

0.4

0.6

0.8

1.2

1.0

2468

Plasma dopa concentration (

g/mL)

Time after L-dopa dose (h)

Figure 21.3:Increased plasma dopa concentrations following
combination with a peripheral dopa decarboxylase inhibitor
(MK 485) in one patient. (Redrawn with permission from Dunner DL
et al. Clinical Pharmacology and Therapeutics1971; 12 : 213.)