A Textbook of Clinical Pharmacology and Therapeutics

PARKINSON’S SYNDROME AND ITS TREATMENT 127

• pulmonary, retroperitoneal and pericardial fibrotic
  reactions have been associated with the ergot-derived
  dopamine agonists (bromocriptine,cabergoline,lisuride
  andpergolide).

APOMORPHINE

Apomorphineis a powerful dopamine agonist at both D 1 and
D 2 receptors, and is used in patients with refractory motor oscil-
lations (on–off phenomena). It is difficult to use, necessitating
specialist input. The problems stem from its pharmacokinetics
and from side effects of severe nausea and vomiting. The gastro-
intestinal side effects can be controlled with domperidone.
Apomorphineis started in hospital after pretreatment with
domperidonefor at least three days, and withholding other anti-
parkinsonian treatment at night to provoke an ‘off’ attack. The
subcutaneous dose is increased and when the individual dose
requirement has been established, with reintroduction of other
drugs if necessary, administration is sometimes changed from
intermittent dosing to subcutaneous infusion via a syringe pump,
with patient-activated extra boluses if needed. Apomorphineis
extensively hepatically metabolized and is given parenterally.
The mean plasma t1/2is approximately 30 minutes.

CATECHOL-O-METHYL TRANSFERASE INHIBITORS

Use

Tolcaponeandentacaponeare used for adjunctive therapy in
patients who are already taking L-dopa/dopa decarboxylase
inhibitor combinations with unsatisfactory control (e.g. end-of-
dose deterioration). These agents improve symptoms with less
on–off fluctuations, as well as reducing the levodopadose
requirement by 20–30%. Adverse effects arising from increased
availability of L-dopa centrally can be minimized by decreas-
ing the dose of levodopacombination treatment prospectively.
Because of hepatotoxicity associated with tolcaponeit is
only used by specialists when entacaponeis ineffective as an
adjunctive treatment.

Mechanism of action

Reversible competitive inhibition of COMT, thereby reducing
metabolism of L-dopa and increasing its availability within
nigrostriatal nerve fibres. It is relatively specific for central ner-
vous system (CNS) COMT, with little effect on the peripheral
COMT, thus causing increased brain concentrations of L-dopa,
while producing less of an increase in plasma concentration.

Adverse effects

These include the following:

• nausea, vomiting, diarrhoea and constipation;


• increased levodopa-related side effects;


• neuroleptic malignant syndrome;


• dizziness;


• hepatitis – rare with entacapone, but potentially life-
  threatening with tolcapone(liver function testing is
  mandatory before and during treatment);


• urine discolouration.

Pharmacokinetics

Tolcaponeis rapidly absorbed and is cleared by hepatic metab-

olism. At recommended doses it produces approximately

80–90% inhibition of central COMT.

Drug interactions

Apomorphine is metabolized by O-methylation, so inter-

action with COMT inhibitors is to be anticipated. COMT

inhibitors should not be administered with MAOIs, as block-

ade of both pathways of monoamine metabolism simultane-

ously has the potential to enhance the effects of endogen-

ous and exogenous amines and other drugs unpredictably.

MONOAMINE OXIDASE INHIBITORS – TYPE B

SELEGILINE AND RASAGILINE

Use

Initial small controlled studies in Parkinson’s disease reported

that disease progression was slowed in patients treated with

selegilinealone, delaying the need to start levodopa. Larger-

scale studies have not confirmed this conclusion. MAO type B

inhibitors, such as selegilineandrasagiline, may be used in

conjunction with levodopato reduce end-of-dose deterioration.

Mechanism of action

There are two forms of monoamine oxidase (MAO), namely

type A (substrates include 5-hydroxytryptamine and tyram-

ine) and type B (substrates include phenylethylamine). MAO-B,

is mainly localized in neuroglia. MAO-A metabolizes endoge-

nous adrenaline, noradrenaline and 5-hydroxytryptamine,

while the physiological role of MAO-B is unclear. Both isoen-

zymes metabolize dopamine. Inhibition of MAO-B raises

brain dopamine levels without affecting other major transmit-

ter amines. Because selegilineand rasagiline selectively

inhibit MAO-B, they are much less likely to produce a hyper-

tensive reaction with cheese or other sources of tyramine than

non-selective MAOIs, such as phenelzine.

Adverse effects

Selegilineis generally well tolerated, but side effects include

the following:

• agitation and involuntary movements;


• confusion, insomnia and hallucinations;


• nausea, dry mouth, vertigo;


• peptic ulceration.

Pharmacokinetics

Oralselegilineis well absorbed (100%), but is extensively metab-

olized by the liver, first to an active metabolite, desmethylselegi-

line (which also inhibits MAO-B) and then to amphetamine and

metamphetamine. Its plasma t1/2is long (approximately 39 h).

Drug interactions

At very high doses (six times the therapeutic dose), MAO-B

selectivity is lost and pressor responses to tyramine are