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

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
and pergolide).
APOMORPHINE
Apomorphine is a powerful dopamine agonist at both D 1 and
D 2 receptors, and is used in patients with refractory motor oscillations
(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 gastrointestinal
side effects can be controlled with domperidone.
Apomorphine is started in hospital after pretreatment with
domperidone for at least three days, and withholding other antiparkinsonian
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. Apomorphine is
extensively hepatically metabolized and is given parenterally.
The mean plasma t 1/2 is approximately 30 minutes.
CATECHOL-O-METHYL TRANSFERASE INHIBITORS
Use
Tolcapone and entacapone are used for adjunctive therapy in
patients who are already taking L-dopa/dopa decarboxylase
inhibitor combinations with unsatisfactory control (e.g. end-ofdose
deterioration). These agents improve symptoms with less
on–off fluctuations, as well as reducing the levodopa dose
requirement by 20–30%. Adverse effects arising from increased
availability of L-dopa centrally can be minimized by decreasing
the dose of levodopa combination treatment prospectively.
Because of hepatotoxicity associated with tolcapone it is
only used by specialists when entacapone is 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 nervous
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 lifethreatening
with tolcapone (liver function testing is
mandatory before and during treatment);
• urine discolouration.
Pharmacokinetics
Tolcapone is rapidly absorbed and is cleared by hepatic metabolism.
At recommended doses it produces approximately
80–90% inhibition of central COMT.
Drug interactions
Apomorphine is metabolized by O-methylation, so interaction
with COMT inhibitors is to be anticipated. COMT
inhibitors should not be administered with MAOIs, as blockade
of both pathways of monoamine metabolism simultaneously
has the potential to enhance the effects of endogenous
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
selegiline alone, delaying the need to start levodopa. Largerscale
studies have not confirmed this conclusion. MAO type B
inhibitors, such as selegiline and rasagiline, may be used in
conjunction with levodopa to reduce end-of-dose deterioration.
Mechanism of action
There are two forms of monoamine oxidase (MAO), namely
type A (substrates include 5-hydroxytryptamine and tyramine)
and type B (substrates include phenylethylamine). MAO-B,
is mainly localized in neuroglia. MAO-A metabolizes endogenous
adrenaline, noradrenaline and 5-hydroxytryptamine,
while the physiological role of MAO-B is unclear. Both isoenzymes
metabolize dopamine. Inhibition of MAO-B raises
brain dopamine levels without affecting other major transmitter
amines. Because selegiline and rasagiline selectively
inhibit MAO-B, they are much less likely to produce a hypertensive
reaction with cheese or other sources of tyramine than
non-selective MAOIs, such as phenelzine.
Adverse effects
Selegiline is generally well tolerated, but side effects include
the following:
• agitation and involuntary movements;
• confusion, insomnia and hallucinations;
• nausea, dry mouth, vertigo;
• peptic ulceration.
Pharmacokinetics
Oral selegiline is well absorbed (100%), but is extensively metabolized
by the liver, first to an active metabolite, desmethylselegiline
(which also inhibits MAO-B) and then to amphetamine and
metamphetamine. Its plasma t 1/2 is 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