Clinical Pharmacology and Therapeutics

PARKINSON’S SYNDROME AND ITS TREATMENT 125
Normal
Parkinsonism due to
excess acetylcholine
Levodopa
Dopaminergic
system
(inhibitory)
Parkinsonism due to
dopamine deficiency
Normal
Cholinergic
system
(excitatory)
Anticholinergic
drugs
Figure 21.2: Antagonistic actions of the dopaminergic
and cholinergic systems in the pathogenesis of
parkinsonian symptoms.
PRINCIPLES OF TREATMENT IN PARKINSONISM
Idiopathic Parkinson’s disease is a progressive disorder, and is
treated with drugs that relieve symptoms and if possible
slow disease progression. Treatment is usually initiated when
symptoms disrupt normal daily activities. Initial treatment is
often with a dopamine receptor agonist, e.g. bromocriptine,
particularly in younger (70) patients. A levodopa/decarboxylase
inhibitor combination is commonly used in patients with
definite disability. The dose is titrated to produce optimal
results. Occasionally, amantadine or anticholinergics may be
useful as monotherapy in early disease, especially in younger
patients when tremor is the dominant symptom. In patients on
levodopa the occurrence of motor fluctuations (on–off phenomena)
heralds a more severe phase of the illness. Initially, such
fluctuations may be controlled by giving more frequent doses
of levodopa (or a sustained-release preparation). The addition
of either a dopamine receptor agonist (one of the non-ergot
derivatives, e.g. ropinirole) or one of the calechol-O-methyl
transferase (COMT) inhibitors (e.g. entacapone, tolcapone) to
the drug regimen may improve mobility. In addition, this usually
allows dose reduction of the levodopa, while improving
‘end-of-dose’ effects and improving motor fluctuations. If on–off
phenomena are refractory, the dopamine agonist apomorphine
can terminate ‘off’ periods, but its use is complex (see below).
Selegiline, a MAO-B inhibitor, may reduce the end-of-dose
deterioration in advanced disease. Physiotherapy and psychological
support are helpful. The experimental approach of
implantation of stem cells into the substantia nigra of severely
affected parkinsonian patients (perhaps with low-dose
immunosuppression) is being investigated. The potential of
stereotactic unilateral pallidotomy, for severe refractory cases of
Parkinson’s disease is being re-evaluated.
Drugs that cause parkinsonism, notably conventional
antipsychotic drugs (e.g. chlorpromazine, haloperidol) (see
Chapter 19) are withdrawn if possible, or substituted by the
Key points
Parkinson’s disease
• Clinical diagnosis is based on the triad of tremor,
rigidity and bradykinesia.
• Parkinsonism is caused by the degeneration of
dopaminergic pathways in basal ganglia leading to
imbalance between cholinergic (stimulatory) and
dopaminergic (inhibitory) transmission.
• It is induced/exacerbated by centrally acting dopamine
antagonists (e.g. haloperidol), but less so by clozapine,
risperidone or olanzapine.
newer ‘atypical’ antipsychotics (e.g. risperidone or olanzapine),
since these have a lower incidence of extrapyramidal side effects.
Antimuscarinic drugs (e.g. trihexyphenidyl) are useful if changing
the drug/reducing the dose is not therapeutically acceptable,
whereas drugs that increase dopaminergic transmission are contraindicated
because of their effect on psychotic symptoms.
ANTI-PARKINSONIAN DRUGS
DRUGS AFFECTING THE DOPAMINERGIC SYSTEM
Dopaminergic activity can be enhanced by:
• levodopa with a peripheral dopa decarboxylase inhibitor;
• increasing release of endogenous dopamine;
• stimulation of dopamine receptors;
• inhibition of catechol-O-methyl transferase;
• inhibition of monoamine oxidase type B.
LEVODOPA AND DOPA DECARBOXYLASE INHIBITORS
Use
Levodopa (unlike dopamine) can enter nerve terminals in the
basal ganglia where it undergoes decarboxylation to form
dopamine. Levodopa is used in combination with a peripheral
(extracerebral) dopa decarboxylase inhibitor (e.g. carbidopa or
benserazide). This allows a four- to five-fold reduction in levodopa
dose and the incidence of vomiting and dysrhythmias is
reduced. However, central adverse effects (e.g. hallucinations)
are (predictably) as common as when larger doses of levodopa
are given without a dopa decarboxylase inhibitor.
Combined preparations (co-careldopa or co-beneldopa)
are appropriate for idiopathic Parkinson’s disease. (Levodopa
is contraindicated in schizophrenia and must not be used for
parkinsonism caused by antipsychotic drugs.) Combined
preparations are given three times daily starting at a low dose,
increased initially after two weeks and then reviewed at
intervals of six to eight weeks. Without dopa decarboxylase
inhibitors, 95% of levodopa is metabolized outside the brain.
In their presence, plasma levodopa concentrations rise (Figure
21.3), excretion of dopamine and its metabolites falls, and the
availability of levodopa within the brain for conversion to
dopamine increases. The two available inhibitors are similar.
Adverse effects
These include the following:
• nausea and vomiting;
• postural hypotension – this usually resolves after a few
weeks, but excessive hypotension may result if
antihypertensive treatment is given concurrently;