A Textbook of Clinical Pharmacology and Therapeutics

PARKINSON’SSYNDROME AND ITSTREATMENT 125

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/decarboxy-
lase inhibitor combination is commonly used in patients with
definite disability. The dose is titrated to produce optimal
results. Occasionally, amantadineor 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 phenom-
ena) 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 usu-
ally 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 psycho-
logical 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Chapter 19) are withdrawn if possible, or substituted by the

newer ‘atypical’ antipsychotics (e.g. risperidoneorolanzapine),

since these have a lower incidence of extrapyramidal side effects.

Antimuscarinic drugs (e.g. trihexyphenidyl) are useful if chang-

ing the drug/reducing the dose is not therapeutically acceptable,

whereas drugs that increase dopaminergic transmission are con-

traindicated because of their effect on psychotic symptoms.

ANTI-PARKINSONIAN DRUGS

DRUGS AFFECTING THE DOPAMINERGIC SYSTEM

Dopaminergic activity can be enhanced by:

• levodopawith 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.Levodopais used in combination with a peripheral

(extracerebral) dopa decarboxylase inhibitor (e.g. carbidopaor

benserazide). This allows a four- to five-fold reduction in levo-

dopadose 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-careldopaor 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 levodopais metabolized outside the brain.

In their presence, plasma levodopaconcentrations rise (Figure

21.3), excretion of dopamine and its metabolites falls, and the

availability of levodopawithin 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;

Normal

Normal

Parkinsonism due to

excess acetylcholine

Cholinergic

system

(excitatory)

Anticholinergic

drugs

Dopaminergic

system

(inhibitory)

Parkinsonism due to

dopamine deficiency

Levodopa

Figure 21.2:Antagonistic actions of the dopaminergic

and cholinergic systems in the pathogenesis of

parkinsonian symptoms.

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.