A Textbook of Clinical Pharmacology and Therapeutics

PARKINSON’S SYNDROME AND ITS

TREATMENT

PATHOPHYSIOLOGY

James Parkinson first described the tremor, rigidity and
bradykinesia/akinesia that characterize the syndrome known
as Parkinson’s disease. Most cases of Parkinson’s disease are
caused by idiopathic degeneration of the nigrostriatal path-
way. Atherosclerotic, toxic (e.g. related to antipsychotic drug
treatment, manganese or carbon monoxide poisoning) and
post-encephalitic cases also occur. Treatment of parkinsonism
caused by antipsychotic drugs differs from treatment of the
idiopathic disease, but other aetiologies are treated similarly to

●Parkinson’s syndrome and its treatment 124

●Spasticity 128

●Chorea 129

●Drug-induced dyskinesias 129

●Treatment of other movement disorders 129

●Myasthenia gravis 129

●Alzheimer’s disease 131

CHAPTER 21

MOVEMENT DISORDERS AND

DEGENERATIVE CNS DISEASE

Striatum

Substantia nigra

Motor

cortex

ACh

DA

GABA

Figure 21.1:Representation of relationships between cholinergic

(ACh), dopaminergic (DA) and GABA-producing neurones in the

basal ganglia.

the idiopathic disease. Parkinsonian symptoms manifest after

loss of 80% or more of the nerve cells in the substantia nigra.

The nigrostriatal projection consists of very fine nerve fibres

travelling from the substantia nigra to the corpus striatum.

This pathway is dopaminergic and inhibitory, and the motor

projections to the putamen are more affected than either those

to the cognitive areas or to the limbic and hypolimbic regions

(Figure 21.1). Other fibres terminating in the corpus striatum

include excitatory cholinergic nerves and noradrenergic and

serotoninergic fibres, and these are also affected, but to vary-

ing extents, and the overall effect is a complex imbalance

between inhibitory and excitatory influences.

Parkinsonism arises because of deficient neural transmission

at postsynaptic D 2 receptors, but it appears that stimulation of

both D 1 and D 2 is required for optimal response. D 1 receptors

activate adenylyl cyclase, which increases intracellular cyclic

adenosine monophosphate (cAMP). The antagonistic effects of

dopamine and acetylcholine within the striatum have suggested

that parkinsonism results from an imbalance between these

neurotransmitters (Figure 21.2). The therapeutic basis for treat-

ing parkinsonism is to increase dopaminergic activity or to

reduce the effects of acetylcholine. 1-Methyl-4-phenyl-1,2,5,6-

tetrahydropyridine (MPTP) has been used illicitly as a drug of

abuse and it causes severe parkinsonism. MPTP is converted by

monoamine oxidase-B (MAO-B) in neuronal mitochondria to a

toxic free-radical metabolite (MPP), which is specifically toxic

to dopamine-producing cells. This led to the hypothesis that

idiopathic Parkinson’s disease may be due to chronically

increased free-radical damage to the cells of the substantia nigra.

However, clinical studies of anti-oxidants have so far been

disappointing.

The free-radical hypothesis has raised the worrying possibil-

ity that treatment with levodopa (see below) could accelerate

disease progression by increasing free-radical formation as the

drug is metabolized in the remaining nigro-striatal nerve fibres.

This is consistent with the clinical impression of some neurolo-

gists, but in the absence of randomized clinical trials it is

difficult to tell whether clinical deterioration is due to the natu-

ral history of the disease or is being accelerated by the therapeu-

tic agent.