A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition
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PARKINSON’S SYNDROME AND ITS TREATMENT 125<br />
Normal<br />
Parkinsonism due to<br />
excess acetylcholine<br />
Levodopa<br />
Dopaminergic<br />
system<br />
(inhibitory)<br />
Parkinsonism due to<br />
dopamine deficiency<br />
Normal<br />
Cholinergic<br />
system<br />
(excitatory)<br />
Anticholinergic<br />
drugs<br />
Figure 21.2: Antagonistic actions <strong>of</strong> the dopaminergic<br />
<strong>and</strong> cholinergic systems in the pathogenesis <strong>of</strong><br />
parkinsonian symptoms.<br />
PRINCIPLES OF TREATMENT IN PARKINSONISM<br />
Idiopathic Parkinson’s disease is a progressive disorder, <strong>and</strong> is<br />
treated with drugs that relieve symptoms <strong>and</strong> if possible<br />
slow disease progression. Treatment is usually initiated when<br />
symptoms disrupt normal daily activities. Initial treatment is<br />
<strong>of</strong>ten with a dopamine receptor agonist, e.g. bromocriptine,<br />
particularly in younger (70) patients. A levodopa/decarboxylase<br />
inhibitor combination is commonly used in patients with<br />
definite disability. The dose is titrated to produce optimal<br />
results. Occasionally, amantadine or anticholinergics may be<br />
useful as monotherapy in early disease, especially in younger<br />
patients when tremor is the dominant symptom. In patients on<br />
levodopa the occurrence <strong>of</strong> motor fluctuations (on–<strong>of</strong>f phenomena)<br />
heralds a more severe phase <strong>of</strong> the illness. Initially, such<br />
fluctuations may be controlled by giving more frequent doses<br />
<strong>of</strong> levodopa (or a sustained-release preparation). The addition<br />
<strong>of</strong> either a dopamine receptor agonist (one <strong>of</strong> the non-ergot<br />
derivatives, e.g. ropinirole) or one <strong>of</strong> the calechol-O-methyl<br />
transferase (COMT) inhibitors (e.g. entacapone, tolcapone) to<br />
the drug regimen may improve mobility. In addition, this usually<br />
allows dose reduction <strong>of</strong> the levodopa, while improving<br />
‘end-<strong>of</strong>-dose’ effects <strong>and</strong> improving motor fluctuations. If on–<strong>of</strong>f<br />
phenomena are refractory, the dopamine agonist apomorphine<br />
can terminate ‘<strong>of</strong>f’ periods, but its use is complex (see below).<br />
Selegiline, a MAO-B inhibitor, may reduce the end-<strong>of</strong>-dose<br />
deterioration in advanced disease. Physiotherapy <strong>and</strong> psychological<br />
support are helpful. The experimental approach <strong>of</strong><br />
implantation <strong>of</strong> stem cells into the substantia nigra <strong>of</strong> severely<br />
affected parkinsonian patients (perhaps with low-dose<br />
immunosuppression) is being investigated. The potential <strong>of</strong><br />
stereotactic unilateral pallidotomy, for severe refractory cases <strong>of</strong><br />
Parkinson’s disease is being re-evaluated.<br />
Drugs that cause parkinsonism, notably conventional<br />
antipsychotic drugs (e.g. chlorpromazine, haloperidol) (see<br />
Chapter 19) are withdrawn if possible, or substituted by the<br />
Key points<br />
Parkinson’s disease<br />
• <strong>Clinical</strong> diagnosis is based on the triad <strong>of</strong> tremor,<br />
rigidity <strong>and</strong> bradykinesia.<br />
• Parkinsonism is caused by the degeneration <strong>of</strong><br />
dopaminergic pathways in basal ganglia leading to<br />
imbalance between cholinergic (stimulatory) <strong>and</strong><br />
dopaminergic (inhibitory) transmission.<br />
• It is induced/exacerbated by centrally acting dopamine<br />
antagonists (e.g. haloperidol), but less so by clozapine,<br />
risperidone or olanzapine.<br />
newer ‘atypical’ antipsychotics (e.g. risperidone or olanzapine),<br />
since these have a lower incidence <strong>of</strong> extrapyramidal side effects.<br />
Antimuscarinic drugs (e.g. trihexyphenidyl) are useful if changing<br />
the drug/reducing the dose is not therapeutically acceptable,<br />
whereas drugs that increase dopaminergic transmission are contraindicated<br />
because <strong>of</strong> their effect on psychotic symptoms.<br />
ANTI-PARKINSONIAN DRUGS<br />
DRUGS AFFECTING THE DOPAMINERGIC SYSTEM<br />
Dopaminergic activity can be enhanced by:<br />
• levodopa with a peripheral dopa decarboxylase inhibitor;<br />
• increasing release <strong>of</strong> endogenous dopamine;<br />
• stimulation <strong>of</strong> dopamine receptors;<br />
• inhibition <strong>of</strong> catechol-O-methyl transferase;<br />
• inhibition <strong>of</strong> monoamine oxidase type B.<br />
LEVODOPA AND DOPA DECARBOXYLASE INHIBITORS<br />
Use<br />
Levodopa (unlike dopamine) can enter nerve terminals in the<br />
basal ganglia where it undergoes decarboxylation to form<br />
dopamine. Levodopa is used in combination with a peripheral<br />
(extracerebral) dopa decarboxylase inhibitor (e.g. carbidopa or<br />
benserazide). This allows a four- to five-fold reduction in levodopa<br />
dose <strong>and</strong> the incidence <strong>of</strong> vomiting <strong>and</strong> dysrhythmias is<br />
reduced. However, central adverse effects (e.g. hallucinations)<br />
are (predictably) as common as when larger doses <strong>of</strong> levodopa<br />
are given without a dopa decarboxylase inhibitor.<br />
Combined preparations (co-careldopa or co-beneldopa)<br />
are appropriate for idiopathic Parkinson’s disease. (Levodopa<br />
is contraindicated in schizophrenia <strong>and</strong> must not be used for<br />
parkinsonism caused by antipsychotic drugs.) Combined<br />
preparations are given three times daily starting at a low dose,<br />
increased initially after two weeks <strong>and</strong> then reviewed at<br />
intervals <strong>of</strong> six to eight weeks. Without dopa decarboxylase<br />
inhibitors, 95% <strong>of</strong> levodopa is metabolized outside the brain.<br />
In their presence, plasma levodopa concentrations rise (Figure<br />
21.3), excretion <strong>of</strong> dopamine <strong>and</strong> its metabolites falls, <strong>and</strong> the<br />
availability <strong>of</strong> levodopa within the brain for conversion to<br />
dopamine increases. The two available inhibitors are similar.<br />
Adverse effects<br />
These include the following:<br />
• nausea <strong>and</strong> vomiting;<br />
• postural hypotension – this usually resolves after a few<br />
weeks, but excessive hypotension may result if<br />
antihypertensive treatment is given concurrently;