++
Strategies for the treatment of Parkinson’s disease
involve restoring dopamine activity in the brain by either increasing
the activity of dopamine already available or by providing exogenous dopamine,
restoring the normal balance of cholinergic and dopaminergic influences
on the basal ganglia with antimuscarinic drugs, or a combination
of both. The difficulty arises in finding a drug regimen that works
effectively without serious adverse effects over a period of time.
Since Parkinson’s disease is a progressive disorder, drug
regimens must be closely monitored by all professionals involved
in the care of the patient. The primary drug used in the treatment
of Parkinson’s disease is levodopa.
Other agents such as dopamine agonists, monoamine oxidase (MAO)
inhibitors, amantadine (an antiviral agent with some dopamine-altering
properties), and anticholinergic drugs can be used alone or in conjunction
with levodopa, depending on the needs of the patient. An overview
of the drugs used to treat Parkinson’s disease is shown
in Table 17–3 and nonpharmacologic and neuroprotective
therapies are discussed in Box 17–1.
++
Dopamine does not cross the blood-brain barrier and thus has
no therapeutic effect in Parkinson’s disease if given as
such. However, its precursor, l-dopa
(levodopa), is transported across the blood brain barrier into the
brain where it is rapidly converted to dopamine by l-amino acid decarboxylase (DOPA decarboxylase),
an enzyme present in many body tissues including the brain. To prevent
premature conversion of levodopa to dopamine in peripheral tissue,
levodopa is usually given with a DOPA decarboxylase inhibitor such
as carbidopa, which does not cross
the blood-brain barrier and thus prevents the conversion of levodopa
to dopamine in peripheral tissues. This combination may reduce the
daily requirements of levodopa by approximately 75% and
results in fewer peripheral adverse effects (Figure 17–4).
++
++
Levodopa can ameliorate all the clinical features of Parkinson’s
disease, but is particularly effective in relieving bradykinesia
and its associated disabilities. The best results with levodopa
are obtained in the first few years of treatment, and the response
may be dramatic. Although it does not stop the progression of Parkinson’s
disease, early initiation of treatment with levodopa lowers the
mortality rate. However, responsiveness to the drug usually decreases
with time, which may reflect progression of the disease. Some patients
also begin to develop adverse effects at dosages previously well
tolerated, which may be caused by selective denervation-induced
or drug-induced supersensitivity.
++
After a period (usually months to years) of good or excellent
clinical response, the response to the drug may begin to fluctuate
quite rapidly, changing from akinesia to dyskinesia over a few hours. These
fluctuations in response (the so-called on-off phenomena) may be
related in part to changes in levodopa levels in the plasma or in
the brain. Most patients ultimately require dosing three to four
times daily, but on-off phenomena are not completely eliminated
by changes in dose interval. The debilitating effects of such response
fluctuations on daily activities can sometimes be reduced by including
dopamineagonists in the drug regimen. Catechol-O-methyltransferase (COMT) inhibitors
used adjunctively may also improve levodopa responses (see discussion
below). While “drug holidays” sometimes reduce
toxic effects of levodopa, they rarely affect response fluctuations
and are no longer recommended.
++
Most adverse effects associated with levodopa are dose dependent.
Gastrointestinal effects include anorexia, nausea, and emesis and
occur in about 80% of the patients when the drug is given
without a peripheral decarboxylase inhibitor. These adverse effects
can be reduced by taking the drug in divided doses, with or immediately
after meals, and by increasing the total daily dose very slowly.
Tolerance to the emetic action of levodopa usually occurs after
several months. Centrally acting antiemetics such as phenothiazines
should be avoided because they may reduce the antiParkinson’s
disease effects of levodopa and exacerbate symptoms. When levodopa
is given in combination with carbidopa to reduce its extracerebral
metabolism, adverse gastrointestinal effects are much less common,
occurring in less than 20% of cases, so that patients can
tolerate proportionately higher doses.
++
Among cardiovascular effects, postural hypotension is common,
especially in the early stage of treatment, but often is asymptomatic.
Other cardiac effects include tachycardia and cardiac arrhythmias
(rare). Hypertension may also occur, especially in the presence
of nonselective monoamine oxidase inhibitors or when massive doses
of levodopa are being taken.
++
Dyskinesias occur in up to 80% of patients receiving
levodopa therapy for long periods. The form and nature of dyskinesias
vary widely but tend to remain constant in character in individual patients.
Choreo-athetosis of the face and distal extremities is the most
common presentation. Chorea, ballismus, athetosis, dystonia, myoclonus,
tics, and tremor may occur individually or in any combination in
the face, trunk, or limbs. The development of dyskinesias is dose-related,
but there is considerable individual variation in the dose required
to produce them.
++
A wide variety of adverse mental effects have been reported including
depression, anxiety, agitation, insomnia, somnolence, confusion,
delusions, hallucinations, nightmares, euphoria, and other changes
in mood or personality. Such adverse effects are more common in
patients taking levodopa in combination with a decarboxylase inhibitor
rather than levodopa alone, presumably because higher levels are
reached in the brain. Atypical antipsychotic agents, such as clozapine and
risperidone, may be helpful in counteracting the behavioral complications
of levodopa. Levodopa is contraindicated in patients with a history
of psychosis.
++
Other reported but rare adverse effects include various blood
dyscrasias; hot flushes; aggravation or precipitation of gout; abnormalities
of smell or taste; brownish discoloration of saliva, urine, or vaginal
secretions; priapism; and mydriasis.
+++
Dopamine Receptor
Agonists
++
Dopamineagonists act directly on dopamine receptors and may
have a beneficial effect additive to that of levodopa. These drugs
do not require enzymatic conversion to an active metabolite and readily
cross the blood-brain barrier. They are active by the oral route.
The older dopamine agonists, bromocriptine and pergolide, are ergot derivatives and
act as partial agonists at dopamine D2 receptors in the
brain. The newer nonergot agents, pramipexole and ropinirole, are selective D3 and
D2 agonists, respectively, with efficacy similar to that
of the older agents. These drugs increase the functional activity
of dopamine neurotransmitter pathways, including those involved
in extrapyramidal functions.
++
Bromocriptine is absorbed to a variable extent from the gastrointestinal
tract and reaches peak plasma levels within 1 to 2 hours after an
oral dose. To minimize adverse effects, the dose is built up slowly
over 2 or 3 months to the desired therapeutic level. Bromocriptine
is excreted in the bile and feces. Pramipexole and ropinirole are
rapidly absorbed after oral administration, reaching peak plasma
levels in approximately 2 hours. Both pramipexole and ropinirole
are usually dosed three times daily, starting with a smaller dose
and building up to a therapeutic dose in approximately three to
four weeks’ time. Pramipexole is excreted largely unchanged
in the urine, whereas ropinirole is metabolized in the liver by
CYP1A2, which also metabolizes other drugs such as warfarin and
caffeine.
++
Dopamineagonists have been used as individual drugs, in combination
with levodopa and with anticholinergic drugs, and in patients who
are refractory to or cannot tolerate levodopa. Bromocriptine has
been widely used to treat Parkinson’s disease and the endocrine
disorder hyperprolactinemia (Chapter 22). Pergolide has also been
used, and in comparative studies with bromocriptine, has been shown
to be more effective in decreasing response fluctuations and prolonging
the effectiveness of levodopa. The newer agents, pramipexole and
ropinirole, have fewer adverse effects than bromocriptine and pergolide,
and are currently considered to be first-line drugs in the initial
management of Parkinson’s disease. Pramipexole may be neuroprotective because
it has been reported to act as a scavenger for hydrogen peroxide.
Another dopamine receptoragonist, apomorphine,
has been approved recently for rescue treatment of acute immobility
(“off periods”) in Parkinson’s disease.
Apomorphine is administered subcutaneously and necessitates pretreatment
with antiemetic drugs to prevent severe nausea and vomiting.
++
As with levodopa, most of the adverse effects associated with
dopamineagonists are dose dependent. Gastrointestinal effects include
anorexia, nausea, and vomiting. These are more pronounced with initial
use of the drug and can be minimized by taking the medication with
meals. The most common cardiovascular effect is postural hypotension,
particularly at the initiation of therapy. Cardiac arrhythmias may
also occur and are an indication for discontinuing treatment. Peripheral edema
has been reported. Dyskinesias similar to those caused by levodopa
may occur. Behavioral effects include confusion, hallucinations,
and delusions and are more common and severe with bromocriptine
and pergolide than with levodopa. Like levodopa, bromocriptine and
pergolide are contraindicated in patients with a history of psychosis.
Ergot-related effects include pulmonary infiltrates, cardiac valvular
disorders, and erythromelalgia.
+++
Monoamine Oxidase
Inhibitors
++
Selegiline is a partially selective
inhibitor of monoamine oxidase (MAO) type B, the enzyme isoform
that metabolizes dopamine in preference to norepinephrine and serotonin.
Selegiline retards the breakdown of dopamine and thus may increase
brain dopamine levels, both endogenous or those provided by levodopa
treatment. At higher doses, it is less selective and inhibits both
MAO-A and MAO–B, producing effects like those of the antidepressant
MAO inhibitors (Chapter 19).
++
Selegiline is used as an adjunct to levodopa in Parkinson’s
disease and has also been used as the sole agent in newly diagnosed
patients. The drug may reduce the mild on-off or wearing-off phenomena
seen with levodopa therapy. Selegiline has only a minor therapeutic
effect on Parkinson’s disease when given alone. Hepatic
metabolism of selegiline results in the formation of desmethylselegiline
(possibly neuroprotective owing to antiapoptotic mechanisms) and
small quantities of both amphetamine and methamphetamine. Rasagiline, another MAO type B inhibitor
recently approved for treatment of Parkinson’s disease,
does not form these metabolites.
++
The most prominent adverse effect associated with selegiline
use is insomnia, which can be minimized by taking the medication
early in the day. Other less prominent effects include mood changes,
dyskinesias, gastrointestinal distress, and hypertension. Rasagiline
is reported to cause fewer central nervous system (CNS) stimulatory
effects. Selegiline should not be taken by patients receiving meperidine,
tricyclic antidepressants, or serotonin reuptake inhibitors because of
the risk of acute toxic interactions.
++
Amantadine, an antiviral agent, was by chance found to have antiParkinson’s
disease properties. Amantadine inhibits the N-methyl-d-aspartic acid (NMDA) receptor-mediated
stimulation of acetylcholine release in rat striatum. In addition
to this anticholinergic effect, amantadine may enhance dopaminergic
neurotransmission by increasing synthesis or release of dopamine
or by inhibiting dopamine reuptake.
++
Amantadine has limited but favorable influence on the bradykinesia,
rigidity, and tremor of Parkinson’s disease. It is less
potent than levodopa and usually effective for only a few weeks.
++
Amantadine has a number of undesirable CNS effects such as restlessness,
agitation, insomnia, confusion, and acute toxic psychosis, all of
which can be reversed by discontinuing the drug. Peripheral edema
is another well-recognized complication, and it responds to diuretics.
Livedo reticularis (a dermatologic reaction) sometimes occurs and
usually clears within a month after the drug is withdrawn.
+++
Catechol-O-Methyltransferase Inhibitors
++
Entacapone and tolcapone are
selective inhibitors of COMT, the enzyme that converts levodopa
to 3-O-methyldopa (3OMD). Inhibition
of dopa decarboxylase (by carbidopa) is associated with compensatory
activation of other pathways of levodopa metabolism, especially
COMT. Increased plasma levels of 3OMD are associated with poor therapeutic
response to levodopa, partly because the compound competes with
levodopa for active transport into the CNS. Such selective COMT inhibitors
prolong the action of levodopa by increasing the amount transported
into the brain and diminishing its peripheral concentration.
++
These agents may be helpful in patients receivinglevodopa who
have developed response fluctuations, improving response and prolonging “on” time.
They may also provide the option of reducing the total daily levodopa
dose. Tolcapone and entacapone are both widely available, but entacapone
is generally preferred because it has not been associated with hepatotoxicity.
++
Tolcapone has been associated with hepatotoxicity requiring routine
monitoring of liver function tests. Other adverse effects of both
medications relate to increased levels of levodopa and include dyskinesias,
hypotension, confusion, and gastrointestinal distress.
+++
Acetylcholine-Blocking
Drugs (Antimuscarinic Drugs)
++
These drugs decrease the excitatory actions of cholinergic neurons
on cells in the striatum by blocking muscarinic receptors. Antimuscarinic
drugs used in Parkinson’s disease include benztropine, orphenadrine, procyclidine,
and trihexyphenidyl.
++
Antimuscarinic drugs may improve the tremor and rigidity of Parkinson’s
disease in 50% of patients but have little effect on bradykinesia.
Treatment is usually started with low doses and gradually increased
until benefit occurs or adverse effects limit further increments.
If a patient does not respond to one drug, a trial with another
drug may prove more successful. In some patients, antimuscarinic
agents may decrease the effects of levodopa. These drugs have value
in attenuating the parkinson-like extrapyramidal adverse effects
of typical antipsychotic drugs such as haloperidol.
++
Antimuscarinic medications have both CNS and peripheral adverse
effects. CNS toxicity includes drowsiness, inattention, confusion,
delusions, and hallucinations. Peripheral adverse effects are typical
of atropine-like drugs and include dry mouth, blurred vision, mydriasis,
urinary retention, nausea, constipation, and tachycardia. These
agents also exacerbate tardive dyskinesias that result from prolonged
use of antipsychotic drugs. Withdrawal of medication should be accomplished
gradually in order to prevent acute exacerbation of tremor.