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P A R T 4
Drugs acting on the central and peripheral nervous systems
(see Table 24.1 for usual indications for each of these
agents). Levodopa is the mainstay of treatment for
Parkinson’s disease. This precursor of dopamine crosses
the blood–brain barrier and is converted into dopamine.
In this way, it acts like a replacement therapy. Although
levodopa is almost always given in combination form
with carbidopa as a fixed-combination drug (
Sinemet
),
other drugs besides carbidopa may be used (see Adjunct
ive agents). When used with carbidopa, the enzyme dopa
decarboxylase is inhibited in the periphery, diminish
ing the metabolism of levodopa in the gastrointestinal
(GI) tract and in peripheral tissues, thereby leading to
higher levels crossing the blood–brain barrier. Because
the carbidopa decreases the amount of levodopa needed
to reach a therapeutic level in the brain, the dose of
levodopa can be decreased, which reduces the incidence
of adverse side effects.
Amantadine is an antiviral drug that also seems to
increase the release of dopamine, being effective as long
as there is a possibility of more dopamine release.
Apomorphine is a newer adjunctive therapy for
Parkinson’s disease that directly binds with postsyn-
aptic dopamine receptors. Similar to apomorphine,
bromocriptine, pergolide and pramipexol act as direct
dopamine agonists on dopamine-receptor sites in the
substantia nigra. Because bromocriptine does not depend
on cells in the area to biotransform it or to increase the
release of already produced dopamine, it may be effect
ive longer than levodopa or amantadine.
Ropinirole and rotigotine are newer drugs that
directly stimulate dopamine receptors. They are also
used to treat restless leg syndrome.
Pharmacokinetics
The dopaminergics are usually given orally and are
generally well absorbed from the GI tract and widely
distributed in the body. Apomorphine, however, must be
given subcutaneously. The dopaminergics are metabo-
lised in the liver and peripheral cells and excreted in the
urine. They cross the placenta and enter breast milk.
Contraindications and cautions
The dopaminergics are contraindicated in the presence
of any known allergy to the drug or drug components
to prevent hypersensitivity reactions
, and in angle-
closure glaucoma,
which could be exacerbated by these
drugs.
Dopaminergics enter breast milk and should not
be used during breastfeeding because of the potential
for adverse effects in the baby. In addition, levodopa is
contraindicated in people with history or presence of
suspicious skin lesions
because this drug has been asso-
ciated with the development of melanoma.
Administer dopaminergic agents cautiously with
people who have
any condition that could be exacerbated
by dopamine receptor stimulation
,
such as cardiovascular
disease, including myocardial infarction, arrhythmias and
hypertension; bronchial asthma; history of peptic ulcers;
urinary tract obstruction; and psychiatric disorders. Care
is also necessary during pregnancy
because these drugs
cross the placenta and could adversely affect the fetus
,
and in people with renal and hepatic disease,
which could
interfere with the metabolism and excretion of the drug.
Closely monitor cardiac status in people receiving apo-
morphine because of the associated risk for hypotension
and prolonged QT interval.
Adverse effects
The adverse effects associated with the dopaminergics
usually result from stimulation of dopamine receptors.
CNS effects may include anxiety, nervousness, headache,
malaise, fatigue, confusion, mental changes, blurred
vision, muscle twitching and ataxia. Peripheral effects
may include anorexia, nausea, vomiting, dysphagia, and
constipation or diarrhoea; cardiac arrhythmias, hypo-
tension and palpitations; bizarre breathing patterns;
urinary retention; and flushing, increased sweating and
hot flushes. Bone marrow depression and hepatic dys-
function have also been reported.
Clinically important drug–drug interactions
If dopaminergics are combined with monoamine
oxidase (MAO) inhibitors, therapeutic effects increase
and a risk of hypertensive crisis exists. The MAO inhib
itor should be stopped 14 days before beginning therapy
with a dopaminergic.
Prototype summary: Levodopa
Indications:
Treatment of parkinsonism and
Parkinson’s disease.
Actions:
Precursor of dopamine, which is deficient
in parkinsonism; crosses the blood–brain barrier,
where it is converted to dopamine and acts as a
replacement neurotransmitter; effective for 2 to
5 years in relieving the symptoms of Parkinson’s
disease.
Pharmacokinetics:
Route Onset
Peak
Duration
Oral
Varies
0.5–2 hours 5 hours
T
1/2
:
1 to 3 hours; metabolised in the liver, excreted
in the urine.
Adverse effects:
Adventitious movements, ataxia,
increased hand tremor, dizziness, numbness,
weakness, agitation, anxiety, anorexia, nausea,
dry mouth, dysphagia, urinary retention, flushing,
cardiac irregularities.
