Basic and clinical pharmacology of dopamine receptor agonists

1. Dopamine receptor
agonists
Domina Petric, MD

2. Dopamine receptor agonists
• These drugs do not require enzymatic
conversion to an active metabolite.
• They have no potentially toxic
metabolites.
• They do not compete with other
substances for active transport into the
blood and across the blood-brain barrier.
• Drugs selectively affecting certain
dopamine receptors may have more
limited adverse effects than levodopa.

3. Dopamine receptor agonists
• Dopamine agonists have an important
role as first-line therapy for Parkinson´s
disease.
• Their use is associated with a lower
incidence of the response fluctuations
and dyskinesias that occur with long-term
levodopa therapy.
• Dopaminergic therapy may be best
initiated with a dopamine agonist.

4. Dopamine receptor agonists
• The dose of the dopamine agonist is
built up gradually depending on
response and tolerance.
• Dopamine agonists may be given to
patients with parkinsonism who are
taking levodopa and have end-of-dose
akinesia, or on-off phenomenon, or are
becoming resistant to treatment with
levodopa.

5. Dopamine receptor agonists
The response to a
dopamine agonist is
generally disappointing in
patients who have never
responded to levodopa.

6. Bromocriptine
• Bromocriptine is D2 agonist.
• It is now rarely used for
parkinsonism.
• The usual daily dose of
bromocriptine for parkinsonism
varies between 7,5 and 30 mg.
• To minimize adverse effects, the dose
is built up slowly over 2 or 3 months.

7. Pergolide
Pergolide directly stimulates
both D1 and D2 receptors.
It is not used for parkinsonism any
more because its use has been
associated with the development of
valvular heart disease.

8. Pramipexole
• It is effective as monotherapy for mild
parkinsonism.
• It is also helpful in patients with
advanced disease, permitting the
dose of levodopa to be reduced and
smoothing out response fluctuations.
• Pramipexole may ameliorate affective
symptoms.

9. Pramipexole
• Possible neuroprotective effect: ability of
pramipexole to scavenge hydrogen
peroxide and enhance neurotrophic
activity in mesencephalic dopaminergic
cell cultures.
• Pramipexole is rapidly absorbed after oral
administration, reaching peak plasma
concentrations in about 2 hours.
• It is excreted largely unchanged in the
urine.

10. Pramipexole
• Starting dose is 0,125 mg three times
daily.
• Dose is doubled after 1 week and
again after another week.
• Further increments in the daily dose
are by 0,75 mg at weekly intervals.
• Most patients require between 0,5
and 1,5 mg three times daily.

11. Pramipexole
• Renal insufficiency may
necessitate dosage adjustment.
• Extended-release preparation is
taken once daily.
• This preparation is more
convenient for patients and avoids
swings in blood levels of the drug
over the day.

12. Ropinirole
• It is a relatively pure D2 receptor agonist.
• It is effective as monotherapy in patients
with mild disease.
• It is also helpful in patients with more
advanced disease using levodopa for
smoothing the response fluctuations.
• Start dose is 0,25 mg three times daily.
• The total daily dose is increased by 0,75 mg at
weekly intervals until the fourth week, after that
increment is by 1,5 mg.

13. Ropinirole
In most cases dosage between 2 and
8 mg three times daily is necessary.
Ropinirole is metabolized by
CYP1A2.
A prolonged-release preparation
taken once daily is available.

14. Rotigotine
• The dopamine agonist rotigotine
is delivered daily through a skin
patch: more continuous
dopaminergic stimulation than
oral medication in early disease.
• Its efficacy in more advanced
disease is less clear.

15. Adverse effects
Dopamine receptor agonists

16. Gastrointestinal effects
• Anorexia, nausea and vomiting may
occur when a dopamine agonist is
introduced.
• These side effects can be minimized by
taking the medication with meals.
• Constipation, dyspepsia and symptoms
of reflux esophagitis may also occur.
• Bleeding from peptic ulceration!

17. Cardiovascular effects
• Postural hypotension may occur,
particularly at the initiation of therapy.
• Painless digital vasospasm is a dose-
related complication of long-term
treatment with the ergot derivatives
(bromocriptine, pergolide).
• Cardiac arrhythmias: indication for
discontinuing treatment.
• Peripheral edema.
• Cardiac valvulopathy with pergolide.

18. Dyskinesias
Abnormal movements
similar to those introduced
by levodopa may occur and
are reversed by reducing the
total dose of dopaminergic
drug being taken.

19. Mental disturbances
• Confusion, hallucinations, delusions and
other psychiatric reactions are more
common and severe with dopamine
receptor agonists than with levodopa.
• Disorders of impulse control may lead to
compulsive gambling, shopping, betting,
sexual activity and other behaviors.
• These behaviors clear on withdrawal of
the offending medication.

20. Miscellaneous
• Ergot-derived dopamine agonists
(bromocriptine, pergolide): headache,
nasal congestion, increased arousal,
pulmonary infiltrates, pleural and
retroperitoneal fibrosis, erythromelalgia.
• Pergolide: cardiac valvulopathies.
• Erythromelalgia consists of red, tender,
painful, swollen feet and, occasionally,
hands, at times associated with arthralgia.

21. www.erythromelalgia.org

22. Miscellaneous
In rare instances, an
uncontrollable tendency to fall
asleep at inappropriate times
has occured, particularly in
patients receiving pramipexole
or ropinirole.

23. Contraindications
• Dopamine agonists are
contraindicated in patients with a
history of psychotic illness or
recent myocardial infarction, or
with active peptic ulceration.
• The ergot-derived agonists are
best avoided in patients with
peripheral vascular disease.

24. Apomorphine
Dopamine agonist

25. Apomorphine
• Apomorphine is a potent dopamine
agonist.
• Subcutaneous injection of apomorphine
hydrochloride (Apokyn) is effective for the
temporary relief (rescue) of off-periods of
akinesia in patients on optimized
dopaminergic therapy.
• It is rapidly taken up in the blood and
then the brain.

26. Apomorphine
• Clinical benefit begins within 10
minutes of injection and persists for up
to 2 hours.
• The optimal dose is identified by
administering increasing test doses
until adequate benefit is achieved or a
maximum of 10 mg is reached.
• Most patients require a dose of 3-6 mg,
but no more than three times daily!

27. Apomorphine
• Nausea at the initiation of apomorphine
treatment: pretreatment with the
antiemetic trimethobenzamide (300 mg
three times daily) for 3 days and then for
at least 1 month after.
• Other adverse effects: dyskinesias,
drowsiness, chest pain, sweating,
hypotension, bruising at the
injection site.

28. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
• www.erythromelalgia.org