Basic and clinical pharmacology of levodopa

1. Levodopa
Domina Petric, MD

2. Introduction
• Dopamine does not cross the blood-brain barrier
and if given into the peripheral circulation has no
therapeutic effect in parkinsonism.
• Levodopa or (-)-3-(3,4-dihydroxyphenyl)-L-alanine
is the immediate metabolic precursor of
dopamine.
• Levodopa enters the brain via an L-amino acid
transporter (LAT), where it is decarboxylated to
dopamine.
Katzung, Masters, Trevor.
Basic and clinical

3. Dopamine receptors
D1 receptors
• Postsynaptically on
pars compacta of the
substantia nigra.
• Presynaptically on
striatal axons coming
from cortical neurons
and dopaminergic cells
in the substantia nigra.
D2 receptors
• Postsynaptically on
striatal neurons.
• Presynaptically on
axons in the
substantia nigra
belonging to neurons
in the basal ganglia.
Katzung, Masters, Trevor.
Basic and clinical

4. Dopamine receptors
• The benefits of dopaminergic antiparkinsonism
drugs appear to depend mostly on stimulation of
the D2 receptors.
• D1 receptor stimulation may also be required for
maximal benefit.
• Antiparkinsonism properties have dopamine
agonists and partial agonist ergot derivatives
(lergotrile, bromocriptine), both stimulators of D2
receptors.
• Dopamine antagonists can induce parkinsonism.
Katzung, Masters, Trevor.
Basic and clinical

5. Chemistry of levodopa
Dopa is the amino acid precursor
of dopamine and norepinephrine.
Levodopa is the levorotatory
stereoisomer of dopa.
Katzung, Masters, Trevor.
Basic and clinical

6. Pharmacokinetics
• Levodopa is rapidly absorbed from the small
intestine.
• Its absorption depends on the rate of gastric
emptying and the pH of the gastric contents.
• Ingestion of food delays the appearance of
levodopa in the plasma.
• Certain amino acids from ingested food can
compete with the drug for absorption from the gut
and for transport from the blood to the brain.
Katzung, Masters, Trevor.
Basic and clinical

7. Pharmacokinetics
• Plasma concentrations usually peak between 1
and 2 hours after an oral dose.
• The plasma half-life is usually between 1 and 3
hours.
• About two thirds of the dose appears in the
urine as metabolites within 8 hours of an oral
dose: 3-methoxy-4-hydroxyphenyl acetic acid
(homovanillic acid, HVA) and
dihydroxyphenylacetic acid (DOPAC).
Katzung, Masters, Trevor.
Basic and clinical

8. Pharmacokinetics
• Only about 1-3% of administered levodopa
actually enters the brain unaltered.
• The remainder is metabolized extracerebrally,
predominantly by decarboxylation to
dopamine.
• Dopamine does not penetrate the blood-brain
barrier.
• Levodopa must be given in large amounts when
used alone.
Katzung, Masters, Trevor.
Basic and clinical

9. Pharmacokinetics
• When given in combination with a dopa
decarboxylase inhibitor, that does not
penetrate the blood-brain barrier, the
peripheral metabolism (only peripheral) of
levodopa is reduced.
• Plasma levels of levodopa are higher.
• Plasma half-life is longer.
• More dopa is available for entry into the brain.
Katzung, Masters, Trevor.
Basic and clinical

10. Pharmacokinetics
Concomitant administration of a
peripheral dopa decarboxylase
inhibitor (carbidopa) may reduce
the daily requirements of
levodopa by approximately 75%.
Katzung, Masters, Trevor.
Basic and clinical

11. Clinical use
• The best results of levodopa treatment are
obtained in the first few years of treatment.
• This is sometimes because the daily dose of
levodopa must be reduced over time to avoid
adverse effects.
• Some patients become less responsive: loss of
dopaminergic nigrostriatal nerve terminals,
pathologic process directly involving striatal
dopamine receptors.
Katzung, Masters, Trevor.
Basic and clinical

12. Clinical use
• The benefits of levodopa treatment often
begin to diminish after about 3 or 4 years of
therapy.
• Levodopa therapy does not stop the
progression of parkinsonism, but its early
initiation lowers the mortality rate.
• Long-term therapy may lead to on-off
phenomenon and other problems.
Katzung, Masters, Trevor.
Basic and clinical

13. Clinical use
• Levodopa is generally given in combination with
carbidopa.
• Carbidopa is a peripheral dopa decarboxylase
inhibitor which reduces peripheral conversion
to dopamine.
• Start dose is 25 mg of carbidopa and 100 mg of
levodopa three times daily 30-60 minutes
before meals.
Katzung, Masters, Trevor.
Basic and clinical

14. Clinical use
• Maintenance dose is 25 mg of carbidopa
and 250 mg of levodopa three or four
times daily.
• It is generally preferable to keep
treatment with as low doses as possible
and to use a dopamine agonist instead:
reduction of response fluctuations.
Katzung, Masters, Trevor.
Basic and clinical

15. Clinical use
• Parcopa: formulation of carbidopa-levodopa
(10/100, 25/100, 25/250) that disintegrates in
the mouth and is swallowed with the saliva.
• Stalevo: levodopa, carbidopa and catechol-O-
methyltransferase inhibitor (entacapone).
• Intraduodenal infusion of levodopa-carbidopa
appears to be safe and may be superior to a
number of oral combination therapies.
Katzung, Masters, Trevor.
Basic and clinical

16. Clinical use
• Levodopa can ameliorate all the clinical
features of parkinsonism.
• It is particularly effective in relieving
bradykinesia and any disabilities resulting
from it.
• When first introduced, one third of
patiens respond to levodopa very well
and one third less well.
Katzung, Masters, Trevor.
Basic and clinical

17. Adverse effects
LEVODOPA
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Basic and clinical

18. Gastrointestinal effects
• Levodopa without carbidopa: anorexia, nausea
and vomiting (80% of patients).
• These effects can be minimized by taking the
drug in divided doses, with or immediately after
meal, and by increasing the total daily dose
very slowly.
• Antacids taken 30-60 minutes before levodopa
may be also helpful.
Katzung, Masters, Trevor.
Basic and clinical

19. Gastrointestinal effects
• Vomiting: stimulation of the
chemoreceptor trigger zone located in the
brainstem, but outside the blood-brain
barrier.
• Antiemetics such as phenothiazines
should be avoided: reduction of the
antiparkinsonism effects of levodopa,
exacerbation of the disease.
Katzung, Masters, Trevor.
Basic and clinical

20. Cardiovascular effects
• Cardiac arrhythmias: tachycardia,
ventricular extrasystoles, atrial fibrillation
(rarely).
• Cause: increased catecholamine
formation peripherally.
• The incidence is low, even in the presence
of established cardiac disease.
Katzung, Masters, Trevor.
Basic and clinical

21. Cardiovascular effects
• Postural hypotension is common, but
often asymptomatic.
• Hypertension may occur in the
presence of nonselective
monoamine oxidase inhibitors or
sympathomimetics, or in the case of
massive doses of levodopa.
Katzung, Masters, Trevor.
Basic and clinical

22. Behavioral effects
• depression
• anxiety
• agitation
• insomnia
• somnolence
• confusion
• delusions
• hallucinations
• nightmares
• euphoria
Katzung, Masters, Trevor.
Basic and clinical

23. Behavioral effects
• More common in patients taking
combination of levodopa and carbidopa:
higher levels of levodopa reach the brain.
• Treatment: atypical antipsychotic agents
with low affinity for dopamine D2
receptors (clozapine, olanzapine,
quetiapine, risperidone), withdrawal of
the medication.
Katzung, Masters, Trevor.
Basic and clinical

24. Dyskinesias
Dyskinesias occur in up to 80% of patients receiving
levodopa therapy for more than 10 years.
Choreoathetosis of the face and distal extremities is the
most common presentation.
The development of dyskinesias is dose related.
Katzung, Masters, Trevor.
Basic and clinical

25. Response fluctuations
• On-off phenomenon: off-periods of marked
akinesia alternate over the course of a few
hours with on-periods of improved
mobility, but often marked dyskinesia.
• Treatment: apomorphine sc.
• The dyskinesias may relate to an unequal
distribution of striatal dopamine.
Katzung, Masters, Trevor.
Basic and clinical

26. Response fluctuations
Dopaminergic denervation plus chronic
pulsatile stimulation of dopamine receptors
with levodopa has been associated with
development of dyskinesias:
• It is better to administer levodopa
continuously (intraduodenally,
intrajejunally)!
Katzung, Masters, Trevor.
Basic and clinical

27. Response fluctuations
Other response
fluctuations are:
•wearing-off reactions
•end-of-dose akinesia
Katzung, Masters, Trevor.
Basic and clinical

28. Miscellaneous
Mydriasis may occur and
may precipitate an
attack of acute glaucoma
in some patients.
Katzung, Masters, Trevor.
Basic and clinical

29. Miscellaneous
• hemolysis
• hot flushes
• aggravation or
precipitation of gout
• abnormalities of
smell or taste
• priapism
• brownish
discoloration of salive,
urine or vaginal
secretions
• mild and transient
elevations of blood
urea nitrogen and
serum transaminases,
alkaline phospatase
and bilirubin
Katzung, Masters, Trevor.
Basic and clinical

30. Drug holidays
• Drug holiday is discontinuance of the drug
for 3-21 days.
• It may temporarily improve
responsiveness to levodopa and alleviate
some of its adverse effects.
• It is usually of little help in the
management of the on-off phenomenon.
Katzung, Masters, Trevor.
Basic and clinical

31. Drug holidays
Drug holiday carries the risk from the
immobility accompanying severe
parkinsonism:
• aspiration pneumonia
• venous thrombosis
• pulmonary embolism
• depression
Katzung, Masters, Trevor.
Basic and clinical

32. Drug interactions
• Pharmacologic doses of pyridoxine
(vitamin B6) enhance the extracerebral
metabolism of levodopa: decrease of
therapeutic effect.
• Levodopa should not be given to patients
taking monoamine oxidase A inhibitors or
within 2 weeks of their discontinuance:
hypertensive crises.
Katzung, Masters, Trevor.
Basic and clinical

33. Contraindications
• Psychotic patients: exacerbation of the mental
disturbance.
• Angle-closure glaucoma!
• Patients with cardiac disease and active peptic
ulcer: carefully.
• Patients with the history of melanoma:
levodopa is a precursor of skin melanin and
may activate malignant melanoma.
Katzung, Masters, Trevor.
Basic and clinical

34. Literature
• Katzung, Masters, Trevor.
Basic and clinical
pharmacology.
Katzung, Masters, Trevor.
Basic and clinical