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 pharmacology.

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

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 minutes before meals.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

17. Adverse effects LEVODOPA
Katzung, Masters, Trevor. Basic and clinical pharmacology.

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 minutes before levodopa may be also helpful.
Katzung, Masters, Trevor. Basic and clinical pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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

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

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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 pharmacology.

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