Pharm 101: Levodopa

Class

Dopamine precursor

Pharmacodynamics

• Dopamine precursor
• Transported into the CNS where it is decarboxylated to dopamine
• Also converted to dopamine in periphery (does not enter CNS)
• Clinical effects are mainly due to stimulation of D2 receptors (substantia nigra), as well as D1 receptors for maximal benefit:
  • Ameliorates all motor symptoms of Parkinson’s
  • Significant peripheral dopaminergic effects

Pharmacokinetics

• PO administration
• Rapid absorption
  • Ingestion of food delays absorption
• Peak plasma concentrations in 1-2 hours
• Plasma half-life 1-3 hours
• Only 1-3% reaches brain unaltered when administered alone:
  • Remainder metabolised extra-cerebrally, by decarboxylation to dopamine
  • Carbidopa is a peripheral dopa decarboxylase inhibitor that does not penetrate the blood-brain barrier
  • Co-administration of carbidopa reduces peripheral metabolism, facilitating increased entry into brain, and reducing daily dosage requirements by 75%
• Metabolised to homovanillic (HVA) and dihydroxyphenylacetic acid (DOPAC)
• 2/3 excreted in urine as metabolites within 8 hours of an oral dose

Clinical uses

• Parkinson’s disease:
  • Most efficacious therapy, but not always used as first line due to development of disabling response fluctuations over time
  • Benefits diminish after 3-4 years
  • Does not stop progression of disease but lowers mortality
  • Given in combination with carbidopa (peripheral dopa decarboxylase inhibitor)
  • Response rate is in thirds: one-third respond well, one-third partial response, one-third do not respond or have intolerance

Adverse effects

• Gastrointestinal disturbance:
  • Nausea/vomiting/anorexia in 80% when given alone
  • 20% in combination with carbidopa
• Arrhythmias
• Dyskinesias:
  • 80% in therapy > 10 years
• Response fluctuations:
  • On-off phenomenon unrelated to dose timing
  • Wearing-off reactions
• Behavioural disturbances
• Other:
  • Mydriasis, can precipitate acute angle closure glaucoma (AACG)
  • Positive Coomb’s test
  • Brown urine

Precautions/contraindications

• Psychosis
• AACG
• History of melanoma or suspicious skin lesion

Further reading

• Nickson C. Parkinsonism. LITFL

References

• Katzung BG. Basic & Clinical Pharmacology. 14e. 2018: 494-497, 508