(FETT) Dopamine precursors/L-Amino Acid Decarbocylase Inhibitors

Antiparkinson Agents

CO-CARELDOPA (Carbidopa-levodopa)

Dopamine precursors

• L-DOPA is converted to dopamine by DOPA decarboxylase at the presynaptic neuron → direct dopaminergic effect (especially at D2 receptors)

• L-DOPA, in contrast to dopamine, can cross the blood-brain barrier.

• Predominantly controls bradykinetic symptoms

• Initial treatment option for most patients with PD, especially older patients

• Nausea and vomiting, orthostatic hypotension(reduced by carbidopa)

• Hallucinations, anxiety

• Hypokinesia, dyskinesia, akinetic crisis

Decarboxylase inhibitors

Blockage of DOPA decarboxylase → ↓ peripheral conversion of L-DOPA to dopamine →↑ bioavailability and ↓ peripheral side effects of L-DOPA (e.g., orthostatic hypotension, nausea, vomiting)

• Mostly given as monotherapy in combination with decarboxylase inhibitors

• Most effective drug for reducing symptoms

• However, increased risk of severe motor dysfunction with long-term use (see “Side effects” below)

• Administer between meals (e.g., 30 minutes before a meal) to increase gastrointestinal absorption (→ avoid high-protein diets)

• Always administered alongside L-DOPA

• Becomes less effective over time: may require a shorter interval between doses

• Autonomic symptoms

  • Nausea and vomiting

  • Orthostatic hypotension

  • Carbidopa reduces the risk of orthostatic hypotension, nausea, and vomiting.

• Psychiatric symptoms [6][7]

  • Hallucinations (often visual) and other psychotic symptoms → treat with clozapine

  • Anxiety, insomnia, agitation, and aggressive behavior

  • Increased risk in elderly patients, women, concurrent dementia or other psychiatric disorders (e.g., depression), long duration of levodopa treatment, and high doses

• Motor fluctuations

  • Hypokinesia

    • End-of-dose akinesia/wearing-off phenomenon

    • Freezing

    • On-off phenomenon: Phases of good mobility (“on” phases) alternate with phases of poor mobility (“off” phases) as a result of reduced reaction to L-DOPA or wearing off of medication.

  • Dyskinesia (hyperkinesia)

    • On-period dystonia

    • Off-period dystonia

    • Diphasic dyskinesias

• Increased intraocular pressure

  • Open-angle glaucoma: Levodopa (and anticholinergics) should be used with caution.

  • Closed-angle glaucoma: Levodopa (and anticholinergics) are not recommended.

• Akinetic crisis

  • Definition: condition caused by severe dopamine deficiency (e.g., after discontinuation of L-DOPA therapy or insufficient L-DOPA absorption)

  • Clinical features: complete inability to move , incomprehensible speech, possibly hyperthermia → increased risk of dehydration, deep-vein thrombosis, and pneumonia

  • Treatment: intensive medical care, volume substitution, administration of L-DOPA, apomorphine, amantadine