Summary

There are many pharmacologic options available for the treatment of Parkinson disease; regimens are tailored to the patient's age, symptoms, and symptom severity. While only symptomatic treatment is available at this point in time, drugs that may slow or reverse the course of the disease are currently being investigated. Since treatment of Parkinson disease at an early stage can significantly improve a patient's subjective well-being (honeymoon period), medical therapy should be initiated as soon as symptoms begin to interfere with the patient's daily life. For most patients, first-line treatment consists of levodopa (L-DOPA) or dopamine receptor agonists, e.g., ropinirole and pramipexole. Other drugs that are used to treat Parkinson disease include amantadine, MAO-B inhibitors, and COMT inhibitors.

Overview

Substance class		Agent	Mode of action	Indication	Additional information
Dopamine precursors		L-DOPA (levodopa)	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	First-line treatment for patients > 65 years of age or patients with comorbidities Second-line treatment for patients < 65 years of age	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)
Decarboxylase inhibitors		Carbidopa Benserazide	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)		Always administered alongside L-DOPA
Dopamine agonists	Non-ergot	Ropinirole Pramipexole Apomorphine Rotigotine	Act directly at striatal dopamine receptors Predominantly control bradykinetic symptoms	First-line treatment for patients < 65 years of age Adjunctive treatment for patients of any age	Less effective than L-DOPA, but fewer motor side effects Effective in advanced disease stages
Dopamine agonists	Ergot	Bromocriptine		Second-line treatment for patients < 70 years of age
COMT inhibitors		Entacapone Tolcapone	Inhibition of catechol-O-methyltransferase (COMT) → ↓ peripheral metabolization of L-DOPA to 3-O-methyldopa (3-OMD) → ↑ availability Tolcapone also prevents central COMT from breaking down dopamine to 3-methoxytyramine (3-MT) by crossing the blood-brain barrier → ↑ dopamine effect → ↓ demand for L-DOPA and longer therapeutic effect for each dose	Entacapone: If L-DOPA loses effect or motor symptoms fluctuate during L-DOPA therapy Tolcapone: for refractory Parkinson disease	COMT inhibitor monotherapy is ineffective; therefore, it should always be combined with L-DOPA and carbidopa.
NMDA antagonists		Amantadine	Acts antagonistically at the glutamate N-methyl-D-aspartate (NMDA) receptor → dopaminergic effect ↑ Dopamine release and ↓ dopamine reuptake in central neurons Mostly controls bradykinetic symptoms	Short-term treatment of mild symptoms Drug of choice during akinetic crisis Reduction of L-DOPA-induced dyskinesia	Loss of effect after several months of treatment → cannot be used for long-term therapy May have cardiac side effects (prolonged QT interval)
MAO-B inhibitors		Rasagiline Safinamide Selegiline	Selective inhibition of MAO-B → ↓ metabolization of dopamine into DOPAC in the brain → prolonged dopamine availability and effect→ ↓ demand for L-DOPA	Alternative to L-DOPA or dopamine agonists for short-term therapy in patients with mild symptoms in early disease stages	Can also be given in combination with L-DOPA → ↓ motor fluctuations
Anticholinergic drugs (muscarinic antagonists)		Benztropine Trihexyphenidyl Biperiden	Inhibition of excitatory cholinergic neurons → ↓ concentration of acetylcholine	Useful as monotherapy in patients < 65 years of age with tremor as the main symptom Beneficial regarding tremor and rigidity but does not improve bradykinesia	Usually avoided in patients > 65 years because they are more prone to anticholinergic side effects (e.g., urinary retention, delirium, constipation)

Patients who do not respond to levodopa therapy will not respond to dopamine agonist therapy!

Selegiline has high selectivity for the monoamine oxidase B found predominantly in the brain.

To remember that anticholinergics like benztropine and trihexyphenidyl are used in the treatment of Parkinson disease, think of “A Benz for a trip to the park.”

To remember the main drugs used to treat Parkinson disease, think of A²B²C²D²: Antimuscarinics and Amantadine; Bromocriptine and MAO-B inhibitors; COMT inhibitors and Carbidopa; L-DOPA and nonergot Dopamine agonists.

References:^[1]^[2]^[3]^[4]^[5]

Side effects

Carbidopa-levodopa

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.
Psychotic symptoms
- Hallucinations (often visual); , insomnia, anxiety, and aggressive behavior → treat with clozapine
- 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)
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

Dopamine agonists

Side effects common to all dopamine agonists
- Autonomic: nausea; , vomiting, orthostatic hypotension; , dizziness, increased daytime drowsiness and sleep attacks
- Motor function: dyskinesia (rare)
- Psychiatric: unrest, confusion, hallucinations, impulse control disorders (e.g., compulsive gambling; , sexual activity, or shopping), psychosis
- Dopamine agonist withdrawal syndrome
  - Etiology: abrupt discontinuation of dopamine agonist therapy
  - Clinical features: similar to malignant hyperthermia and neuroleptic malignant syndrome → hyperthermia and rigor; akinesia; reduced vigilance; increased creatine kinase levels, transaminases, and leukocytes
  - Treatment: intensive medical care, volume substitution, administration of L-DOPA, apomorphine, amantadine
Side effects of ergotamine-derived agonists: (e.g., bromocriptine): fibrosis (cardiac fibrosis, Raynaud disease, pleural pulmonary fibrosis, and retroperitoneal fibrosis)

Other substances

NMDA antagonists (amantadine): side effects are similar to L-DOPA but much less pronounced
- Ataxia
- Livedo reticularis
- Peripheral edema

NMDA antagonists can cause prolonged QT intervals! Do not administer NMDA antagonists to patients with a history of cardiac disorders!

MAO-B inhibitors
- Headache, dyskinesia, psychological disorders (e.g., hallucinations)
- Inhibition of MAO-A with higher doses → reduced peripheral degradation of catecholamines → adrenergic side effects (e.g., tachycardia, sweating, nervousness)
Muscarinic antagonists (anticholinergics): See antimuscarinic side effects.

Administration of antimuscarinic drugs to patients with mental disorders or delirium will likely worsen psychiatric symptoms!

COMT inhibitors
- Gastrointestinal side effects
- Dyskinesia and psychiatric symptoms (e.g., hallucinations or confusion)

References:^[6]^[7]

We list the most important adverse effects. The selection is not exhaustive.