Parkinson’s Disease Medications

Medications for the management of Parkinson’s disease improve the symptoms of tremor, rigidity, and postural instability by increasing dopamine levels in the brain. While levodopa is the drug of choice in individuals of any age with moderate or severe symptoms, other agents can be used as monotherapy for milder symptoms or in conjunction with levodopa–carbidopa for symptom control. Other classes of medications work by preventing central and peripheral dopamine metabolism (monoamine oxidase (MAO) type B inhibitors, catechol O-methyltransferase (COMT) inhibitors, and carbidopa), or by exerting an antidyskinetic effect (amantadine). Serious side effects include arrhythmias and psychiatric symptoms ranging from mood disorders to hallucinations and psychosis. Abrupt withdrawal can result in neuroleptic malignant syndrome–like symptoms, which can be life-threatening. Drug interactions may occur with other agents that are metabolized by the hepatic cytochrome P450 enzymes, and caution must be used to avoid serotonin syndrome.

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Overview

Definition

Parkinson’s disease (PD) is a degenerative disease of the basal ganglia characterized by a clinical syndrome manifesting with diminished facial expression, bradykinesia, festinating gait (progressively shortened and accelerated steps), cogwheel rigidity, and a “pill-rolling” tremor at rest.

Pathophysiology

  • Cell death in basal ganglia
  • Degeneration of dopaminergic neurons of the substantia nigra → loss of central dopamine supply → symptoms begin
  • Alpha-synuclein clumps together → Lewy bodies
  • PD has no cure; decreased dopamine levels → motor symptoms

Pharmacotherapy for Parkinson’s disease

  • Medications restore dopaminergic activity → reduce symptoms, improve quality of life
  • Therapeutic options:
    • Levodopa (increases dopamine supply)
    • Dopamine agonists (increase activation of D2 and D3 receptors)
    • N-methyl-D-aspartate (NMDA) receptor antagonists
    • Monoamine oxidase (MAO) type B inhibitors 
    • Catechol O-methyltransferase (COMT) inhibitors
Pharmacologic strategies for the management of Parkinson’s disease

Pharmacologic strategies for the management of Parkinson’s disease
COMT: catechol O-methyltransferase
3-MT: 3-Methoxytyramine
3-OMD: 3-O-methyldopa
DOPAC: 3,4-dihydroxy-phenylacetic acid
L-DOPA: levodopa
MAO-B: monoamine oxidase type B

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Levodopa

Chemistry and pharmacodynamics

  • Structure:
    • Amino acid precursor of dopamine
    • Levorotatory stereoisomer of dopa (L-dopa)
  • Mechanism of action: 
    • Levodopa crosses the blood–brain barrier (BBB); dopamine itself cannot cross the BBB.
    • Converted to dopamine in the brain, even if the dopaminergic neurons are dying.
    • Protected in the plasma from decarboxylation by concomitant administration of carbidopa (pills come as levodopa–carbidopa combination, previously known as brand name Sinemet)
    • In the brain parenchyma, levodopa is decarboxylated to dopamine.
    • Dopamine supply is restored → stimulates dopaminergic receptors

Pharmacokinetics

  • Absorption:
    • Absorbed in 30–60 minutes, increased with high-fat/high-protein meals
    • Oral preparations include carbidopa to prevent decarboxylation in the plasma.
  • Distribution: 
    • Crosses the BBB
    • Peak plasma concentration: 20–30 minutes 
  • Half-life: 30 minutes to 4 hours, depending on form (immediate-release or extended-release) 
  • Metabolism: in the brain parenchyma → metabolized into dopamine
  • Excretion: urine

Indications

Recommended as 1st-line therapy for moderate to severe symptoms of PD

Adverse effects

  • Nausea 
  • Dizziness
  • Headache
  • Somnolence
  • Arrhythmias: 
    • Ventricular extrasystole
    • Atrial fibrillation
  • Orthostatic hypotension
  • Neuroleptic malignant syndrome (NMS)–like symptoms can be seen with the sudden withdrawal of levodopa:
    • Hyperthermia/very high fever
    • Other symptoms:
      • Confusion
      • Muscle rigidity
      • Diaphoresis
      • Tachycardia

Drug–drug interactions

  • Dopamine antagonists may reduce therapeutic effects.
  • Pyridoxine (vitamin B6) increases extracerebral metabolism → decreased bioavailability 

Contraindications

  • Preexisting neuropathy
  • Combination with monoamine oxidase inhibitors (MAOIs) → hypertensive crisis
  • Requires 14 day washout period between either drug (MAOI or levodopa–carbidopa)

Dopamine Agonists

Chemistry and pharmacodynamics

  • Dopamine agonists:
    • Greater affinity for D2 and D3 receptors
    • Inhibit anterior pituitary prolactin secretion 
    • Medications for PD-associated neurologic symptoms:
      • Bromocriptine (generic)
      • Pramipexole (Mirapex)
      • Ropinirole (Requip)
      • Rotigotine (Neupro transdermal patch)
    • For PD-associated acute intermittent hypomobility: apomorphine
  • Mechanism of action: 
    • Bind to dopamine receptors directly on the postsynaptic terminal
    • The D2, D3, and D4 receptors couple to the Gi/o family of G proteins, and dopamine agonists inhibit adenylyl cyclase and thus cAMP synthesis.

Pharmacokinetics

  • Absorption:
    • Oral medications except for rotigotine transdermal patch
    • Absorbed quickly, with peak plasma concentration in 30 minutes to 6 hours
    • Available in immediate-acting or extended-release forms
  • Distribution: 
    • Crosses the BBB
    • Half-life: 5–12 hours, depending on the agent and age of individual
  • Metabolism: hepatic cytochrome P450 system (CYP1A2 and CYP3A4)
  • Excretion: renal and fecal, in different proportions depending on the agent

Indications

  • Mild to moderate symptoms of PD that impact daily living.
  • Other non-Parkinson indications for dopamine agonists:
    • Pramipexole, ropinirole, and rotigotine: restless legs syndrome
    • Bromocriptine:
      • Hyperprolactinemia due to prolactin-secreting pituitary adenoma
      • Acromegaly
      • New indication (as of 2020) for uncontrolled type 2 diabetes mellitus (DM; brand name, Cycloset); guidelines do not consider bromocriptine a common treatment for type 2 DM except with specific considerations.

Adverse effects

  • Sleep attacks, particularly with pramipexole and ropinirole
  • Nausea/vomiting
  • Dizziness
  • Orthostatic hypotension
  • Headache
  • Cardiac arrhythmia
  • Dyskinesias
  • Long-term use may cause:
    • Choreiform and dystonic movements
    • Psychiatric symptoms: 
      • Mania or depression (different reactions in different individuals)
      • Hallucinations/psychosis
      • Delusions

Drug–drug interactions

  • MAOIs
  • Dopamine antagonists (1st- and 2nd-generation antipsychotics)
  • Other drugs that are metabolized by cytochrome P450 enzymes

Contraindications

  • History of psychotic illness
  • Severe cardiovascular disease
  • Postpartum or breastfeeding
  • Type 1 diabetes
  • Sleep disorder
  • Alcohol use

Amantadine (N-methyl-D-aspartate Antagonist)

Chemistry and pharmacodynamics

  • Structure: synthetic tricyclic amine
  • Mechanism of action: 
    • Antagonist of the NMDA-type glutamate receptor → antidyskinetic effect
    • May influence synthesis, release, or reuptake of dopamine 
    • Antagonizes the effects of adenosine at adenosine alpha-2-adrenergic (A2A) receptors (may inhibit D2 receptors)

Pharmacokinetics

  • Absorption: oral
  • Distribution: 
    • Cross the BBB
    • Onset of action: within 48 hours
    • Peak plasma concentration: 2–12 hours, depending on the dosage form
    • Half-life: 9–31 hours
  • Metabolism: conjugation, other unknown mechanisms
  • Excretion: urine (up to 90% unchanged)

Indications

  • Originally used as a treatment for influenza A
  • Recommended for mild Parkinsonian symptoms, specifically dyskinesia and rigidity:
    • May be used in combination with other agents
    • Only for individuals with symptoms that have a minimal impact on daily living
    • Therapeutic effect lasts only 1st few weeks.

Adverse effects

While generally a well-tolerated medication, there are some side effects to be aware of: 

  • Restlessness
  • Depression
  • Suicidal ideation
  • Somnolence
  • Insomnia
  • Agitation
  • Hallucinations/psychosis

Drug–drug interactions

  • Clozapine: may cause severe constipation or ileus
  • Trimethoprim: may increase amantadine levels and risk of psychosis
  • Bupropion: may increase risk of adverse CNS effects
  • Influenza nasal vaccine (amantadine is an antiinfluenza agent)

Contraindications

  • Pregnancy (likely teratogenic effect) and breastfeeding
  • End-stage renal disease because amantadine is metabolized by the kidneys
  • Potassium chloride or citrate: may increase risk of GI ulceration

Monoamine Oxidase (MAO) Inhibitors

Chemistry and pharmacodynamics

  • Classified as:
    • Irreversible inhibitors: selegiline (generic) and rasagiline (Azilect)
    • Reversible inhibitors: safinamide (Xadago)
  • Mechanism of action: 
    • Types of MAO:
      • Type A metabolizes norepinephrine, serotonin, and dopamine (used for depression but largely replaced by newer, safer agents).
      • Type B metabolizes dopamine selectively (used for PD).
    • In the brain parenchyma, MAO type B (MAO-B) is selectively inhibited → increased intracerebral concentration of dopamine

Pharmacokinetics

  • Absorption: oral or transdermal
  • Distribution: 
    • Crosses the BBB
    • Peak plasma concentration: 1–3 hours, depending on the agent
    • Onset of action: 2–3 weeks
    • Half-life: 3–26 hours, depending on the agent
    • Metabolism: hepatic (substrate of CYP1A2, CYP2D6, and other CYP450 enzymes)
    • Excretion: renal and fecal, in different proportions, depending on the agent

Indications

  • Recommended as an adjunct therapy for individuals with PD taking levodopa–carbidopa who exhibit a deterioration in response to it.
  • Transdermal form has also been used in individuals with major depressive disorder.

Adverse effects

  • Drug–food interactions can lead to a hypertensive crisis:
    • Avoid foods with high tyramine levels: aged cheese, cured meats (sausage, salami), fava beans, and fermented foods (marmite, soy sauce, sauerkraut)
    • Avoid fermented beverages: red wine, beer
  • Xerostomia (dry mouth)
  • Nausea
  • Diarrhea or constipation (different reactions in different individuals)
  • Drowsiness or insomnia
  • Dizziness

Drug–drug interactions and contraindications

  • Other drugs that use the cytochrome P450 enzymes for metabolism interact with MAO-B inhibitors: CYP1A2, CYP2A6, and CYP2B6 substrates
    • Some NSAIDs: naproxen, nabumetone
    • Some beta-blockers (e.g., bisoprolol) → additive hypotension
    • Antidepressant bupropion → increased risk of hypertension
    • Opioid pain medications:
      • Tramadol
      • Methadone
      • Codeine
    • Risk of serotonin syndrome with:
      • Selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, paroxetine)
      • Serotonin–norepinephrine reuptake inhibitors (SNRIs) (e.g., duloxetine)
      • Tricyclic antidepressants (TCAs) (e.g., amitriptyline)
      • Migraine medications (e.g., sumatriptan, rizatriptan)
      • Symptoms include altered mental status, autonomic instability, tremors, myoclonus, and seizures.
  • Other drugs that cause CNS depression (any sedative medications):
    • Benzodiazepines
    • 1st-generation antihistamines
    • Sedative/hypnotics
  • Other MAOIrs used for psychosis:
    • 1st-generation antipsychotics (e.g., thioridazine, haloperidol): 
      • Increased risk of extrapyramidal side effects (dystonia, bradykinesia)
      • Increased risk of CNS depression, hypotension
      • Decreased efficacy of selegiline
    • 2nd-generation antipsychotics (e.g., aripiprazole, clozapine): 
      • Increased risk of CNS depression, psychomotor impairment, hypotension, and syncope
      • Decreased selegiline efficacy
    • Avoid for 14 days, as the combination may increase the risk of serotonin syndrome:
      • Dextromethorphan cough syrup 
      • Muscle relaxant: cyclobenzaprine
      • Supplement: St. John’s wort 
      • ADHD medication: atomoxetine (Strattera) 
Clinical characteristics of serotonin syndrome

Clinical characteristics of serotonin syndrome:
Serotonin syndrome occurs from any combination of drugs that have the net effect of increasing serotonergic neurotransmission, causing altered mental status, autonomic instability, and neuromuscular abnormalities.

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Catechol O-methyltransferase (COMT) Inhibitors

Chemistry and pharmacodynamics

  • Structure: parent compound is 3-nitrobenzene-1,2-diol, also called nitrocatechol.
  • Drug names:
    • Entacapone (Comtan)
    • Tolcapone (Tasmar)
    • Opicapone (Ongentys)
  • Mechanism of action: 
    • COMT peripherally metabolizes levodopa into 3-O-methyldopa.
    • COMT is selectively inhibited → increased bioavailability of levodopa → prolonged action of levodopa
    • Clearance of levodopa is also decreased → greater bioavailability

Pharmacokinetics

  • Absorption: oral
  • Distribution: 
    • Act peripherally
    • Peak plasma concentration: 1–2 hours, depending on the agent
    • Half-life: 1–3 hours, depending on the agent
  • Metabolism: hepatic
  • Excretion: renal and fecal

Indication

For mild PD symptoms that have a minimal impact on daily living

Adverse effects

  • Dyskinesia
  • Hallucinations/psychosis
  • Orthostatic hypotension
  • Abdominal pain
  • Sleep disturbances
  • Orange discoloration of the urine
  • Hepatotoxicity
  • Abrupt discontinuation can cause NMS-like symptoms

Drug–drug interactions

  • Codeine
  • Metoclopramide
  • Selegiline
  • Promethazine
  • Calcium channel blockers
  • Benzodiazepines
  • TCAs

Contraindications

  • History of neuroleptic malignant syndrome 
  • Liver disease: Agents should be withdrawn as soon as liver toxicity is detected as indicated by elevated liver enzymes.

Comparison of Drug Classes

Table: Comparison of Parkinson’s disease (PD) medications
AgentMechanism of actionIndicationsSide effectsContraindications
LevodopaDecarboxylated into dopamineModerate to severe PD symptoms
  • Arrhythmias
  • NMS-like symptoms if abrupt withdrawal
Combination with MAOIs
Dopamine agonistsIncrease dopaminergic activity by binding to postsynaptic dopamine receptorsCurrent 1st-line therapy for mild to moderate PD symptoms that impact daily living
  • Choreiform and dystonic movements
  • Mania
  • Depression
  • Hallucinations
  • Confusion
  • Pregnancy
  • History of psychotic illness
  • Severe cardiovascular disease
  • Combination with monoamine oxidase inhibitors (MAOIs)
Amantadine (NMDA antagonist)Antagonist of the NMDA-type glutamate receptor → antidyskinetic effectRecommended for mild PD symptoms that have minimal impact on daily living
  • Restlessness
  • Depression/suicide
  • Somnolence
  • Insomnia
  • Agitation
  • Hallucinations
  • Confusion
  • Pregnancy
  • End-stage renal disease
MAO-B inhibitorsMAO-B is selectively inhibited → increased intracerebral concentration of dopamineRecommended for mild PD symptoms that have minimal impact on daily living
  • Xerostomia
  • Nausea
  • Constipation
  • Diarrhea
  • Drowsiness
  • Dizziness
  • Insomnia
Individuals receiving meperidine, tramadol, methadone, propoxyphene, cyclobenzaprine, or St. John’s wort → increased risk of serotonin syndrome
Catechol O-methyltransferase (COMT) inhibitorsSelective inhibition of COMT → increased bioavailability of levodopa → prolonged action of levodopaRecommended for mild PD symptoms that have minimal impact on daily living
  • Dyskinesia
  • Nausea
  • Confusion
  • Abdominal pain
  • Orthostatic
  • Hypotension
  • Sleep disturbances
  • History of neuroleptic malignant syndrome
  • Liver disease

References

  1. Aminoff, M.J. (2021). Pharmacologic management of parkinsonism & other movement disorders. In Katzung B.G., & Vanderah T.W. (Eds.), Basic & Clinical Pharmacology, 15th ed. McGraw-Hill. https://accessmedicine-mhmedical-com.ezproxy.unbosque.edu.co/content.aspx?bookid=2988&sectionid=250598520 
  2. National Center for Biotechnology Information. (2021). PubChem compound summary for CID 6047, Levodopa. Retrieved July 7, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Levodopa
  3. Lexicomp. (2021). Carbidopa and levodopa: drug information. UpToDate. Retrieved August 17, 2021, from https://www.uptodate.com/contents/carbidopa-and-levodopa-drug-information
  4. Deik, A., Tarsy, D. (2021) Essential tremor: treatment and prognosis. UpToDate. Retrieved August 17, 2021, from https://www.uptodate.com/contents/essential-tremor-treatment-and-prognosis
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  6. Spindler, M.A., Tarsy, D. (2021). Initial pharmacologic treatment of Parkinson disease. UpToDate. Retrieved July 8, 2021, from https://www.uptodate.com/contents/initial-pharmacologic-treatment-of-parkinson-disease
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