Movement Disorder Medications

Movement disorders can be characterized as hypokinetic or hyperkinetic and often require pharmacologic management to improve the individual’s level of function. Common movement disorders include essential tremor, tics (Tourette syndrome), Parkinson disease, Huntington disease, and Wilson disease. Each of these conditions requires unique pharmacologic interventions depending on the pathophysiology and symptom severity. For example, Parkinson disease requires restoration of dopaminergic activity, while symptoms of Huntington disease are ameliorated by reducing dopamine concentrations. Although these agents can be highly beneficial, no agent is innocuous and some have potentially severe adverse events.

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Overview

Definition

Movement disorders are a group of neurologic conditions that cause excessive voluntary or involuntary movements; these disorders can also cause reduced or slow movements.

Classification

  • Hypokinetic:
    • Parkinson’s disease
    • Progressive supranuclear palsy
    • Multiple system atrophy
  • Hyperkinetic:
    • Dystonia
    • Torticollis
    • Blepharospasm
    • Essential tremor
    • Myoclonus
    • Chorea:
      • Seen with Huntington disease and Wilson disease
      • Can be a side effect of neuroleptic and dopaminergic medications
      • Seen with toxic/metabolic conditions (e.g., alcohol abuse, thyrotoxicosis)
    • Tic disorders, including Tourette syndrome
    • Tardive dyskinesia: associated with dopamine receptor–blocking agents: 
      • Antipsychotic drugs
      • Antiemetic agents (metoclopramide and prochlorperazine)

Essential Tremor

Definition

Essential tremor, also called familial tremor, causes a benign postural tremor of the hands that can cause significant distress for individuals who are affected by it.

Therapeutic options

  • Propranolol
  • Primidone (off-label)

Mechanism of action

  • Propranolol: nonselective beta blocker
  • Primidone: exact mechanism is unknown; acts on GABA receptors, increasing synaptic inhibition

Pharmacokinetics

  • Both propranolol and primidone are oral medications 
  • Both are metabolized by the liver and excreted in the urine
  • Onset of action and half-life:
    • Propranolol:  
      • Onset of action: 1–2 hours for the short-acting form; must be taken 2–3 times a day
      • Also available in an extended-release form to be taken once a day
      • Half-life: 3–6 hours
    • Primidone: 
      • Onset of action: 3 hours
      • Dosed once daily at bedtime
      • Half-life: 5–16 hours
      • Has active metabolites, including phenobarbital, with a half-life of up to 125 hours

Adverse effects

  • Propranolol:
    • Bradycardia
    • Hypotension
    • Heart failure
    • Fatigue
    • Bronchospasm (beta-receptor–mediated)
    • Stevens-Johnson syndrome
    • Erythema multiforme
  • Primidone:
    • Possible drug-induced systemic lupus erythematosus
    • Sedation
    • Nausea/vomiting
    • Ataxia
    • Diplopia
    • Vertigo
    • Megaloblastic anemia

Drug–drug interactions

Table: Drug–drug interactions of agents used to treat essential tremors
AgentEffects
Propranolol
  • Concentrations are increased by:
    • Alcohol
    • Tobacco
  • Amiodarone enhances bradycardic effects
  • Barbiturates enhance hypotensive effects
  • Propranolol enhances the effects of:
    • Ergot alkaloids (vasoconstriction)
    • Insulin (hypoglycemia)
    • Levodopa
Primidone
  • CYP3A4 inducer; causes a significant reduction in serum concentrations of CYP3A4 substrates:
    • Buspirone
    • Benzodiazepines
    • Calcium channel blockers (e.g., verapamil)
    • Anticoagulants: apixaban, dabigatran, and rivaroxaban
  • Sedation/CNS depressant effects are enhanced by:
    • Alcohol
    • Other barbiturates
    • Magnesium sulfate
    • Metoclopramide
  • May decrease contraceptive levels
    • Levonorgestrel
    • Medroxyprogesterone

Contraindications

  • Propranolol
    • Decompensated heart failure
    • Conduction abnormalities/heart block
    • Asthma
    • 2nd or 3rd trimester of pregnancy
    • Renal or hepatic impairment
  • Primidone
    • Porphyria
    • Depression
    • Pulmonary insufficiency
    • Renal or hepatic impairment
    • Substance abuse disorders

Tics (Tourette syndrome)

Definitions

Tics are sudden, coordinated, abnormal, repetitive movements (e.g., repetitive shoulder shrugging or sniffing). 

Tourette syndrome is a movement disorder with onset during childhood and characterized by motor and phonic tics.

Therapeutic options

Listed alphabetically, not in order of use:

  • Aripiprazole
  • Botulinum toxin A 
  • Clonidine
  • Haloperidol
  • Pimozide

Mechanism of action

  • Aripiprazole: Antagonist on postsynaptic D2 receptors and partial activator of serotonin
  • Botulinum toxin A: Presynaptic blocker of the calcium-dependent release of acetylcholine at the neuromuscular junction
  • Clonidine: Alpha-adrenergic–receptor agonist
  • Haloperidol: Nonselective D2-receptor antagonist
  • Pimozide: Selective dopaminergic (D2) receptor antagonist

Pharmacokinetics

Table: Pharmacokinetics of drugs used to treat essential tremors
AgentAdministrationElimination half-lifeOnset of actionExcretion
PimozideOral111 ± 57 hours in adultsWithin 1 weekRenal (urine)
HaloperidolOral14–37 hours1–2 weeksRenal
AripiprazoleOral75 hours1–2 weeksRenal and fecal
ClonidineOral12–16 hours1–2 weeksRenal
Botulinum toxin ALocal injectionUp to 2 hoursAround 2 weeksUnknown

Adverse effects

  • Pimozide:
    • Sedation
    • Behavioral changes
    • Xerostomia (dry mouth)
    • Constipation
    • QT prolongation
    • Neuroleptic malignant syndrome
    • Tardive dyskinesia
  • Haloperidol:
    • Extrapyramidal symptoms: 
      • Parkinsonism:  tremor/bradykinesia
      • Akathisia
      • Dystonia
    • Anticholinergic effects:
      • Hyperthermia
      • Xerostomia
      • Sedation
      • Constipation
      • Urinary retention
    • QT prolongation
  • Aripiprazole:
    • Akathisia
    • Orthostatic hypotension
    • Headache
    • Weight gain
    • Anxiety or depression
    • Insomnia
  • Clonidine:
    • Hypotension
    • Bradycardia
    • Dizziness
    • Drowsiness
  • Botulinum toxin A:
    • Bruising, edema, pain at the site of injection
    • Headache
    • Hypersensitivity

Drug–drug interactions

  • Pimozide 
    • Decreases effects of:
      • Amphetamines 
      • Antiparkinson agents
    • Enhances QT-prolonging effects of:
      • Haloperidol
      • Fluoxetine
      • Ondansetron
  • Haloperidol:
    • Tobacco use decreases the concentration
    • Enhanced effect with:
      • Lithium
      • Ethyl alcohol
      • Methyldopa
    • Diminishes the effects of:
      • Amphetamine 
      • Epinephrine 
  • Aripiprazole:
    • Enhances the effects of:
      • Alcohol 
      • Oxycodone
    • Diminishes the effects of: 
      • Amphetamines 
      • Dopamine agonists
  • Clonidine:
    • Enhances the effects of:
      • Alcohol 
      • Oxycodone
      • Beta-blockers
      • Levodopa-containing formulations
    • Decreased effect with amphetamines
  • Botulinum toxin A: effects magnified by aminoglycosides

Contraindications

  • Aripiprazole:
    • Caution in individuals who are poor CYP2D6 metabolizers
    • Caution in individuals with dementia-related psychosis
    • Caution in 3rd trimester of pregnancy
    • Caution in individuals with cardiovascular disease
  • Clonidine:
    • Hypotension
    • Severe coronary artery disease
    • Elderly individuals
    • Renal impairment
    • Alcohol or CNS depressant use
  • Botulinum toxin A: 
    • Keloid scarring
    • Pregnancy/lactation
    • Amyotrophic lateral sclerosis
  • Haloperidol:
    • Congenital long-QT syndrome
    • Hypersensitivity 
    • Parkinson disease
    • Lewy-body dementia
    • Severe CNS depression
  • Pimozide:
    • Congenital long-QT syndrome
    • Severe CNS depression
    • Cardiac arrhythmias
    • Hypokalemia 
    • Hypomagnesemia

Huntington disease

Definitions

  • Huntington disease: Inherited autosomal dominant disease characterized by progressive movement disorders and dementia.
  • Chorea: Irregular, unpredictable, and involuntary movements that flow randomly from 1 part of the body to another; caused by functional overactivity in dopaminergic nigrostriatal pathways.

Treatment

  • 1st-line: vesicular monoamine transporter type 2 (VMAT2) inhibitors:
    • Tetrabenazine
    • Deutetrabenazine
  • 2nd-line agents occasionally used:
    • 2nd-generation antipsychotics
    • Benzodiazepines

Mechanism of action

  • Transport of dopamine into vesicles of VMAT2 inhibitors is impeded at the presynaptic terminal.
  • Vesicles are depleted of dopamine and its transmission is decreased.

Pharmacokinetics

  • Distribution: 
    • Peak plasma concentration: 1–4 hours, depending on the agent
    • Half-life: 7–10 hours, depending on the agent
  • Metabolism: hepatic (CYP2D6)
  • Excretion: primarily renal; fecal in a small proportion

Adverse effects

  • Depression/suicidal ideation, which may already be a concern with Huntington disease
  • Sedation
  • Akathisia
  • Parkinsonism
  • QT prolongation
  • Neuroleptic malignant syndrome (NMS)
  • Orthostatic hypotension

Drug–drug interactions

  • Enhance toxic effects of antipsychotics and monoamine oxidase (MAO) inhibitors 
  • Haloperidol can exacerbate QT prolongation

Contraindications

  • Combination with monoamine oxidase (MAO) inhibitors requires a 14-day washout period
  • Underlying hepatic disease

Wilson disease

Definition

Wilson disease is an autosomal recessive disorder that leads to copper accumulation in the liver, brain, and cornea. The disease has neurologic manifestations including dystonia, choreoathetosis, cerebellar ataxia, and tremor.

Pharmacologic therapeutic options

  • Copper chelators:
    • 1st line: D-penicillamine
    • 2nd-line: trientine (triethylenetetramine)
  • Reaccumulation prevention: zinc salts

D-penicillamine

  • Mechanism of action: chelator
    • Sequesters copper (or other heavy metals) through the formation of multiple bonds
    • Results in urinary excretion of heavy metals
  •  Pharmacokinetics:  
    • Half-life: 2–7 hours
    • Metabolism: hepatic (small amounts)
    • Excretion: renal
  • Adverse effects
    • Aplastic anemia or agranulocytosis
    • Nephropathy
    • Hepatotoxicity
    • Myasthenic syndrome (myasthenia gravis)
    • Lupus erythematosus–like syndrome
    • Penicillin cross-sensitivity
  • Drug–drug interactions
    • D-penicillamine decreases the concentration of digoxin.
    • Antacids with zinc, aluminum, or magnesium as polyvalent cations
  • Contraindications:
    • Pregnancy
    • Previous history of penicillamine-related aplastic anemia
    • Penicillin allergy documented as an immune reaction
    • Renal insufficiency 
    • Rheumatoid arthritis treated with immunosuppressants

Comparison of Medications

Table: Comparison of drugs used for movement disorders
DrugMovement disorder disease indicationMechanismSide effects
PropranololEssential tremorNonselective beta antagonist
  • Bradycardia
  • Hypotension
  • Heart failure
  • Fatigue
  • Bronchospasm (beta-receptor–mediated)
  • Stevens-Johnson syndrome
  • Erythema multiforme
PimozideTics (Tourette syndrome)Selective dopaminergic (D2) receptor antagonist
  • Sedation
  • Akathisia
  • Behavioral changes
  • Anticholinergic effects
  • Depression
  • QT prolongation
  • Neuroleptic malignant syndrome
HaloperidolTics (Tourette syndrome)Nonselective D2 receptor antagonist
  • Extrapyramidal symptoms
  • Anticholinergic effects
  • QT prolongation
ClonidineTics (Tourette syndrome)Alpha-adrenergic–receptor agonist
  • Hypotension
  • Bradycardia
  • Dizziness
  • Drowsiness
TetrabenazineHuntington diseaseTransport of dopamine into vesicles inhibited at presynaptic terminal
  • Depression/suicidal ideation
  • Sedation
  • Akathisia
  • QT prolongation
  • Neuroleptic malignant syndrome (NMS)
  • Orthostatic hypotension
D-penicillamineWilson diseaseChelator
  • Aplastic anemia or agranulocytosis
  • Nephropathy
  • Hepatotoxicity
  • Myasthenia gravis
  • Lupus-like syndrome
  • Penicillin cross-sensitivity

References

  1. Agarwal, S., Biagioni, M. C. (2021). Essential tremor. StatPearls. Retrieved August 13, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK499986/ 
  2. Deik, A., Tarsy, D. (2021). Essential tremor: treatment and prognosis.  UpToDate. Retrieved August 16, 2021, from https://www.uptodate.com/contents/essential-tremor-treatment-and-prognosis
  3. Shahrokhi, M., Gupta, V. (2021). Propranolol. StatPearls. Retrieved August 16, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK557801/ 
  4. Lenkapothula, N., Cascella, M. (2021). Primidone. StatPearls. Retrieved August 16, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK562297/ 
  5. National Center for Biotechnology Information. (2021). PubChem Compound Summary for CID 60795, Aripiprazole. Retrieved July 5, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Aripiprazole
  6. National Center for Biotechnology Information. (2021). PubChem Compound Summary for CID 2803, Clonidine. Retrieved July 5, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Clonidine
  7. Jankovic, J. (2021). Tourette syndrome: management. UpToDate. Retrieved July 5, 2021, from https://www.uptodate.com/contents/tourette-syndrome-management
  8. Lexicomp, Inc. (2021). Pimozide: Drug information. Retrieved August 16, 2021, from https://www.uptodate.com/contents/pimozide-drug-information
  9. Boushra, M., Nagalli, S. (2021). Neuroleptic agent toxicity. StatPearls. Treasure Island (FL): StatPearls Publishing. Retrieved July 5, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK554608/ 
  10. Rahman, S., Marwaha, R. (2021). Haloperidol. StatPearls. Retrieved July 5, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK560892/ 
  11. Manzon, L., et al. (2021). Clonidine toxicity. StatPearls. Retrieved July 5, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK459374/ 
  12. National Center for Biotechnology Information. (2021). PubChem Compound Summary for CID 5565, Triethylenetetramine. Retrieved July 9, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Triethylenetetramine
  13. Schilsky, M. L. (2020). Wilson disease: treatment and prognosis. UpToDate. Retrieved August 16, 2021, from  https://www.uptodate.com/contents/wilson-disease-treatment-and-prognosis
  14. Mejias, S. G., Ramphul, K. (2021). Penicillamine. StatPearls. Retrieved July 8, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK513316/ 
  15. Padda, I. S., Tadi, P. (2021). Botulinum toxin. StatPearls. Retrieved July 8, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK557387/

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