Parkinson’s Disease

  • Most commonly onsets in people over 80
  • Characterized by a loss of dopaminergic neurons & an imbalance between dopamine & ACh (ACh overactivity)
  • Environmental & genetic factors are thought to play a role
  • No definitive lab test & diagnosis is based on patients having 2 hallmark symptoms present at the time of diagnosis & having their symptoms relieved w/ dopamine replacement
  • Symptoms:  resting tremor, bradykinesia, rigidity, postural reflex impairment
    • usually start out unilaterally & then spread bilaterally
    • Bradykinesia:  slow movement (aka hypokinesia), eventually will affect all voluntary movements, makes ADLs difficult
    • Resting tremor (most recognizable sign):  pill rolling movement of hands, can affect limbs, jaw, face, tongue
    • Rigidity:  resistance to passive movement, can manifest as stiffness or pain, mask-face (lack of expression), jerkiness of arms (cogwheeling)
    • Postural reflex impairment:  flexion at hips, knees &/or waist
  • Depression may precede parkinson’s in up to 25% of patients
    • Often is underrecognized (it’s the first symptom of parkinson’s in up to 25% of patients though)
  • 15-20% of patients will develop psychosis  (most commonly exhibited by hallucinations)
    • Meds used to treat parkinsons are a common cause of this
      • Order of d/c:  anticholinergics > amantadine > MAO inhibitors > DA agonists > COMT inhibitors > levodopa
    • Treatment choices for psychosis:  quetiapine (seroquel) & clozapine
  • Dementia is associated with an increased risk of mortality in parkinsons patients
    • s/s:  fluctuating attention, recognition, language is preserved
    • Treatment:  rivastigmine (exelon)
  • Sleep disorders are also a comorbid condition with parkinsons
    • Insomnia is the most common type  (use common meds for this)
    • Ropinirole, pramipexole & levodopa are all used to treat restless leg syndrome as well
    • Excessive daytime sleepiness is often treated with either modafanil (provigil) or methylphenidate
    • REM behavior disorder is often treated with Clonazepam
  • Falls are another common problem with parkinson’s patients and they have a much higher risk of fracture than the normal population so they should receive an osteoporosis test
  • GI dysfunction (impaired gastric emptying, constipation, nausea) is the most common of all non-motor symptoms
    • Parkinsons patients commonly experience weight loss due to decreased intake & swallowing difficulties (dysphagia)
  • Orthostatic & postprandial hypotension are common & may be exacerbated by dopamine agonists & selegiline
    • Don’t need to treat hypotension if it’s asymptomatic
      • But if you do, do non-drug treatments first followed by midodrine & fludrocortisone
  • Sexual dysfunction is another common problem in parkinson’s patients (although levodopa may increase libido)
  • Melanomas show an increased incidence in patients with parkinson’s disease
  • 5 stages
    • I: Mild unilateral symptoms, posture becomes poorer, abnormal facial expressions become apparent, no major problems, may last for several years
    • II: Bilateral symptoms, minimal disability and effect on ADLs, walking and balance become involved
    • III: Moderate disease, symptoms are more debilitating, major impairments in walking and posture, movements slow considerably, falling becomes more common
    • IV: Advanced disease, ability to complete ADLs is severely compromised if possible at all, patients unable to live alone, typically wheelchair bound
    • V: Patients require around the clock care, cachexia is common, frequent hospitalizations due to infection, incontinence, difficulty speaking
  • Initiating drug treatment:  primary target is the replacement of dopaminergic activity with the goal of therapy being to decrease symptoms while minimizing the risk of adverse SE
  • Carbidopa/levodopa  (GOLD standard)
    • All patients will eventually get this b/c it covers all of the symptoms of the disease
    • Levodopa gets converted to DA, carbidopa (decarboxylase inhibitor) prevents its conversion to dopamine in the periphery
      • Min daily dose of levodopa = 75-100 mg
      • Maintenance dose of levodopa = 500-6000 mg
      • Controlled release are less well absorbed but have fewer fluctuations in concentration
      • Try to take on an empty stomach or with minimal protein
    • Exhibits both a short duration & long duration response (the long duration response though wanes over time as the brain’s ability to store of dopamine diminishes)
    • Wearing off:  return of a patients symptoms prior to the next dose  (predictable)
      • May want to add another drug or shorten the intervals to treat
      • Preferred to do more frequent smaller doses rather than less frequent larger doses
    • On-off phenomenon:  unpredictable periods of drug resistance
    • SE:  dyskinesias (coincide with higher doses), nausea, dizziness, insomnia, hallucinations, confusion, hypotension
      • Taper medication in order to avoid neuroleptic malignant syndrome
  • Dopamine Agonists
    • Helpful for all med responsive symptoms
    • May be used in combo w/ sinemet
    • SE:  hallucinations, fatigue, edema, nausea, hypotension, pleuropulmonary fibrosis, impulsivity
      • Dyskinesias may occur especially when added to levodopa
        • Decrease levodopa dose by 1/3 when using these in combo
    • Ergot alkaloid derivatives (bromocriptine)
      • Maintenance dose of bromocriptine:  30-60 mg divided BID
    • Non-ergolines (pramipexole, ropinirole, rotigotine, apomorphine)
      • Maintenance dose of pramipexole (mirapex):  up to 4.5 mg/day
      • Maintenance dose of ropinirole (requip):  up to 24 mg/day
      • Maintenance dose of Rotigotrine (neupro):  6 mg/day transdermally (unavailable currently)
        • Transdermal would be good for decreasing breakthrough symptoms overnight, decreasing the variability of absorption, adherence & smooth motor fluctuations
      • Maintenance dose of apomorphine (apokyn):  6 mg/day SQ
  • Amantadine  (Symmetrel—Antiviral)
    • Not too effective at treating PD symptoms but it has been thought to help control dyskinesias
    • SE:  anticholinergic, nightmares, insomnia, confusion, levido reticularis, withdrawal encephalopathy
    • Dosing:  need to adjust for renal dysfunction, need to taper
  • Anticholinergics
    • Primarily are used to control tremor
    • SE:  psychiatric disturbances, dry mucous membranes, tachycardia, orthostatic BP changes, urinary retention, constipation
    • Benztropine (Cogentin):  up 6 mg/day
    • Trihexyphenidyl (Artane):  up to 10 mg/day
    • Diphenhydramine (benadryl):  up to 200 mg/day
  • MAO-B inhibitors   (selegiline & rasagiline)
    • Used as both mono (rasagaline) & adjunct therapy
    • Only drugs shown to slow he progression of the disease   (dopamine is metabolized by MAO)
    • Rasagiline is approved for monotherapy & doesn’t have amphetamine metabolites & won’t cause as many hallucinations like selegiline
      • Halve the dose when using with levodopa
    • Since they interact at MAO-B, tyramine is less likeyl to interact at normal doses
    • Some accounts of serotonin syndrome have been documented
  • COMT inhibitors
    • Inhibit the breakdown of dopamine via COMT
    • Only used as an adjunct to levodopa therapy
    • Increases levodopa’s AUC & half life
      • May need to decrease levodopa dose by 25%
    • Significantly increases “on” time  (may be more dyskinesias)
    • Tolcapone crosses the BBB
    • Entacapone acts in the periphery only
      • Up to 1600 mg/day               has been used in combo products with Levodopa/carbidopa  (stalevo)
    • SE:  urine discoloration, diarrhea, same as levodopa , but tolcapone may also cause hepatotoxicity

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