Parkinsons Disease

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Parkinsons Disease

• Review of Pathophysiology, Diagnosis, Current
  Therapy

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Historical Perspective

• Dr. James Parkinson (1755-1828)
• 1817
• involuntary tremulous motion
• pass from a walking to a running pace
• shaking palsy
• London home

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Epidemiology

• Average incidence is 20 per 100,000 in North
  America
• 1 Million affected in the United States
• 50,000 new cases per year
• Cost estimated to exceed 5.6 Billion annually

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Epidemiology

• Average age of onset 62.5
• Men and women affected equally
• Genetic Link
• African-Americans and Asians less likely than
  Caucasians to develop Parkinsons
• Caffeine and smoking shows some protective effects

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Case Example

• JJ is a 66 y/o Caucasian man who underwent
  surgical management for spinal stenosis and was
  admitted for rehabilitation. JJ has a past
  history of Parkinsons, hypertension, coronary
  artery disease, GERD, and depression. Upon
  admission appropriate measures were taken for
  pain management and aforementioned medical
  conditions. JJs surgical management and
  rehabilitation was complicated by advanced
  Parkinsons. During his stay advances were made
  in his strength, endurance, and ADLs. JJ was
  discharged and will receive assistive care from
  his wife. Overall, the care for JJ was
  appropriate and followed standard of care
  practices.

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Medication Profile

• Carbidopa/Levodopa (Sinemet) 25/100/po-6times
  daily-(Parkinson's)
• Lansoprazole (Prevacid) 30mg/po-ACBR-(GERD)
• Baclofen (Lioresal) 10mg/po-qhs-(Parkinson's
  Dystonia)
• Quinine sulfate (Quinidine) 260mg/po-qhs-(Muscle
  Cramps)
• Quetiapine (Seroquel) 25mg/po-qhs-(Hallucinations)
  
• Ropinirole (Requip) 1mg/po-1mg5Xdaily2mgq6am-(Par
  kinson's)
• Docusate Sodium (Colace) 100mg/po-bid-(Constipatio
  n)
• Metoprolol (Lopressor) 50mg/po-qd-(Hypertension)
• Calcium Carbonate (Tums) 500mg/po-1000mgbid-(Calci
  um supplement)
• Oxaprozin (Daypro) 600mg/po-qd-(Osteoarthritis)
• Propoxyphen/APAP (Darvocet N-100)
  100mg/650mg/po-1q4hprn-(Pain Management)
• Bethanechol (Urecholine) 10mg/po-20mgprn-(Urinary
  Retention)
• Docusate Sod-Casanthranol (Pericolace)
  100mg/30mg/po-qdprn-(Constipation)
• Bisacodyl Supp (Ducolax) 10mg/pr-qodprn-(Constipat
  ion)

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Pathogenesis

• Four Theories
• Oxidative damage
• Impaired protection
• Environmental toxins
• MPTP-Methyl-phenyl tetrahydropyridine
• Genetic predisposition
• Mutations in the gene for the protein
  alpha-synuclein located on chromosome 4
• Accelerated aging

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Pathophysiology

• Imbalance of dopamine and acetylcholine
• Loss of 80 to 90 of dopaminergic production in
  the substantia nigra
• Lewy Bodies

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Diagnostic Features

• Four Cardinal Signs
• T remor
• R igidity
• A kinesian and bradykinesia
• P ostural instability

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Characteristic Problems

• Micrographia-small handwriting
• Hypomimia-decreased facial animation
• Hypophonia-soft speech
• Dysarthria-unclear pronunciation
• Dyspnea-labored breathing
• Festination-Shuffling gait

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Diagnosis

• Bradykinesia must be present with at least two of
  the following limb muscle rigidity, resting
  tremor (abolished with movement), or postural
  instability.
• Need to eliminate secondary causes
• Postencephalitic
• Drug-Induced
• Toxic
• Stroke
• Trauma
• Neoplasm
• Other neurodegenerative conditions
• Wilsons disease
• Alzheimers
• Lewy Body dementia

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Hoehn and Yahr Staging of Severity of Parkinsons
Disease
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Schwab England Activities of Daily Living Scale
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Pharmacotherapy

• Levodopa
• Dopamine agonists
• COMT inhibitors
• Amantadine
• Anticholinergics
• Selegiline

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Levodopa

• L-Dopa (Larodopa by Roche)
• Introduced in the late 1960s
• Gold Standard
• Crosses the blood-brain barrier
• Adverse effects such as nausea, vomiting,
  postural hypotension, involuntary movements,
  restlessness, and cardiac arrhythmias

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Levodopa

• Today L-dopa/carbidopa (Sinemet) used almost
  exclusively
• Initial dose of 25/100mg ½ QD for 7 days,
  increase by ½ tab daily for 7 days until up to 1
  tablet TID. Extended release dosed as 25/100mg
  QD and titrated up to TID over a months time.
  Maximum dose of L-dopa is 800mg/day.
• Adverse effects minimized with carbidopa
• End-of-dose wearing-off effect
• On-off effect

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Dopamine AgonistsSynthetic Dopamine

• Bromocriptine Mesylate (Parlodel)
• Pergolide Mesylate (Permax)
• Pramipexol (Mirapex)
• Ropinirole HCL (Requip)

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Dopamine Agonists

• Monotherapy or combination
• Are particulary usefull for
• Prolonging the effective treatment period in
  patients with deteriorating response.
• Delaying the onset of L-dopa therapy.
  Particularly in younger patients.
• Treating patients who cannot tolerate high doses
  of L-dopa.
• Associated with more side effects than L-dopa
• Potential adverse effects include somnolence,
  dyskinesias, nausea, vomiting, orthostatic
  hypotension, nightmares, hallucinations,
  confusion, dizziness

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Ergot Agonist Dosing

• Bromocriptine (Parlodel)
• Initial 1.25mg QD-BID
• Titrate 1.25mg to 2.5mg/d every week
• Average dose lt30mg/day. Some patients may
  require up to 120mg/day
• Pergolide (Permax)
• 13 times more potent than bromocriptine
• Initial 0.05mg/d for 2 days, increasing by 0.1 to
  0.15mg/d every 3 days over a 12 day period
• May increase by 0.25mg every 3 days until
  symptoms are eliminated or adverse effects occur
• Mean dose 3mg/d

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Nonergot Agonist Dosing

• Pramipexole (Mirapex)
• Monotherapy or Adjunct
• Initial dose of 0.125 mg TID and increased every
  5 to 7 days as tolerated up to 3 to 4.5mg/d
• Higher doses are not more effective than 1.5mg/d
  and are associated with more side effects
• Mean 27 reduction of L-Dopa
• Decrease dose with renal function impairment
• Drugs that are secreted by the cationic transport
  system may decrease the clearance of pramipexole
  by 20. These include cimetidine, diltiazem,
  quinidine, quinine, ranitidine, triamterene, and
  verapamil.

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Nonergot Agonist Dosing

• Ropinirole (Requip)
• Monotherpy or Adjunct
• Initial dose of 0.25mg TID and increased by
  0.25mg TID on a weekly basis. After the fourth
  week doses may be increased by 1.5mg/d up to
  9mg/d. Further adjustment may be obtained by
  3mg/d increases up to 24mg/day
• Mean 19 reduction of L-dopa
• Drugs that inhibit or induce CYP1A2 will affect
  the clearance of ropinirole. Inhibitors such as
  cimetidine, ciprofloxacin, clarithromycin,
  diltiazem, enoxacin, erythromycin, fluvoxamine,
  mexiletine, norfloxain, omeprazole, ritonavir,
  and troleandomycin. Inducers such as
  carbamazepine, phenobarbital, phenytoin, and
  rifampin.
• If therapy is stopped, discontinue over seven days

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COMT Inhibitors

• Entacapone (Comtan)
• Tolcapone (Tasmar)

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COMT Inhibitor Dosing

• Entacapone (Comtan)
• Adjunct therapy
• Initial dose of 200mg with each dose of levodopa
  up to 8 times daily
• Decrease of L-dopa may be necessary
• Exacerbation of L-dopa side effects , diarrhea,
  urine discoloration, abdominal pain

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COMT Inhibitor Dosing

• Tolcapone (Tasmar)
• Adjunct therapy
• Initial 100mg TID up to 200mg TID
• More potent and longer acting than entacapone
• Decrease L-dopa by 25 to 50
• Exacerbation of L-dopa side effects, diarrhea,
  urine discoloration, liver toxicity.
• Monitor LFTs every 2 weeks for 1 year, every 4
  weeks for 6 months, then every 8 weeks

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Amantadine

• Amantadine HCL (Symmetrel)
• Inhibits dopamine recapture
• Blocks acetylcholine and glutamate receptors
• Dose 100mg BID to TID
• Caution in renal failure patients
• Currently used to reduce choreic movements
• Narrow therapeutic range
• Unpleasant side effects such as nausea,
  dizziness, confusion, hallucinations, nightmares,
  dry mouth peripheral edema, and livedo
  reticularis

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Anticholinergics

• Trihexyphenidyl HCL (Artane)
• Benztropine Mesylate (Cogentin)
• Monotherapy or adjunct
• Predopaminergic therapy
• Long touted as most effective for reducing tremor
• Use Limited by side effects especially in the
  elderly.

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Anticholinergics

• Trihexyphenidyl HCL (Artane)
• Initial dose of 1mg and increase by 2 mg every 3
  to 5 days until 6 to 10 mg/day. Usually given
  TID with meals or QID with meals and at bedtime.
• Possible adverse effects include dry mouth,
  blurred vision, somnolence, hallucinations,
  memory impairment, confusion, urinary retention,
  and constipation.
• Benztropine Mesylate (Cogentin)
• Initial dose of 0.5 to 1 mg at bedtime. Increase
  by 0.5mg every 5 to 6 days up to a total daily
  dosage of 6mg.
• Possible adverse effects include dry mouth,
  blurred vision, somnolence, hallucinations,
  memory impairment, confusion, urinary retention,
  and constipation.

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Selegiline

• Selegiline HCL(Eldepryl)

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Selegiline

• Selegiline HCL (Eldepryl)
• Monotherapy or adjunct
• MOA-inhibits monoamine oxidase-B (MAO-B)
• Inhibition of MAO-A does not occur
• Dosage of 5 mg BID with breakfast and lunch
• When used as monotherapy delays the need of
  L-dopa by an average of nine months.
• Possible adverse effects include nausea,
  dizziness, abdominal pain, confusion, and
  exacerbation of L-dopa side effects
• Controversial theory of decreased rate of
  neuronal death due to a reduction of free
  radicals.

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Surgical Options

• Pallidotomy and Pallidal Stimulation
• Thalamotomy and Thalamic Stimulation
• Introduced in 1950
• Pallidotomy improves tremor, rigidity, and
  bradykinesia
• Thalamotomy relieves tremor, rigidity, but not
  bradykinesia
• Neurosurgical treatment came to a end with the
  introduction of L-dopa in late 1960s
• Resurgence of neurosurgical intervention with the
  failure of pharmacological treatments after 10 to
  15 years of disease progression
• Two methods Ablation and deep brain stimulation

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Grafting

• Suprarenal to brain transplantation
• Fetal tissue transplantation
• Cell culture transplantation

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Under Investigation

• Implantable pumps
• Implantable capsules containing
  dopamine-producing cells
• New medications to target one of the five
  individual brain receptors for dopamine
• Continued genetic research

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References

• Cosgrove, G. Rees, Eskandar, Emad N., Shinobu,
  Leslie A. Surgical Treatment of Parkinson
  Disease. JAMA December 26, 20012863056-3059.
• Dipiro, Joseph T., ed. Pharmacotherapy Fourth
  Edition. Stamford, Connecticut Appleton
  Lange, 1999.
• Early Parkinsons Disease Dopamine Agonists
  Have Increasingly Important Role in Symptom
  Management. Drug Ther Perspect 200117(17)5-9.
• Faulkner, Thomas P. Parkinsons Disease. 7
  December 1999. http//www.onu.edu/user/FS/tfaulkne
  r/parkinso.html 23 May 2002.
• Hermanowiez, Neal. Management of Parkinsons
  Disease. Postgraduate Medicine
  2001110(6)15-28
• Korczyn, Amos D. Hallucinations in Parkinsons
  Disease. Lancet 2001358(9287)1031-1032.
• Lindvall, Olle. Stem Cell Transplantation.
  Lancet 2001358(Supplement)s47.
• Nicholl, David. Parkinsons Disease. 22 April,
  1998. http//medweb.bham.ac.uk/http/depts/clin_neu
  ro/teaching/tutorials/parkinsons/parkinsons1...
  27 May, 2002.
• Ninds. Parkinsons Disease-Hope Through
  Research. http//accessible.ninds.nih.gov/health
  _and_medical /pubs/parkinson_disease_htr.htm
• Referenced on 5/27/02.
• Stephenson, Joan. Exposure to Home Pesticides
  Linked to Parkinson Disease. JAMA June 21,
  2000283(23)3055-3058.