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					Parkinson’s Disease
 Review of Pathophysiology,
 Diagnosis, & Current Therapy
       Historical Perspective
Dr. James Parkinson (1755-1828)
   1817
      “involuntary tremulous motion”
      “pass from a walking to a running pace”
      “shaking palsy”

      London home
           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
          Epidemiology
Average age of onset 62.5
Men and women affected equally
Genetic Link
African-Americans and Asians less likely
than Caucasians to develop Parkinson’s
Caffeine and smoking shows some
protective effects
              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 Parkinson’s,
hypertension, coronary artery disease, GERD, and
depression. Upon admission appropriate measures
were taken for pain management and aforementioned
medical conditions. JJ’s surgical management and
rehabilitation was complicated by advanced Parkinson’s.
During his stay advances were made in his strength,
endurance, and ADL’s. JJ was discharged and will
receive assistive care from his wife. Overall, the care for
JJ was appropriate and followed standard of care
practices.
            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-1mg5Xdaily&2mgq6am-(Parkinson's)
Docusate Sodium (Colace) 100mg/po-bid-(Constipation)
Metoprolol (Lopressor) 50mg/po-qd-(Hypertension)
Calcium Carbonate (Tums) 500mg/po-1000mgbid-(Calcium 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-(Constipation)
              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
        Pathophysiology
Imbalance of dopamine and acetylcholine
Loss of 80 to 90% of dopaminergic
production in the substantia nigra
Lewy Bodies
          Diagnostic Features
Four Cardinal Signs
   T   remor
   R   igidity
   A   kinesian and bradykinesia
   P   ostural instability
   Characteristic Problems
Micrographia-small handwriting
Hypomimia-decreased facial animation
Hypophonia-soft speech
Dysarthria-unclear pronunciation
Dyspnea-labored breathing
Festination-Shuffling gait
                     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
       Wilson’s disease
       Alzheimer’s
       Lewy Body dementia
        Hoehn and Yahr Staging of
      Severity of Parkinson’s Disease
      Stage                               Description

0             No clinical signs evident

I             Unilateral involvement

II            Bilateral involvement but no postural abnormalities

III           Bilateral involvement with mild postural imbalance on
              examination or history of poor balance or falls; patient leads
              independent life
IV            Bilateral involvement with postural instability; patient requires
              substantial help
V             Sever, fully developed disease; patient restricted to bed or
              wheelchair
    Schwab & England Activities of
         Daily Living Scale
100% Completely independent. Able to do all chores without slowness,
difficulty or impairment. Essentially normal. Unaware of any difficulty
80% Completely independent in most chores. Takes twice as long.
Conscious of difficulty and slowness
60% Some dependency. Can do most chores, but exceeding slowly
and with much effort. Error; sometimes impossible
40% Very dependent. Can assist with all chores, but few alone

20% Nothing alone. Can be slight help with some chores.

0% Cannot swallow, bladder and bowel not functioning, Bed-ridden.
      Pharmacotherapy
Levodopa
Dopamine agonists
COMT inhibitors
Amantadine
Anticholinergics
Selegiline
             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
               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”
       Dopamine Agonists
      “Synthetic Dopamine”

Bromocriptine Mesylate (Parlodel)
Pergolide Mesylate (Permax)
Pramipexol (Mirapex)
Ropinirole HCL (Requip)
           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
         Ergot Agonist Dosing
Bromocriptine (Parlodel)
   Initial 1.25mg QD-BID
   Titrate 1.25mg to 2.5mg/d every week
   Average dose <30mg/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
     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.
     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
        COMT Inhibitors
Entacapone (Comtan)
Tolcapone (Tasmar)
      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
      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
                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
            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.
               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.
               Selegiline
Selegiline HCL(Eldepryl)
                   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.
             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
               Grafting
Suprarenal to brain transplantation
Fetal tissue transplantation
Cell culture transplantation
       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
                           References
Cosgrove, G. Rees, Eskandar, Emad N., Shinobu, Leslie A. “Surgical Treatment of Parkinson
Disease.” JAMA December 26, 2001;286:3056-3059.
Dipiro, Joseph T., ed. Pharmacotherapy Fourth Edition. Stamford, Connecticut: Appleton &
Lange, 1999.
“Early Parkinson’s Disease: Dopamine Agonists Have Increasingly Important Role in Symptom
Management.” Drug Ther Perspect 2001;17(17):5-9.
Faulkner, Thomas P. “Parkinson’s Disease.” 7 December 1999.
http://www.onu.edu/user/FS/tfaulkner/parkinso.html 23 May 2002.
Hermanowiez, Neal. “Management of Parkinson’s Disease.” Postgraduate Medicine
2001;110(6):15-28
Korczyn, Amos D. “Hallucinations in Parkinson’s Disease.” Lancet 2001;358(9287):1031-1032.
Lindvall, Olle. “Stem Cell Transplantation.” Lancet 2001;358(Supplement);s47.
Nicholl, David. “Parkinson’s Disease.” 22 April, 1998.
http://medweb.bham.ac.uk/http/depts/clin_neuro/teaching/tutorials/parkinsons/parkinsons1... 27
May, 2002.
Ninds. “Parkinson’s 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,
2000;283(23):3055-3058.