Parkinsons Disease

Review of Pathophysiology, Diagnosis, & Current Therapy

Historical Perspective
Dr. James Parkinson (1755-1828) (1755

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 AfricanAfrican-Americans and Asians less likely than Caucasians to develop Parkinsons 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 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.

Medication Profile
Carbidopa/Levodopa (Sinemet) 25/100/po-6times daily-(Parkinson's) 25/100/podailyLansoprazole (Prevacid) 30mg/po-ACBR-(GERD) 30mg/po-ACBRBaclofen (Lioresal) 10mg/po-qhs-(Parkinson's Dystonia) 10mg/po-qhsQuinine sulfate (Quinidine) 260mg/po-qhs-(Muscle Cramps) 260mg/po-qhsQuetiapine (Seroquel) 25mg/po-qhs-(Hallucinations) 25mg/po-qhsRopinirole (Requip) 1mg/po-1mg5Xdaily&2mgq6am-(Parkinson's) 1mg/po-1mg5Xdaily&2mgq6amDocusate Sodium (Colace) 100mg/po-bid-(Constipation) 100mg/po-bidMetoprolol (Lopressor) 50mg/po-qd-(Hypertension) 50mg/po-qdCalcium Carbonate (Tums) 500mg/po-1000mgbid-(Calcium supplement) 500mg/po-1000mgbidOxaprozin (Daypro) 600mg/po-qd-(Osteoarthritis) 600mg/po-qdPropoxyphen/APAP (Darvocet N-100) 100mg/650mg/po-1q4hprn-(Pain N100mg/650mg/po-1q4hprnManagement) Bethanechol (Urecholine) 10mg/po-20mgprn-(Urinary Retention) 10mg/po-20mgprnDocusate Sod-Casanthranol (Pericolace) 100mg/30mg/po-qdprnSod100mg/30mg/po-qdprn(Constipation) Bisacodyl Supp (Ducolax) 10mg/pr-qodprn-(Constipation) 10mg/pr-qodprn-

Pathogenesis
Four Theories


Oxidative damage
Impaired protection

Environmental toxins
MPTP-MethylMPTP-Methyl-phenyl tetrahydropyridine

Genetic predisposition
Mutations in the gene for the protein alphaalphasynuclein 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 R A P

remor igidity kinesian and bradykinesia ostural instability

Characteristic Problems
MicrographiaMicrographia-small handwriting HypomimiaHypomimia-decreased facial animation HypophoniaHypophonia-soft speech DysarthriaDysarthria-unclear pronunciation DyspneaDyspnea-labored breathing FestinationFestination-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 DrugDrug-Induced Toxic Stroke Trauma Neoplasm Other neurodegenerative conditions

Wilsons disease Alzheimers Lewy Body dementia

Hoehn and Yahr Staging of Severity of Parkinsons Disease

Stage 0 I II III No clinical signs evident Unilateral involvement Bilateral involvement but no postural abnormalities Bilateral involvement with mild postural imbalance on examination or history of poor balance or falls; patient leads independent life Bilateral involvement with postural instability; patient requires substantial help Sever, fully developed disease; patient restricted to bed or wheelchair Description

IV V

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. Bed-

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 bloodAdverse effects such as nausea, vomiting, postural hypotension, involuntary movements, restlessness, and cardiac arrhythmias

Levodopa
Today L-dopa/carbidopa (Sinemet) used almost Lexclusively Initial dose of 25/100mg QD for 7 days, increase by 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 L800mg/day. Adverse effects minimized with carbidopa End-of-dose wearing-off effect End-ofwearingOnOn-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 Lpatients. Treating patients who cannot tolerate high doses of L-dopa. L-

Associated with more side effects than L-dopa LPotential adverse effects include somnolence, dyskinesias, nausea, vomiting, orthostatic hypotension, nightmares, hallucinations, confusion, dizziness

Ergot Agonist Dosing

Bromocriptine (Parlodel)
  

Initial 1.25mg QD-BID QDTitrate 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 LDecrease 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 LDrugs 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 LExacerbation of L-dopa side effects , diarrhea, Lurine 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% LExacerbation of L-dopa side effects, diarrhea, Lurine 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 MOAMOA-inhibits monoamine oxidase-B (MAO-B) oxidase- (MAOInhibition of MAO-A does not occur MAODosage of 5 mg BID with breakfast and lunch When used as monotherapy delays the need of LLdopa by an average of nine months. Possible adverse effects include nausea, dizziness, abdominal pain, confusion, and exacerbation of LLdopa 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 LResurgence 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 dopaminedopamine-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. 2001;286:3056Dipiro, 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 2001;17(17):5-9. 2001;17(17):5Faulkner, Thomas P. Parkinsons Disease. 7 December 1999. http://www.onu.edu/user/FS/tfaulkner/parkinso.html 23 May 2002. Hermanowiez, Neal. Management of Parkinsons Disease. Postgraduate Medicine 2001;110(6):152001;110(6):15-28 Korczyn, Amos D. Hallucinations in Parkinsons Disease. Lancet 2001;358(9287):1031-1032. 2001;358(9287):1031Lindvall, Olle. Stem Cell Transplantation. Lancet 2001;358(Supplement);s47. Nicholl, David. Parkinsons Disease. 22 April, 1998. http://medweb.bham.ac.uk/http/depts/clin_neuro/teaching/tutorials/parkinsons/parkinsons1... http://medweb.bham.ac.uk/http/depts/clin_neuro/teaching/tutorials/parkinsons/parkinsons1... 27 May, 2002. Ninds. Parkinsons Disease-Hope Through Research. Diseasehttp://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):30552000;283(23):3055-3058.