Parkinson’s Disease Review of Pathophysiology, Diagnosis and Current Therapy

7/28/2019 Parkinsons Disease Review of Pathophysiology, Diagnosis and Current Therapy

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Parkinsons Disease

Review of

Pathophysiology,

Diagnosis, & CurrentTherapy


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http://medweb.bham.ac.uk/http/depts/clin_neuro/teaching/tutorials/parkinsons/gait_after.movhttp://medweb.bham.ac.uk/http/depts/clin_neuro/teaching/tutorials/parkinsons/gait_before.mov


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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


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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

Average age of onset 62.5 Men and women affected equally

Genetic Link

African-Americans and Asians less likely than

Caucasians to develop Parkinsons


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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 and

locus coeruleus

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 Dysphagia


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Diagnosis

Bradykinesia must be present with at least two of thefollowing: limb muscle rigidity, resting tremor (abolishedwith movement), or postural instability.

Need to eliminate secondary causes; Drug-Induced

Toxic

Stroke

Trauma

Neoplasm

Other neurodegenerative conditions

Alzheimers Lewy Body dementia


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Hoehn and Yahr Staging of

Severity of Parkinsons DiseaseStage 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


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Schwab & England Activities of

Daily Living Scale100% 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 slowlyand 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.

Cli i l f t


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Clinical features


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Pharmacotherapy

Levodopa

Dopamine agonists

COMT inhibitors Amantadine

Anticholinergics

Selegiline


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Drug used in Parkinson disease


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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, involuntarymovements, restlessness, and cardiac

arrhythmias


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Levodopa

Today L-dopa/carbidopa (Sinemet) used almostexclusively

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 as25/100mg QD and titrated up to TID over amonths time. Maximum dose of L-dopa is800mg/day.

Adverse effects minimized with carbidopa


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Dopamine Agonists

Synthetic 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 youngerpatients.

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


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Nonergot Agonist Dosing

Pramipexole (Mirapex) Monotherapy or Adjunct

Initial dose of 0.125 mg TID and increased every 5 to7 days as tolerated up to 3 to 4.5mg/d

Higher doses are not more effective than 1.5mg/d andare 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 pramipexoleby 20%. These include cimetidine, diltiazem,quinidine, quinine, ranitidine, triamterene, andverapamil.


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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 aweekly basis. After the fourth week doses may be increased by1.5mg/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 ofropinirole. Inhibitors such as cimetidine, ciprofloxacin,clarithromycin, diltiazem, enoxacin, erythromycin, fluvoxamine,

mexiletine, norfloxain, omeprazole, ritonavir, andtroleandomycin. 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 thanentacapone

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, every4 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

Narrow therapeutic range

Unpleasant side effects such as nausea, dizziness,

confusion, hallucinations, nightmares, dry mouthperipheral 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 theelderly.


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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 mealsand 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.

Algorithm for tretaing early parkinson


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Algorithm for tretaing early parkinsondisease


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Algorithm for treating advanced Prakinson disease


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Non pharmacology therapy

Phisical therapy, exercise, nutrition

Surgical theraphy

Antioxidant (Vit E, Tocoferol)


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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

Resurgence of neurosurgical intervention with thefailure of pharmacological treatments after 10 to 15

years of disease progression


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Parkinson’s Disease Review of Pathophysiology, Diagnosis and Current Therapy