Parkinson's Disease Review Of Pathophysiology, Diagnosis And Current Therapy 6t1z27

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

Historical Perspective • Dr. James Parkinson (1755-1828) – 1817 • “involuntary tremulous motion” • “ from a walking to a running pace” • “shaking palsy”

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 Parkinson’s

Pathogenesis • Four Theories – Oxidative damage • Impaired protection

– Environmental toxins • MPTP-Methyl-phenyl tetrahydropyridine

– Genetic predisposition • Mutations in the gene for the protein alphasynuclein located on chromosome 4

– Accelerated aging

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

Diagnostic Features • Four Cardinal Signs –T –R –A –P

remor igidity kinesian and bradykinesia ostural instability

Characteristic Problems • • • • • • •

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

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; – – – – – –

Drug-Induced Toxic Stroke Trauma Neoplasm Other neurodegenerative conditions • 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 Sever, fully developed disease; patient restricted to bed or wheelchair

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.

Clinical features

Pharmacotherapy • • • • • •

Levodopa Dopamine agonists COMT inhibitors Amantadine Anticholinergics Selegiline

Drug used in Parkinson disease

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

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 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 Ldopa by an average of nine months. – Possible adverse effects include nausea, dizziness, abdominal pain, confusion, and exacerbation of Ldopa side effects – Controversial theory of decreased rate of neuronal death due to a reduction of free radicals.

Algorithm for tretaing early parkinson disease

Algorithm for treating advanced Prakinson disease

Non pharmacology therapy • Phisical therapy, exercise, nutrition • Surgical theraphy • Antioxidant (Vit E, Tocoferol)

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 the failure of pharmacological treatments after 10 to 15 years of disease progression