Parkinson s disease
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Parkinson’s disease. Robert Thompson PharmD Candidate 2014 Roseman University. Learning Objectives. Parkinson’s disease Define Parkinson’s Disease. Describe epidemiology, etiology, and pathophysiology Recognize signs and symptoms Identify diagnostic criteria. Compare current therapies

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Parkinson s disease

Parkinson’s disease

Robert Thompson

PharmD Candidate 2014

Roseman University


Learning objectives

Learning Objectives

  • Parkinson’s disease

    • Define Parkinson’s Disease.

    • Describe epidemiology, etiology, and pathophysiology

    • Recognize signs and symptoms

    • Identify diagnostic criteria.

    • Compare current therapies

      • carbidopa/levodopa (Sinemet®)

      • Alternative therapies

      • Rotigotine (Neupro®)


Parkinson s disease1

Parkinson’s Disease

  • Parkinson’s Disease is a chronic and progressive movement disorder. It involves the malfunction and cell death of neurons in the substantia nigra. The presence of tremor at rest, rigidity, bradykinesia, and postural instabilityare considered the hallmark motor features of Parkinson's disease.

Parkinson’s Disease Foundation: Available from: http://www.pdf.org/en/about_pd


Epidemiology

Epidemiology

  • Parkinson’s Disease affects over one million people in United States

  • Men are at greater risk than women (3:2)

  • Incidence:

    • 50–59 years old  10 new cases per 100,000 people/year

    • 80–89 years old  120 new cases per 100,000 people/year

  • Prevalence:

    • 65 years and over  1%

    • 80 years and over  2.5%

Browner N, et al. Nati’l Parkinson’s Foundation. Available from: http://www.parkinson.org


Etiology

Etiology

  • The exact cause of Parkinson’s is not known

  • Likely from aging, genetics, and exposure to environmental factors

  • Environmental factors

    • Pesticides, heavy metals, rural living, and drinking well water

Browner N, et al. Nati’l Parkinson’s Foundation. Available from: http://www.parkinson.org


Pathophysiology

Pathophysiology

  • Loss of dopamine producing neurons

  • Presence of Lewy bodies (protein filaments in neurons)

  • Parkinson’sis typically detectable when 70% to 80% of dopamine neurons are lost

Pahwa R, et al. American Academy of Neurology; 66:983-95.


Pathophysiology1

Pathophysiology

http://medicalcenter.osu.edu/patientcare/healthcare_services/parkinsons_disease/Pages/index.aspx

http://www.cell.com/neuron/retrieve/pii/S0896627303005683


Diagnosis

Diagnosis

  • When two or more of the following are present:

    • Limb rigidity, resting tremor, bradykinesia, and postural instability

  • Good response to dopaminergic therapy

    • Significant improvement in symptoms.

  • There are not labs or tests to positively

    diagnose Parkinson’s Disease

Browner N, et al. Nat’l Parkinson Foundation: Available from: http://www.parkinson.org


Signs and symptoms

Signs and Symptoms

  • Resting tremor, rigidity, bradykinesia  typically an asymmetric symptom.

  • Decreased manual dexterity, slurred speech, voice volume reduction, diminished arm swing, dysphagia (difficulty swallowing), festinating gait (shuffling), freezing, microphagia (reduced facial animation), micrographia (abnormally small, compressed handwriting)

Parkinson’s Disease Foundation. Available from: http://www.pdf.org/en/about_pd


Signs and symptoms nonmotor

Signs and Symptoms – nonmotor

  • Autonomic and Sensory Symptoms

    • constipation, fatigue, olfactory dysfunction, orthostatic hypotension, pain, numbness or tingling of the extremities, excessive salivation, excessive sweating, recurrent vascular flushing, flaky or scaly skin rashes, and sexual dysfunction

  • Cognitive symptoms

    • anxiety, reduced cognitive abilities, dementia, depression, hallucination/psychosis, and sleep disorders

Parkinson’s Disease Foundation. Available from: http://www.pdf.org/en/about_pd


The unified parkinson s disease rating scale

The Unified Parkinson's Disease Rating Scale 

  • Part I: evaluation of mentation, behavior, and mood

  • Part II: self evaluation of the activities of daily life (ADLs) including speech, swallowing, self feeding, handwriting, dressing, hygiene, maneuvering in bed, and walking

  • Part III: clinician-scored motor evaluation

  • Part IV: Hoehn and Yahr stating of severity of Parkinson disease

  • Part V: Schwab and England ADL scale

Goetz C, et al. 2008 Movement Disorders; 23(15):2129-70.


Hoehn and yahr staging

Hoehn and Yahr Staging

  • Stage One

    • Signs and symptoms on one side only

    • Symptoms mild

    • Symptoms inconvenient but not disabling

    • Usually presents with tremor of one limb

    • Friends have noticed changes in posture, locomotion and facial expression

  • Stage Two

    • Symptoms are bilateral

    • Minimal disability

    • Posture and gait affected

Pahwa R, et al. American Academy of Neurology; 66:983-95


Hoehn and yahr staging1

Hoehn and Yahr Staging

  • Stage Three

    • Significant slowing of body movements

    • Early impairment of equilibrium on walking or standing

    • Generalized dysfunction that is moderately severe

  • Stage Four

    • Severe symptoms

    • Can still walk to a limited extent

    • Rigidity and bradykinesia

    • No longer able to live alone

    • Tremor may be less than earlier stages

Pahwa R, et al. American Academy of Neurology; 66:983-95


Hoehn and yahr staging2

Hoehn and Yahr Staging

  • Stage Five

    • Cachectic stage

    • Invalidism complete

    • Cannot stand or walk

    • Requires constant nursing care

Pahwa R, et al. American Academy of Neurology; 66:983-95


Parkinson s disease guidelines

Parkinson’s Disease Guidelines

  • USA – 2006 (some parts reaffirmed in 2009)

    • American Academy of Neurology

  • Canada – 2012

    • Canadian Neurological Sciences Federation

https://www.aan.com/

http://www.cnsfederation.org/


Treatment

Treatment

  • Parkinson’s disease is a progressive disease that is not curable

  • Individualized to the patient, based on level of impairment

  • Goals

    • Slow disease progression

    • Maintain/improve mobility

    • Minimize adverse side effects

Pahwa R, et al. American Academy of Neurology; 66:983-95.


Definitions

Definitions

  • Wearing off

    • Loss of function near the end of a dosing interval

  • On-off fluctuations

    • Erratic changes between on and off periods (not dosing related)

  • Freezing

    • Inability to initiate movement

Pahwa R, et al. American Academy of Neurology; 66:983-95.


Current therapy

Current Therapy

http://www.nimh.nih.gov/health/topics/brain-stimulation-therapies.shtml

  • Anticholinergics

  • Amantadine

  • Selegiline, Rasagiline (MAO-B inh)

  • COMT inhibitors

  • Apomorphine

  • Deep brain stimulation – surgery

Pahwa R, et al. American Academy of Neurology; 66:983-95.


Current therapy1

Current Therapy

  • Levodopa + carbidopa (Sinemet)

  • Gold Standard in controlling motor symptoms

  • Chronic use associated with:

    • Motor response fluctuations – “off periods”

    • Drug induced dyskinesias

  • Hallucinations, orthostatic hypertension, nausea

  • Does not treat

    • Postural instability, freezing, dementia

Pahwa R, et al. American Academy of Neurology; 66:983-95.


Current therapy2

Current Therapy

  • For “off periods”, treatment options are:

    • 1st line – rasagiline, entacapone

    • 2nd line – pergolide, pramipexole, ropinirole, tolcapone

    • 3rd line – apomorphine, cabergoline, selegiline

    • Deep Brain Stimulation of the subthalamic nucleus has been shown to be effective but it lacks enough evidence to get a strong recommendation

Pahwa R, et al. American Academy of Neurology; 66:983-95.


Rotigotine neupro transdermal system

Rotigotine (Neupro®)– transdermal system

Indications and Dosing

  • Early Parkinson’s disease

    • 2-6 mg/24 hours

  • Advanced Parkinson’s disease

    • 4-8 mg/24 hours

    • Discontinuation: taper ≤ 2 mg/day

Rotigotine Transdermal System:Package insert. 2012.


Mechanism of action

Mechanism of Action

  • Rotigotine is a non-ergoline dopamine agonist

  • Precise mechanism unknown, although it is thought to be related to its ability to stimulate dopamine receptors within the caudate-putamen in the brain.

Clinical Pharmaclology. Rotigotine; 2012


Pharmacokinetics

Pharmacokinetics

  • Metabolism

    • Heptatic: There is little evidence of inhibition or induction of CYP enzymes with the exception of low risk inhibition of CYP2C19 and CYP2D6

  • Measurable serum levels: 1-8 hours

  • Tmax - 15-18 hours after dosing

  • No peak concentration

  • Protein binding - 89.5%

Rotigotine Transdermal System:Package insert. 2012.


Pharmacokinetics1

Pharmacokinetics

  • Metabolism

    • Multiple CYP isoenzymes, sulfotransferases and two UDP-glucuronosyltransferases catalyze metabolism

  • Elimination

    • T1/2: 5-7 hours after the removal of the patch

    • Biphasic, primarily eliminated in the urine as inactive conjugates.

    • Urine (~71%), Feces (~23%), Renally (~11%)

Rotigotine Transdermal System:Package insert. 2012.


Recommendation

Recommendation

  • Rotigotine (Neupro®) is an acceptable therapy option for:

    • Patients with severe Parkinson’s disease experiencing on-off fluctuations that have oral medication compliance issues

    • Guidelines don’t give any recommendations on rotigotine as it received it’s first indication after guidelines were written

https://www.adlershop.ch/p4668/neupro-matrixpfl-2-mg-24h-7-stk

Clinical Pharmacolgy. Rotigotine; 2012


Review

Review

  • Parkinson’s Disease is a progressive motor disorder that cannot be cured

  • The prevalence of PD is greater with advanced age and in it is more common in men

  • An exact cause is not known, but environmental factors are believed to be involved

  • Parkinson’s is marked by cell death of dopamine producing neurons and the accumulation of Lewy Bodies


Review1

Review

  • Diagnosis can be made if 2 or more of the following are present - limb rigidity, resting tremor, bradykinesia, and postural instability

  • Autonomic and Sensory Symptoms

  • Cognitive Symptoms

  • Treatment is tailored for each individual patient

    • Multiple medications or deep brain stimulation


References

References

  • DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 8th edition. Available from: www.accesspharmacy.com. Login required

  • JankovicJ, Watts RL, Martin W, Boroojerdi B. Transdermal rotigotine: double-blind, placebo-controlled trial in Parkinson disease. Arch Neurol. 2007;64(5):676-682.

  • LeWittPA, Lyons KE, Pahwa R. Advanced Parkinson disease treated with rotigotine transdermal system: PREFER Study. Neurology. 2007;68(16):1262-1267.

  • NEUPRO ® (Rotigotine Transdermal System). UCB, Inc. 1950 Lake Park Drive Smyrna, Georgia 30080. September 2012.

  • What is Parkinson’s Disease? [Internet]. New York(NY): Parkinson’s Disease Foundation; 2013 [cited 2013 Jul 26]. Available from: http://www.pdf.org/en/about_pd

  • Clinical Pharmacology [Internet]. Tampa, (FL): Gold Standard, Inc. rotigotine;[Updated 2012 Apr 4; Cited 2013 Jul 26]; [about 2 screen]. Available from: http://www.clinicalpharmacology.com Registration and login required.


References1

References

  • Browner N, Pagan F. How does your doctor make a PD diagnosis? [Internet]. Miami(FL): National Parkinson Foundation; 2013 [cited 2013 Jul 26]: Available from: http://www.parkinson.org/Parkinson-s-Disease/Diagnosis/How-does-your-doctor-make-a-PD-diagnosis

  • R. Pahwa, S. A. Factor, K. E. Lyons, et al. Practice Parameter: Treatment of Parkinson’s Disease with motor fluctuations and dyskinesia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology [Internet]. 2006 Apr 2[cited 2013 Jul 27];66:983-95. http://www.neurology.org/content/66/7/983.full.html

  • Clinical Pharmacology [Internet]. Tampa, (FL): Gold Standard, Inc. carbidopa; levodopa ;[Updated 2009 Oct 9; Cited 2013 Jul 26]; [about 2 screen]. Available from: http://www.clinicalpharmacology.com Registration and login required.

  • Goetz C, Tilley B, LaPelle N, et al. Movement Disorder Society-Sponsored Revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): Scale Presentation and Clinimetric Testing Results. Movement Disorders [Internet]. 2008 [cited 2013 Jul 30]; 23(15): 2129-70.


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