Parkinson’s DiseaseParkinson’s Disease

Dr. Andrew Schmelz, Dr. Andrew Schmelz, PharmDPharmD

anschmel@purdue.eduanschmel@purdue.edu

Post-Doctoral Teaching Post-Doctoral Teaching FellowFellow

Dept of Pharmacy PracticeDept of Pharmacy PracticePurdue UniversityPurdue University

March 4, 2009March 4, 2009

ObjectivesObjectives

Describe physiologic changes in Describe physiologic changes in patients with Parkinson’s Diseasepatients with Parkinson’s Disease

List symptoms with which Parkinson’s List symptoms with which Parkinson’s patients typically presentpatients typically present

List and define extrapyramidal List and define extrapyramidal symptomssymptoms

For each drug class, state one example For each drug class, state one example drug, mechanism of action, common drug, mechanism of action, common dose, and associated side effectsdose, and associated side effects

BackgroundBackground Parkinson’s disease: Parkinson’s disease:

a degenerative a degenerative disease of the brain disease of the brain that impairs motor that impairs motor skills, speech, and skills, speech, and other functionsother functions

Especially prevalent Especially prevalent in elderly white in elderly white malesmales

Characterized by Characterized by specific changes in specific changes in motor functionmotor function

PathophysiologyPathophysiology

Substantia nigraSubstantia nigra– Region in brain that plays a role in Region in brain that plays a role in

movementmovement– Parkinson’s is characterized by loss of Parkinson’s is characterized by loss of

neuronal cells in this regionneuronal cells in this region

Pathophysiology (cont.)Pathophysiology (cont.)

Neurons depleted in the substantia Neurons depleted in the substantia nigra result in imbalance of nigra result in imbalance of dopamine and acetylcholinedopamine and acetylcholine– Reduced Reduced dopamine activitydopamine activity– Normal Normal acetylcholine activityacetylcholine activity

DopamineAcetylcholine

Dopamine

Acetylcholine

SymptomsSymptoms

Tremor (and pill rolling)Tremor (and pill rolling) BradykinesiaBradykinesia Rigid muscles (cogwheel rigidity)Rigid muscles (cogwheel rigidity) Impaired posture/balanceImpaired posture/balance Loss of autonomic movementLoss of autonomic movement Speech changesSpeech changes DementiaDementia

YouTube VideoYouTube Video

http://http://www.youtube.com/watch?vwww.youtube.com/watch?v=S5EE8EVv600&feature=related=S5EE8EVv600&feature=related

Extrapyramidal (EPS) Extrapyramidal (EPS) SymptomsSymptoms

EPS symptoms usually occur EPS symptoms usually occur secondary to medicationsecondary to medication

Dyskinesias Dyskinesias (Movement disorders)(Movement disorders)– Irregular body movementsIrregular body movements– Tongue movements, lip smackingTongue movements, lip smacking– Finger movements, arm/leg movementsFinger movements, arm/leg movements

Akathisia Akathisia (Restlessness)(Restlessness)– Extreme form of internal/external Extreme form of internal/external

restlessnessrestlessness– Can be exhausting and debilitatingCan be exhausting and debilitating

EPS Symptoms (cont.)EPS Symptoms (cont.)

Dystonia Dystonia (Muscle tension disorders)(Muscle tension disorders)– Very strong, painful muscle contractionsVery strong, painful muscle contractions– Unusual twisting of parts of the bodyUnusual twisting of parts of the body

““Tardive” DisordersTardive” Disorders– Indicates long-term observation of EPS Indicates long-term observation of EPS

symptomssymptoms– Can be of any classification listed aboveCan be of any classification listed above– Often indicate permanenceOften indicate permanence

YouTube VideosYouTube Videos

DyskinesiasDyskinesias– http://http://www.youtube.com/watch?vwww.youtube.com/watch?v

=FUr8ltXh1Pc&feature=related=FUr8ltXh1Pc&feature=related AkithisiasAkithisias

– http://http://www.youtube.com/watch?vwww.youtube.com/watch?v=pSXzuCNlI6Q=pSXzuCNlI6Q

DystoniasDystonias– http://http://www.youtube.com/watch?vwww.youtube.com/watch?v

=nG1XrmEasVk&feature=related=nG1XrmEasVk&feature=related

PharmacotherapyPharmacotherapy

Approaches of therapyApproaches of therapy– Slow loss of dopamine in brainSlow loss of dopamine in brain– Improve symptoms by other meansImprove symptoms by other means– Prevent/delay non-muscular Prevent/delay non-muscular

complicationscomplications– Prevent/delay institutionalizationPrevent/delay institutionalization

Choice of medications used early in Choice of medications used early in therapy will have a therapy will have a STRONGSTRONG impact impact on long-term course of the disease on long-term course of the disease

Levodopa/CarbidopaLevodopa/Carbidopa

ExampleExample: Sinemet: Sinemet®® (levodopa/carbidopa) (levodopa/carbidopa) MOAMOA::

– L-Dopa - converted to DA in brainL-Dopa - converted to DA in brain– Carbidopa – inc effectiveness and reduces SEsCarbidopa – inc effectiveness and reduces SEs

DoseDose: 25mg/100mg carbi/levo TID: 25mg/100mg carbi/levo TID SESE: EPS symptoms, orthostatic : EPS symptoms, orthostatic

hypotension, “wearing off”, N/Vhypotension, “wearing off”, N/V Most effective, used as late as Most effective, used as late as

possiblepossible

““Wearing-Off” PhenomenonWearing-Off” Phenomenon

Loss of effectiveness of levodopa Loss of effectiveness of levodopa before next dosebefore next dose– Increased with duration of therapyIncreased with duration of therapy– Indicates need for dosage increaseIndicates need for dosage increase– Limits duration of therapyLimits duration of therapy

Dopamine AgonistsDopamine Agonists

ExampleExample:: MirapexMirapex®® (pramipexole) (pramipexole) MOAMOA: Dopamine receptor agonist: Dopamine receptor agonist DoseDose: 0.125mg – 1.5mg TID: 0.125mg – 1.5mg TID SEs:SEs: orthostatic hypotension, orthostatic hypotension,

impulsive behavior, hallucinations, EPS impulsive behavior, hallucinations, EPS (especially when taken with levodopa)(especially when taken with levodopa)

Often used as initial treatmentOften used as initial treatment Can be used concurrently with Can be used concurrently with

levodopalevodopa

COMT InhibitorsCOMT Inhibitors

ExampleExample: Comtan: Comtan®® (entacapone) (entacapone) MOAMOA: inhibit COMT, responsible for : inhibit COMT, responsible for

breakdown of L-Dopa in peripherybreakdown of L-Dopa in periphery DoseDose: 200mg with each : 200mg with each

levodopa/carbidopa doselevodopa/carbidopa dose SEsSEs: increase in EPS symptoms, N/V, : increase in EPS symptoms, N/V,

dry mouthdry mouth Used in combination with Used in combination with

levodopa/carbidopa levodopa/carbidopa

MAO-B InhibitorsMAO-B Inhibitors

ExampleExample: Deprenyl: Deprenyl®® (selegiline) (selegiline) MOAMOA: inhibit MAO-B, responsible for : inhibit MAO-B, responsible for

breakdown of DA in brainbreakdown of DA in brain DoseDose: 5mg BID: 5mg BID SEsSEs: dizziness, N/V, EPS symptoms: dizziness, N/V, EPS symptoms Use with low-tyramine diet Use with low-tyramine diet

may be required may be required Potential for drug interactionsPotential for drug interactions

Anti-cholinergic DrugsAnti-cholinergic Drugs

ExampleExample: Cogentin® (benztropine): Cogentin® (benztropine) MOAMOA: inhibit ACh; restore balance to : inhibit ACh; restore balance to

DA-ACh relationshipDA-ACh relationship DoseDose: 0.5-6mg daily: 0.5-6mg daily SEsSEs: anti-ACh effects (see prev : anti-ACh effects (see prev

lecture!)lecture!) Can impair cognitive function which Can impair cognitive function which

limits uselimits use

AmantadineAmantadine

ExampleExample: Symmetrel: Symmetrel®® (amantadine) (amantadine) MOAMOA: enhance dopamine release, : enhance dopamine release,

anti-ACh properties, NMDA antagonistanti-ACh properties, NMDA antagonist DoseDose: 100-400mg/day (daily to BID): 100-400mg/day (daily to BID) SEsSEs: dizziness, anxiety, N/V/D, anti-: dizziness, anxiety, N/V/D, anti-

ACh effectsACh effects Most commonly used later in Most commonly used later in

therapy as adjuncttherapy as adjunct

PT ConsiderationsPT Considerations

Coordinate therapy session with peak Coordinate therapy session with peak effects of drugseffects of drugs– After breakfast dose of levodopaAfter breakfast dose of levodopa

Need to monitor BP while receiving Need to monitor BP while receiving antiparkinsons medsantiparkinsons meds– Concern for orthostatic hypotensionConcern for orthostatic hypotension

PT can reduce need for Parkinson’s PT can reduce need for Parkinson’s drugsdrugs

Features of PT ProgramFeatures of PT Program

Regular exerciseRegular exercise– Walking (1+ miles/day), swimming, golf, Walking (1+ miles/day), swimming, golf,

etcetc Stretching and strengtheningStretching and strengthening Exaggerated or patterned movementsExaggerated or patterned movements Mobility aids, orthoticsMobility aids, orthotics Training in transfer techniquesTraining in transfer techniques Training in techniques to improve Training in techniques to improve

posture and walkingposture and walking

Questions?Questions?

Alzheimer’s DiseaseAlzheimer’s Disease

ObjectivesObjectives

Describe physiologic changes in Describe physiologic changes in patients with Alzheimer’s Diseasepatients with Alzheimer’s Disease

For each drug class, state one For each drug class, state one example drug, mechanism of action, example drug, mechanism of action, common dose, and associated side common dose, and associated side effectseffects

BackgroundBackground

Alzheimer’s Disease is an age-Alzheimer’s Disease is an age-related, non-reversible brain disorderrelated, non-reversible brain disorder– Characterized by memory loss and Characterized by memory loss and

confusionconfusion– Gradually leads to personality and Gradually leads to personality and

behavioral changesbehavioral changes Most common cause of dementia in Most common cause of dementia in

patients age 65 and older patients age 65 and older

PathophysiologyPathophysiology

Etiology of Alzheimer’s disease is Etiology of Alzheimer’s disease is unknownunknown

Disease is characterized by:Disease is characterized by:– Amyloid plaquesAmyloid plaques– Neurofibrillary tanglesNeurofibrillary tangles– Loss of connection of neurons Loss of connection of neurons

responsible for memory and learningresponsible for memory and learning

PharmacotherapyPharmacotherapy

Currently, no FDA-approved Currently, no FDA-approved treatment for slowing progression of treatment for slowing progression of diseasedisease

Pharmacotherapy aimed at treating Pharmacotherapy aimed at treating symptoms and improving cognitive symptoms and improving cognitive functionfunction

Cholinesterase InhibitorsCholinesterase Inhibitors

ExampleExample: Aricept: Aricept® ® (donepazil)(donepazil) MOAMOA: Increase ACh, increasing : Increase ACh, increasing

cholinergic functioncholinergic function DoseDose: 5 – 10mg daily at bedtime: 5 – 10mg daily at bedtime SEsSEs: SLUD, N/V, bradycardia, : SLUD, N/V, bradycardia,

hypotension, GI bleeding (rare)hypotension, GI bleeding (rare)

Cholinesterase Inhibitors Cholinesterase Inhibitors (cont.)(cont.)

Other examples:Other examples:– ExelonExelon®® (rivastigmine) (rivastigmine)– ReminylReminyl®® (galantamine) (galantamine)

Appear to help patients for months to Appear to help patients for months to a few yearsa few years

Indicated for mild to moderate Indicated for mild to moderate Alzheimer’s symptomsAlzheimer’s symptoms

NMDA AntagonistNMDA Antagonist

ExampleExample: Namenda: Namenda®® (memantine) (memantine) MOAMOA: inhibit NMDA receptor, which : inhibit NMDA receptor, which

plays a role in transmission of plays a role in transmission of excitatory neurotransmissionexcitatory neurotransmission

DoseDose: 5mg daily to 10mg BID: 5mg daily to 10mg BID SEsSEs: Drowsiness/dizziness: Drowsiness/dizziness

PT ConsiderationsPT Considerations

Cognitive impairment will have Cognitive impairment will have negative effect on ability to follow negative effect on ability to follow instructioninstruction

Questions?Questions?