Parkinson ’ s A Review and Practical Guide to a Common and Complex Disease

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A neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra (pc) leading to a clinical syndrome which manifests in movement and non- movement related symptoms.

Epidemiology Second most common neuro- degenerative disease. Affects million people in U.S. Prevalence 1% of all people over 60yo, 4% of those over 80yo. Lifetime risk: 1 in 40. In U.S., number affected expected to double by 2030.

Etiology Idiopathic >80% loss of DA neurons in the substantia nigra pars compacta Multifactoral etiology  Genetic (α-synuclein)  Environment (pesticide exposure) Iatrogenic Antipsychotics: DA-receptor antagonists Antiemetics: prochlorperazine, metoclopramide Others: lithium, VPA, amiodarone

Signs & Symptoms Motor Symptoms Cardinal Manifestations  Tremor  Bradykinesia  Rigidity Non-Motor Symptoms Neuropsychiatric Autonomic Dysfunction

Motor Symptoms Cardinal Manifestations Tremor – “pill-rolling” characteristically a rest tremor.  Worse at rest and lessens with purposeful action Bradykinesia – generalized slowness of movement  Major cause of disability Rigidity – increased resistance to passive movement around a joint  Can be “cogwheel” or “lead pipe”

Non-Motor Symptoms Neuropsychiatric Cognitive dysfunction and dementia Psychosis and hallucinations Depression, anxiety, and apathy Sleep disturbances Fatigue

Non-Motor Symptoms Neuropsychiatric Autonomic dysfunction Olfactory dysfunction Pain and sensory disturbances Dermatologic findings

Non-Motor Symptoms Cognitive dysfunction and dementia Independent predictor of mortality Parkinson Disease Dementia (PDD) Psychomotor retardation, memory loss, altered personality Deficits in executive function seen early in disease PDD occurs late in the course of PD and is often confused with Lewy body dementia

Non-Motor Symptoms Psychosis and Hallucinations All PD meds can cause psychotic symptoms DA agonists produce more than levodopa Delusions are often paranoid in nature

Typical Physiology

Pathophysiology

DA Metabolism

DA is a Hatch of Sea Turtles

Peripheral LDOPA/DA Metabolism AADC COMT

Central LDOPA/DA Metabolism COMT MAO-B

DA Metabolism

Drugs Used to Treat PD Dopamine replacement ✓ Levodopa (LDOPA) Dopamine receptor agonists (D2) ✓ Pramipexole ✓ Ropinirole ✓ Bromocriptine Anticholinergics ✓ Trihexylphenidyl ✓ Benztropine Drugs which reduce the metabolism of Dopamine ✓ AADC inhibitor (Carbidopa) ✓ COMT inhibitor (Entacapone, Tolcapone) ✓ MAOI-B inhibitor (Selegiline, Rasagiline)

Targets of Available Drug Therapy Periphery: - AADC – Carbidopa - COMT – Etacapone, Tolcapone Central: - COMT – Tolcapone - MAO-B – Selegeline, Rasagiline

Targets of Drug Therapy

DA Replacement Therapy Levodopa Most effective agent Short t1/2 Competes with dietary AA for absorption Almost always administered with AADC/COMT inhibitor Effectiveness decreases with prolonged use

DA Replacement Therapy Levodopa - side effects High doses cause dyskinesias Hallucination/delusions Peripheral conversion to DA causes: N/V/D Orthostatic hypotension Taper dose when discontinuing to avoid neuroleptic malignant syndrome

Carbidopa/Levodopa Products Immediate release (Sinemet) 10/100; 25/100; 25/250 Sustained release (Sinemet CR) 12.5/50; 25/100; 50/200 Combo with entacapone (Stalevo) 50; 75; 100; 125; 150; 200 ✓ Number is the LDOPA component ✓ 50 contains 12.5mg carbidopa, 75 contains 18.5mg carbidopa, all others have 25mg and all contain 200mg of entacapone

Drugs to Reduce Metabolism of LDOPA AADC antagonist (Carbidopa) COMT inhibitor (Entacapone; Tolcapone) MAO-B inhibitor (Selegeline, rasagiline)

Drugs to Reduce Metabolism of LDOPA COMT inhibitors (entacapone; tolcapone) Primary activity is blocking peripheral COMT Entacapone given with every dose of LDOPA Not used as monotherapy If used early, may shorten time to developing treatment related dyskinesias Side effects similar to LDOPA

Drugs to Reduce Metabolism of LDOPA AADC antagonist (Carbidopa) Blocks dopa decarboxylase in the periphery only Reduces premature transformation of LDOPA to DA Reduces SE from excessive DA in the periphery Effective dose is at least 75mg per day

Drugs to Reduce Metabolism of LDOPA MAO-B inhibitors (selegiline, rasagiline, rotigitine) Selegiline metabolized to amphetamines ODT and patch reduce these metabolites Only rasagiline approved as monotherapy No tyramine reactions reported Generally well tolerated May delay clinical progression

Modulators of DA Metabolism Available Products Carbidopa 25mg available as a single agent Entacapone (Comtan) 200mg as a single agent Selegeline ODT: 1.25mg Oral: 5mg Patch: 6mg; 9mg; 12mg/24 hours Rasagiline (Azilect) 0.5mg up to 2mg (1mg most common and effective)

DA Agonists D-2 Receptor agonists (ropinirole; pramipexole) Longer duration of action than LDOPA (8-24hrs) LDOPA “sparing” agents Particularly effective for on/off syndrome Both are available as IR and XR formulations Often prescribed in early onset PD to postpone LDOPA SE’s: hallucinations, N, fatigue/somnilence Bromocriptine rarely used due to SE’s

Amantadine Amantadine (Symmetrel) NMDA antagonist, increased DA release and decreased reuptake, some anticholinergic effects Mildly effective May be used to counter treatment related dyskinesias SE: anticholinergic, insomnia, confusion, livedo reticularis

Anticholinergics Trihexyphenidyl (Artane); benzotropine (Cogentin) Block over-activity of cholinergic neurons in striatum resulting from DA loss. Modest benefit (mostly for tremor) SE profile (Anticholinergic) prevents use in older patients

Common Dosing Strategies DA agonists: Pramipexole: start at 0.125mg TID and increase to 0.75 mg TID over 4- 6 weeks Ropinerole: start at 0.25mg TID and increase to 3-4 mg TID over 6 weeks DA replacement: IR or SR Begin with 25/100 BID or TID and increase slowly to 50/200 BID, TID, or QID Entacapone most often given with each dose if it is being used

Common Dosing Strategies MAO-B inhibitors Selegiline:  ODT: begin with 1.25 mg qd and increase to 2.5mg (max dose) after 6 weeks  Oral tab/cap: 5mg QAM and increase to max of 5mg QAM and 5mg Qnoon Rasagiline:  Begin with 0.5mg qd and increase to 1mg (max 2mg)  1mg preferred and shown more efficacious than 2mg

Treatment Related Sequelae: Wearing Off Wearing off = return to unmedi- cated state Intra-daily fluctuations (early morning, end-of-dose, random) Treatment: Increased frequency and/or dose of LDOPA DA agonist, entacapone, rasagiline Deep brain stimulation (STN)

Treatment Related Sequelae: Dyskinesias Dyskinesias = involuntary move-ments of the head, neck, torso, and limbs “shakes, wiggles, extra- movements” Treatment: Reduce dose of DA drugs (includes metabolism inhibitors) Add amantadine Deep brain stimulation (STN and/or Gpi)

Treatment Overview Drug sequence in naïve, early onset patient: DA agonists MAO-B inhibitor Anticholinergic (optional) Carbidopa/Levodopa  Add Entacapone Amantadine

Two Case Studies

Study #1 KD 49 yom with PD since 1996 s/p DBS (R) in 2005 now with worsening sx’s including: difficulty walking, rigidity, shuffling/falling, freezing episodes and tremors. Also c/o dyskinesias and dystonias in the non-stim side. Refractory to further medications and dependent on current regimen. Admitted for DBS of (L) side. Current regimen as documented in Impact and note: Stalevo 125 TID-WA Carbidopa/levodopa (Sinemet) 25/100 TID-WA

Study #2 DB 54yom s/p DBS, refractory to meds with significant worsening of movement requiring sgy. Has long hx of intolerance and resistance to meds. Home regimen as entered in Impact: Ropinerole 15mg qd Entacapone 200mg 5 times daily Sinemet CR 50/200 nightly Sinemet 25/100 2 tabs QID Pt actually took: Ropinerole 3mg 5 times a day at 0600, 1000, 1400, 1800, and Entacapone 200mg 5 times a day at those times (lucky) Sinemet IR 25/100 2 tabs QID at 0600, 1000, 1400, 1800 Sinemet CR 50/200 at 2200

Practical Issues Polypharmacy Many patients have multiple comorbidities Average PD patient on 5-7 drugs Complex regimens necessitate pharmacist vigilance Dosing schedule Very precise dosing times with multiple formulations of DA agents Many will want to take personal supply