Parkinson’s

A Review and Practical Guide to a Common and Complex

Disease

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.

EpidemiologySecond most common neuro-degenerative disease. Affects 1-1.5 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.

EtiologyIdiopathic

>80% loss of DA neurons in the substantia nigra pars compacta

Multifactoral etiology-Genetic (α-synuclein)-Environment (pesticide exposure)

IatrogenicAntipsychotics: DA-receptor antagonists

Antiemetics: prochlorperazine, metoclopramide

Others: lithium, VPA, amiodarone

Signs & SymptomsMotor Symptoms

Cardinal Manifestations

-Tremor-Bradykinesia-Rigidity

Non-Motor SymptomsNeuropsychiatricAutonomic Dysfunction

Motor SymptomsCardinal 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 SymptomsNeuropsychiatric

Cognitive dysfunction and dementia

Psychosis and hallucinations

Depression, anxiety, and apathy

Sleep disturbances

Fatigue

Non-Motor SymptomsNeuropsychiatric

Autonomic dysfunction

Olfactory dysfunction

Pain and sensory disturbances

Dermatologic findings

Non-Motor SymptomsCognitive 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 SymptomsPsychosis 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, TolcaponeCentral: - COMT – Tolcapone - MAO-B – Selegeline, Rasagiline

Targets of Drug Therapy

DA Replacement Therapy

LevodopaMost 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 effectsHigh 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 agentEntacapone (Comtan)

•200mg as a single agentSelegeline

•ODT: 1.25mg

•Oral: 5mg

•Patch: 6mg; 9mg; 12mg/24 hoursRasagiline (Azilect)

•0.5mg up to 2mg (1mg most common and effective)

DA AgonistsD-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

AmantadineAmantadine (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

AnticholinergicsTrihexyphenidyl (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 StrategiesDA 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 StrategiesMAO-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 2200.

•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