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Transcript
Parkinson’s A Review and Practical Guide to a Common and Complex Disease Financial Disclosure • Still paying off school loans. • No one has offered to help. • If you work in industry and would like a shill, call me! •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 nonmovement related symptoms. Epidemiology Second most common neurodegenerative 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. 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 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 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 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) 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 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 46 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 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 Treatment Related Sequelae: Wearing Off Wearing off = return to unmedicated 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, extramovements” Treatment: • Reduce dose of DA drugs (includes metabolism inhibitors) • Add amantadine • Deep brain stimulation (STN 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 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