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Flashcards in Parkinson's Disease Deck (78):
1

Pathophysiology of Parkinson's

loss of dopaminergic neurons, decreased cortical activation, sysmptom severity correlates with nigrostriatal dopamine loss, environmental? MPTP

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Loss of dopaminergic neurons causes

increased GABA, increased relative cholinergic activity

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Drug induced Parkinson's

associated with drugs that disturb the DA/ACh balance and usually only at high doses, it is reversible

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Drugs associated with drug induced Parkinson's

Antipsychotic agents, Metoclopramide, Misc anticonvulsants, TCAs

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Complications associated with Advanced disease

Motor and dyskinesias (TRAP), neuropsychiatric manifestations, sleep disturbances, autonomic dysfunctions, falls

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TRAP

Tremor, muscular rigidity, Akinesia, bradykinesia, postural/gait defects

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Goals of therapy

provide maximal function, individualize treatment to minimize ADRs, manage long-term disease progression&subsequent symptoms, restore NT balance (minimize disturbances in movement and balance)

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Non-pharm therapy

Exercise, PT/OT, nutrition (fiber, increased fluid intake), procedures, support, education

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Pharmacotherapy

Carbidopa/Levodopa (Sinemet), COMT inhibitors, anticholinergics, dopamine agonists, amantadine (Symmetrel), Monoamine oxidase B inhibitors

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Stages of PD progression

Honeymoon-meds work well at low dose, middle stage- meds effective but PT/OT more influential, late- meds lose effectiveness, battle loss of function vs ADRs, consider brain stimulation

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Levodopa

most effective drug for PD, dec morbidity/mortality, ALL pts will respond, if not question diagnosis, never monotherapy

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MOA of Levodopa

precursor to DA, crosses BBB, converted by DDC in periphery and CNS to dopamine

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Carbidopa MOA

inhibits peripheral DDC, prevents l-dopa metabolism here, more drug crosses BBB, carbidopa doesn't cross BBB

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How much carbidopa do you need for L-dopa to cross BBB

75 mg

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Carbidopa/Levodopa (Sinemet)

Gold standard, pt need>1000 mg prob won't benefit, try to hold off adding until needed,

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Benefit of Sinemet

dec bradykinisia/rigidity

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Dosage forms of Sinemet

IR (10mg carbidopa/100 Ldopa-25mg carbidopa/250 ldopa), CR (25mg carbidopa/100mg ldopa, 50 mg cdopa/200mg ldopa), oral disintegrating

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Sinemet IR dosing

inc dose no sooner than every 3 days, use lowest possible to control sx, take an hour before or after eating to avoid drug food interactions

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Sinemet ER dosing

initial dose CR 50/200 mg BID, inc 1/2-1 tab every 3 days, slower onset than IR

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Drug-Drug interactions

antacids, oral iron, isoniazid, dopamine receptor antagonists, metoclopramide, phenytoin

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ADRs of levodopa

N/V, anorexia, arrhythmias, orthostatic hypotension, sedation, insomnia, dyskinesia, cog impairment, psychosis, choreiform movements

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What is the most rate limiting ADR of sinemet

choreiform movements, dyskinesias

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Contraindications of Sinemet

non-selective MAO-I in previous 14 days, narrow-angle glaucoma

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Precautions w/ sinemet

orthostatic hypotension, hx depression/psychosis, hx of PUD, renal impairment, may inc liver enzymes

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Complications of long term use of sinemet

dramatic improvement intially, after 5 y 50-90% develop motor issues, wearing off after 4 hrs, delayed ON or no ON response, no response, unpredictable off, freezing, suboptimal response, diphasic, dystonia

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How to manage wearing off of sinemet

manipulate LD dose, Cr for early stages or overnight use, add dopamine agonist, add COMT-I, SQ apomorphine for severe off episodes

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How to manage delayed ON or no ON response of sinemet

increase LD dose, administer on empty stomach or add agent that inc GI motility, add dopamine agonist, add COMT-I

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How to manage no response of sinemet

dose above 1000mg and still no response, Pt may have atypical PD and be unresponsive to this therapy

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How to manage Freezing w/ sinemet

inc LD dose if off period, dec DA drug if on period, nonpharm techniques

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how to manage Suboptimal response w/ sinemet

gradually inc dose of LD, start low dose DA agonist, COMT-I+ldopa

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How to manage diphasic w/ sinemet

overlap multiple doses of LD/CD at intervals just enough to preclude the development of dyskinetic phase at end of each cyle, switch form CR to IR, SQ apomorphine

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how to manage dystonia w/ sinemet

if from PD give bedtime dose of CR LD, if from LD dec size of individual dose, add DA agonist

33

Counseling pts of CD/LD

do not d/c abruptly, IR can be split, crushed or chewed, but CR can only be split, changes in diet and meds may affect absorption, morning dose of CR has delayed onset, body fluids amy be discolored

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Advantages of CD/LD

most symptomatically efficacious, virtually all pts respond intially

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Disadvantages of CD/LD

most develop ADRs, sedation, does not treat freezing. postural instability, autonomic dysfunction, or dementia, does not stop disease progression, potentially harmful metabolites

36

Catechol-O-methyltransferase inhibitors

increase efficiency of LD, Entacapone (Comtan), Tolcapone (Tasmar)

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entacapone (comtan) MOA

inhibits peripheral COMT from metabolizing DA- no central inhibition because doesn't cross BBB

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Tolcapone (Tasmar) MOA and pearl

inhibits peripheral and central COMT, not used often because of hepatoxicity, last line

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Advantages of COMT-I

inc LD bioavailability and plasma T1/2 by 50%, dec "off' time association w/ wearing-off phenomenon

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Dosing COMT-I

dec LD by ~30% when starting, entacapone-200 mg w/ every LD dose

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ADRs of COMT-I

Entacapone is very well tolerated, may cause diarrhea, orange urine, dyskinesia, dystonia, nausea, cramps, tolcapone causes liver toxicity and explosive diarrhea

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COMT-I advantages

no titration, easy admin, dec off time, inc on time, enhanced motor responses in pt w/ LD motor fluctuation

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Disadvantages of COMT-I

dopaminergic ADR, urine discoloration

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Anticholinergic MOA

antagonize excitatory neurotransmitter acetylcholine in substantia nigra to minimize the relative increase in cholinergic sensitivity

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Use of anticholinergics

mostly beneficial for tremor, early in disease, initial tx for mild-moderate disease, adjunct to dopaminergic agents in mod to severe disease, for younger pts w/ tremores and preserved cog function, dec efficacy in eldely

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Stavelo

compo carbidopa, levodopa, and entacapone

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ADRs of anticholinergics

dry mouth, blurred vision, constipation, urinary retention, confusion, sedation, hallucinations, memory impairment

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Benzropine (Cogentin)

dose 1-3 mg PO BID, start low, titrate slowly

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Trihexyphenidyl (Artane)

dose 1-5 mg TID, start low and titrate slowly

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Anticholinergics used

Benztropine (Cogentin), Trihecyphenidyl (Artane), Diphenhydramine (Benadryl)

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Anticholinergic advantage

efficacy for tremors, peripherally acting agents useful for sialorrhea

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Anticholinergic disadvantage

relatively ineffective for more advanced PD, cognitive ADR, muscarinic ADR

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Dopamine Agonists

Ropinirole (Requip), Pramipexole (Mirapex), Bromocriptine (Parlodel), Apomorphine (Apokyn)

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Dopamine agonist MOA

direct stimulation of striatal dopamine receptors

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Place for DA agonists in therapy

1st line monotherapy for symptomatic pts if younger than 70, adjunct to dec response fluctuation w/ CD/LD, permits reduction in LD, decreases dyskinesias

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DA agonist advantages

may delay need for LD for 4-5 years, may delay development of motor functions, may be neuroprotective

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DA agonist disadvantages

eventually will need LD, does not prevent LD complications, should provide better response than they do, complicating titrating dose

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Ropinirole (Requip) and pramipexole (Mirapex) MOA, Benefits

non-ergot derived, stimulate D2/D3 receptor site, more effective than bromocriptine at reducing motor sx, reduces off time associated w/ wearing off, may reduce LD requirement

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Ropinirole (Requip) dose, DI

low dose (.5 mg ish but complex titration), hepatically metabolized, DI- inhibits CYP1A2, induces CYP1A2, may switch from IR to similar dose ER

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Pramipexole (Mirapex) dose, Di

low dose (.25 mg ish, but complex titration), renally excreted (dec if CrCl

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Bromocriptine (Parlodel)

ergot derived dopamine agonist, stimulates D2 and antagonizes D1, not used much

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Apomorphine (Apokyn)

derived from morphine, sub-cut injection, stimulates D1/D2, adjunct/supp to LD in advanced disease, use for acute intermittent tx of hypomobility off episodes associated w/ wearing off/ on-off episodes

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Apomorphine (Apokyn) adrs, dosing, contraindications

2-6mg sq during acute, max dose 6 mgx5/day, sig N/V, skin nodules at injection, contra w/ sulfite allergy, 5GT3 receptor blockers, hypotension and syncope

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DA agonists class ADRs

nausea, orthostatic hypotension, confusion, hallucinations, light-headedness, lower edema, sleep attacks, psychosis, compulsive behaviors

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Advantages of DA agonists

efficacy as monotherapy, dec risk of LD related motor complications, NO oxidative metabolites, potentially neuroprotective

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disadvantages of DA agonists

neuropsychiatric ADRs, do not treat all PD features (freezing, postural inability, dementia), does not stop progression

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amantadine (Symmetrel)

antiviral, improvement in trmor, rigidity, akinesia, unknown MOA, augments DA release form presynaptic nerve terminals, inhibits reuptake, stimulates releases, anticholinergic effects, NMDA-I

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Amantadine in therapy

initial monotherapy in early disease, delays LD time, limited by rapid development of tacyphylaxis, possible use in late stage, adjunct, synergist w/ CD/LD

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Amantadine contraindications, ADRs

CHF, seizure disorder, other CNS stimulants, adjust dose in renal, do not abrupt w/drawal, cause edema, CHF, seizures, hallucinations, orthostatic hypotension, dizziness, confusion

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Amantadine advantages

some antiparkinson efficacy, may have antidyskinetic effect, possible neuroprotective

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Amantadine disadvantage

antiparkinson effects limited, tolerance can develop, cog SE

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Monoamine Ocidase B inhibitors

Selegiline (Eldepryl, Zelapar), Rasagiline (Azilect)

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MAO-B I MOA

irreversibly and selectively inhibits MAO-B, prevents breakdown of DA in CNS, can be monotherapy for neuroprotection, adjunct in all stages

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Selegiline (Eldepryl)

as dose inc MAO-I specificity is lost, dec LD at initiation

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Selegiline (Zelapar)

Oral disintegrating tab, dose 1.25 mg daily x 6 weeks then 2.5 mg, bypasses 1st pass metabolism, dec SE, dec off time by 2 hrs, do not swallow medication immediately

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Rasagiline (Azilect)

monotherapy in early PD, adjunct to LD in late stages, greater potency MAO-B inhibition, 1 mg daily, w/ LD- .5 mg daily, avoid tyramine rich foods

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Rasagiline (Azilect) and selegiline (Eldepryl) DIs

opiates, SSRIs, SNRI, TCAs, lithium, dextromethorphan, linezolid, ephedrine, phenylephrine, pseudoephedrine

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Rasagiline (Azilect) ADRs

wt changes, balance difficulties, bp changes, edema, dizziness, hallucinations, sleep changes