Parkinson's Disease Flashcards
Pathophysiology of Parkinson’s
loss of dopaminergic neurons, decreased cortical activation, sysmptom severity correlates with nigrostriatal dopamine loss, environmental? MPTP
Loss of dopaminergic neurons causes
increased GABA, increased relative cholinergic activity
Drug induced Parkinson’s
associated with drugs that disturb the DA/ACh balance and usually only at high doses, it is reversible
Drugs associated with drug induced Parkinson’s
Antipsychotic agents, Metoclopramide, Misc anticonvulsants, TCAs
Complications associated with Advanced disease
Motor and dyskinesias (TRAP), neuropsychiatric manifestations, sleep disturbances, autonomic dysfunctions, falls
TRAP
Tremor, muscular rigidity, Akinesia, bradykinesia, postural/gait defects
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)
Non-pharm therapy
Exercise, PT/OT, nutrition (fiber, increased fluid intake), procedures, support, education
Pharmacotherapy
Carbidopa/Levodopa (Sinemet), COMT inhibitors, anticholinergics, dopamine agonists, amantadine (Symmetrel), Monoamine oxidase B inhibitors
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
Levodopa
most effective drug for PD, dec morbidity/mortality, ALL pts will respond, if not question diagnosis, never monotherapy
MOA of Levodopa
precursor to DA, crosses BBB, converted by DDC in periphery and CNS to dopamine
Carbidopa MOA
inhibits peripheral DDC, prevents l-dopa metabolism here, more drug crosses BBB, carbidopa doesn’t cross BBB
How much carbidopa do you need for L-dopa to cross BBB
75 mg
Carbidopa/Levodopa (Sinemet)
Gold standard, pt need>1000 mg prob won’t benefit, try to hold off adding until needed,
Benefit of Sinemet
dec bradykinisia/rigidity
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
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
Sinemet ER dosing
initial dose CR 50/200 mg BID, inc 1/2-1 tab every 3 days, slower onset than IR
Drug-Drug interactions
antacids, oral iron, isoniazid, dopamine receptor antagonists, metoclopramide, phenytoin
ADRs of levodopa
N/V, anorexia, arrhythmias, orthostatic hypotension, sedation, insomnia, dyskinesia, cog impairment, psychosis, choreiform movements
What is the most rate limiting ADR of sinemet
choreiform movements, dyskinesias
Contraindications of Sinemet
non-selective MAO-I in previous 14 days, narrow-angle glaucoma
Precautions w/ sinemet
orthostatic hypotension, hx depression/psychosis, hx of PUD, renal impairment, may inc liver enzymes
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
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
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
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
How to manage Freezing w/ sinemet
inc LD dose if off period, dec DA drug if on period, nonpharm techniques
how to manage Suboptimal response w/ sinemet
gradually inc dose of LD, start low dose DA agonist, COMT-I+ldopa
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
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
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
Advantages of CD/LD
most symptomatically efficacious, virtually all pts respond intially
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
Catechol-O-methyltransferase inhibitors
increase efficiency of LD, Entacapone (Comtan), Tolcapone (Tasmar)
entacapone (comtan) MOA
inhibits peripheral COMT from metabolizing DA- no central inhibition because doesn’t cross BBB
Tolcapone (Tasmar) MOA and pearl
inhibits peripheral and central COMT, not used often because of hepatoxicity, last line
Advantages of COMT-I
inc LD bioavailability and plasma T1/2 by 50%, dec “off’ time association w/ wearing-off phenomenon
Dosing COMT-I
dec LD by ~30% when starting, entacapone-200 mg w/ every LD dose
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
COMT-I advantages
no titration, easy admin, dec off time, inc on time, enhanced motor responses in pt w/ LD motor fluctuation
Disadvantages of COMT-I
dopaminergic ADR, urine discoloration
Anticholinergic MOA
antagonize excitatory neurotransmitter acetylcholine in substantia nigra to minimize the relative increase in cholinergic sensitivity
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
Stavelo
compo carbidopa, levodopa, and entacapone
ADRs of anticholinergics
dry mouth, blurred vision, constipation, urinary retention, confusion, sedation, hallucinations, memory impairment
Benzropine (Cogentin)
dose 1-3 mg PO BID, start low, titrate slowly
Trihexyphenidyl (Artane)
dose 1-5 mg TID, start low and titrate slowly
Anticholinergics used
Benztropine (Cogentin), Trihecyphenidyl (Artane), Diphenhydramine (Benadryl)
Anticholinergic advantage
efficacy for tremors, peripherally acting agents useful for sialorrhea
Anticholinergic disadvantage
relatively ineffective for more advanced PD, cognitive ADR, muscarinic ADR
Dopamine Agonists
Ropinirole (Requip), Pramipexole (Mirapex), Bromocriptine (Parlodel), Apomorphine (Apokyn)
Dopamine agonist MOA
direct stimulation of striatal dopamine receptors
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
DA agonist advantages
may delay need for LD for 4-5 years, may delay development of motor functions, may be neuroprotective
DA agonist disadvantages
eventually will need LD, does not prevent LD complications, should provide better response than they do, complicating titrating dose
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
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
Pramipexole (Mirapex) dose, Di
low dose (.25 mg ish, but complex titration), renally excreted (dec if CrCl
Bromocriptine (Parlodel)
ergot derived dopamine agonist, stimulates D2 and antagonizes D1, not used much
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
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
DA agonists class ADRs
nausea, orthostatic hypotension, confusion, hallucinations, light-headedness, lower edema, sleep attacks, psychosis, compulsive behaviors
Advantages of DA agonists
efficacy as monotherapy, dec risk of LD related motor complications, NO oxidative metabolites, potentially neuroprotective
disadvantages of DA agonists
neuropsychiatric ADRs, do not treat all PD features (freezing, postural inability, dementia), does not stop progression
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
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
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
Amantadine advantages
some antiparkinson efficacy, may have antidyskinetic effect, possible neuroprotective
Amantadine disadvantage
antiparkinson effects limited, tolerance can develop, cog SE
Monoamine Ocidase B inhibitors
Selegiline (Eldepryl, Zelapar), Rasagiline (Azilect)
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
Selegiline (Eldepryl)
as dose inc MAO-I specificity is lost, dec LD at initiation
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
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
Rasagiline (Azilect) and selegiline (Eldepryl) DIs
opiates, SSRIs, SNRI, TCAs, lithium, dextromethorphan, linezolid, ephedrine, phenylephrine, pseudoephedrine
Rasagiline (Azilect) ADRs
wt changes, balance difficulties, bp changes, edema, dizziness, hallucinations, sleep changes
