movement disorders pharm Flashcards
Pathophys of parkinson’s
- tx goal?
- normally high conc of dopamine in basal ganglia is reduced in parkinsonism
- pharm attempts to restore dopaminergic activity in the brain is the goal of tx
- tx goals also include management of SEs of dopaminergic therapy
Levadopa/carbidopa (sinemet)? Use?
- GOLD STD of Tx!!!!
- traditionally used first line, but selegaline often given to pts with mild parkinsons
- tends to be less effective with prolonged use in some pts
- effectiveness greatly decreases after 3rd year of tx and may return to pretx levels in 6-7 years
- completely or partially relieves akinesia, rigidity, and tremor in about 80%
- preferred initial tx in pts over 70, particulary those with dementia
What sxs will sinemet tx?
- may be useful to tx dysphasia, seilorrhea, seborrhea, and improve fxnl ability and otehr secondaray motor sxs
- most effective against rigidity and slowness
- less benefit for tremor, balance and gait
- produces a general altering response, increases vigor, and sense of well-being
Is Sinemet neuroprotective?
- no, concern is taht prolonged use of levodopa may directly hasten degeneration of dopamine neurons in substantia nigra by promoting the generation of free radicals and oxidative stress is basis for delaying use of levodopa in tx of PD
- but it is very effective!
MOA of Sinemet?
- levodopa is immed metabolic precursor to dopamine, penetrates the brain, where it is decarboxylated into dopamine (1-5% of admin levadopa enters the brain, rest is metabolized extracerebrally by decarboxylation to dopamine)
- Carbidopa is decarboxylase inhibitor, peripheral metabolism is reduced and plasma levels of levadopa are higher and more is available to enter the brain
- thus combo produces better effects
- effective but short acting
AEs of sinement?
- phyiscal: low BP arrhythmia GI effects (when levodopa used alone) hair loss dyskinesias (80%)
psych/mental: confusion anxiety vivid dreams hallucinations
prevention: try giving smaller doses more frequently, reduce or stop evening dose if severe psych effects occur
What is wearing off effect of sinement? How is this prevented?
- may occur w/in 4-6 years of tx
- initially may be bradykinesia or tremor in am b/f next dose (motor fluctuations - alt b/t periods of being on, during which pt enjoys a good response to med, and being off during which pt experiences underlying sxs of PD)
- on-off effect in 15-20%
- sometimes sxs switch back in forth w/in minutes or even seconds - this transition may follow sxs as intense anxiety, sweating and rapid heartbeats
- prevention:
mult small doses on empty stomach, liquid form, controlled release formulation
CIs and precautions in sinemet?
- CIs: concurrent use with MAOIs psych pts angle closure glaucoma hx of melanoma (dopamine driven)
- precautions:
cardiac disease
PUD
Why does wearing off effect occur with sinemet?
- theories:
disease progresses beyond ability of levodopa to control it
some pts become tolerant to prolonged exposure to dopamine and at same time disease is progressing
brain’s own dopamine neurons become incapable of storing dopamine and when levadopa wears off - little or no natural dopamine remains
levadopa itself accel disease by producing oxygen free radicals, unstable particles that increase injuries to brain and dopamine degradation
How can we prevent the wearing off effect?
- maintain consistent level of dopamine as possible
- unfortunately, levadopa is poorly absorbed and may remain in stomach for long time
- thus it’s beneficial for add of dopamine agonists, MAOBs and COMT inhibitors to the regimen
What class is Selegiline (Elderlyl, Zelapar)? MOA?
- MAO-B inhibitor
- stops breakdown of dopamine
- enhances peak levadopa levels
- may have neuroprotective properties by reducing oxidative metabolism of dopamine
- lipophilic and penetrates BBB rapidly
- 5 mg w/ breakfast and 5 mg with lunch, shouldn’t take later in day due to insomnia
What class is Rasagiline (Azilect)? MOA?
- MAO-B inhibitor
- more potent than selegiline
- stops breakdown of dopamine
- enhances peak levadopa levels
- may have neuroprotective properties by reducing oxidative metabolism of dopamine
- lipophilic and penetrates BBB rapidly
- 1 mg qd when used alone, .5 mg qd when used w/ sinemet
Adverse effects of all MAO-Bs?
- insomnia
- jitteriness
- dykinesias
- orthostatic hypotension
- may enhance levadopa adverse effects
Cautions and CIs with MAO-B inhibitors?
caution with: impaired liver fxn CV disease cerebral vascular disease seizure disorder hyperthyroidism diabetes psych disorders
CIs: concurrent use with TCAs, SSRIs and demerol
When are MAO-B inhibitors used first line?
- in pts with mild disease to slow progression and delay need for levodopa (has neuroprotection)!!!
- used as adjunctive therapy to decrease “wearing off”
