9/20 Movement Disorder Drugs - Dorovkov Flashcards
(37 cards)
drugs for PD
- levodopa
- dopamine agonists
- MAO-B inhibitors
- COMT inhibitors
- anticholinergics
- amantadine
PD characteristics and symptoms
progressive disorder of movement occuring most commonly in elderly (mean onset: 55yo; onset variable 50-80)
- resting tremor (abates with voluntary/intentional movement)
- muscle rigidity
- bradykinesia (slow movement)
- impairment of postural balance leading to distubance of gait/falling
within 10-20 yrs, total immobility for most patients
- death from PD usually due to complications related to immobility (ex. aspiration pneumonia, CV/cerebrovasc disease)
neuropathology of PD
- loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) in basal ganglia
- decrease in number of DA terminals in striatum
proposed causes of PD
- genetic
- environmental
- oxidative stress (free radicals)
- aging
genetic factors for PD
contribution of identified genetic factors approx 10%
- protein degradation (Parkin)
- mitochondrial function (PINK1)
- response to oxidative stress (DJ1)
- LRRK2 (kinase with many domains)
most predispose to early onset of PD (< 50yo)
at what stage of SN cell loss do PD symptoms manifest?
why?
PD symptoms appear at advanced stage of cell loss (80% loss)
- there is likely an adaptive increase in dopamine receptors in response to cell death
- when this effect “maxes out”, adaptation/compensation fails and symptoms appear
environmental factors for PD
risk factors
protective stuff
in 1980s, people developed sx similar to PD after using synthetic recreational drug MPPP, later found to be contaminated with MPTP
- MPTP is metabolized to free radical MPP+ → oxidative stress resulting in cell death
mechanism: MPP+ inhibits ComplexI → ATP decrease → cell death
others: pesticides, heavy metals, vitD deficiency
protective stuff: exercise, coffee, cigarettes, anti-infl drugs, elevated levels of uric acid
oxidative stress
possible that metabolism of DA → free radicals which lead to oxidative stress
[dopamine → DOPAC + hydrogen peroxide]
- if H2O2 is not deactivated fast enough, produces free radicals → cell death
basic principle of treatment
facilitate dopaminergic neurotransmission
- exogenous DA precursors
- drugs to increase release of endog DA
- direct DA agonists
- inhibitors of DA metabolism
L-Dopa
Levodopa
single most effective agent in treating PD
natural pathway: Tyr → Dopa → dopamine
- pretty much pharmacologically inert, buuuut
- L-Dopa is converted to dopamine via decarboxylation
- unlike dopamine, penetrates bbb
metabolism of levodopa
levodopa → dopamine [L-a.a. decarboxylase] → 3,4 dihydroxyphenylacetic acid (DOPAC) [monoamine oxidase, aldehyde dehydrogenase]
- all three substances can be degraded by COMT
levodopa can be turned into melanin
dopamine can be norepinephrine
Levodopa PK
absorption: where/how?
pl concentration and half life
rate and extent of absorption depend on:
- rate of gastric emptying
- pH of gastric juice
- time of exposure to degradative enzymes of gastric/intestinal mucosa
transported into brain by active transport system
- competes with dietary protein → transport is reduced with high protein diet
peak pl concentration occurs 1-2hr after oral dose
half-life is 1-3hr
metabolism of levodopa
enzymes involved, metabolites formed, characteristics
implications
metabolized in peripheral tissues by…
- L-aromatic a.a. decarboxylase (L-AAD, 60%)
- → dopamine. does not enter CNS.
- catechol-O-methyltransferase (COMT, 10%)
- → 3-O-methyl-dopa, which competes with levodopa for transport into brain (15hr half life)
implications:
- administered alone, less than 1% makes it into CNS
- peripheral conversion produces side effects
carbidopa
L-aromatic amino acid decarboxylase inhibitor (L-AAD inhibitor)
- doesn’t penetrate bbb
- serves purpose of increasing fraction of levodopa that remains unmetabolized by L-AAD in peripheral tissues such that it’s available to enter CNS
- increases plasma half-life and plasma conc of levodopa
- allows for lower dosing → lower side effects!
levodopa + carbidopa
Sinemet
carbidopa: levodopa at fixed 1:4 or 1:10 ratio (1 =25mg)
adverse effects of levodopa tx
GI
without peripheral L-AAD inhibitor (carbidopa), 80% of patients experience…
- anorexia
- nausea
- vomiting (stimulation of emetic center located in brainstem OUTSIDE OF BBB)
combo with carbidopa? reduction of GI effects to 20% of patients!
adverse effects of levodopa tx
cardiovascular
- arrhytmias
- postural hypotension (activation of vascular DA receptors)
- admin with nonspecific MAO inhibitors improves levodopa action, could lead to hypertensive crisis
hypotension and hypertension? whaaaat?
- at low concentrations, levodopa has affinity for certain subtypes of receptors
- subtypes affected change at high concentrations
adverse effects of levodopa tx
CNS effects
desired
- decrease in tremor, rigidity, bradykinesia
undesired
- abnormal involuntary movements (dyskinesias)
- psych disturbances : confusion, hallucinations, anxiety
- conventional antipsychotics (phenothiazines) effective but worson Parkinsonism
- clozapine (atypical) does not worsen Parkinsonism, can be used
long term effects of levodopa tx
- response fluctuations
- 50% pts after 5 years
- 70% pts after 15 years
- end of dose deterioration aka wearing off (predictable)
- on-off phenomenon (unpredictable)
- increase in side effects
- dyskinesias
- psych disturbances
may require adjunctive tx
end of dose deterioration
predictable
in early PD, duration of beneficial effects of levodopa exceeds plasma lifetime of drug
- implication: nigrostriatal dopamine system retains some capacity to store/release DA (“buffering” effect”
after long term use of levodopa tx, “buffering” capacity appears to be lost → pt’s motor state can fluctuate dramaticaly with each dose
- “wearing off” phenomenon: each dose of levodopa effectively improves mobility for 1-2 hr, but sx return rapidly at the end of the dosing interval
on/off phenomenon
unpredictable
patients fluctuate rapidly between feeling no apparent effects (“off”) and feeling effects (“on”) of their meds
- off periods: marked akinesia alternative over couse of few hours
- on periods: improved mobility, often marked dyskinesia
mechanism is unknown → prob result of brain response to variation in levodopa levels & alteration in fx of dopamine receptors
severe off-period that wont respond to other measures?
apomorphine
levodopa
drug interactions
- pyridoxine (B6) : enhances extracerebral metabolism of levodopa
- MAO-A inhibitors : accentuate peripheral effects (can cause hypertensive crisis)
levodopa
contraindications
psychotic patients
angle-closed glaucoma (bc can increase IOP)
- chronic angle-open? OK, as long as IOP is controlled/monitored
active peptic ulcer (GI bleeding)
hx of melanoma (levodopa is precursor of melanin!)
secondary pharmacologic tx of PD
agonists
- pramipexole: D3 agonist, non-ergot-derivative
- ropinirole: D2 agonist, non-ergot derivative
- bromocriptine: D2 agonist, ergot derivative
- pergolide: D1&D2 agonist, ergot derivative
- all act as agonists at dopamine receptors
not as effective as levodopa at fighting sx of PD, BUT some key advantages:
- don’t compete for active transport with other compounds
- less motor fluctuations in pts (signif less dyskinesia, esp in younger pt)
- less response fluctuations than levodopa as well
