Parkinson's & Alzheimers Flashcards
Parkinson’s dz basic def/pathology
degeneration of DA neurons projecting from the SUBSTANTIA NIGRA (SN) to the corpus striatum (NIGROSTRIATAL PATHWAY)
-leads to ~80% decrease in striatal dopamine
Primary symptoms of Parkinson’s Disease (4)
- occur once ~70% of striatal DA is lost
- stiffness, tremor
- bradykinesia (slowness and poverty of movement)
- difficulty with balance and walking
Parkinson’s secondary symptoms
depression, dementia, postural deformity, difficulty in speaking
Parkinson’s dz pathophysiology
degeneration of DA neurons in the pars compacta of the substantia nigra ->OVERractivity in INdirect pathway and UNDERactivity of DIRECT pathway
=increased glutamatergic output from subthalamic nucleus and increased GABA input into the thalamus
end result: decreased glutamate input into the cortex
DA synthesis & Metabolism
- tyrosine is converted into L-dopa
- L-dopa is converted to DA by dopa decarboxylase in the nerve terminal
- DA is sequestered in vesicles & released from pre-synaptic nerve terminal upon stimulation
- DA in synapse activates post synaptic receptors to induce intracellular signaling
- excess DA in synaptic cleft is take back up inot pre-synaptic terminal cia DAT (aka DA transporter)
- DA is metabolized by MAINLY MAO-B in the nerve terminal
- DA also metabolized by MAO-A & COMT
Interactions of DA & ACh
degeneration of DA neurons in SN->imbalance btwn DA & ACh (ACh pathways are then dominant)
-normally, DA pathways INHIBIT GABA output from striatum & ACh stimulates it,
so LOSS OF DA=overactivity of inhibitory GABA neurons
5 Tx Strategies in Parkinson’s
- increase DA levels
- increase the synthesis of DA
- decrease the metabolism of DA
- stimulate postsynaptic DA receptors
- decrease ACh activity in the striatum
L-dopa (levo-Dopa, Dopar, Laradopa): how does it work, SEs
DA cannot cross BBB
L-dopa is the immediate precursor to dompamine
probs: L-dopa is converted to DA in GI tract and peripheral tissues, only abt 1-3% reaches the brain
so HIGH DOSES NEED to tx PD sxs
high doses cause adverse peripheral effects, esp N/V
L-Dopa/Carbidopa (Sinemet): mechanism
Sine=without
Emet=vomiting; so “without vomiting”
CARBIDOPA is a DOPA DECARBOXYLASE INHIBITOR that doesn’t cross BBB-> it inhibits synth of DA from L-dopa in periphery but doesn’t affect DA synthesis in the brain
-so more L-dopa gets to the brain, smaller therapeutic dose needed
-adding carbidopa to L-dopa greatly decreases the amt of L-dopa that must be administered by abt 75%
L-dopa/Carbidopa (Sinemet) pharmokinetics (route of admin and 3 other things)
- given orally
- ABSORPTION IS DELAYED BY FOOD & some amino acids will compete for absorption
- SHORT HALF-LIFE, must be taken 3-4 times daily
-sustained release form is available, which is tolerated better & more effective
Clinical Uses/effectiveness of L-dopa/carbidopa (Sinemet)
-L-dopa/Carbidopa may provide dramatic improvement of sxs for abt 3-4 years, but doesn’t alter the progression of the dz
-over the years, a person w/Parkinson’s has fewer & fewer dopaminergic neurons->so effectiveness decreases over time
incidence of SEs increase over time
-effective against all PD sxs, but esp. useful for bradykinesia
1/3 of pts respond very well, 1/3 respond less well
1/3 don’t respond at all or are unable to
Adverse effects of L-dopa (5 main categories)
GI: N/V in 80% if L-dopa taken alone, decreases to 20% when taken w/carbidopa
CV: small chance of arrhythmia in susceptible ppl, postural hypotension at start, HTN w/MAOIs or sympathomimetics
DYSKINESIAs: develop over time, present in 80%, MORE COMMON w/ L-dopa/carbidopa combo
BEHAVIORAL: depression, anxiety, agitation, insomnia, confusion, delusions, hallucinations; psychosis is tx w/atypical antipsychotics
ON-OFF PHENOMENON: only occurs in pts tx w L-dopa, tx by taking med at more frequent intervals, w/a dietary protein, can add dopamine agonists or selegiline to increase effectiveness
Drug holidays in Parkinson’s dz
risky & not recommended: aspiration pneumonia, venous thrombosis, pulmonary embolism may result
L-dopa drug intrxns
MAOIs: may cause HYPERTENSIVE CRISIS, wait 2 weeks after d/c
pyridoxine (vit B6) increases peripheral metabolism of L-dopa, can decrease L-dopa effectiveness unless carbidopa also administered
Contraindications to L-dopa or L-dopa/carbidopa (5)
PSYCHOSIS: increases DA
CLOSED-ANGLE GLAUCOMA: increases intraocular pressure
CARDIAC DZ: decreases peripheral effects and risk is small
ACTIVE PEPTIC ULCER: L-dopa can increase GI bleeding
MALIGNANT MELANOMA: L-dopa is a precursor of melanin
What are the major metabolic route of DA metabolism in CNS?
minor pathways?
MAO-B
MAO-A & COMT are minor pathways
Selegine: class, mechanism, administration, adverse effects
MAOI
selectively inhibits MAO-B (the predominant form in the striatum) at therapeutic levels=reduces striatal metabolism of DA
well absorbed orally, taken 2x/day, at breakfast & lunch
AEs:
- insomnia if taken late in the day
- anxiety (metabolites are amphetamine-like), may increase SEs of L-dopa later in course of dz
- DO NOT COMBINE W/MEPERIDINE: may produce stupor, rigidity, agitation, hyperthermia
