CNS I Pharm - PD Drugs Flashcards
3 major symptoms of PD
Akinesia – problems with or slowness in initiating movements
Resting “pill rolling” tremor – early hallmark
Rigidity/Postural Instability – most debilitating part of the disease; gets progressively worse, patients can also fall and hurt themselves
Pathophysiology of PD (quick)
DA producing neuronal cells in the SNPc die and their terminals in the striatum (C + P) also degenerate
When we lost ~75% of our DA in the striatum and 50-60% in the substantia nigra, we see symptoms
Compensatory Mechanisms to increase DA when 25-30% is lost
25-30% lost –> Passive mechanisms: 1) Tyr hydroxylase is activated to a higher extent (rate limiting step in DA synthesis, so the rate of DA synthesis increases) and 2) Uptake of DA via transporter – as neurons die, transporters are lost; so the uptake compensates by DECREASING, so that we have more DA at the synapse
Compensatory mechanism of replacing DA (50% lost)
Increased Firing Rate –> SNPc sends axons to the striatum, which then send inhibitory inputs back to the SNPc –> if there is not enough striatum activity, it fires LESS so there are fewer inhibitory inputs on the SNpc (so more DA firing! Fewer neurons but fire FASTER since there is no neg feedback)
Compensatory mechanism of replacing DA (> 50% lost)
DA receptor UPREGULATION; last ditch attempt; post-synaptic receptors in striatum upregulate to catch as much DA as possible; when we lave receptors in PD patients (radiolabel) we see an increased signal in one hemisphere)
DA Pathway Review
Cortex sends stimulatory signals to the Striatum
DA neurons from the SNpc project to striatum, activating it
Striatum, when active, sends GABA inhibitory signals to the SNpr and GPi
SNpr/GPi usually INHIBIT the THALAMUS/reticular formation/superior colliculus to prevent movement
When the active striatum sends INHIBITORY signals to the GPi/SNpr it INHIBITS the INHIBITOR and thus the thalamus is NOT inhibited and movement can occur!
There is also an indirect pathway which does the opposite, and DA from the SNpc can INHIBIT that pathway (still initiating movement)
ALSO, too much DA –> Striatum inhibits the SNpc DA neurons
Pathway in PD
The DA neurons in the SNpc are LOST and so are their inputs in the striatum
Striatum no longer active – continual inhibition of the thalamus from the GPi/SNpr –> unopposed inhibition = no movement
DOPAMINE AGONISTS
First drugs administered to NEWLY DIAGNOSED PD patients
They are given as monotherapy at first, but are NOT AS GOOD AS L-DOPA
However, they DELAY THE NEED for L-DOPA by a year or more, and they have less side effects!
As the dose is slowly increased, the patient may show symptoms of increased DA in the brain (dyskinesias - too much movement, and vomiting are most common)
LEVODOPA
Crosses the BBB unlike regular DA
Very effective at treating PD! Actively transported across BBB and gut-blood barrier
Once inside body, it is converted to DA by L-Aromatic Amino Acid Decarboxyalse
Half-life = 90 minutes
Only 1-2% of LDOPA SURVIVES FIRST PASS and GETS INTO BRAIN!!!!
LEVODOPA in the periphery
Converted to DA by LAAD and methyldopa by COMT
Too much DA in periphery TRIGGERS AREA POSTREMA (VOMIT CENTER)
Most common side effect is EMESIS
Increased DA in periphery can also act on kidneys and cause orthostatic hypotension
LEVODOPA in the brain
Converted to DA, broken down by MAO and COMT
Side effects of too much DA = DYSKINESIA (mimics huntingtons)
Too much L-DOPA in frontal lobes = PSYCHOSIS!
but DONT treat with haloperidol like we would normally for psychosis –> blocks DA in the brain in a PD patient —> won’t be able to move!
CARBIDOPA
Blocks LAAD JUST in the periphery, so more L-DOPA can get to the brain
Decarboxylase inhibitor that DOES NOT cross BBB - so only LDOPA goes to brain
No DA in the GI tract = no EMESIS!
CARBIDOPA + L-DOPA IS A VERY COMMON TREATMENT FOR PD!!!!! 8-10% more DA survives first pass
Dose has to be about 4x LESS than LDOPA alone to compensate for all the extra DA
High protein diet and PD?
Protein can compete with L-DOPA at the amino acid BBB transporter –> so less L-Dopa will get into the brain –> at least be careful when eating lots of protein!
Wearing off Syndrome
After a patient uses L-Dopa for a while, DA receptors will DOWN REGULATE
Thus, a dose of L-Dopa will not last as long or be as effective as it once was
How do we deal with this? Increase L-Dopa, Increase frequency of dosing, Switch to slow release formulas, slow degradation via COMT/MAO inhibitors (preserve L-Dopa in brain and in periphery)
EVENTUALLY all these drugs won’t help and wearing off will cause L-Dopa to be ineffective :(
On-Off Syndrome
Big problem in treating PD with L-Dopa
Usually occurs 5-7 years after initiating therapy – Drug works sometimes (on) and sometimes just doesn’t (off)
Don’t know when it happens, no rhyme or reason; increasing dose will not help
It is NOT a pharmacokinetic problem or down-regulation issue – no reason
DEEP BRAIN STIMULATION + L-Dopa may work!
