Parkinsons Med Chem Flashcards
What is the pathophysiology of PD since it is a neurodegenerative disorder?
progressive and irreversible loss of neurons
Neuronal loss in what area of the brain results in loss of control of movement?
basal ganglia
Neuronal loss in what area of the brain results in cognitive impairment?
cortex
What are the 4 major features of PD?
- resting tremor
- brady kinesia
- muscular rigidity
- Postural imbalance leading to problems with gait and falling
How many neurons are lost before PD is typically diagnosed?
80% of DA neurons
What other diseases or drugs may cause Parkinsonism?
- stroke
- other Lewy body producing neurodegenerative disorder
- DA antagonists
Identification of what is confirmatory of PD?
Lewy bodies
What is a Lewy body?
clumps of individual misfolded a- synuclein proteins; can continue to recruit misfolded proteins
What areas do Lewy bodies form in early PD?
- brain stem
- olfactory bulb
What areas do Lewy bodies form in the clinical stage?
- misotemporal cortex
- midbrain
What areas do Lewy bodies form in late stage PD?
cerebral cortex
The loss of what major dopaminergic pathway causes motor symptoms?
- Nigrostriatal- substantia nigra to striatal pathways
- A9 cell bodies die in substantia nigra- loss DA production and of DA1 and DA2 receptors in the cortex and stiatum
The loss of what major dopaminergic pathway causes non-motor symptoms like emotional responsiveness?
Mesocortical (reward pathway)- VTA to olfactory bulb, amygdala, hippocampus, and medial prefrontal areas
What enzymes responsible for DA metabolism do we inhibit when treating PD?
- MAO-B inhibitor
- COMT inhibitor
What genetic factors lead to PD?
- mutations
- genetic risk (park genes: a- synuclein processing)
- epigenetic changes
What environmental factors lead to PD?
Mitochondrial disruptors:
1. MPTP found in street drugs
2. Paraquat in fertilizer
What are the normal roles of a- synuclein protein?
- protects DNA/ RNA from oxidative stress
- clustering and release of synaptic vesicles
- stabilization of electron transport chain
What is the normal structure and function of Park-1 gene?
- amphipathic region- lipid membrane-binding region
- hydrophobic region- fibrillation core
- Acidic region- N-terminus interacting region interacts with DNA/RNA
How do Selegiline, Deprenyl, and Rasagiline inactivate MAO-B to increase DA?
propargyl amine mimics DA and covalently modifies the active site of the enzyme resulting in an imine and MAO-B Flavin
Why is Deprenyl considered a selective MAO-B inhibitor?
Ki Deprenyl»_space;> Ki Selegiline, Rasagiline
What is a by-product of the inhibition of MAO-B with selegiline and Deprenyl ?
L-amphetamine due to first pass metabolism resulting in amphetamine-like side effects
What are the side effects of Selegiline and Rasagiline inactivating MAO-A?
- cheese effect- taste aversion to cheese, pickled fish, cured meat
- increased Tyramine –> release of NE and EP —> may cause hypertensive crisis
Why does Rasagiline not produce amphetamine-like byproducts?
different base, same propargyl amine; no first pass metabolism
What is the MOA of Safinamide XADAGO?
a-aminoamide (AAA) inhibitors:
1. reversible, MAO-B selective inhibitor
2. inhibits DAT
3. inhibits voltage-dependent sodium channel blocker
4. blocks glutamate release
What is the MOA of Levodopa?
precursor of DA
What usually starts to happen around years 4-6 of L-DOPA treatment?
end-of-dose akinesia
What usually starts to happen around years 6-10 of L-DOPA treatment?
drug induced dyskinesia from supratherapeutic dose
What drugs are in Stalevo?
Entacapone
L-DOPA
Carbidopa
What is the MOA of Benserazide and Carbidopa?
reversible and competative inhibition of DOPA decarboxylase in the periphery
Why do Benserazide and Carbidopa only act in the periphery?
cannot cross the BBB
Why does reversible and competative inhibition of DOPA decarboxylase in the periphery help with PD?
Less L-DOPA coversion to dopamine; more L-DOPA can be transported across the BBB to be covered to DA in the brain
What is the MOA of COMT inhibitors?
reversible and competative inhibition of L-DOPA degredation by inhibiting COMT in the periphery
What are the 3 COMT inhibitor agents?
- Entacapone
- Tolcapone
- Opicapone
Why is Tolcapone banned in Canada?
induces liver damage
What is the difference between Opicapone and the other COMT inhibitors?
- 2 site binding results in high affinity
- pyridine N-oxide prevents CNS penetration and reduced toxicity
What medications can cause secondary PD?
- Traditional antipsychotics
- anti-dopaminergic antiemetics
- central dopamine depleting antihypertensives (Reserpine, methyldopa)
- cholinesterase inhibitors
What clinical presentations are identified by TRAP?
- Tremor (resting/ one sided tremor)
- Rigidity
- Akinesia/ bradykinesia
- Postural instability
What are mental status changes seen in PD?
- confusion
- dementia
- psychosis
- sleep disturbances
What are symptoms of autonomic dysfunction in PD?
- incontinence
- constipation
- orthostasis
- flushing
- sexual disturbances
What is the gold standard for monitoring the response to medications used to decrease signs and symptoms of PD at any stage?
UPDRS
When should we treat PD or increase intensity of therapy?
when symptoms affect quality of life
What are the SEs of SINEMET?
- N/V
- orthostatic hypotension
- hallucinations
- delusions
- confusion
- agitation
- cardiac arrhythmias
What are long-term effects of SINEMET?
- wearing on/off
- involuntary movements (dyskinesias)
What agents are in SINEMET?
L-DOPA / Carbidopa
What is the wearing off phenomenon?
return of PD symptoms before the next dose
What is the on-off phenomenon?
unpredictable return of PD symtptoms
What are dyskinesias?
drug-induced involuntary movements; dose-limiting prompts change in treatment
What are interactions with Benserazide and Carbidopa that decrease effectiveness?
- avoid Fe salts within 3 hours
- excessive vit B6 decreases absorption
- avoid high fat meals
What type of diet should be followed to maximize clinical effects of SINEMET?
lower protein meals throughout the day with main protein meal at supper
What are advantages to using levodopa/ carbidopa CR?
- less frequent dosing results in higher morning levels
- less peak-trough variation
- less motor fluctuations
What are disadvantages to using levodopa/ carbidopa CR?
- night time hallucinations/ vivid dreams
- 25-30% dose increased required
What are the levodopa/ carbidopa extended release agents?
- SINEMET CR
- RYTARY
Risk of what SE increases when using RYTARY?
GI bleed
What is an advantage to the RYTARY capsule dosage form?
can be opened and sprinkled on applesauce
What role does Parcopa have in therapy?
levodopa/ carbidopa ODT:
1. first morning dose
2. PRN for acute wearing off effects associated with freezing
3. can be a substitute for IR Sinemet
What are disadvantages to Parcopa?
- more peak dose dyskineasia
- hypotension
What role does Inbrija have in therapy?
levodopa/ carbidopa orally inhaled powder:
1. rescue for severe “off” episodes
2. NOT a substitute for IR Sinemet
What are SEs / exacerbations seen with Inbrija?
- falling asleep
- IOP in glaucoma
- invoke bronchospasm
- low BP
- hallucinations
- uncontrollable impulses
- dyskinesia
- change in sputum color
What can be done if Sinemet dose modifications do not help with hypotension proportional to blood peak?
- fludrocortisone
- midodrine
- droxidopa
How can wearing off be managed with Sinemet?
- add dopamine agonist
- MAO-B inhibitor
- COMT inhibitor
- increase frequency / dose
- change to CR
How can on-off be managed with Sinemet?
- add COMT inhibitor- Entacapone
- add MAO-B inhibitor rasagiline/ selegiline
- add DA agonist- pramipexole/ ropinrole
- redistribute dietary protein
How can dyskinesias with Sinemet be managed?
- decrease levodopa dose
- add amantadine
What are SEs with Amatadine?
- dry mouth
- sedation
- vivid dreams
- LIVIDO RETICULARIS RASH
What is the role of Istradefylline in PD?
for off episodes
How are hallucinations/ delusions managed from Sinemet and PD?
- avoid nighttime dosing especially ER
- Antipsychotics (Clozapine, Quetiapine)
- Pimvanserin
What are the SEs with Pimvanserin?
- QT prolongation
- interacts with CYP3A4 inhibitors and inducers
What is the MOA of Pimvanserin?
serotonin 2A inverse agonist/ antagonist atypical antipsychotic
What is Selegilene and Rasagliline role in therapy?
- younger patients/ early theray
- adjunct to allow for Sinemet dose reduction
What are SEs with MAO-B inhibitors Selegiline, Rasagiline, Safinamide?
- hallucinations
- anxiety
- insomnia (amphetamine-like metabolites)
- dyskinesia
- delirium
- hypertensive crisis
What increases the risk of hyperensive crisis?
concurrently or within 14 days of:
1. antidepressants
2. narcotics (meperidine)
3. MAO inhibitors (also linezolid)
4. cyclobenzaprine
5. DM
6. St. John’s wort
7. general anesthesia
tyramine containing foods
What is the role of Safinamide in therapy?
add-on treatment in patients expirencing wearing off from Sinemet
What role do dopamine agonists have in PD?
- first line monotherapy in younger patients
- add on for late stage allowing for lower doses or longer intervals
- some evidence in secondary parkinsonism due to ischemic brain trauma
What are SEs of non-ergot DA agonists Pramiprexole, Ropinerole, Rotigotine?
- somolence
- nausea
- hypotension
- compulsive behaviors (gambling, sex, substance abuse)
How are oral DA agonists dosed when starting therapy?
titrated from low to high at weekly increments as tolerated
What is the role of injectable Apomorphine?
acute on-off dyskinesias (mostly freezing episodes in patients on high dose Sinemet
What are SEs with Apomorphine injection?
- dyskinesias
- falls
- hallucinations
- headaches
- injection site reaction
- N/V
- somnolence
What are CIs to using Apomorphine inj?
- sodium metabisulfite allergy
- 5HT3 antagonists including antiemetics (ondencetron etc) and alosetron
