Parkinson's Disease

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Parkinson's Disease

Side effect Management

Drug-induced hallucination and psychosis

Pimavanserin -FDA approved (5HT-2A inverse agonist) for hallucinations and delusions assoc. w/ PD -metabolized by CYP3A4/3A5 -DDI: decrease dose by 50% if combined with CYP inhibitors, increase if inducers -can cause QTc prolongation

What agent is FDA approved for the txt of PD psychosis? Pimavanserin

-Correct electrolyte imbalance -simply drug regimen -consider low-dose atypical antipsychotics (Quetiapine, Clozapine) -consider antidepressants

N/V W/ Apomorphine

Pre-dose w/ timethobenzamide

Treatment

• Carbidopa/L-DOPA, DA agonist or amantadine for bradykinesia, moderate tremors or rigidity

Others:

Apomorphine SQ: -extensive 1st pass metabolism -used as rescue/PRN -N/V common, prepose w/ trimethobenzamide to minimize -severe hypoTN when w/ 5HT-3 blockers (ondansetron). careful monitoring

DA Agonists

Agents: Ergotamine (bromocriptine, old, not used, pulmonary fibrosis) Nonergotamine (pramipexole/ropinirole) -reduce levo exposure, delay need to start levo tx -used as initial tx, in young adult pts or adjunct in older -Ropini: CYP1A2, used for RLS (restless leg syndrome), causes pts to fall asleep suddenly -Prami: sudden falling asleep, renal elimination -AEs: n, confusion, sedation, edema, vivid dreams -Uses: -younger pts (<65): for motor fluctuations -older (>65): hallucinations/ortho HypoTN

COMT Inhibitors

Can COMT inhibitors and dopamine agonists be used in combination to treat PD? Yes

Agents: Entacopone, Tolcapone -combo w/ carb/levo -also indicated for "off" eps -Tol causes liver problems, monitor LFTs -Delayed diarrhea, brownish-orange urine discoloration

MAO-B Inhibitors

Agents: Selegiline & Rasagiline -used early in tx, neuroprotective -sele: metab by CYP2B6/2C19 to L-methamphetamine. ODT bypasses GI and dec formation of the agent -AE's: N, dec appetite, ortho HypoTN, hallucinations, dyskinesias, insomnia -Rasa: metab by CYP1A2 to inactive metabolite. Ads like placebo.

Adjunct for "Off" Episodes

Istradefylline: -Adenosine A2 receptor antagonist -adj w/ levo/carb for "off" eps -max dose for smokers >20 cig/d -DDI: metabolized by CYP1A1/CYP3A4

Safinamide: -selective, reversible MAO-B inhibitor -approved for adj txt w/ levo/carb for "off" eps -may also improve motor function

Amantadine

-mild disease +tremors -renal elimination, dec dose w/ dec creatinine clearance -ADEs: confusion, dry mouth, dizziness, hallucinations -skin discoloration, molting -limited use in tx -MOA: DA release, also implicated inhibition of glutamate -useful in suppressing L-dopa induced dyskinesias

Anticholineragics

-Most useful for tremors -careful in geriatrics (>65), inc confusion and drying -other disease: BPH, glaucoma, constipation, Alzheimer's

Carbidopa/L-DOPA

What does carbidopa do in the formulation with levodopa?? Prevent the GI effects of DOPA decarboxylase to allow increase L-Dopa absorption

What are the 4 motor complications assoc. w/ levo/carb therapy? End of dose wearing "off", delayed "on", freezing, and dyskinesias

Tx Levodopa-induced Dyskinesia

PK: -meals delay -antacids inc emptying -absorbed in duodenum by LNAA -not protein bound

-L-Dopa is the precursor to Dopamine -it crosses BBB, but carbidopa DOES NOT -Carbodpa dec conversion of L-dopa to DA = > inc amount to the CNS and reduces GI ADEs -Need at least 75mg carbidopa -Max dose of L-dopa unknown, limited by ADEs (N, HTN, sedation, vivid dreams, vomiting)

-Cornerstone of PD tx -Preferred for geriatrics who are cog + functionally impaired -Honeymoon period of 5-7yrs

Dyskinesias: L-dopa "on" periods -assoc. w/ peak DA lvls -lower drug dose = balance with AE vs. symptoms -add amantadine "off-period" dystonia: muscle contractions -feet, early morning hours, improvs w/ first drug dose -HS use of CR products L-Dopa or DA agonist -Baclofen and botox (??)

Delayed On: due to delayed gastric emptying or reduced absorption -chewing or crushing tabs/ODT on empty stomach -apopmorphine SQ, possible drug holidays Freezing: feeling like stuck to the floor -physiotherapy or walking devices -increase drug dose, MAO B inhibitor or DA agonist

Issues to be aware of. End of Dose Wearing Off AKA On/Off: occurs prior to next dose -happens due to inc loss of storage for DA and short L-DOPA 1/2 life -peripheral PK effects >> CNS effects -Give more frequently, add COMT or MAO B inhibitor. CR formulation can be useful -consider DA agonist during day or HS use of PO products

Rasagiline: -considered 1st line agent, (-) functional impairment, (+) DA agonist **consider pt age (<65 or >65?)

What agent can be initially used in PD pts that have symptoms WITHOUT significant impairment? Rasagiline

Algorithm

Staging: Hoehn & Yahoo Staging

What is stage IV of PD according to the Hoehn and Yahr staging of severity scale? Bilateral symptoms and postural instability

V = severe sx, confined to bed or wheelchair

IV = bilateral sx, postural sx

III = Bilateral sx, mild posturing

II = Bilateral sx, no posturing

I = unilateral sx

0 = no clinical signs evident

Factors to consider

Protective factors:

Cigarette smoking, caffeine consumption (CYP1A2 stimulation), NSAID use

Risk factors:

Rural areas, drinking well water, heavy metal and hydrocarbon exposure

Pathology

Pathways of DA neurons from SNc to the striatum

DA metabolism: L-tyrosine --(TH)-> L-DOPA --(L-AAD)-> DA --> converted to metabolites by MAO-B and COMT

L-AAD can be blocked by drugs like carbidopa that do not pass the BBB, thereby increasing L-DOPA lvls from meds and reducing AEs. L-DOPA is also metabolized by L-AAD.

Cont: Nigrostriatal degeneration --> loss of inhibition by the direct path + activates GPi by the indirect path --> dec motor cortex activation --> dec motor output --> clinical symptoms

NTs involved: -acetylcholine -GABA -Glutamate -enkephalins -Sub.P -adenosine -serotonin

Indirect: D2 inhibit inhibitory GABA/Enkephalin efferents --> projects inhibitory GABA to STN --> excitatory glutaminergic neurons project to the GPi

Direct: D1 receptors stim GABA/Sub.P efferents in the GPi

Etiology

Antioxidative molecules (glutathione) limits damage from free radicals BUT the system may be overwhelmed/impaired. Free radical --> lipid peroxidation -->damage cell membranes --> slow cell death --> apoptosis

Substantia nigra has inc oxidative stress (free radicals from dopamine autoxidation)

Chemical MPTP produces a form of PD -MPTP --> MPP+ --> TOXIC --> cell death ☠️

Key feature: degeneration of dopaminergic neurons in the substania nigra

Familial parkinson's, autosomal dominant, recessive and x-linked

Genetics - sig role <50 yo Autosomal dom: a-synuclein mutation (PARK1,4) and leucine-rich repeat kinase 2 genes (LRRK) Auto recessive: parkin (PARK2) and PINK1 genes

Other neurodegenerative diseases (Alzheimer's, CJD)

Secondary parkinson's - medications, infections, environment, tumors

Essential tremors

Idiopathic PD

Features

Non-Motor

Neuropsychiatric (depression), autonomic dysfunction (constipation), sleep disturbance (insomnia)

Motor

Why do these signs/sxs occur?

-Reduced DA lvls -Inc ACh lvls (DA inhibits ACh, when it dec then ACh is inc, leading to tremors) -DA cells cont. to be destroyed and DA production declines -Progressive disease, sxs+severity will worsen

-upper extremity tremors at rest -upper and lower extremity rigidity -bradykinesia (slow movement) -postural instability -other psychiatric disorders can occur

Cardinal features/presentation: Bradykinesia, resting tremors, rigidity, postural instability

Symptoms: -decreased dexterity -dysarthria (difficulty speaking) -dysphagia (diff swallowing) -flexed posture -freezing at movement initiation -bladder problems Autonomic symptoms: -bladder problems Mental status changes: -dementia at later stages