Pharm - AD and PD

Which drug class corrects decreased dopamine synthesis?

Carbidopa/Levodopa

Treatment strategy is to replace dopamine precursor

Which drug class corrects decreased receptor stimulation?

Dopamine agonists

Treatment strategy is to directly stimulate D2 receptors

Which drug class corrects dopamine broken down by MAO-B?

MAO-B inhibitors

Treatment strategy is to block central breakdown

Which drug class corrects levodopa broken down by COMT?

COMT inhibitors

Treatment strategy is to prolong levodopa (adjunct only)

Which drug class corrects relative Ach excess?

Anticholinergics

Treatment strategy is to reduce cholinergic tone (tremor)

Which drug class corrects glutamate/dyskinesia?

Amantadine

Treatment strategy is NMDA antagonism and increased DA release.

What medications may cause or worsen drug-induced Parkinsonism?

Central D2 blockade, like antipsychotics and antiemetics/prokinetics.

Which antipsychotics have a high risk of causing/worsening drug-induced parkinsonism?

First generation: highest risk with haloperidol and fluphenazine

Second generation: Risperidone, paliperidone, lurasidone

Which antiemetics/prokinetics cause or worsen drug-induced parkinsonism?

Metoclopramide (prokinetic): crosses BBB, high risk

Prochlorperazine (low risk)

Promethazine (low risk)

Central D2 blockade worsens motor symptoms.

What are the safer alternatives of anti-psychotics and antiemetics?

Quetiapine, clozapine, pimavanserin, ondansetron, and other 5-HT3 antagonists.

What are other contributing drugs to parkinsonism?

Dopamine depleters like tetrabenazine, deutetrabenazine, valbenazine, reserpine

Tremorgenic: valproate, lithium, amiodarone (anti-arrhythmic)

Lithium and valproate may unmask parkinsonism

Which drugs worsen non-motor symptoms?

Anticholinergics (confusion, constipation, urinary retention)

Sedatives/benzos (falls, daytime sedation)

Antihypertensives and diuretics (orthostatic hypotension)

High anticholinergic burden is especially harmful

What is the most effective PD drug?

Carbidopa/Levodopa

What is the MOA of Levodopa and Carbidopa?

Levodopa crosses BBB and is converted to dopamine (dopamine is hydrophilic)

Carbidopa blocks peripheral DOPA decarboxylase (no BBB entry)

Increases CNS levodopa, decreases peripheral nausea and orthostasis.

What are the key ADE of Carbidopa/Levodopa?

Early: nausea, orthostatic hypotension

Chronic: dyskinesias, motor fluctuations

Hallucinations; impulse control (less than agonists)

What is the clinical role of Carbidopa/Levodopa?

Greatest efficacy, best for bradykinesia and rigidity.

Backbone, especially older/cognitively impaired.

What are the specific pearls for Carbidopa/Levodopa?

Give 30-60 minutes before meals; protein competes with absorption

Do not stop abruptly (parkinsonism-hyperpyrexia risk) (NMS-like syndrome)

Titrate to effect; watch BP and dyskinesia

What are the DDI of Levodopa?

Antipsychotics, like dopamine receptor antagonists can block the effect of levodopa and worsen parkinsonism symptoms.

MAOis may cause exaggerated response (hypertensive crisis, arrhythmias) when used with levodopa. Avoid MAOis within 2 weeks before starting/after stopping levodopa.

How much of levodopa is lost before reaching the brain?

98% of the oral dose. 70% lost to gut wall and 28% lost to liver and other peripheral tissues.

Which drugs are dopamine agonists?

Pramipexole

Ropinirole

Rotigotine

Apomorphine non-ergot

What is the MOA of dopamine agonists?

Directly stimulate striatal D2/D3 receptors. Bypass degenerating dopamine neurons. Longer half-life leads to smoother receptor stimulation

What is the clinical role of dopamine agonists?

Monotherapy in younger patients to delay levodopa.

Adjunct to levodopa in more advanced PD

What are the key ADE of dopamine agonists?

Impulse-control disorders: gambling, shopping, hypersexuality

Somnolence/sudden sleep attacks

Hallucinations, peripheral edema, nausea, orthostasis

What are the pearls of dopamine agonists?

Ask about impulse control disorders at every visit

Caution with driving; avoid in elderly/cognitive impairment

Taper to avoid dopamine agonist withdrawal syndrome

What is Apomorphine approved for?

DA approved for the acute, intermittent treatment of hypomobility during episodic "off" periods in patients with advanced PD. (when drugs wear off)

Not indicated for routine management of PD

What ADE are seen with Apomorphine?

Postural hypotension and fainting occur in 2% of patients.

Nausea is common; pretreat with trimethobenzamide 3 days before first dose. Cannot use serotonin receptor antagonists (ondansetron) or dopamine receptor antagonists (prochlorperazine)

What is the MOA of Pramipexole?

Non-ergot dopamine agonist that selectively stimulates postsynaptic D2 and D3 dopamine receptors in the striatum, mimicking dopamine and improving motor symptoms.

What are the common ADEs of Pramipexole?

Nausea

Dizziness

Somnolence

Insomnia

Constipation

What are the serious warnings of Pramipexole?

Sleep attacks (driving caution)

Orthostatic hypotension

Impulse control behaviors

Neuropsychiatric effects

What are the MAO-B inhibitor agents?

Selegiline

Rasagiline (more favored!)

Safinamide (reversible MAO-B inhibitor and modulates glutamate release)

All have modest benefits

What is the MOA of MAO-Bi?

Inhibit MAO-B, leading to blockage of central dopamine breakdown

Prolong action of endogenous and levodopa-derived dopamine

Selective for MAO-B at therapeutic doses

What is the clinical role of MAO-Bi?

Early monotherapy in mild disease (modest benefit)

Adjunct to levodopa, reduces "off" time

Safinamide only as levodopa add-on

What are the pearls for MAO-Bi?

Avoid with SSRIs/SNRIs/TCAs, meperidine, tramadol, dextromethorphan

Watch drug interactions; modest efficacy overall

Rasagiline once daily and favorable safety profile

What are the key ADE of MAO-Bi?

Generally well tolerated

Insomnia (selegiline leads to amphetamine metabolites)

Serotonin syndrome risk; tyramine caution at high dose

What are the DDI of Rasagiline?

CI with other MAO inhibitors (including linezolid), risk of hypertensive crisis. Allow ≥14 days washout when switching.

Use caution with serotonergic drugs due to risk of serotonin syndrome.

Caution with sympathomimetics, risk of HTN.

No significant dietary restrictions, can take with or without food.

What are the COMT inhibitors?

Entacapone, opicapone, tolcapone - effective ONLY when given with levodopa.

What is the MOA of COMT inhibitors?

Inhibit COMT which blocks levodopa breakdown. Prolong levodopa half-life, so more reaches brain.

Tolcapone also acts centrally.

What is the clinical role of COMT inhibitors?

Adjunct to reduce "wearing off"/ "off" time

No benefit as monotherapy

Entacapone in combo pill; opicapone QD

What are the key ADE of COMT inhibitors?

Worsened dyskinesia (more levodopa effect)

Diarrhea, nausea, orthostasis

Harmless orange/brown urine discoloration (most commonly with entacapone)

What are the pearls of COMT inhibitors?

Tolcapone: hepatotoxicity (boxed warning), LFT monitoring

Prefer entacapone/opicapone (no hepatotoxicity)

Often reduce levodopa dose to limit dyskinesia

Which COMT inhibitor extends levodopa's effect?

Entacapone

What are the anticholinergic drugs?

Benztropine, trihexyphenidyl - muscarinic antagonists (tremor-predominant, younger)

What is the MOA of anticholinergic drugs?

Block striatal muscarinic Ach receptors

Restore the dopamine-Ach balance

Minimal effect on bradykinesia/rigidity

What is the clinical role of anticholinergics?

Tremor-predominant PD in younger patients

Drug induced parkinsonism and acute dystonia

Adjunct, not a first-line backbone

What are the key ADE of anticholinergics?

Confusion, memory loss, hallucinations

Dry mouth, constipation, urinary retention

Blurred vision, tachycardia

What are the pearls of anticholinergics?

AVOID in older/cognitively impaired (AGS Beers criteria)

CI: BPH, narrow-angle glaucoma

Taper to avoid rebound; watch anticholinergic burden

What are the NMDA Antagonist drugs?

Amantadine IR; extended release Gocovri, Osmolex ER - the anti-dyskinesia drug

What is the MOA of NMDA antagonists (Amantadine)?

NMDA-receptor antagonism (anti-dyskinesia)

Enhances dopamine release, blocks reuptake

Mild anticholinergic activity

What is the clinical role of NMDA antagonists (Amantadine)?

Reduces levodopa-induced dyskinesia (LID)

ER is FDA approved!

Modest monotherapy benefit in early disease

Can also help fatigue

What are the key ADE of NMDA antagonists (Amantadine)?

Livedo reticularis, ankle edema after 1 month of use

Confusion, hallucinations (especially elderly)

Insomnia, dizziness and dry mouth.

What are the pearls for NMDA antagonists?

Renally cleared, reduce dose in renal impairment

Avoid abrupt discontinuation

Caution in elderly/cognitive impairment

What is the favored initial drug choice AND drug to avoid if predominant feature is bradykinesia/rigidity with functional impact?

Favored: Carbidopa/Levodopa (most effective)

Avoid: delaying levodopa when function is affected

What is the favored initial drug choice AND drug to avoid if predominant feature is tremor-predominant, younger patient?

Favored: Levodopa or DA agonist; anticholinergic if isolated

Avoid: anticholinergics if older/cognitively impaired

What is the favored initial drug choice AND drug to avoid if predominant feature is older age or cognitive impairment?

Favored: Levodopa - simplest, best tolerated

Avoid: DA agonists, anticholinergics, amantadine

What is the favored initial drug choice AND drug to avoid if predominant feature is orthostatic hypotension?

Favored: Levodopa cautiously; treat the OH

Avoid: DA agonists (worsens OH)

What is the favored initial drug choice AND drug to avoid if predominant feature is ICD risk/daytime somnolence?

Favored: Levodopa

Avoid: DA agonists (impulse control, sleep attacks)

What is the favored initial drug choice AND drug to avoid if predominant feature is psychosis/hallucinations?

Favored: Simplify meds, use quetiapine or pimavanserin

Avoid: DA agonists, anticholinergics, amantadine

When is peak-dose dyskinesia most common?

More common in young-onset PD.

How do you manage wearing-off?

Shorten interval; add COMT inhibitor or MAO-Bi; ER levodopa

How do you manage on-off?

Continuous delivery (infusion); consider DBS

How do you manage delayed on/dose failure?

Take with empty stomach; decrease protein; soluble/ER; apomorphine rescue

How do you manage peak dose dyskinesia?

Lower each dose + increase dosing frequency + add amantadine; add DA while lowering LD; avoid controlled release LD

How do you manage diphasic dyskinesia?

Increase LD dose or dosing frequency; overlap doses; avoid controlled release LD (can prolong suboptimal plasma level); SC apomorphine; DBS

How do you manage freezing of gait?

Optimize levodopa; gait rehab with cueing (walking to a beat; shifting weight before stepping, walking over an object); DBS variable

What are the steps to manage motor complications?

1. Optimize oral levodopa

2. Add adjuncts to extend or smooth.

3. Continuous/ ER delivery

4. Advanced therapies (DBS)

How do you manage orthostatic hypotension?

Midodrine (a1-agonist) (can cause/worsen supine HTN)

Droxidopa (expensive)

How do you manage urinary frequency?

Solifenacin (anti-cholinergic), be careful in older patients.

How do you manage drooling?

Botox (block Ach)

Glycopyrrolate

Sucking on hard candy or chewing gum

How do you manage constipation?

Probiotics and fiber

Miralax

How do you manage erectile dysfunction?

PDE5i

How do you manage excessive daytime drowsiness?

Modafenil

How do you manage periodic limb movements of sleep?

Levodopa/carbidopa

Pramipexole

How do you manage insomnia?

Levodopa/carbidopa

Melatonin

How do you manage depression?

Amitriptyline, could exacerbate dementia

How do you manage dementia?

Donepezil and rivastigmine, increases Ach, can cause tremors

How do you manage psychosis?

Withdraw amantadine and anticholinergics

Reduce levodopa to lowest effective amount

Use clozapine, quetiapine and pimavanserin.

How does age affect the initial regimen?

Younger tolerate dopamine agonists

Older use levodopa (fewer neuropsych ADEs)

How does severity/function affect initial regimen?

Greater functional impact, so start levodopa sooner.

How does predominant symptom affect initial regimen?

Bradykinesia/rigidity: use levodopa

Isolated tremor: dopamine agonist or anti-cholinergic (

How does cognitive status affect initial regimen?

Impairment: avoid anticholinergics

Dopamine agonists, amantadine

How does occupation/demands affect initial regimen?

High dexterity or performance needs: prioritize efficacy (levodopa)

Which drug class corrects cholinergic deficit (decrease in Ach)?

Cholinesterase inhibitors. Treatment strategy is to inhibit acetylcholinesterase, which increases synaptic ACh

Which drug class corrects glutamate NMDA excitotoxicity?

Memantine. Treatment strategy is to block excessive NMDA activity.

Which drug class corrects amyloid-B plaque accumulation?

Anti-amyloid mAbs. Treatment strategy is antibody-mediated clearance (disease-modifying)

What drugs are cholinesterase inhibitors?

Donepezil, rivastigmine, galantamine

What is the MOA of Cholinesterase inhibitors?

Inhibit acetylcholinesterase which increases synaptic Ach

Rivastigmine also inhibits butyrylcholinesterase

Symptomatic - does not stop progression

What is the clinical role of Cholinesterase inhibitors?

First line for mild-moderate; donepezil for all stages

Modest gains in cognition, function, behavior

Rivastigmine patch has better GI tolerability and adherence.

What is the key ADE of Cholinesterase inhibitors?

Cholinergic GI: nausea, vomiting, diarrhea, weight loss

Bradycardia, syncope

Vivid dreams, insomnia, muscle cramps

What are the pearls of Cholinesterase inhibitors?

Titrate slowly; give with food

Caution: bradycardia/heart block, PUD, COPD, seizures

Assess response over months; do not expect reversal

What is the MOA of Memantine?

Helps protect neurons from excess glutamate activity, which may help slow symptoms of Alzheimer's disease.

What is the monitoring and clincal pearls of Memantine?

Start low, go slow

Full therapeutic effect may take several weeks to months

Dose adjustment recommended in moderate to severe renal impairment

Well tolerated compared to cholinesterase inhibitors; lower risk of GI side effects and bradycardia.

What is the MOA of Lecanemab?

A humanized IgG1 monoclonal antibody that selectively binds to soluble, aggregated amyloid B protofibrils. Targets amyloid B plaques in the brain to slow the progression of AD.

What is the dosing of Lecanemab?

10 mg/kg IV infusion every 2 weeks.

What should be monitored for with Lecanemab use?

Signs of ARIA (amyloid related imaging abnormalities). Look for vasogenic edema or sulcal effusions seen on MRI, or microhemorrhages or superficial siderosis on MRI.

Monitor for headache, confusion, dizziness, or other new neurological symptoms.

What are the main CI of Lecanemab?

Hypersensitivity

APOE 4 homozygotes (higher risk of ARIA)

Cerebral amyloid angiopathy (CAA) or evidence of prior lobar hemorrhage

Anticoagulant or antiplatelet therapy (use with EXTREME caution)

What is the BBW of antipsychotics in dementia?

DO NOT USE IN DEMENTIA!!! Increased chance of death.

How do you manage the behavioral and psych symptoms of dementia?

First-line is non-pharm. Identify and treat triggers. Structured routine, calm environment.

What should be done if a medication is needed for BPSD?

Target a specific symptom; set realistic goals

Lowest effective dose, shortest duration

Document risk/benefit discussion, and consent

Reassess often, attempt taper; avoid in Lewy body dementia

What med should be used for AD agitation?

Brexipiprazole

What med has the best evidence for aggression and psychosis help in BPSD?

Risperidone