Parkinson's Disease Flashcards
Cardinal Motor Symptoms of PD
TRAP: 2 out of 3 (TRA) suggests PD
1. Tremors at Rest
2. Rigidity (Cogwheel)
3. Akinesia (Subjective weakness, facial)
4. Postural Instability
5 Non-motor symptoms associated with PD
- Cognitive (Dementia)
- Psychiatric (Depression, Psychosis)
- Sleep disorder
- Autonomic disorder (Constipation, GI motility, Orthostatic hypotension, Sialorrhea)
- Fatigue
Activities of Daily Living: DEATH
Dressing
Eating
Ambulating
Toileting
Hygiene
Pathophysiology of PD
Dopaminergic Neuron Degeneration in the Substantia Nigra which normally inhibit a number of motor systems
- Hypoactivation of D1 receptors weaken striatal inhibition
- Hypokinesia
Accumulation of toxic Lewy body protein
Nigrostriatal pathway dysfunction
Reduced basal ganglia “action selection” and poor motor control
How to treat drug-induced Parkinsonism?
May not always be reversible
Prevention is key
Anticholinergics and Amantadine can be used
Differentiate drug-induced PD and idiopathic PD
DIP VS iPD
Age Onset: Elderly vs ≥ 60 years old
Symptom Onset: Symmetrical vs Asymmetrical
Time Onset: Acute vs Chronic Progressive
Levodopa Test: Poor vs Marked
List 5 medications associated with drug-induced Parkinsonism
- Antipsychotics
- Anti-seizure Medications
- Antiemetics (Metoclopramide)
- Calcium Channel Blockers (NDHP)
- Lithium, Tetrabenazine, Reserpine, Methyldopa
Drug Classes and MOA for PD management
Central Dopamine Pathway:
1. Levodopa (Synthetic precursor)
2. Dopamine agonists (Pramipexole, Rotigotine)
3. MAO-B Inhibitors (Selegiline, Rasagiline)
4. COMT Inhibitors (Entacapone)
Other Pathways to correct Imbalance:
1. Anticholinergics (Trihexyphenidyl)
2. NMDA Receptor Antagonist (Amantadine)
Levodopa Brands, Combinations, Formulations and Rationale
Combination with Carbidopa / Benserazide
- DCI 75-100 mg required
- Peripheral Conversion by DOPA decarboxylase in the gut => DCI increases bioavailability
Brands (L-dopa : DCI)
- Sinemet (1:4, 1:10)
- Madopar (1:4)
Formulation
- Immediate or Controlled / Modified Release
- Considerations for wearing off effect
Levodopa ADME, DDI and considerations for counseling
Absorption is affected by protein and fat intake because levodopa is absorbed by an active saturable carrier system for large neutral amino acids. Take on empty stomach.
Drug Interactions:
- Pyridoxine high dose (Not a problem if DCI combination as pyridoxine is a cofactor for DOPA decarboxylase)
- Iron: Space out administration
- Protein: Space out administration
- Dopamine antagonists (Antipsychotics, antiemetics): Antiemetic of choice is domperidone
Levodopa ADRs and when does dyskinesia commonly onset?
- GI effects: N/V
- DA effects: Orthostatic Hypotension
- CNS effect: Drowsy, sudden sleep onset, hallucination, psychosis
- Long term: Dyskinesia (After 3 to 5 years of initiation)
What is dyskinesia? How do you manage it?
Involuntary uncontrollable twitching, jerking, and dystonia
Add amantadine or replace specific doses with CR Levodopa
List 2 motor complications of levodopa and how to manage them
- On-off Phenomena: Unpredictable
- Wearing Off Effect as disease progresses:
- Modify timing of medication intake
- Modify formulation use
(Increased to 4-6h release period)
Formulation conversion for levodopa
IR to CR: Increase the dose by 25-50%
Types of dopamine agonists and the disadvantage of one over the other
Ergot: Lower bioavailability (First pass)
- Bromocriptine
- Cabergoline
- Pergolide
Non-ergot
- Rotigotine (Transdermal)
- Pramipexole
- Apomorphine (Subcut)
- Ropinirole
What is better about dopamine agonists compared to levodopa?
Longer half-life and duration of action
Comment on the elimination of dopamine agonists
Ropinirole: Liver metabolism to inactive metabolites
Pramipexole: Renal excretion unchanged
Dopamine agonist ADRs
Central Dopaminergic:
- Hallucination
- Somnolence, Day-time sleepiness
- Compulsive behaviors
Peripheral Dopaminergic:
- Nausea, vomiting
- Orthostatic hypotension
- Leg edema
Non-dopaminergic:
- Fibrosis
- Valvular heart disease
Compare the ADRs, efficacy and place in therapy of levodopa and dopamine agonists.
Levodopa has more motor complications but dopamine agonists have more hallucinations, sleep disturbances, leg edema, orthostatic hypotension
Efficacy is similar
Dopamine agonists for younger patients (Young onset PD monotherapy) or adjunct to severe PD
Why do MAO-B Inhibitors have a 14-day washout period?
Selegiline and Rasagiline are IRREVERSIBLE inhibitors.
MAO regeneration takes 14-28 days
Why should selegiline be dosed no later than 4pm?
Hepatic metabolism to amphetamine increases wakefulness (stimulating) and have no effect on MAO-B.
Dosing of MAO-B Inhibitors
- Selegiline 5 mg OM to BD
- Rasagiline 0.5 to 2 mg QD
MAO-B Inhibitor DDIs
- Antidepressants (SSRIs, SNRIs, TCAs)
- Linezolid
- Opioids (Pethidine, Tramadol)
- Sympathomimetics
- Dextromethorphan
MAO-B Inhibitor Food interactions
- Cheese (Tyramine rich food)
- Red Meat
- Fermented Food
When do we use MAO-B Inhibitors?
Monotherapy in early stages
Adjunct in later stages
Young Onset PD (Common)
When are COMT Inhibitors considered effective?
When used concurrently with levodopa. When DCI is used, COMT is the major metabolizer.
What are COMT inhibitor DDIs?
- Iron, calcium
- Concurrent non-selective MAOi
- Catecholamine drugs
- Warfarin
Entacapone ADRs (4D)
Diarrhea
Urine discoloration (Orange)
Dyskinesia (Initiation: Reduce Levodopa dose)
Dopaminergic effects potentiated (Orthostatic hypotension, N/V)
In whom should COMT inhibitors be used with caution?
Hepatic impairment
But not needed to monitor LFTs
When is amantadine dose reduction needed?
Renal impairment (Because renal excretion)
When should amantadine be dosed?
BD dosing with the second dose in the afternoon because it can be stimulating
What ADRs and DDIs to take note off for amantadine?
DDI: Memantine
ADR: Nausea, lightheadedness, insomnia, confusion, hallucination, livedo reticularis (skin discoloration)
Amantadine Place in Therapy
Adjunct
Manage Levodopa-induced dyskinesias
