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PARKINSON'S DISEASE - GPAT NOTES

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1. INTRODUCTION & PATHOPHYSIOLOGY

• Normal state: Dopamine (inhibitory) and Acetylcholine (excitatory) are balanced in the striatum.
• In PD: Dopamine decreases → Acetylcholine becomes relatively dominant → motor dysfunction.
• Dopaminergic neurons from SNpc normally inhibit GABAergic output from the striatum.
• Loss of dopaminergic neurons → excess GABAergic and glutamatergic activity → clinical features.

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2. CLINICAL FEATURES (Cardinal Signs - "TRAP")

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3. CLASSIFICATION OF ANTI-PARKINSON DRUGS

ANTI-PARKINSON DRUGS
├── A. Dopaminergic Agents (Increase dopamine activity)
│   ├── 1. Dopamine Precursor
│   │   └── Levodopa (+ Carbidopa / Benserazide)
│   ├── 2. Dopamine Agonists
│   │   ├── Ergot derivatives: Bromocriptine, Pergolide, Cabergoline, Lisuride
│   │   └── Non-ergot derivatives: Pramipexole, Ropinirole, Rotigotine, Apomorphine
│   ├── 3. MAO-B Inhibitors (↓ dopamine degradation)
│   │   └── Selegiline (Deprenyl), Rasagiline, Safinamide
│   └── 4. COMT Inhibitors (↓ levodopa peripheral degradation)
│       ├── Peripheral + Central: Tolcapone
│       └── Peripheral only: Entacapone, Opicapone
├── B. Glutamate Antagonists (NMDA receptor blockers)
│   └── Amantadine
├── C. Anticholinergic Agents (Reduce ACh dominance)
│   └── Trihexyphenidyl (Benzhexol), Biperiden, Orphenadrine, Procyclidine, Benztropine
└── D. Adenosine A2A Receptor Antagonist
    └── Istradefylline

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4. DETAILED DRUG PROFILES

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4.1 LEVODOPA (+ CARBIDOPA)

• Levodopa = L-DOPA = metabolic precursor of dopamine.
• Dopamine cannot cross the blood-brain barrier (BBB), but levodopa can (via L-amino acid transporter, LAT).
• Inside the brain, levodopa is decarboxylated by aromatic L-amino acid decarboxylase (DOPA decarboxylase) → dopamine → acts on D1 and D2 receptors in the striatum.
• Benefits mainly from D2 receptor stimulation; D1 stimulation also contributes.

• Carbidopa = peripheral DOPA decarboxylase inhibitor that cannot cross the BBB.
• Prevents peripheral conversion of levodopa → dopamine (which causes nausea, vomiting, hypotension).
• Carbidopa increases bioavailability of levodopa reaching the brain by ~5-fold.
• Reduces levodopa dose requirement by ~75%.
• Combined preparation: Sinemet (carbidopa + levodopa), Syndopa.
• Benserazide is an alternative peripheral decarboxylase inhibitor (combined as Madopar).

• Primary drug for all stages of PD (most effective symptomatic treatment).
• Preferred in: older patients (>65 years), patients with cognitive dysfunction, severe disability needing rapid improvement.

• Oral absorption; competes with dietary amino acids for absorption and BBB transport (high-protein meals reduce efficacy).
• Short plasma half-life (~90 minutes) → responsible for motor fluctuations.

• Wearing-off (end-of-dose deterioration): Benefit lasts shorter - managed by increasing dose frequency, adding COMT/MAO-B inhibitor.
• On-Off phenomenon: Sudden, unpredictable fluctuations between mobility ("on") and immobility ("off").
• Peak-dose dyskinesia: Involuntary movements when plasma levodopa is at maximum.
• Pyridoxine (Vit B6) interaction: Enhances peripheral decarboxylation of levodopa → reduces its central effect (this interaction is overcome when carbidopa is co-administered).

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4.2 DOPAMINE AGONISTS

Ergot Derivatives

Non-Ergot Derivatives (PREFERRED over ergots)

• Monotherapy in early PD (especially in patients <65 years to delay levodopa initiation).
• Adjunct to levodopa in advanced PD to smooth out motor fluctuations.

• Nausea, vomiting, postural hypotension
• Hallucinations, confusion, psychosis (more than levodopa)
• Dyskinesias
• Excessive daytime sleepiness (EDS) - "sleep attacks" - important for driving
• Impulse control disorders (compulsive gambling, hypersexuality, binge eating) - up to 45% prevalence
• Peripheral edema

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4.3 MAO-B INHIBITORS

• Monoamine oxidase B (MAO-B) is the enzyme responsible for degrading dopamine in the CNS.
• MAO-B inhibitors block this enzyme → ↑ dopamine availability in the striatum.
• Selegiline also metabolized to amphetamine and methamphetamine → mild stimulant effect.
• Rasagiline is a pure MAO-B inhibitor (no amphetamine metabolites) - more potent and cleaner profile.
• May have neuroprotective effect by preventing MPTP conversion to toxic MPP+ (relevant to disease modification hypothesis).

• Early PD monotherapy (mild symptoms).
• Adjunct to levodopa to extend "on" time and reduce wearing-off.
• Possible disease-modifying effect (controversial).

• Insomnia (selegiline - give morning dose to avoid)
• Nausea, dizziness
• Mild hypertension
• At high doses: lose selectivity for MAO-B → risk of hypertensive crisis ("cheese reaction") with tyramine-rich foods (but at therapeutic doses, MAO-B selectivity is maintained)

• Selegiline + Meperidine (pethidine): Potentially fatal - serotonin syndrome (hyperpyrexia, rigidity, convulsions, death) - CONTRAINDICATED.
• Selegiline + SSRIs/TCAs: Serotonin syndrome risk.

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4.4 COMT INHIBITORS

• Catechol-O-methyltransferase (COMT) converts levodopa → 3-O-methyldopa (inactive) peripherally, reducing levodopa bioavailability.
• COMT inhibitors block this enzyme → more levodopa reaches the brain → extends duration of action of each levodopa dose.
• Must always be used WITH levodopa (no effect as monotherapy).

• Adjunct to levodopa/carbidopa to reduce "wearing-off" fluctuations.

• Orange-brown discoloration of urine (harmless - due to catechol metabolite)
• Nausea, diarrhea (especially tolcapone)
• Dyskinesias (may need to reduce levodopa dose)
• Tolcapone: HEPATOTOXICITY - potentially fatal (Tolcapone contraindicated in liver disease)
• Urine discoloration

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4.5 AMANTADINE

• NMDA glutamate receptor antagonist (anti-dyskinetic effect - primary mechanism)
• Potentiates dopaminergic function: enhances dopamine synthesis, release, and inhibits reuptake
• Anticholinergic properties
• Adenosine A2A receptor antagonism (inhibits D2 receptor suppression)

• Anti-dyskinetic agent - reduces levodopa-induced peak-dose dyskinesias (main current use)
• Mild early PD symptoms (monotherapy) - but benefits may be short-lived (weeks)
• Drug-induced parkinsonism

• CNS: Restlessness, insomnia, hallucinations, confusion, psychosis (toxic psychosis in overdose)
• Livedo reticularis (mottled, purple skin discoloration - pathognomonic/distinctive side effect)
• Peripheral edema
• Postural hypotension, urinary retention
• Seizures (avoid in epilepsy)
• Abrupt withdrawal: acute confusional state, hyperpyrexia, worsening parkinsonism

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4.6 ANTICHOLINERGIC AGENTS

• Block muscarinic (M1) receptors in the striatum.
• Reduce the relative dominance of acetylcholine when dopamine is depleted.
• Restore the dopamine-acetylcholine balance.

• Mainly for tremor and rigidity (little effect on bradykinesia - GPAT key point).
• Drug-induced parkinsonism (caused by antipsychotics/metoclopramide) - preferred treatment.
• Younger patients with tremor-predominant PD.

• Antimuscarinic effects: Dry mouth, blurred vision, urinary retention, constipation, tachycardia
• Blurred vision (cycloplegia, mydriasis)
• Cognitive impairment: Confusion, memory impairment, hallucinations (especially elderly)
• Drowsiness, dizziness

• Elderly patients (cognitive impairment, falls risk)
• Glaucoma (angle-closure)
• Prostatic hypertrophy
• Tardive dyskinesia (may worsen it)

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4.7 ADENOSINE A2A ANTAGONIST

• Caffeine analog; selective adenosine A2A receptor antagonist.
• A2A receptors are co-localized with D2 receptors; adenosine normally inhibits D2 function.
• Blockade of A2A → enhances D2 dopaminergic transmission.
• Adjunct to carbidopa-levodopa to reduce "off" time.
• Side effects: Dyskinesias, dizziness, constipation, hallucinations, insomnia.

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5. DRUGS NOT PREFERRED / CONTRAINDICATED IN PARKINSON'S DISEASE

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6. TREATMENT ALGORITHM (GPAT OVERVIEW)

NEWLY DIAGNOSED PD
│
├── Age < 65, Cognitively intact, Mild symptoms
│   └── DOPAMINE AGONIST (Pramipexole/Ropinirole) ± MAO-B inhibitor (Rasagiline)
│       └── If inadequate → ADD LEVODOPA
│
├── Age > 65 OR Cognitive dysfunction OR Severe disability
│   └── LEVODOPA + CARBIDOPA (Drug of Choice)
│
└── Tremor-dominant, young patient
    └── Anticholinergic (Trihexyphenidyl) may be considered
    
ADVANCED PD / MOTOR FLUCTUATIONS
├── Add COMT inhibitor (Entacapone) → extend levodopa "on" time
├── Add MAO-B inhibitor (Rasagiline/Selegiline)
├── Increase levodopa dose frequency
├── Switch to controlled-release levodopa
└── Amantadine for dyskinesias

DRUG-INDUCED PARKINSONISM
├── Stop offending drug
└── Anticholinergic (Trihexyphenidyl) if needed
    Note: Levodopa is NOT useful here

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7. QUICK COMPARISON TABLE (GPAT HIGH YIELD)

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8. MNEMONICS (GPAT)

• Drugs NOT to use in PD: "HARM" - Haloperidol, Antipsychotics (typical), Reserpine, Metoclopramide
• Levodopa side effects: "POND" - Psychosis, On-off, Nausea, Dyskinesia
• Anticholinergic side effects: "Can't see, can't pee, can't spit, can't sh*t" (blurred vision, urinary retention, dry mouth, constipation)
• COMT inhibitors remember: "Tolcapone = Toxic to liver; Entacapone = safe for Everyday use"
• Non-ergot DA agonists: "PRAmipexole, ROpinirole, ROTigotine, APOmorphine"

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9. DISEASE MODIFICATION CONTROVERSY

• No drug currently proven to halt or reverse PD progression.
• Rasagiline (ADAGIO trial) and Selegiline - hypothesized neuroprotective effects by:
  • Preventing MPTP → MPP+ conversion (MAO-B inhibition)
  • Antioxidant effects (reducing free radical formation from dopamine catabolism)
• Clinical evidence remains inconclusive.

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1. Pathophysiology - Substantia nigra degeneration, Lewy bodies, dopamine-ACh imbalance, basal ganglia circuitry
2. Clinical features - TRAP mnemonic (Tremor, Rigidity, Akinesia, Postural instability)
3. Full drug classification - 7 categories with all major drugs
4. Detailed drug profiles for each class:
   • Levodopa/Carbidopa (mechanism, why carbidopa is added, motor fluctuation complications)
   • Dopamine agonists (ergot vs non-ergot differences - high yield)
   • MAO-B inhibitors (selegiline vs rasagiline differences)
   • COMT inhibitors (tolcapone hepatotoxicity - high yield)
   • Amantadine (livedo reticularis - classic exam finding)
   • Anticholinergics (avoid in elderly - high yield)
   • Istradefylline (newest mechanism)
5. Drugs NOT preferred in PD - a dedicated table (haloperidol, metoclopramide, reserpine, typical antipsychotics, etc.)
6. Treatment algorithm by patient profile
7. Quick revision comparison table
8. Mnemonics for rapid recall

• Metoclopramide worsens PD - use domperidone instead as antiemetic
• Pramipexole causes impulse control disorders and sleep attacks
• Tolcapone = hepatotoxic; Entacapone = safe
• Amantadine's unique side effect = livedo reticularis
• Selegiline + meperidine = fatal serotonin syndrome
• Anticholinergics only help tremor and rigidity, not bradykinesia