Overview
This lecture provides a comprehensive overview of Parkinson's disease, focusing on its pathophysiology, diagnosis, and pharmacological management, especially through modulation of dopamine and acetylcholine in the central nervous system.
Neurotransmitter Systems in Parkinson’s Disease
- Parkinson's disease is characterized by decreased dopamine and increased acetylcholine activity in the CNS.
- Dopamine is crucial for movement control; therapeutic strategies aim to increase its CNS availability.
- Acetylcholine also influences muscle coordination; its overactivity contributes to symptoms.
- Glutamate (excitatory) and GABA (inhibitory) play roles in neuronal signaling and disease manifestations.
- Imbalance between neurotransmitters leads to the motor symptoms of Parkinson's.
Pathophysiology & Causes
- Loss of dopaminergic neurons in the substantia nigra results in reduced dopamine and excess cholinergic activity.
- Possible causes: genetics, environmental toxins, neuroinflammation, drug-induced (e.g., antipsychotics, metoclopramide).
- Dopamine metabolism may produce neurotoxic metabolites contributing to disease progression.
Clinical Presentation & Diagnosis
- Key symptoms: resting tremor (suppressed by movement), muscle rigidity (cogwheel phenomenon), bradykinesia (slowness), postural instability.
- Other features: micrographia (small handwriting), drooling, hypophonia (soft speech), dysphagia (swallowing difficulty), constipation.
- Diagnosis is clinical, based on at least two major symptoms; imaging is rarely necessary.
Pharmacologic Treatments
- Goal: Restore dopamine/acetylcholine balance to improve motor symptoms.
- Levodopa/Carbidopa (Sinemet): Gold standard; increases CNS dopamine. Carbidopa prevents peripheral conversion, reducing required dose and side effects.
- Controlled-release formulations prolong effect but may increase hallucinations.
- High-protein meals and excess vitamin B6 can interfere with levodopa efficacy.
- Side effects: nausea, vomiting, hypotension, hallucinations, dyskinesias; long-term efficacy declines after ~5-15 years.
Adjunct & Alternative Therapies
- Dopamine Agonists (e.g., pramipexole, ropinirole, rotigotine): Directly stimulate dopamine receptors; used in early or adjunctive therapy. Risk of impulse control disorders (e.g., gambling, hypersexuality) and sleep attacks.
- COMT Inhibitors (entacapone, tolcapone): Prolong levodopa effect by inhibiting dopamine metabolism; tolcapone has risk of fatal liver failure.
- MAO-B Inhibitors (rasagiline, selegiline): Inhibit dopamine breakdown; dietary and drug interactions possible—stop before surgery.
- Anticholinergics (trihexyphenidyl, benztropine): Used mainly for tremor; antimuscarinic side effects.
- Amantadine: Enhances dopamine release; not first-line due to less efficacy and renal dosing issues.
Management of Complications and Special Issues
- Wearing-off effects are managed by dose or frequency adjustments and medication diaries.
- Parkinson's-associated psychosis may be treated with pimavanserin, an atypical antipsychotic with specific safety considerations.
Key Terms & Definitions
- Dopamine — Neurotransmitter involved in movement control; deficient in Parkinson’s.
- Acetylcholine — Neurotransmitter involved in muscle activation; relatively increased in Parkinson’s.
- Bradykinesia — Slowness of movement.
- Cogwheel Rigidity — Ratchety resistance during passive limb movement.
- Resting Tremor — Tremor occurring when muscles are not voluntarily activated.
- Levodopa/Carbidopa — Primary treatment; precursor and enzyme inhibitor to increase CNS dopamine.
- COMT Inhibitors — Drugs that prevent breakdown of dopamine.
- MAO-B Inhibitors — Drugs that block dopamine degradation.
- Dyskinesias — Involuntary, erratic movements, often from long-term levodopa use.
Action Items / Next Steps
- Review pharmacological classes, mechanisms, and side effects of Parkinson’s drugs.
- Study the balance of neurotransmitters in motor control and their clinical consequences.
- Prepare for questions on medication interactions, side effects, and mechanisms of agents.