Parkinson's Disease and Motor Neurons

Categories of Motor Neurons

• Pyramidal neurons control voluntary skeletal muscle movements.
• Extrapyramidal neurons control automatic, involuntary movements like trunk support, blinking, and swallowing.
• Dopamine (inhibitory) and Acetylcholine (excitatory) are central neurotransmitters that balance each other for smooth muscle movement.
• Dopamine inhibits muscle excitation, therefore relaxes
• Acetylcholine excites muscle contract
• Dopamine deficiency in PD leads to rigidity, tremors, and bradykinesia.
• Dopamine deficiency causes abnormal blinking, tilted posture, blank facial expression, and drooling.

Medications for Parkinson's Disease

• Levodopa
• Levodopa/Carbidopa (Sinemet)
• Pramipexole (Mirapex)
• Selegiline (Deprenyl)
• Anticholinergics

Levodopa

• It enters the brain and converts to dopamine to restore the balance between acetylcholine and dopamine.
• It is indicated for Parkinson's Disease.
• It reduces symptom severity and improves the ability to carry out activities of daily living.
• It doesn't cure PD or delay disease progression.
• It is administered orally.
• It typically takes several months to see therapeutic results.
• It is considered the most effective drug for PD.
• Its effectiveness decreases over time, with symptoms usually well-controlled in the first 2 years.
• It crosses the blood-brain barrier and converts to dopamine once it reaches the brain
• Only a small fraction reaches the brain alone, so often taken with another medication.

Levodopa/Carbidopa (Sinemet) Combination

• Carbidopa has no therapeutic effects of its own.
• Levodopa alone means only a small portion reaches the CNS.
• Carbidopa delays peripheral drug metabolism, allowing more levodopa to enter the brain.

Levodopa Adverse Effects

• Nausea and vomiting is caused by dopamine receptor activation in the medulla's chemoreceptor trigger zone.
• Dyskinesias can cause movement disorders like tics, head bobbing, grimacing, rapid involuntary jerking and writhing.
• Other potential adverse effects include postural hypotension and psychosis.
• Psychosis includes visual hallucinations, vivid dreams, and paranoia.
• CNS effects are anxiety, agitation, memory loss, cognitive impairment, and issues with impulse control.
• Can darken sweat and urine.
• Contraindicated for those with hypersensitivity.

Levodopa Considerations

• Avoid high protein meals
• Assess for Parkinsonian and extrapyramidal symptoms before and during therapy
• Monitor blood pressure frequently.
• Transfer to a standing position should not be done abruptly.

Levodopa Acute Loss of Effect

• On/Off Phenomenon: An abrupt return of PD symptoms can occur at any time during dosing intervals, even when drug levels are still high.
• Therapeutic effect and symptom reduction define is "On"
• Sudden return of the PD symptoms is is "Off"
• The intensity and frequency may increase over time.
• Wearing-off Phenomenon: A gradual return of PD symptoms related to gradual loss of effect, generally seen at the dose interval's end when drug levels are low may occur.
• Both can be minimized by adding a dopamine agonist or MAO-B inhibitor to therapy and avoid high-protein meals.
• To minimize the wearing-off phenomenon, dose frequency can be increased (shorter intervals), adding medication can prolong Levodopa's half-life or adding a medication that will increase beneficial action.

Pramipexole (Mirapex)

• Classification: Non-ergot dopamine receptor agonist
• Mechanism: Stimulates dopamine receptors in the striatum.
• Indication: Used on its own in early PD
• Effects take several weeks to develop
• It improves the ability to do activities of daily living.
• It improves motor symptoms by reducing fluctuations in motor control
• Given orally
• Levodopa benefits are increased while reducing on/off phenomenon & wearing off

Pramipexole Adverse Effects

• Nausea, dizziness, sleepiness, confusion, and hallucinations results from activating dopamine receptors.
• When taken on its own, patients typically do not experience dyskinesias.
• Orthostatic hypotension, hallucinations, and dyskinesias have an increased risks when taken with levodopa.
• Sleep attacks are overwhelming and irresistibly dangerous drowsiness that come on without warning.
• The medication should be discontinued, if sleep attacks are experienced
• There can be impulse control disorders like compulsive gambling, shopping, binge eating, and hypersexuality.

Pramipexole Considerations

• Warn patients about the potential for drowsiness, and to avoid alcohol or sedating medications. Monitor blood pressure and advise patients to change positions slowly.
• Patients recently starting on pramipexole should avoid driving until they know if affects wakefulness.

Selegiline (Deprenyl)

• Classification: MAO-B Inhibitor
• Mechanism: Selective inhibitor of MAO-B (which inactivates dopamine in the striatum)
• May be combined with levodopa to reduce on-off and wearing-off effects by prolonging levodopa action
• Indicated for Parkinson's Disease and/or depression.
• It is considered a first-line drug for newly diagnosed PD.
• Improves motor function.
• Benefits last about 12-24 months.
• Given orally.

Selegiline (Deprenyl) Adverse Effects

• Insomnia
• Hypertensive Crisis taken in high doses that can lead to increased risk within younger people
• Orthostatic hypotension, dyskinesias, and psychiatric symptoms can be worsened when In combination with Levodopa.
• Should not be taken with meperidine or SSRIs

Selegiline (Deprenyl) Considerations

• Assess gait and motor function to assess effectiveness of treatment and identify side effects related to dyskinesia
• Monitor for changes in behavior and psychiatric symptoms.
• Should be especially careful for falls and monitor blood pressure combined with Levadopa.

Anticholinergics

• Blocks action of acetylcholine
• Other Parkinson's treatments affect dopamine, while anticholinergics work on correcting the imbalance by focusing on acetylcholine.
• Often combined with other antiparkinsonian medications
• Indicated for Parkinson's, asthma, COPD, incontinence, dizziness, and diarrhea
• Show it can greatly improve tremors but do not improve bradykinesia
• Used in younger patients with mild symptoms
• Blurred vision, dry mouth, constipation, and urinary retention are common side effects
• Older adults have an increased risk of cognitive decline, developing dementia and confusion, and are not to be prescribed to those above the age of 70.

Medications for Multiple Sclerosis (MS)

• Methylprednisolone (Solu-Medrol)
• Interferon Beta Drugs (Betaseron)
• Mitoxantrone (Novantrone)

Methylprednisolone (Solu-Medrol)

• Mimics cortisol
• Potent anti-inflammatory and immunosuppressant.
• Works rapidly and is often only used for a short period.
• Treats exacerbation of MS ex. neurologic symptoms and increased disability or impairments in vision, strength, or cerebellar function
• Has anti-inflammatory and immunosuppressive effects.
• Available as IV and IM.
• Monitors closely for acute infection signs (fever, increased WBC, cough, soft tissue pain/swelling, UTI symptoms) because glucocorticoids are immunosuppressive and can exacerbate infections

Interferon Beta Drugs (Betaseron)

• Classification: Immunomodulator
• Mechanism: Naturally occurring glycoprotein that suppresses T-helper cells and inhibits migration of proinflammatory leukocytes across the blood brain barrier
• Indication: Multiple Sclerosis. Given Intramuscular or Subcutaneous, depending on the specific drug.
• Reduces lesions by decreasing frequency and severity of relapse in addition to delays progression of disability.

Interferon Beta Drugs (Betaseron) Adverse Effects

• Flu-like symptoms (headache, fever, chills, malaise, muscle aches, and stifness)
• Decreases over time and can be minimized by starting on a lower dose, gradually increasing, and administering an antipyretic, like Tylenol.
• Can cause hepatotoxicity, damaging liver cells and suppressing bone marrow function/production of all blood cells.
• May lead to depression and suicidal thoughts..

Interferon Beta Drugs (Betaseron) Considerations

• Assess for MS symptoms during therapy.
• Monitor liver function tests and CBC (hgb, platelets, wbc) prior to treatment and at 1, 3, and 6 months.
• Important to educate patients about likelihood of flu-like symptoms and risks of depression.

Mitoxantrone (Novantrone)

• Classification: Immunosuppressant, Cytotoxic
• Mechanism: Binds with DNA/RNA synthesis (causing breakage of DNA) and suppresses immune system cell production to decrease system destruction of myelin
• Indication: Was developed to treat cancer, also used for MS
• Therapeutic Effect: Can delay relapse in MS patients, disability progression, and can decrease lesions

Mitoxantrone (Novantrone) Adverse Effects and Considerations

• Hair loss, nausea/vomiting, and mouth sores (stomatitis) results from the rapidly dividing cells
• Potential for myelosuppression, cardiotoxicity, and fetal harm.
• Monitor for bone marrow depression and GI symptoms.
• Carefully assess fluid and electrolytes, baseline EKG, chest x-ray, and heart failure.
• IV administration requires careful handling (gloves, gown, and mask).
• Monitor IV site carefully and stop infusion if pain, swelling, or redness develops.

Other Neuromuscular Medications

• Baclofen (Lioresel)
• Gabapentin (Neurontin)

Baclofen (Lioresel)

• Skeletal muscle relaxant
• Mechanism: Acts within the spinal cord (CNS) to suppress hyperactive reflexes
• Indication: Treats MS and spinal cord injuries
• Injected PO or intrathecal route
• Helps relieve spasticity and decreases flexor and extensor spasms; suppressing resistance to passive movement.

Baclofen (Lioresel) Adverse Effects and Considerations

• CNS depressants (drowsiness, dizziness, weakness & fatigue) due to overtime, long-term use
• Severe withdrawal symptoms with stopping abruptly that should be tapered over 1-2 weeks for discontinuation of therapy.
• Use Extreme caution with other CNS depressants. Monitor for withdrawal symptoms, respiratory status & infusion system.

Gabapentin (Neurontin)

• GABA Analog (antiseizure agent)
• It may enhance GABA release (increasing GABA-mediated inhibition neuronal firing)
• It treats postherpetic neuralgia, off-label uses (neuropathic pain relief).
• Very well tolerated.
• Common side effects are somnolence, dizziness, ataxia, fatigue, nystagmus, and peripheral edema that is usually mild to moderate and diminishes with continued drug use.
• Monitor for signs of CNS depression and mood changes.

Overview of motor neuron categories, including pyramidal and extrapyramidal neurons. Key neurotransmitters like dopamine and acetylcholine are discussed. Parkinson's disease, its relation to dopamine deficiency, and medications like Levodopa are explained.