Chapter 15: Parkinsons and Huntingtons Flashcards
Found: In the Reticular formation of the Pons and Medulla
Target: Neurons in the spinal cord involved in reflexes, locomotion, complex movements, and postural control.
What are the extrapyramidal tracts modulated by?
CNS: Nigrostriatal Pathway, Basal Ganglia, Cerebellum, Vestibular Nuclei, Cerebral Cortex.
These can also be considered part of the Extrapyramidal system.
What can all be considered part of the Extrapyramidal system?
All components that modulate motor activity without directly innervating motor neurons.
What is the mechanism in which the EPS acts to regulate fine motor activity?
EPS output reflects a balance between dopamine-mediated inhibtion and Ach mediated exciation of GABA output neurons.
How is the Mechanism of the EPS affected in Parkinsonism?
When dopamine inhibition becomes deficient, due to the death of SN neurons (or a presence of dopamine antagonists) Ach excitation is unchecked and GABA output becomes excessive.
Optional Information.
What is Parkinson’s Disease?
A neurodegenerative disorder of the central nervous system in the elderly (>65).
Named after James Parkinson who described it in 1817.
What are the symptoms of Parkinson’s disease?
Motor
- Akinesia - can’t intiate movement
- Bradkinesia - slow movement, shuffle
- muscle rigidity - stiff lumbs, trunk
- tremor at rest - pill rolling
- mask-like-faces - face is expressionless
- cogwheel locomotion
Other
- Many patients have cognitive (dementia) and mood (depression) symptoms as well in later stages.
Parkinson’s can rise from inflammation
What is cogwheel rigidity?
An abnormal rigor in muscle tissue characterized by jerky movements when the muscle is passively stretched. The condition is often found in cases of Parkinson’s disease.
What happened in regards to Parkinson’s in the 1920s?
The flu epidemic of 1918 produced post-enchaphilitic Parkinsonism.
Parkinsonism occurs largely after infection-mediated encephalitis (Up to several Years)
Caused due to inflammation
Describe the neuropathology of Parkinson’s Disease.
- Death of dopamine cell bodies in the Substantia Nigra
- Loss of dopamine nerve terminals in the Neostriatum (Basal Ganglia)
- When about 80% of original number of dopamine neurons in the substantia nigra have died, the symptoms appear.
- Dopamine neurons continue to die and symptoms progressively worsen.
Can take decades for symptoms to appear.
What are Lewy Bodies and A-Synuclein?
Explain how Dopamine replacement therapy works in the treatment of Parkinson’s.
- Dopamine cannot cross the BBB (5 times more Mitochondria)
- Levodopa (L-Dopa), the immediate precursor of dopamine, is actively transported across the BBB(Has its own transporter) and taken up by dopamine neurons.
- Restores Dopamine/Ach balance and normal output fo EPS (smooth movement)
Only Dopamine neurons take up L-dopa and released under physiological conditions.
What is the metabolic pathway that converts L-dopa into Dopamine.
Levodopa is metabolized by Aromatid Amino Acid Decarboxylase into Dopamine which is metabolized by dopamine beta hydoxylase into noradrenaline which is metabolized by Phenylethanolmaine-N-Methyltransferase into adrenaline.
What are the peripheral effects of taking L-dopa?
Taking levodopa increaes the levels of dopamine, noradrenaline and adrenaline in the periphery as well as in the brain.
Effects
- Stimulation of Noradrenaline and adrenaline receptors increases the SNS activity leading to hypertension, tachycardia and arrythmias.
- Stimulation of Dopamine receptors in chemoreceptive trigger zone produces nausea and vomiting (CTZ outside the BBB)
What are the Central effects of taking L-Dopa?
- Over stimulation of dopamine receptors in the meso-limbic areas produces psychosis.
- Stimulating dopamine receptors in the pituitary inhibits prolactin release (not big problem for elderly Parkinson patients)
- Over-stimulation of dopamine receptors in motor contral areas produces abnormal motor movements (dyskinesias)
- Stimulating noradrenaline receptors in the reticular activating system and limbic system produces insomnia and anxiety
How can we limit the peripheral side effects of L-dopa, what two drugs, what is their mechanism of action?
Carbidopa and Benserazide
Peripheral Decarboxylase Inhibitor —> AAAD
Carbidopa and Benserazide create more L dopa - All 3 do not cross BBB
What drugs are MAO-B inhibitors and what is their mechanism of action?
Selegine/Rasagiline/Safinamide
Inhibit the breakdown of Dopamine (Lowers dose necessary)(Slows progression of disease -> Lowers Free Radicals)
What are some characteristics of Huntington’s Disease and what is Chorea?
What is the mechanism which Tetrabenazine/Deutetrabenazine uses to treat Huntingsons?
- Reversible depletion of DA, 5HT, NE, and HA from nerve terminals.
- Reversible Inhibitor of vesicular monamine transporter 2.
- Deuterabenazine is an isomer of tetrabenazine in which six hydrogens.
- Slows rate of drug metabolism, allowing less frequent/lower dosing for improved tolerability.
