Parkinsons Treatment Flashcards
What is the final common pathway of neuronal damage to result in parkinsons?
- Destruction of dopaminergic cells in the pars compacta of the substantia nigra
- Thus the treatment of dopamine replacement with L-DOPA
MPTP can cause cause parkinsons how?
- Meperidine analog
- Killing dopamine neurons in humans and experimental animals
- Basal ganglia are super active in production of dopamine as a NT and are thus disproportionately sensitive to dopaminergic neuronal loss
Describe the signaling pathways between the cortex and basal ganglia in a healthy patient
• Cortex (normal)
○ (strong) Signals to brain stem and spinal cord (corticospinal)
○ Sends excitatory info to striatum
○ Sends excitatory info to thalamus
§ CM, VA,VL
○ (strong) Sends info directly to the subthalamic nucleus
• Striatum (normal)
○ Receives excitatory input from cortex
○ Gives inhibitory signals to the Globus Pallidus externa
○ (directly and indirectly) Gives inhibitory signals to Globus pallidus interna
○ Gives inhibitory signals to substantia nigra (reticula)
○ Receives information both inhibitory and excitatory from the substantia nigra pars compacta
• CM, VA, VL thalamus (normal) ○ (strong) excitatory signal loop between thalamus and cortex ○ (Strong) excitation of the striatum ○ Receives inhibitory stimuli from pedunculopontine nucleus (PPN) - CM thalamus (centromedian nucleus of the thalamus) ○ Receives inhibitory stimuli from Gpi and SNr - VA/VL thalamus • Globus Pallidus externa (normal) ○ Receives stimulatory input from STN ○ Receives inhibitory input from striatum ○ Gives inhibitory signals to the subthalamic nucleus ○ Gives excitatory signals to Globus pallidus interna (remember that indirect pathway can inhibit certain motor pathways at the same time direct pathway is activating the other pathways so there is overlap of stimulation and inhibition)
• Subthalamic nucleus (normal)
○ (strong) excitatory input from PPN
○ (medium) excitatory output to Gpe
○ Receives inhibitory stimuli from Gpe
• Globus Pallidus interna (normal)
○ Receives stimulatory input from STN
○ Receives inhibitory input from Globus pallidus externa
○ Gives inhibitory signals to the VA/VL thalamus
• PPN - peduncopontine nucleus
○ Normally gives and recieves inhibitory information to/from the CM thalamus
○ Normally gives excitatory output to the corticospinal tract
○ Normally gives excitatory output to the subthalamic nucleus
What is the major difference between the signaling pathways in the parkinsons patient and the normal patient?
*Parkinsons - death of dopaminergic neurons in the substantia nigra pars compacta (SNc)
• The SNc is wiped out
• No more inhibitory and/or excitatory modulation of the striatum from this nucleus
• Results in INCREASED INHIBITORY SIGNALS
○ Striatum inhibits Gpe
○ Leads to less inhibition than normal of STN and Gpi
○ Leads to more than normal inhibtion of thalamus
○ Leads to less excitation than normal of cortex and PPN
○ Leads to less motor pathway activation
• Results in DECREASED EXCITATORY SIGNALS
○ Decreased corticospinal pathway signals directly
○ Decreased PPN activation of STN
○ Decreased cortical excitation of striatum
○ INCREASED STN activation of Gpe but it only matches the increased striatum inhibition
What causes parkinsons?
- Unknown, though there is both an environmental and genetic component of the disease
- Usually a susceptability to dissolution of the dopamine biosynthesis pathway
- No DA, no DA neurons, resulting in parkinsons
- Alpha-synuclein is protein of interest (autosomal dominant) - ends up in lewy bodies
What is the most important drug treatment of parkinsons?
• L-DOPA
• Combined usually with carbidopa (sinemet)
○ Peripheral decarboxylase inhibitor
• Many other dopamine agonists and MAO or COMT inhibitors that only slightly alter the efficacy of L-DOPA
What protein do you think of when you see lewy bodies?
- Alpha-synuclein
* Autosomal dominant inheritance of parkinsons predisposition
What are the pharmacokinetic properties of L-DOPA?
• Can be absorbed orally
• Crosses BBB and is converted in the brain to dopamine
○ Aromatic L-amino acid decarboxylase
○ In DA nerve terminals
• 95% of L-DOPA is decarboxylated in the intestine, liver and peripheral organs thus the need to admin with carbidopa (peripheral decarboxylase inhibitor)
○ Carbidopa does not cross BBB
• Side effects short term - GI problems
• Side effects at advanced stage doses - dyskinesia and psychosis
what are the side effects of L-DOPA treatment?
- Side effects short term - GI problems
* Side effects at advanced stage doses - dyskinesia and psychosis
What are the dopamine receptor agonists that can be used to modulate parkinsons treatment?
• Directly stimulate dopamine receptors in caudate/putamen
• Not usually a substitute for sinemet
• Most work at D2 receptor (indirect pathway)
• Mostly given to smooth the short half-life of L-DOPA
○ Less risk of dyskinesia, can be starting treatment
What are the 5 dopamine receptor agonists used in parkinsons treatment?
- Bromocriptine (Brady)
- Pergolide (purposefully)
- Pramipexole (practices)
- Ropinirole (ridiculous)
- Cabergoline (crap)
What drugs used in parkinsons release endogenous dopamine?
- Amantadine (symmetryl)
- Also glutamate receptor antagonist
- Amphetamines and cocaine are not useful in parkinsons treatment
What is the use of anticholinergic drugs for?
• Alone, not near as effective as L-DOPA
• The idea here is to treat the over-active cholinergic interneurons (which are usually balanced by DA but not in the disease state)
• Disease state - no endogenous DA inhibtion of cholinergic neurons which innervate medium spiny neurons that project to globus pallidus
• Anticholinergics used for parkinsons are muscarinic receptor blockers
• Side effects are from peripheral cholinergic block
○ Dry mouth, constipation, urinary retention
○ Aggravate existing swallowing, bowel function and bladder control dysfunction in parkinsons
What are the specific drugs used in anticholinergic treatment of parkinsons?
- Trihexyphenidyl
- Benztropine
- Diphenhydramine (benadryl)
What does MAO inhibition do for parkinson’s patients?
- Prevent the breakdown of dopamine
- Prolong the action of L-DOPA
- MAO-B inhibitors are safer as MAO-A have sympathetic NE termination block (results in hypertension)
- Side effects of MAO-B - postural hypotension
