Antiparkinsonian Drugs Flashcards
What are the four key characteristics of Parkinson’s?
- Bradykinesia
- Muscular rigidity
- Resting tremor
- Postural instability
What are the proteins that are deposited in Parkinson’s?
Lewy bodies
What is the cause of parkinson’s?
Progressive loss of dopaminergic neurons in the basal ganglia
What happens to Parkinsonian pts without treatment?
rigid, akinetic state, leading to secondary complication like pneumonia or PE
What is the goal of pharmacologic treatment of Parkinson’s?
Improve functionality
Where is the loss of dopaminergic neurons in Parkinson’s greatest? What other brain regions are affected?
Basal ganglia
Brainstem
Hippocampus
Cerebral cortex
What are the 3 main characteristics of Neurodegenerative disorders?
- Progressive and irreversible loss of neurons
- Etiology relates to specific neuronal loss
- Aggregation of misfolded proteins
What is the neuron/neurotransmitter lost in AD?
Ach in hippocampal areas
What is the protein that is accumulate in Parkinson’s? Where?
Alpha-synuclein in intracytoplasmic aggregates
What is the protein that is accumulate in AD? Where?
Extracellular beta-amyloid plaques, and intracellular neurofibrillary tangles
What is the protein that is accumulated in Huntington’s disease?
Intranuclear Huntingtin protein
What age does Parkinson’s usually start?
50 and 60s
What are the non-motor effects of PD?
Cognitive decline
Affective disorder
Sleep disorders
Personality changes
Resting tremor = what dysfunction?
Basal ganglia (PD)
Why is it that cerebellar dysfunction are usually ipsilateral to the lesion?
Crosses twice
What part of the basal ganglia specifically, is affected by PD?
Substantia nigra
What are the components of the motor loop?
Cortex
Striatum
Pallidum
Thalamus
What is the principal input structure of the basal ganglia? Where does this receive input from? What kind of input?
Striatum, receives excitatory input from the cortex
What is the neurotransmitter used in the striatum?
Dopamine
What are the two pathways from the striatum?
Direct pathway = striatum to substantia nigra pars reticularis and GP
Indirect = From the striatum through the GP and subthalamic nucleus (GABA links)
What is the primary defect in PD?
Destruction of the dopaminergic neurons of the substantia nigra pars compacta
What are the neurotransmitters from the cerebral cortex to the striatum?
Glu (+)
What are the neurotransmitters from the striatum to the globus pallidus?
GABA (-)
What is the neurotransmitter from the globus pallidus to the subthalamic nucleus?
GABA (-)
What is the neurotransmitter from the globus pallidus to the substantia nigra?
Glu (+)
What is the neurotransmitter from the substantia nigra to the VA/VL thalamus?
(GABA) (-)
What is the neurotransmitter from the thalamus, back to the cortex?
Glu (+)
Draw out the neurotransmitter/ basal ganglia relationship pathway (pg 4 of the handout).
Draw, and mark the pathway destroyed in PD
What is the net effect off the loss of dopaminergic neurons in the basal ganglia?
neurons in
the SNpr and GPi become more active. This leads to
increased inhibition of the VA/VL thalamus and
reduced excitatory input to the cortex
Which BG pathway is overactive and which is under active in PD?
Indirect is overactive
Direct in not active
What pathway is increased in PD? What is the neurotransmitter here?
Direct–ACh
What is the major effect of alpha synuclein accumulation?
ROS generation
What are the three net effects of degeneration of the direct pathway?
- Increased VA/VL thalamus
- Reduced excitatory input to the cortex
- Diminished execution of motor movement
What do the interneurons of the corpus striatum use for a neurotransmitter? What inhibits these interneurons?
ACh
Normally, dopaminergic neurons from the SN inhibit these, but in PD there is none.
What is the basis for treating PD with ACh antagonists?
Interneurons of the Striatum which secrete ACh to stimulate the pallidus, are normally inhibited by dopaminergic neurons from the substantia nigra. Antagonizing these will reduce the ssx of parkinson’s
What are the five treatment strategies for PD?
- DA replacement
- DA receptor agonists
- L-DOPA degradation inhibitors
- Increase DA release
- Anticholinergic agents
What is the MOA of L-DOPA? Why not just use dopamine?
replaces dopamine in the brain–dopamine itself cannot cross the BBB
What is the major drawback of using L-DOPA?
Tolerance builds up over years
What is the MOA of carbidopa? What is the benefit of administering it with L-DOPA?
Inhibitor of decarboxylase in the periphery
Reduces the amount of L-DOPA needed to have an effect
What are the major side effects of L-DOPA?
Dyskinesias
Wearing off (end of dose akinesia)
Postural hypotension
Behavioral disturbances
What vitamin can enhance the therapeutic effect of L-DOPA metabolism?
B6
Can carbidopa cross the BBB? How, then, does it work?
No–reduces the metabolism of L-DOPA in the periphery
What are the GI problems with L-DOPA?
n/v
What are the cardio effects of L-DOPA?
Hypotension
Cardiac dysrhythmias
What are the behavioral disturbances associated with L-DOPA?
Depression/anxiety
Insomnia
Agitation and confusion
What is the interaction of MAO-A inhibitors and L-DOPA?
hypertensive reaction d/t increase norepi levels
What is the interaction of L-DOPA with antipsychotics
DA receptor blockade
What is the interaction of L-DOPA and protein-rich meals?
Competition for GI and BBB absorption
What is the MOA of pramipexole?
Direct agonist preferentially at dopamine D3 receptors; nonergot
What are the effects of pramipexole?
Reduces PD symptoms
What are the side effects of pramipexole?
impulse control
Psychotic episodes
What is the MOA of ropinirole?
D2 agonist
What is the use of apomorphine?
Rescue treatment for L-DOPA induced dyskinesias
What part of the brain is affected by dopamine agonists, and cause impulse control?
Reward pathway
What is the MOA of Rasagiline?
MAO-B inhibitor, causing an increase in dopamine. At higher doses, also inhibits MAO-A
What is the use of Rasagiline and selegiline?
PD adjuvant to levadopa
What are the two major categories of drugs that Rasagiline reacts with?
SSRIs and TCAs
What is the MOA of Selegiline?
MAO-B inhibitor, causing an increase in dopamine. At higher doses, also inhibits MAO-A
What is the MOA of entacapone?
Inhibits COMT in the periphery; does not enter CNS. Reduces the metabolism of L-DOPA
What are the side effects of entacapone?
dyskinesias
Confusion
What is the MOA of Tolcapone?
COMT inhibition in the CNS and in the periphery
What is the main difference between Tolcapone and entacapone?
Tolcapone works in the CNS and periphery
Entacapone works only in the periphery
Why is Entacapone preferentially used over Tolcapone?
Entacapone it has not been associated with hepatotoxicity
What is the MOA of amantadine?
Antiviral agent that has antiparkinsonian properties. MOA unclear
What is the half life of amantadine?
Short
What are the side effects of Amantadine?
Restlessness Depression Irritability Insomnia Hallucinations
What is the livedo reticularis associated with Amantadine?
Blotchy reddend pattern, usually on the legs, clears w/in 1 month after stopping
What is the MOA of benztropine?
Antagonist at M receptors in basal ganglia
What is the MOA of Trihexyphenidyl?
Antagonist at M receptors in the basal ganglia
What are the main pharmacological effects of Benztropine and Trihexyphenidyl on PD?
Reduces tremor and rigidity; little effect on bradykinesia
What are the surgical techniques used to treat PD? (2)
Stimulate subthalamic nucleus or globus pallidus by an implanted electrode and stimulator
Transplant of dopaminergic tissue
