Pharmacology-Neurodegeneration Flashcards
Anatomically speaking, when do patients typically start exhibiting Parkinsonian symptoms?
70% of the substantia nigra pars compacta dopaminergic neurons are depleted
Which basal ganglia pathway is over-excited in patients with Parkinson’s?
Absence of DA causes decreased activation of GABA/substance P neurons in the striatum (D1) -> increased activity of MPS and SNr -> GABA mediated inhibition of thalamus -> decreased movement. It also causes decreased inhibition of GABA/Enkephalin neurons in the striatum (D2) -> GABA-mediated inhibition of LPS -> disinhibition of STN -> activation of MPS & SNr -> Inhibition of thalamus -> decreased movement.
How does Parkinson’s disease affect the interneurons of the basal ganglia?
The interneurons also have D2 receptors that inhibit their cholinergic action that activates the GABA neurons. In absence of DA, interneurons actively stimulate the the indirect pathway.
How are D1 receptors excitatory? How are D2 receptors inhibitory?
When DA binds to D2 receptors, Go shuts down Ca2+ influx channels and Gi opens K+ leak channels, preventing depolarization of the post-synaptic terminal. When DA binds to D1 receptors, Gs turns on adenylyl cyclase, ATP is converted to cAMP and signal transduction continues.
How is DA managed after it is released from the presynaptic dopaminergic nerve terminal?
DAT takes it up, it is repackaged or oxidized to DOPAC via MAO.
What is the most effective treatment of Parkinson’s disease during the early phase of treatment?
L-dopa, crosses the BBB via aromatic L-amine acid transporter because it looks like tyrosine. You can’t give direct dopamine because DA cannot cross the BBB. L-dopa is taken up by DAT in the nerve terminal. There L-dopa is converted to DA by dopamine decarboxylase (DDC).
Side effects from L-dopa therapy?
Nausea (D2 activation in area postrema in medulla), orthostatic hypotension (D2 activation on presynaptic sympathetic nerve terminals decreased NE release), increased heart rate (beta-1 receptor stimulation), better sex life, pleasure seeking, hallucinations/delusions, dyskinesias (too much movement), symptoms’ on-off phenomenon
When would dopamine cause hypertension?
Very high concentration of dopamine can activate alpha-1 adrenergic receptors
What is L-dopa therapy always combined with?
Carbidopa. It inhibits peripheral DDC and prevents peripheral side effects of L-dopa because carbidopa cannot cross the BBB. Note that the level of L-dopa will be increased, more will cross the BBB and dosage of L-dopa can be reduced.
Rasagiline
MAO B inhibitor that prevents metabolism of dopamine, increasing levels of dopamine. Used to boost L-dopa efficacy. It also prevents MPTP activation.
What drug might you prescribe to reduce the off time in the on-off phenomenon?
Entacapone. It is a COMT inhibitor. COMT deactivates dopamine by methylating it to become 3-O-methyl dopa. 3-O methyl dopa competes with L-dopa for uptake in the brain and decreases L-dopa efficacy. Inhibiting COMT prevents this process.
What drugs will you use very first in the early stages of Parkinson’s?
Selective D2 agonists: Pramipexole and Ropinirole
Side effects of full D2 agonists? How do you prevent peripheral side effects of these drugs?
Same as L-dopa minus activation of beta-1 adrenergic receptors and tachycardia. Peripheral side effects can be prevented by domperidone because it cannot cross the BBB.
Benztropine and trihexyphenidyl
Counteract ACh activation of the indirect pathway by blocking M1 receptors on the interneurons
Amantadine
Normally used as an antiviral drug. Found to increase the release of endogenous dopamine.
