Neuroscience Week 4: AntiParkinsons meds Flashcards
Cardinal motor signs of Parkinson’s Disease
Drug classes to treat Parkinson’s disease
5 listed
- Dopamine Precursors (L-DOPA Carbidopa (Sinemet)
- Dopamine Agonists (Ropinirole, Pramipexole)
- MAO inhibitors (Selegiline)
- COMT Inhibitors (Entacapone)
- Muscarinic antagonists (trihexyphenidyl)
MOA of Drug classes to treat Parkinson’s disease
Dopaminergic nerve terminal
- left-hand presynaptic bouton with dopamine vesicles
- right-hand side postsynaptic neurons within the striatum
- dopamine is produced from the precursor tyrosine by tyrosine hydroxylase to L-DOPA then to Dopamine by aromatic amino acid decarboxylase (dopa carboxylase)
- dopamine is then transported to the presynaptic terminal and released upon activation of the nerve terminal into the synaptic cleft where it binds the postsynaptic dopamine receptors within the striatum
- dopamine is removed from the synaptic cleft and reuptake by dopamine transporter
L-DOPA structure
mainstay for treating Parkinsons
dopamine is produced from the
precursor tyrosine by tyrosine hydroxylase to L-DOPA then to Dopamine by aromatic amino acid decarboxylase (dopa carboxylase)
Dopamine cross the blood brain barrier?
No
L-DOPA cross the blood brain barrier?
Yes
Levodopa does cross and is transported across and reaches the brain is taken up by dopamine transporter at nerve terminals and is converted by amino acid decarboxylase (dopa carboxylase) to dopamine bypassing the rate-limiting step of tyrosine to L-Dopa by tyrosine hydroxylase within singular nerves increasing dopamine production on a per neuron basis
L dopa is transported across BBB by neutral amino acid transporter where it is converted to dopamine by central dopa decarboxylase
L DOPA can be converted in PNS by peripheral dopa carboxylase which is present in many peripheral tissues
to increase bioavailability of L-DOPA in the CNS it is administered to gethetr with a peripheral dopa carboxylase inhibitor (Carbidopa)
Carbidopa does not cross BBB and can only inhibit PDC (peripheral dopa carboxylase)
Carbidopa
L dopa is transported across BBB by neutral amino acid transporter where it is converted to dopamine by central dopa decarboxylase
L DOPA can be converted in PNS by peripheral dopa carboxylase which is present in many peripheral tissues
to increase bioavailability of L-DOPA in the CNS it is administered to gethetr with a peripheral dopa carboxylase inhibitor (Carbidopa)
Carbidopa does not cross BBB and can only inhibit PDC (peripheral dopa carboxylase)
peripheral dopa carboxylase inhibitor
Carbidopa
Sinemet
Carbidopa structure & effects
3 listed
Major side effects of L-Dopa or sinemet
- GASTROINTESTINAL: Nausea is thought to be due to stimulation of dopamine receptors (D2) in the emetic center of the brain (area postrema) where BBB does not exist. Usually subsides with time. Can be treated with domperidone, a D2 antagonist that does not cross BBB, but this is risky in PD patient.
- CARDIOVASCULAR: Side effects include tachychardia, atrial fibrillation due to sympathomimetic action of L-dopa, also a precursor to norepinephrine.
- PSYCHOSIS: Nightmares or hallucinations may occur due to stimulation of dopamine receptors in frontal cortex.
- DYSKINESIA: Long-term treatment with L-dopa may eventually lead to L-dopa-induced dyskinesiasby unknown mechanism
D2 antagonist used to treat GI symptoms of Sinemet
Domperidone
a D2 antagonist that does not cross BBB, but this is risky in PD patient.
Sinemet GI Side Effects
GASTROINTESTINAL: Nausea is thought to be due to stimulation of dopamine receptors (D2) in the emetic center of the brain such as in the (area postrema) where BBB does not exist. Usually subsides with time. Can be treated with domperidone, a D2 antagonist that does not cross BBB, but this is risky in PD patient.
Sinemet Cardiovascular Side effects
CARDIOVASCULAR: Side effects include tachychardia, atrial fibrillation due to sympathomimetic action of L-dopa, which is also a precursor to norepinephrine.
Sinemet Psychosis Side Effects
PSYCHOSIS: Nightmares or hallucinations may occur due to stimulation of dopamine receptors in frontal cortex.
overstimulation of dopamine receptors in the frontal cortex
Sinemet Side Effects Dyskinesia
DYSKINESIA: Long-term treatment with L-dopa may eventually lead to L-dopa-induced dyskinesias by unknown mechanism
Major side effect with long-term use results in unwanted movements such as chorea seen in Huntington’s Disease, Etiology is idiopathic
L-DOPA Pharmacokinetics: Absorption
GI Absorption by LNAA transport
L-DOPA Pharmacokinetics: Time to Peak Plasma Concentration
.5 - 2.0 hours
L-DOPA Pharmacokinetics: Plasma half-life
1 - 3 hours
L-DOPA Pharmacokinetics: Duration of action
4.0 - 6.0 hours
L-DOPA Pharmacokinetics: Caveat
In early stages of PD, the duration of action of L-dopa is longer than plasma half-life because L-dopa is taken up by dopaminergic nerve terminals in striatum, and released as needed. As nigralneurons degenerate, the duration of action becomes shortened. There is less “buffering capacity” of L-dopa as DA neurons are increasingly lost during progressive neuronal degeneration.
L-Dopa Taken with Food
Typically not taken with a protein meal because protein can compete with L-DOPA for uptake with Amino Acid Transport system
