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
Contraindication of L-Dopa (Sinemet)
- psychotic because of the propensity of L-DOPA to cause hallucinations and nightmares psychotic symptoms
- Also, monitor closely in patients with cardiovascular disease
Limitations of long term use of L-Dopa
- “wearing off” phenomenon - diminshment of duration of action, increasing dose and frequency of dose can often lead to dyskinesias
- Dyskinesia - excessive abnormal and involuntary movements
COMT Inhibitors
Catecholo-O-Methyltransferase Inhibitors to further enhance L-Dopa bioavailability
Entacapone
Entacapone MOA
inhibits degradation of L-Dopa to 3-O-methyldopa mediated by Catecholo-O-Methyltransferase
Carbidopa, Levodopa, Entacapone Combination and properties
5 listed
Stalevo
Monamine Oxidase-B Inhibitors MOA
can be used as adjunct therapy w/ Senemet or monotherapy
inhibits Monamine Oxidase-B degradation pathway which converts Dopamine to DOPAC metabolite
Selegilene and properties
- Monamine Oxidase-B inhibitor
- retards catabolism of dopamine in CNS
- used in early PD stages prior to L-dopa or as an adjunct
- prevents dopamine degradation to DOPAC
Dopamine Receptor Agonists MOA
bypass presynaptic terminal altogether and MOA is to directly stimulate postsynaptic Dopamine receptors in striatal cells
Dopamine Receptor Agonists Advantages
4 listed
Dopamine Receptor Agonists Disadvantage
Not as effective as L-Dopa for alleviating motor symptoms of Parkinson’s disease
Ropinirole (Requip) MOA
D2 Receptor Agonist
Ropinirole (Requip) Side Effects
- Nausea
- Orthostatic Hypotension
- Hallucinations
D2 Receptor Agonist
Ropinirole (Requip)
Muscarinic receptor Antagonists MOA
a small population of cholinergic interneurons in the striatum acetylcholine released by these neurons act on muscarinic receptors in postsynaptic striatal nuerons and is thought to antagonize dopaminergic stimulation within the striatum
Benztropine and Trihexyphenidyl MOA
thought to restore Ach:Dopamine balance in the corpus striatum
Benzotropine and Trihexyphenidyl Advantages
modest antiparkinson action
Benzotropine and Trihexyphenidyl disadvantages
Have parasympathetic side effects
Benzotropine and Trihexyphenidyl Use
treat tremor with little effect on bradykinesia
Antiparkinson and other movement disorders Drug Summary
Katsung chapter 28
Combination pill of L-DOPA and Carbidopa
Sinemet
