Drugs Used in Movement Disorders Flashcards
Function of acetylcholine in the movement pathway
Activates the MSNs in the indirect pathway, prevents movement.
L-Dopa
Gold standard for treating PD, pro-drug that gets converted to dopamine by dopa decarboxylase
Why not administer dopamine itself?
Because it doesn’t pass through BBB well. L-dopa passes much faster
What happens when DOPA interacts with COMT?
It gets degraded into an inactive product instead of dopamine
Carbidopa
A peripheral inhibitor of DOPA decarboxylase. Prevents the nausea that occurs when dopa broken down peripherally. Also causes more of the DOPA to reach the brain
L-Dopa pharmacokinetics
Absorbed in small intestine, t1/2 of 3 hours
Does l-dopa ever lose efficacy?
Yes, after months to years of treatment. Mobility declines a few hours after each dose.
Dopa-dyskinesias
L-Dopa can cause dyskinesias, like Michael J. Fox.
Why use direct dopamine agonists?
As monotherapy when PD is mild, delay use of L-dopa and prevent loss of efficacy. Also can use as adjunct with l-dopa.
Which DA agonists are used? Mechanism of action
Pramipexole and Ropinirole. Direct D2 agonists.
Apomorphine, also direct DA agonist
Pramipexole and Ropinirole PK
P: Excreted unchanged.
R: Metabolized by a cyp that also metabolizes caffeine and warfarin, so there can be an interaction there.
How is apomorphine administered?
SC. Use is relatively limited to off periods when nothing else works. Causes nausea and cardiovascular effects. Rapid halflife and is excreted unchanged.
MAO-B inhibitors
Work by preventing the breakdown of dopamine, does not work on 5HT or NE (like MAOa). Irreversible inhibitors, used as adjuncts.
Adverse effect of MAOI and meperidine (opioid analgesic)
Serotonin syndrome– causes agitation, delirium, coma, death. Treat with 5HT antagonists
What MAO-B inhibitors are used?
Selegiline, Rasagiline
Selegiline vs Rasagiline
Selegiline has little value as a monotherapy and is broken down into amphetamines, so causes anxiety and insomnia. Loss of MAO-B selectivity at high doses, can cause serotonin syndrome. Rasagiline is more selective for MAO-B, and doesn’t break down into amph. Can also be neuroprotective.
Do MAO-B inhibitors slow disease course?
No.
COMT inhibitors
Prevents accumulation of 3-O-Methyldopa in the periphery when L-dopa is administered. 3-O-methyldopa competes with L-dopa for entry to brain. Tolcapone, entacapone
Tolcapone
Comt inhibitor, prevents 3-O-methyldopa from competing with L-dopa at BBB. Can cause hepatotoxicity
Entacapone
Another COMT inhibitor. Less hepatotoxicity.
Stalevo
Dopa-carbidopa-entacapone
Amantadine
Antiviral drug, has anti-pd activity. Used as monotherapy for early onset PD. Later used as an adjunct. Few side effects.
Drug induced parkinsonism
Older antipsychotics that block D2 receptors, poisoning by MPTP (causes neurodegeneration, is a designer opioid)
Role of ACh in PD
Prevents movement by activating GABAergic neurons in indirect pathway. In PD, scale is tipped towards. ACh inhibition of movement
Trihexyphenidyl
Muscarinic antagonist. Works mostly in CNS, adjunct only. Can cause confusion/sedation. bad in glaucoma
How to treat HD.
Tetrabenzine, removes dopamine from presynaptic fibers. Can cause depression.
Spasticity
Excessive resting tone of skeletal muscle, stretch reflex response exaggerated. Treat by reducing excitatory output from spinal motorneurons
Anti-spasmotics
Botulinum toxin (interferes with the release of ACh at NMJ)
Dantrolene (prevents release of Ca from SR)
Baclofen (GABA b agonist – inhibits motor neurons directly and dampens corticospinal input)
Tizanidine- Alpha 2 agonist, inhibits motor neuron directly, and inhibits corticospinal inputs presynaptically
