Movement Disorder Drugs Flashcards
Parkinson’s Disease - pathophysiology
Basal ganglia in the brain is responsible for many aspects of coordination of movement. The substantia nigra is one structure within the basal ganglia. Neurons in the substantia nigra release dopamine. Neuronal projections lead to presynaptic inhibitory D2 receptors on cholinergic interneurons in the putamen and caudate nucleus (also in basal ganglia). In Parkinson’s disease these projections in the substantia nigra are progressively lost, leading to inappropriate increased levels of released acetylcholine, causes overactivity in the caudate nucleus and putamen, thus leading to muscular rigidity and tremors.
The exact cause of the loss of these neuronal projections is not well understood but thought to be oxidative in nature.
Known causes: age, brain trauma, tumors, infection/encephalitis, toxin exposure (environmental or otherwise consumed) incl manganese, CO.
Due to redundancy of neuronal connections, no symptomology until 70% of these projections are lost.
Can occur over the age of 40, but usually presents late 50s/early 60s
Drug therapy for Parkinsons (general characteristics)
Drug therapy will affect either actions of dopamine or acetylcholine
Early stage Parkinsons: drugs will work PREsynaptically
Later stage Parkinsons: drugs will work POSTsynaptically
dopa decarboxylase
MOA: catalyzes the removal of a carboxyl group from dopa (specifically, l-dopa “levodopa”), thus converting it to dopamine
- if dopa decarboxylase acts on levodopa (converts to dopamine) in the periphery, it will become trapped there because DOPAMINE DOES NOT CROSS THE BBB
does dopamine cross the blood-brain barrier?
NO!
levodopa
MOA: direct replacement dopamine therapy
precursor to dopamine which can cross the BBB
90% destroyed in the gut
dopa decarboxylase inhibitors (2)
- carbidopa
- benserazide
carbidopa/levodopa combination drug
“sinemet”
combination drug for parkinsons given orally
MOA:
levodopa=dopamine precursor which crosses BBB
carbidopa= inhibits conversion dopa to dopamine
when taken together, a greater amount of dopa leaves the gut, greater availability of dopa to cross BBB
amantadine
MOA: causes PREsynaptic release of dopamine
- not effective in later stage parkinsons bc stored supply of dopamine is already low or depleted
postsynaptic dopamine agonists (list of 4)
bromocriptine - partial D1 agonist / full D2 agonist
pergolide - D1/D2 agonist
pramipexole - highly selective D2 agonist
ropinirole - highly selective for D2 agonist, also given for “restless leg syndrome”
COMT inhibitors
MOA: increase levels of dopamine by inhibiting catechol-0-methyltranferase which degrades dopamine
- entacapone- only active peripherally
- tolcapone- active in periphery and CNS; BLACK BOX warning for hepatotoxicity
selegiline
MOA: MAO type B inhibitor. metabolites include amphetamine and methamphetamine, both of which are indirect acting dopamine agonists (presynaptic uptake causes release of more dopamine)
trihexlphenidyl
MOA: inhibits acetylcholine in key excitatory pathways
- usually used as an adjunct with dopaminergic drugs to control excess SLUDE from Ach activity
- sometimes used to treat early, mid parkinsons
benztropine
MOA: centrally-acting antimuscarinic
- used to control the “cosmetic” effects of excess SLUDE (ie. leaky bladder, excess salivation)
diphenhydramine
MOA: antihistamine/H1 antagonist, also blocks reuptake of dopamine
- adjunct therapy for parkinsonism
ethopropazine
MOA: unusual phenothiazine with marked anticholinergic properties
- adjunct therapy for parkinsonism
procyclidine
MOA: atropine-like muscarinic antagonist
- adjunct therapy for parkinsonism, useful to manage rigidity and excessive salivation (sialorrhea)
general side effects of dopaminergic drugs
- GI: nausea/vomting/anorexia (think antipsychotic drugs that decrease dopamine are anti-emetic and cause weight gain)
- CV: orthostatic hypotension, tachycardia (DA receptors on heart)
- involuntary movements (ataxia, choreiform movements)
- neuroleptic malignant syndrome from sudden decreases in DA levels (sim antipsychotics); therefore caution with missed doses or major changes in dosing or withdrawal)
- drug interactions:CAUTION with any drug that is also directly or indirectly dopaminergic
- MAO-I (hypertensive crisis),
- vitamin B6 (increases dopa decarboxylase activity in gut thus increases peripheral dopamine levels)
side-effects of chronic use dopaminergic drugs
- dyskinesias
- end-of-dose failure
- on-off-phenomenon (day-to-day fluctuations in symptomatic control due to over-exertion)
Amyotrophic Lateral Sclerosis (ALS) Pathophysiology
exact cause unknown. Too much glutamate and NMDA activation
characterized by progressive muscular weakness assoc with progressive degeneration of spinal, bulbar and cortical neurons.
ultimate cause of death due to loss of diaghramatic control and respiratory compromise
riluzole
MOA: inhibits glutamate release presynaptically, blocks postsynaptic NMDA, kainate-type glutamate receptors, inhibits voltage-dependent Na channels
- antispasmodic used for ALS. can increase survival up to 60 days
baclofen
MOA: GABA-B agonist
- GABA-B receptors are g-coupled presynaptic receptors; binding of GABA inhibiting release of glutamate which ultimately inhibits spasticity
- antispasmodic used for ALS
tizanidine
MOA: alpha-2 agonist. antispasmodic action assumed to come from increasing presynaptic inhibition of motor neurons
- used for spasticity in ALS, MS, or post-stroke
Muscarinic antagonists for ALS (list of 5)
dicyclomine flavoxate oxybutinin oxyphencyclimine trihexylphenidyl
- used to control “cosmetic effects” of SLUDE
Huntington’s disease pathophysiology
- genetic autosomal dominant disorder affects the neostriatum
- The Huntingtin gene provides the genetic information for a protein that is also called “huntingtin”. Expansion of a CAG triplet repeat stretch within the Huntingtin gene results in a different (mutant) form of the protein, which gradually damages cells in the brain, through mechanisms that are not fully understood.
- in huntingtons disease, peptide is malformed and may repeat 100x, not cleared by body well
- characterized by incoordination and cognitive decline and severe psychosis
- avg age onset 35-45, but ranges from 2-80
- treatment is symptomatic
