Drugs for neurodegenerative diseases Flashcards
Parkinson’s disease
- loss of dopaminergic neurons in nigrostriatal pathway -> no inhibition of cholinergic neurons in striatum -> excessive and uncoordinated firing of cholinergic fibers
1. provide dopamine Levodopa Carbidopa Benserazide Dopamine agonists: - pergolid - pramipexol - ropinirole - rotigotine - apomorphine - bromocriptine MAO-B inhibitors: - selegiline = deprenyl - rasagiline COMT inhibitors: - entacarpone - tolcapone
- decrease umbalanced Ach in striatum
Ach antagonists:
- benzatropin
- triexyphenydil - increase dopamine release
Amantadine
They decrease symptoms:
- hypokinesis
- resting tremor
- mm rigidity
- cognitive impairment
NONE OF THE DRUGS DECREASES PROGRESSION, THEY ONLY RELIEVE SYMPTOMS!!
Huntington’s disease
- loss of GABA mediated inhibition in basal ganglia
- produces hyperactivity of dopaminergic synapses
- leads to progressive dementia and involuntary jerk movements (choriatic)
Dopamine antagonists: effective in decreasing involuntary movements
- tetrabenazine -> inhibits dopamine storage by inhibiting vesicular monoamine transporter
- chlorpromazine
- baclofen
Alzheimer’s disease
- loss of neurons (mainly cholinergic) w/ brain shrinkage due to deposition of amyloid plaques and neurofibrillatory tangles
- affects mainly hippocampus and basal forebrain
AchE inhibitors: increase availability of Ach in order to improve neurotransmission
- tacrine
- donepezil
- rivastigmine
- galanthamine (competitive)
NMDA Receptor anatgonists:
- memantine
Multiple sclerosis
- AI inflammatory denyelinating disease of CNS
Classic:
- corticosteroids (dexamethazone, prednisone)
- chemotherapies (azathioprine, cyclophosphamide)
- INF B1a and B1b (are modulators)
Newer:
- mitoxantrone
- fingolimab
- glatiramer
- teriflunomide
- dimethyl fumarate
- natalizumab
Amyotrophic lateral sclerosis
Riluzole:
- NMDA R antagonist
- blocks Na and Ca channels
Levodopa
Dopamine percursor, which is able to cross BBB (while dopamine isn’t).
It enhances synthesis of dopaminergic neurons and decrease progression of disease.
Enhances synthesis in remaining dopaminergic neurons by conversion to dopamine via dopa decarboxylase.
Approximately 95% of levodopa is decarboxylated in periphery -> decrease levodopa availability in CNS (and thus levodopa effectiveness) and also increase peripheral side effects -> this may be decreased by co-administration w/ dopamine agonists restricted to PNS -> domperidone.
TU: in 80% improvement of hypokinesia, rigidity and tremor
- no improvement in dysphasia / in cognitive functions
- effectiveness of drug gradually decreases (~5ys)
Carbidopa and Benserazide
Decarboxylase inhibitors which do not cross BBB, thus they’re specific to periphery.
Allow increase in availability of levodopa in CNS and a decrease in peripheral side effects.
TU:
- decrease required dose of levodopa
- decrease side effects
Dopamine agonists
Enhance dopamine like effect on substantia nigra.
Similar effects to levodopa.
- bromocriptine
- pergolid
- pramipexol
- ropinirol
- rotigotine
- apomorphine
TU:
- delay the need to employ levodopa
- work as adjuvants for levodopa
- non-ergot compounds have decreased risk for dyskinesias and are effective in advanced PD
MAO-B inhibitors
Decrease dopamine breakdown in CNS, thus increase its availability.
Used in combination w/ levodopa.
- selegiline -> protects dopamine from extraneuronal degradation
- rasagaline -> irreversible and selective MAO-B inhibitor (new drug)
TU:
- more effective in relieving symptoms and prolongating time
- decrease required dose of levodopa
COMT inhibitors
Decrease dopamine breakdown and thus increase availability.
Used in combination w/ levodopa.
- entacarpone
- talcapone
TU: to conteract fluctuation in plasma and to decrease symptoms of wearing-off phenomenon
Ach antagonists
Decrease umbalanced Ach in striatum
- benzatropine
- trihexyphenidyl
Have CNS selectivity
TU: decrease tremor
Amantadine
Antiviral agent.
Increase dopamine release
