Pharmacology: Neruodegenerative Disorders Flashcards
What are the four classes of medications used in Alzheimer’s patients?
1) cholinesterase inhbitors
- prevents break down of ACh
2) memantine
- memory and cognition retention via upregulating glutamate in specific areas.
3) antidepressants
- patients get depressed so this helps it
4) anti anxiety
- patients often get angry or anxious so this helps
- goal is to delay he progression for the disease, not to treat *
Donepezil, galantamine, rivastigmine, tacrine
Acetylcholinesterase inhibitors
MOA: prevents catabolism of ACh in the brain
- effect is directly proportional to the number of intact cholinergic neurons left.
- gets less effective as Alzheimer’s progresses.
PK:
- is reversible (except for rivastigmine)
- tacrine is no longer in use in the US
(liver damage)
Pregnancy C
Indications:
- mild to moderate Alzheimer’s
ADRs/contraindications
- nausea/vomiting/cramping
- GI hemorrhage
- titration is often needed and people can be discontuied because of this
- CANT USE:
1) asthma/COPD
2) CAD
3) hypotension
Pathology of Alzheimer’s
B-amyloid proteins inhibit glutamate recycling into glia cells
Causes excess glutamate and masks the signal transmission due to down regulation of NMDA receptors
- excess glutamate also causes cellular death due to influx of calcium into cells via constant glutamate interact
Postsynaptic inhibition signals are also detected, further masking signal transduction
Memantine
MOA: non-competitive NMDA receptor antagonist (blocks calcium pores)
- blocks NMDA receptors and inhibits glutamate induced excitotoxicity that is linked to neuronal cell death in Alzheimer’s
Pregnancy B
Indications:
- mild to severe Alzheimer’s
ADRs:
- dizziness
- confusion
- Headache
- no noteworthy contraindication
Parkinson’s disease pathology
Decrease in dopamine neurons in substantia Nigra pars reticulata and the corpus striatum spiny neurons
Causes increased GABA release and increased ACh
- results in janky movements
- to fix, use anticholinergics to balance the levels of dopamine and ACh (without drugs, Parkinson’s patients are normally ACh > dopamine) or increase level of dopamine levels to ACh levels
What is the main dopamine precursor?
L-DOPA
- gold standard for Parkinson’s disease tx
Why is levodopa usually co-administered with carbidopa?
Without carbidopa (which is a peripheral AAD inhibitor) most of L-DOPA gets converted to dopamine in the periphery rather than the CNS (<1% actually makes it to the CNS without carbidopa)
When co-administered, 10% reaches CNS
Can carbidopa affect CNS AAD enzymes?
No it cannot cross the BBB
ADRs of L-DOPA
Dyskinesia (most common)
Anorexia and Nausea/vomiting
- less common with combo carbidopa
Cardiac arrhythmias
Behavioral abnormalities
- more common with combo carbidopa
Contraindications:
- psychotic treatments
- active peptic ulcers
- patients with history’s of melanomas (can reactive them)
Dopamine receptor agonists
Bromocriptine, pramipexole, ropinirole. Apomorphine
MOA: synthetic mimic of dopamine that binds to dopamine receptors and generate dopamine function (motor control)
ADRs/contraindications
- nausea/vomiting
- drowsiness
- behavioral effects
- orthostatic hypotension
- pulmonary fibrosis (long term only)
- hypoglycemia
MAO inhibitors
selegiline, rasagiline
MOA: inhibits dopamine metabolism by blocking monoamine oxidase (MAO) enzymes
Used as adjunct for levodopa/carbidopa
Used for early Parkinson’s patients only
ADRs:
- dyskinesia and hallucinations
- nausea/vomiting
- tyramine toxicity
- serotonin syndrome
- insomnia (selegiline only)
COMT inhibitors
Tolcapone, entacapone
MOA: inhibits dopamine metabolism by blocking catechol-O-methytransferase
Most often used as adjunct for levodopa/carbidopa
For early Parkinson’s only
tolcapone can work in both periphery and CNS, whereas entacapone can only work in the periphery
ADRs:
- levodopa toxicity (increases effects)
- ab pain
- diarrhea
- ortho hypotension
- nausea/vomiting
- orange urine (entacapone only)
- Hepatotoxicty (Tolcapone only)
Why would one only want to use entacapone (periphery acting only) vs tolcapone (CNS and periphery acting) ?
To keep L-DOPA levels high in the periphery (tolcapone doesnt work as well in the periphery as entacapone).
Also tolcapone has serious hepatotoxicty
Anticholinergics for Parkinson’s
Benztropine, trihexyphenidyl, scopolamine
MOA: restores balance of GABAergic signaling by antagonizing Muscarinic receptors
ADRs: (significant amount)
- sedation and confusion (especially high in the elderly)
- nausea
- urinary dysfunction
- xerostomia
- blurred vision
Amantadine
MOA: idiopathic, is normally used for antiviral vaccination for flu.
- hypothesized to antagonize NMDA receptors and D2 neurons
Can be used in Parkinson’s for modest, short lived, benefit in tremor/rigidity and bradykinesia
ADRs:
- anti-SLUD
- restlessness
- insomnia
- depression
- hallucinations
- peripheral edema
- livedo reticularis (lace like purple lesions of the lower extremities)
