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)
ALS (amyotrophic lateral sclerosis)
Kills motor nerve cells which causes muscle atrophy over time
Treated via edaravone and riluzole
Edaravone
MOA: idiopathic, hypothesized to be an antioxidant for oxidative stress damage for motor neurons
- decreases caspase-3 production due to increasing levels of SMN protein
Pregnancy is not fully known, but believed to be teratogenic (is in animals)
Indications for ALS treatment
ADRs:
- contusion
- abnormal gait
- dermatitis
- respiratory failure
- anaphylactic reactions
*is stupid expensive and because of this is usually only used after failure of riluzole
Riluzole
MOA: a glutamate antagonist that inhibits glutamate neurotransmission. Does this by inhibiting release of glutamic acid and blocking NMDA receptors
Pregnant C
Used in treatment for ALS and Huntington’s
ADRs:
- HTN
- nausea/vomiting
- increases liver enzymes (mimics liver failure)
- asthenia
- oral hypoesthesia
- hepatitis
- respiratory depression
Spinal muscular atrophy (SMA)
Autosomal recessive disease that results in a deletion of SMN1 and alternative splicing of SMN2 proteins
- results in muscle atrophy overtime
Treated via nusinersen (increases production of properly spliced SMN2 proteins)
Nusinersen
MOA: antisense oligonucleotide that binds to a specific intron sequence of exon 7 in SMN mRNA.
- blocks splicing silencers and increases production of full-length SMN2 protein
Pregnancy is unknown
Indications = SMA only
ADRs:
- backache/headache
- increased chances of fevers and lower respiratory infections (pneumonia)
- proteinuria
- thrombocytopenia
- atelectasis
- can mess with INR levels
