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Physostigmine
- cholinesterase inhibitor, crosses BBB
- based on "cholinergic hypothesis" where cholinergic deficits correlate with cognitive impairment and disease severity.
- potent allosteric potentiating ligand of nicotinic receptors (same as galantamine); increases Nic channel opening induced by ACh, binds close to ACh-binding site on alpha subunit.
- modest improvement in 3 weeks, side effects resolve in 1-3 weeks, effective for up to 2 years.
- SE: insomnia, abnormal dreams, bradycardia, bronchoconstriction, increased secretion, DNVA, salivation, urinary urgency and incontinence, muscle cramps, profuse sweating.
- Avoid antichol drugs: scopolamine, antihistamines, cough/cold, TCAs...
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Donepezil
- selective acetylcholinesterase inhibitor, crosses BBB
- based on "cholinergic hypothesis" where cholinergic deficits correlate with cognitive impairment and disease severity.
- modest improvement in 3 weeks, side effects resolve in 1-3 weeks, effective for up to 2 years.
- SE: insomnia, abnormal dreams, bradycardia, bronchoconstriction, increased secretion, DNVA, salivation, urinary urgency and incontinence, muscle cramps, profuse sweating.
- Avoid antichol drugs: scopolamine, antihistamines, cough/cold, TCAs...
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Rivastigmine
- acetyl & butyryl -cholinesterase inhibitor (non-competitive), crosses BBB
- based on "cholinergic hypothesis" where cholinergic deficits correlate with cognitive impairment and disease severity.
- modest improvement in 3 weeks, side effects resolve in 1-3 weeks, effective for up to 2 years.
- SE: insomnia, abnormal dreams, bradycardia, bronchoconstriction, increased secretion, DNVA, salivation, urinary urgency and incontinence, muscle cramps, profuse sweating.
- Avoid antichol drugs: scopolamine, antihistamines, cough/cold, TCAs...
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Tacrine
- acetylcholinesterase inhibitor, crosses BBB
- based on "cholinergic hypothesis" where cholinergic deficits correlate with cognitive impairment and disease severity.
- NOT USED ANYMORE: liver toxicity...required liver function monitoring
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Galantamine
- acetyl (weak) & butyryl -cholinesterase inhibitor (competitive), Nicotinic receptor modulation
- based on "cholinergic hypothesis" where cholinergic deficits correlate with cognitive impairment and disease severity.
- potent allosteric potentiating ligand of nicotinic receptors (same as physostigmine); increases Nic channel opening induced by ACh, binds close to ACh-binding site on alpha subunit.
- modest improvement in 3 weeks, side effects resolve in 1-3 weeks, effective for up to 2 years.
- SE: insomnia, abnormal dreams, bradycardia, bronchoconstriction, increased secretion, DNVA, salivation, urinary urgency and incontinence, muscle cramps, profuse sweating.
- Avoid antichol drugs: scopolamine, antihistamines, cough/cold, TCAs...
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Memantine
- N-Methyl-D-Aspartate Receptor Antagonist
- treats mod-severe AD (chol, 5-HT, NA, HA inhibitory neurotransmission decreased, so more NMDA activation)
- block NMDA to prevent calcium entry excitotoxicity, and down-regulation of NMDA receptors...restore balance.
- also blocks alpha7, 9, 10 nicotonic subunits with ACh receptors, regulates release of glutamate from hippocampus and cortical neurons, non-competitive blockade
- also non-competitively blocks 5-HT3 receptors which are ligand-gated ionoropic receptors for cations
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Anti-B-amyloid Antibodies
intended to destroy insoluble, neurooxic beta-amyloid plaques that leads to inflammatory damage, dysfunction, and death of neurons...but trial withdrawn because 7% of subjects developed aseptic meningoencephalitis.
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Cevimeline
- cholinergic agonist, muscarinic selective
- 40x greater affinity for M1/M3 than M2
- decreases extracellular accumulations of beta-amyloid peptide
- may lead to decrease plaque formation
- SE: less bradycardia (M2) than phenserine
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Phenserine
- cholinergic agonist
- phenylcarbamate of physosigmine
- 1. potent AChesterase inhibitor
- 2. normal fxning of Chol system regulates process of beta-amyloid precursor protein (APP)
- therefore, beta-amyloid formation inhibited (same for all AChEs)
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Clioquinol, Alzhemed
- ABeta amyloid aggregation inhibitor
- could prevent formation of plaques
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Ginkgo Biloba
- flavonoids + terpene-lactones + organic/coumaric acid suggested to increase cerebral bf in vitro
- thereby inhibits aggregation of amyloid-beta, but only at high concentrations
- flavonoids are antioxidants...not proven better than placebo
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Vitamin E (alpha-tocopherol)
- antioxidant - decrease inflamm around plaques
- 1000mg/day slow progression of disease?
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Selegiline
- MAO-B inhibitor
- inhibits breakdown of DA & 5-HT
- may improve sx of AD but lacks global effect on disease
- should not be given with many drugs
- value uncertain
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NSAIDS?
People who take NSAIDs regularly have lower incidence of Alzheimer's disease...but no benefit of treatment with an NSAID to persons with AD already
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Estrogen
- post-men women on HRT have lower incidence of AD?
- but combo of E + P increase chance of stroke (impaired cholesterol)
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