Dementia drugs Flashcards
What is the Beta amyloid hypothesis for AD development
1. β-amyloid plaques APP - amyloid precursor protein
The APP protein is a integral membrane protein found on neuronal plasma membranes.
The APP precursor is cleaved by two proteolytic enzymes, β-secretase and γ-secretase, to produce a soluble peptide of 40 amino acids (Aβ40). Aβ is not pathogenic.
Two genes, PS1 (presenilin 1) and PS2 (presenilin 2,) encode subunits of γ-secretase, variants of which result in the production of a peptide of 42 amino acids (Aβ42) derived from APP that is insoluble and forms aggregates that comprise β-amyloid plaques.
Variant forms of PS1 and PS2 forming the Aβ42 are associated with early onset AD.
A variant form of the ApoE, ApoE4 has also been found to be a risk factor for AD. Has to do with cholesterol.
2. Neurofibrillary tangles are found in dead or dying neurons and are linked to the destruction of neuronal microtubules, a process that appears to be downstream of β-amyloid plaque formation.
Degenerating microtubules are associated with hyperphosphorylated forms of the microtubule-associated tau protein.
3. Neurodegeneration
While many parts of the brain are affected in AD, the loss of cholinergic neurons appears to be particularly acute leading to the cholinergic hypothesis
What is the cholinesterase hypothesis for Alzheimer’s
Defects in cholinergic neurotransmission are thought to play a major role in normal and pathological declines in learning and memory associated with dementia
Cholinergic neurons are not the only neurons influenced in regions of the brain affected by AD pathology.
Loss of serotonergic neurotransmission may contribute to comorbidities like depression and anxiety in AD patients.
Whereas loss of norepinephrine neurons can contribute to comorbidities like aggression, agitation, and psychosis.
Glutamate/Neuroexcitatory Hypothesis for AD development
AD pathology has been linked to the dysregulation of postsynaptic glutamate neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors.
The NMDA receptor has been shown to undergo sustained low-level activation in AD, which interferes with normal neurotransmission and may lead to neuronal damage
Dysregulation of NMDA receptors may also contribute to AD pathogenesis by increasing APP production and promoting hyperphosphorylation of the tau protein
What are the cholinesterase Inhibitors
Donepezil, Galantamine, and Rivastigmine
Use of cholinesterase inhibitors
Cholinesterase inhibitors have been shown to provide symptomatic relief to patients with Alzheimer’s disease. These symptoms include:
cognition
daily functions
and certain behavioral manifestation of Alzheimer’s disease.
The benefits of cholinesterase inhibitors in providing symptomatic relief to AD patients is considered modest, but nevertheless statistically significant in numerous studies.
Donezepil MOA
Donepezil is a reversible inhibitor of acetylcholinesterase, the enzyme responsible for the synaptic inactivation of the neurotransmitter acetylcholine.
Donezepil inidications
Donepezil is approved for use in treating mild-moderate AD at 5 or 10 mg doses (oral solutions or tablets) daily.
It is also approved for use in treating moderate to severe AD at higher doses of 10 or 25 mg, daily.
Donepezil is the most widely prescribed drug to treat cognitive symptoms of AD.
Donepezil is also reported to have off-label use for forms of dementia other than AD.
Donezepil drug interactions
Concomitant use with anticholinergics will diminish the effectiveness of cholinesterase inhibitors like donepezil.
Donepezil is subject to first pass metabolism by cytochrome p450s, numerous drug interactions have been identified
Donezepil toxicities
Toxicities associated with donepezil tend to be associated with higher doses used in treating moderate to severe AD (> 10mg daily). These toxicities include:
anorexia
nausea and vomiting
diarrhea
rhinitis
What happens with discontinuation of donezepil
Evidence exists that suggests discontinuation of donepezil in severe AD can cause a worsening of symptoms.
Galantamine MOA
Galantamine is a reversible inhibitor of acetylcholinesterase.
Galantamine also appears to be a allosteric activator of nicotinic acetylcholine receptors.
Despite the additional effect of galantamine on nicotinic acetylcholine receptors head to head trials between galantamine and donepezil have shown no significant differences in therapeutic effects.
Inidications/toxicities for Galantamine
Galantamine is similar to donepezil in many respects (toxicities, drug interactions), with the exception that it is either given twice daily in standard formulations or once a day in an extended release formulation.
Rivastigmine MOA
In contrast to donepezil and galantamine, rivastigmine inhibits both acetylcholinesterase and butyrylcholinesterase.
Butyrylcholinesterase is a non-specific cholinesterase that can break down acetylcholine as well as other types of choline esters.
Butyrylcholinesterase is found in the serum and is also expressed in glia within the brain.
The additional inhibition of butyrylcholinesterase gives rivastigmine more severe GI side effects than the other cholinesterase inhibitors used to treat AD. Can be given as patch
Indications for Rivastigmine
Rivastigmine has been approved for use in mild to moderate AD and in moderate to severe AD.
In contrast to the other cholinesterase inhibitors, rivastigmine has been approved for use in treating Parkinson’s disease dementia
Rivastigmine drug interactions
Concomitant use with anticholinergics will diminish the effectiveness of cholinesterase inhibitors like rivastigmine.
Rivastigmine is not metabolized by cytochrome p450 enzymes, and so lack some of the drug-drug interactions experienced with other cholinesterase inhibitors used for AD.
Safety and effectiveness of the cholionesterase inhibitors
onepezil and rivastigmine may be slightly more efficacious than galantamine, at least as reflected by some outcome measures.
The incidence of common adverse events appears to be lowest with donepezil and highest with rivastigmine.
Example of NMDA inhibitor
Memantine
Memantine MOA
Memantine is a non-competitive inhibitor of the NMDA receptor.
Memantine does NOT act as a traditional antagonist of NMDA receptors as it does not compete with glutamate, the physiological agonist. Memantine is thought to allow the physiological activation of NMDA receptors by glutamate while suppressing pathological overactivation.
Memantine appears to compete with Mg2+ , which is an endogenous blocker of NMDA-mediated calcium influx.
Because it allows normal physiological activation of NMDA receptors, memantine does not exhibit toxicities observed for more typical NMDA receptor antagonists like ketamine.
At higher concentrations, memantine targets a number of other CNS receptors including dopamine and serotonin receptors and nicotinic acetylcholine receptors.
Memantine indication and dosing
Memantine is approved for use in moderate to severe AD either as a monotherapy or in combination with donepezil
Current uses for memantine in treating forms of dementia other than AD are off-label.
Memantine toxicities
Memantine has favorable safety and toxicity profiles with reported side effects including: headache, constipation, confusion and dizziness.
Vitamin E MOA
Vitamin E is an antioxidant.
Oxidative damage is thought to contribute to the pathophysiological mechanisms at play in AD
With its antioxidant properties, vitamin E could limit the role of oxidative damage during AD pathogenesis.
Vitamin E indications
ombined vitamin E and memantine in patients already receiving cholinesterase inhibitors.
Innefective medications for dementia
Statins- Given the association between the ApoE4 allele and risk for AD, it seemed reasonable to test whether lowering serum cholesterol might show some benefit in treating AD.
Trials to date with statins have shown NO benefit on cognitive or functional outcomes in AD.
NSAIDs - Non-steroidal antiinflammatory drugs were considered as a treatment for AD based on their presumed ability to limit amyloid-induced inflammation in AD patients.
Naproxen, aspirin, and diclofenac have NOT demonstrated arrest or slowing of cognitive decline in AD patients.
Gingko and Omega-3 Fatty Acids - no consistent benefit
Non-Pharmacological Approaches to AD (Reducing Risk Factors)
Daily physical activity for at least 30 minutes
Daily mental stimulation e.g., crossword puzzle, word search, computer programs
Brush and floss teeth twice daily. Dental visits twice a year
Diet: Fish, Fruits and vegetables, Fiber, Fluid
Supplements: Vitamin B12 1000 mcg daily and Vitamin D 1000 units daily
