9/28 Drugs for Dementia - Walworth Flashcards
Alzheimers
key neurochem sign
evidence for linkage to that sign
loss of hippocampal and cortical neurons → impairment of memory, cognitive disability
- no disease-modifying tx currently available
- all current tx aim to slow cognitive decline
involves multiple nt systems: glutamate, serotinon, neuropeptides
involves destruction of: cholinergic neurons, cortical/hippocampal targets receiving cholinergic input
cholinergic deficit
- deficiency of ACh due to atrophy/degen of subcortical cholinergic neurons (esp in basal forebrain, which provide cholinergic innervation to cerebral cortex)
- evidence for the role of cholinergic deficit*
- central cholinergic antagonists (ex. atropine) can produce confused state bearing resemblance to Alz disease
why treat Alzheimers with AChE inhibitors?
central cholinergic antagonists (ex. atropine) can produce confused state bearing resemblance to Alz disease
- this supports view of Ach deficiency as key to disease process of AD
AChE antagonists might help reverse ACh deficit
*drugs with anti-cholinergic activity (diphendydramine, tolterodine, imipramine) may diminish benefit!!!
activity of AChE
activity of AChE inhibitors
activity of normal AChE
- AChE hydrolyzes ACh by removing the acetyl group
- acetylated intermed is rapidly converted back to AChE to restore enzyme activity
non-competitive AChE inhibitor (ex. carbamate)
- transfers carbamyl group from drug to enzyme (instead of acetyl group from ACh)
- carbamylated intermed is more stable → inhibition of AChE is prolonged!
implication: duration of action of drug is determined by stability of enzyme-inhibitor complex (NOT by drug plasma halflife)
cholinesteraste inhibitors used for cognitive decline
- affinity and hydrophobicity to cross bbb
- NOT disease-modifying → attempt to slow the decline in cog fx and behavioral manifestation of AD
- also widely used for dementia with Lewy bodies and vascular dementia
- adverse effects for all: nausea/vomiting/diarrhea; bradycardia, syncope
1. galantamine
- competitive CI (potentiates signaling nicotinic AChR)
- metabolism: CYP2D6, 3A4
- indication: mild-mod AD
2. donepezil
- noncompetitive CI
- metabolism: CYP2D6, 3A4
- indication: mild-severe AD
3. rivastigmine
- noncompetitive CI (carbamate)
- metabolism: esterases
- indication: mild-mod AD; mild-mod PD dementia
galantamine
AchE inhibitor for cog decline
1. galantamine
- competitive CI (potentiates signaling nicotinic AChR)
- metabolism: CYP2D6, 3A4
- indication: mild-mod AD
donepezil
AchE inhibitor for cog decline
2. donepezil
- noncompetitive CI
- metabolism: CYP2D6, 3A4
- indication: mild-severe AD
rivastigmine
AchE inhibitor for cog decline
3. rivastigmine
- noncompetitive CI (carbamate)
- metabolism: esterases
- indication: mild-mod AD; mild-mod PD dementia
memantine
noncompetitive NMDA antagonist for cog decline
memantine
- noncompetitive NMDA-R antagonist
- metabolism: 50% unchanged excretion in urine
- indication: mod-severe AD
added to tx regimen (AChE inhibitors) as disease progresses
- well-absorbed, no interactions with CYP450s
- reduces rate of clinical deterioration in patients with severe AD (not clear if a disease-modifying effect of symptomatic effect)
- possibly effective for demential with Lewy bodies and vascular dementia
- adverse effects: headache, dizziness; well-tolerated
tx for Alzheimers and related dementia: summary
BSPD of AD
treating BPSD
behavioral and psych sx in dementia
- anxiety
- depression
- irritability/agitation
- paranoia, delusional thinking
- wandering
prescriptions to treat BPSD (antidepressants, atypical antipsychotics)
- serotonergic antidepressant
- dont want tricyclics because of anticholinergic effects!
- atypical antipsychotic
- agitation/psychosis
- WARNING: higher risk of stroke, overall mortality
- haloperidol for aggression (acute only)
agents to avoid in patients with dementia
drugs likely to aggravate cog impairment
- anticholinergics
- benzodiazepines
- sedative hypnotics
recall: some drugs may have secondary antichol prop
ex. antihistamine diphenhydramine, tricyclic antidepressants
