Kruse: Dementia Pharmacology DSA Flashcards
What AchE inhibitors can we use for pts with dementia
- Donepezil
- Galantamine
- Rivastigmine
- tacrine
Antimuscarinic thing
-atropine
cholinesterase reativator
-pralodoxime
What was the other AchE inhibitor that was kind of just on its own?
-Memantine
What are the 3 chemical groups of cholensterase inhibitors?
- Alcohols
- Carbamic acid esters
- organophosphates: covalent and irreversible binding
is there CNS distribution with quaternary and charged AchE inhibitors?
-no
examples of quaternary and charged AChE inhibitors
-neostigmine, pyridostigmine, edrophonium, echothiophate, ambenonium
PK of tertiary and uncharged AChE inhibitors
- well absorbed from all sites
- CNS happens
- more toxic than polar quaternary carbamates
- Es: physostigmine, donepezil, tacrine, rivastigimine, galantamine
PK for organophosphates
- lipid soluble and readily absorbed fromt he skin, lung, gut, and conjunctiva, which make them particularly dangerous to humnas and highly effective as insecticides
- goes everywhere in body
- CNS toxicity
- covalent and irreversible
- need to regenerate AChE inorder to reestablish the termination of AcH signaling at the nmj
MOA for AChE inhibiotrs
- inhibit AChE
- ACh accumulates throughout the body, which results in activation of nAChRs and mAChRs
how long do Ache inhibitors last?
- depends on what kind
- alcohol is weak so not long
- carbamic acid esters take longer because of formation of a covalent bond between the enzyme and the carbamic acid group… 30 min to 6 hrs
- organophosphates: covalent, AGING happens, makes it difficult to break
Organ system effects of quaternarey ACHE inhibitors
-absorbed poorly froim GI tract or across skin, no CNS , act preferentially at the NMJ of skeletal muscle, less effet at autonomic effector sites and ganglia
What happens if high concentrations of ACHE inhibitors is present in the CNS?
-generalized convulsions due to neuronal hyperstimulation
What happens to the cardiac system with too much AcHE inihibitors?
- lots of Ach floating around
- activates both symp and parasymp
- but parasymp dominates
- heart rate slows**
What happens in the eye with too much AcH?
- sphincter muscle of iris: contraction (miosis)
- ciliary muscle: contraction for near vision
What happens to BV’s with too much Ach?
- dilation (via EDRF= endothelium derived relaxing factor)
- constriction (high dose direct effect)
what happens to the lungs with too much Ach?
- bronchial muscle: contraction (bronchoconstriction)
- Bronchial glands: stimulation
What happens with the GI tract with Ach?
- Motility increases
- Sphincters relax
- Secretion is stimulated
Therapeutic uses of AChE inhibitors
- eye things like glaucoma
- GI and urinary probs
- Myasthenia gravis
- Alzheimer disease
- Dementia**: beause pts with alzheimer type are found to have a deficiency of intact cholinergic neurons
What was the really bad adverse effect with Tacrine that was the reason we stopped using it?
-hepatotoxicity
Drug drug interactions with AChE inhibitors
- nondepolarizing NM blocking agents: combo with these will diminish nm blockade
- exception: mivacurium
- Succinylcholine: will enhance phase 1 block and antagonize phase 2 block
- Cholinergic agonists: direct acting agnets act predominantly on mAChRs, combo will enhance the effects of cholinergic agonists (duh)
- B blockers: may enhace the bradycardic effects
- systemic corticosteroids: enhance muscle weakness seen in pts with myasthenia graavis
Acute intoxication
- miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea
- what is seen depends on route of admin
- primary cause of death is resp failure
Dx and Tx of intoxication
- measure AChE activity in erythrocytes and plasma
- ATROPINE IS THE ANTIDOTE
- maintenance of vital signs
- Atropine is ineffective against the peripheral nm stimucation (nAChRs)
What do we give them to regenerate AChE at the NMJ
-cholinesterase regerators
Which choinesterase regnerator do we use?
- pralodoxime
- removal of the phosphorous gorup from the active site of the enzyme
- must be given before aging occurs
What is the current antidotal therapy for organophosphate exposure resulting from warfare, terrorism, or other source?
-parenteral atropine, an oxime (pralidoxime), and benzodiazepine as an anticonvulsant
What does Memantine help us with?
- the glutamate in the CNS
- glutamate can cause overstimuation and lead to excitotoxicity and neuronal cell death
MOA for Memantine
- antagonist of the NMDA type of glutamate receptors
- normally blocked by Mg ions
- displaced after agonist depolarization happens
- pathologic receptor activation prevents mg froom reentering and blocking tha channel pore… chronically open and excessive calciuminflux
What does MEmantine do
- binds to the intra pore mg site, but with longer dwell time, and thus functions as aneffective receptor blocker only under conditions of excessive stimulation
- does not affect normal neurotransmission
What is the most common side effect with Memantine?
-dizziness
