Kruse: Dementia Pharmacology DSA

Question 1

What AchE inhibitors can we use for pts with dementia

Answer 1

• Donepezil
• Galantamine
• Rivastigmine
• tacrine

Question 2

Antimuscarinic thing

Answer 2

-atropine

Question 3

cholinesterase reativator

Answer 3

-pralodoxime

Question 4

What was the other AchE inhibitor that was kind of just on its own?

Answer 4

-Memantine

Question 5

What are the 3 chemical groups of cholensterase inhibitors?

Answer 5

• Alcohols
• Carbamic acid esters
• organophosphates: covalent and irreversible binding

Question 6

is there CNS distribution with quaternary and charged AchE inhibitors?

Answer 6

-no

Question 7

examples of quaternary and charged AChE inhibitors

Answer 7

-neostigmine, pyridostigmine, edrophonium, echothiophate, ambenonium

Question 8

PK of tertiary and uncharged AChE inhibitors

Answer 8

• well absorbed from all sites
• CNS happens
• more toxic than polar quaternary carbamates
• Es: physostigmine, donepezil, tacrine, rivastigimine, galantamine

Question 9

PK for organophosphates

Answer 9

• 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

Question 10

MOA for AChE inhibiotrs

Answer 10

• inhibit AChE

- ACh accumulates throughout the body, which results in activation of nAChRs and mAChRs

Question 11

how long do Ache inhibitors last?

Answer 11

• 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

Question 12

Organ system effects of quaternarey ACHE inhibitors

Answer 12

-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

Question 13

What happens if high concentrations of ACHE inhibitors is present in the CNS?

Answer 13

-generalized convulsions due to neuronal hyperstimulation

Question 14

What happens to the cardiac system with too much AcHE inihibitors?

Answer 14

• lots of Ach floating around
• activates both symp and parasymp
• but parasymp dominates
• heart rate slows**

Question 15

What happens in the eye with too much AcH?

Answer 15

• sphincter muscle of iris: contraction (miosis)

- ciliary muscle: contraction for near vision

Question 16

What happens to BV’s with too much Ach?

Answer 16

• dilation (via EDRF= endothelium derived relaxing factor)

- constriction (high dose direct effect)

Question 17

what happens to the lungs with too much Ach?

Answer 17

• bronchial muscle: contraction (bronchoconstriction)

- Bronchial glands: stimulation

Question 18

What happens with the GI tract with Ach?

Answer 18

• Motility increases
• Sphincters relax
• Secretion is stimulated

Question 19

Therapeutic uses of AChE inhibitors

Answer 19

• 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

Question 20

What was the really bad adverse effect with Tacrine that was the reason we stopped using it?

Answer 20

-hepatotoxicity

Question 21

Drug drug interactions with AChE inhibitors

Answer 21

• 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

Question 22

Acute intoxication

Answer 22

• miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea
• what is seen depends on route of admin
• primary cause of death is resp failure

Question 23

Dx and Tx of intoxication

Answer 23

• measure AChE activity in erythrocytes and plasma
• ATROPINE IS THE ANTIDOTE
• maintenance of vital signs
• Atropine is ineffective against the peripheral nm stimucation (nAChRs)

Question 24

What do we give them to regenerate AChE at the NMJ

Answer 24

-cholinesterase regerators

Question 25

Which choinesterase regnerator do we use?

Answer 25

• pralodoxime
• removal of the phosphorous gorup from the active site of the enzyme
• must be given before aging occurs

Question 26

What is the current antidotal therapy for organophosphate exposure resulting from warfare, terrorism, or other source?

Answer 26

-parenteral atropine, an oxime (pralidoxime), and benzodiazepine as an anticonvulsant

Question 27

What does Memantine help us with?

Answer 27

• the glutamate in the CNS

- glutamate can cause overstimuation and lead to excitotoxicity and neuronal cell death

Question 28

MOA for Memantine

Answer 28

• 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

Question 29

What does MEmantine do

Answer 29

• 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

Question 30

What is the most common side effect with Memantine?

Answer 30

-dizziness