Cholinergic Agonists

Question 1

What structures make a direct acting cholinergic agonist?

Answer 1

1) ester -> mimics ACh structure, fits in binding site
2) carbamate -> creates resistance to AChE (longer DOA)
3) beta-methylation -> selectivity for muscarinic over nicotinic

Question 2

Varenicline (which receptor?side effects?)

Answer 2

smoking cessation
- nicotinic partial agonist
- activates nicotinic receptor, blocks nicotine
- well tolerated
side effects: Gi issues (nausea/constipation/vomiting), altered dreams

Question 3

Which medications are used for glaucoma? (2)

Answer 3

carbachol
pilocarpine

Question 4

which medications are used for miosis (pupil constriction)? (2)

Answer 4

ACh
Carbachol

Question 5

which medication is used for urinary retention + post-op?

Answer 5

Bethanechol

Question 6

Why are antimuscarinic drugs contraindicated in glaucoma?

Answer 6

they block ciliary muscle contraction which worsens the condition

Question 7

What are the 2 types of cholinesterase?

Answer 7

1) acetylcholinesterase: in synapse, selective for ACh
2) plasma cholinesterase: in plasma, selective for ACh/succunylcholine/local anesthetics

Question 8

Acetylcholinesterase Inhibitors (-stigmine)

Answer 8

• carbamates
• quaternary/tertiary amine groups
• reversible
• covalent mod to AChE

Question 9

Acetylcholinesterase Inhibitors (echothiophate)

Answer 9

• organophosphates
• irreversible
• covalent mod to AChE
• longer acting***
• treats glaucoma

Question 10

Acetylcholinesterase Inhibitors (sarin/soman)

Answer 10

• organophosphates
• nerve gases
• irreversible
• covalent mod to AChE

Question 11

Inhibition of AChE by organophosphates

Answer 11

1) organophosphate binds to AChE and phosphorylates it
(when phosphate sticks = enzyme cannot work)
2) “aging” occurs = tight/stable/permanent bond
3) ACh buildup occurs
muscarinic -> salivate/bronchoconstrict/bradycardia
nicotinic -> muscle twitch/paralysis
CNS -> seizures

Question 12

What is the antidote for AChE poisoning?

Answer 12

1) cholinergic receptor antagonist (Atropine)
**if irreversible
2) Pralidoxime
- pesticide/nerve gas poisoning
- most effective if given within a few hours of exposure

Question 13

How does pralidoxime regenerate AChE?

Answer 13

• it attaches to the organophosphate and pulls it off the enzyme
• phosphate is removed, enzyme functions as normal

Question 14

What are the 4 contraindications to the use of parasympathomimetic drugs?

Answer 14

1) asthma: bronchoconstriction
2) COPD: bronchoconstriction
3) peptic ulcer: gastric acid secretions
4) obstruction of urinary or GI tract: stimulates M3 (smooth muscle contraction)

Question 15

Cholinergic agent side effects and toxicity (SLUD)

Answer 15

Salivation
Lacrimation
Urination
Defecation
- increased sweating/decreased HR/pupil constriction/CNS activation

Question 16

Alzheimer’s Disease

Answer 16

• atrophy of the brain
• widening of sulci and thinning of gyri
• improper processing of beta-amyloid precursor protein leads to toxic form, promoting apoptosis
• loss of cholinergic neurons in the brain

Question 17

Tacrine (MOA, reversibility)

Answer 17

**Alzheimer’s med
- bind to anionic site and block ACh binding
- reversible
- enhances cognitive ability
- does not slow progression of disease

Question 18

Treatment for Alzheimer’s Disease (5)

Answer 18

• Tacrine
• Donepezil
• Rivastigmine
• Galantamine
• Memantine

Question 19

Donepezil (MOA, reversibility, 5)

Answer 19

**Alzheimer’s med
- bind to anionic site and block ACh binding
- reversible
- enhances cognitive ability
- does not slow progression
- approved to treat all stages

Question 20

Rivastigmine (reversibility? what does it do to cognitive ability? effectiveness? SE?)

Answer 20

• reversible carbamate AChE inhibitor
• enhances cognitive ability by increasing cholinergic function
• loses effectiveness as disease progresses
  side effects: nausea, vomiting, anorexia, and weight loss
  newer long-acting carbamate: eptastigmine

Question 21

Galantamine (reversibility/effectiveness?5)

Answer 21

• reversible competitive AChE inhibitor
• extract from daffodil bulbs
• loses effectiveness as disease progresses
• may be a nicotinic receptor agonist
• inhibitors of P450 enzymes will increase galantamine bioavailability

Question 22

Memantine (5)

Answer 22

• NMDA receptor antagonist
• receptors are activated by glutamate in the CNS in areas associated with cognition and memory
• neuronal loss in Alzheimer’s may be related to increased activity of glutamate
• may slow progression
• favorable adverse effects