2 - Cholinergics

Question 1

Describe the pathway of ACh synthesis and secretion in the synapse.

Answer 1

• Choline/Na+ symport into the cell
• AcCoA + Choline –ChAT–> ACh
• transporter pumps ACh into vessicle
• when neuronal signal occurs, Ca2+ imported into the cells triggers vessicles to fuse w the membrane and release ACh into synapse.
• ACh is broken down by AChE

Question 2

What drugs can manipulate ACh synthesis and secretion into the synapse?

Answer 2

hemicholinium inhibs choline import
-AChE I –> incr ACh in synapse
vesamicol-blocks vessicular ACh transporter
-botox - inhibis fusion of vessicle w plasma membrane

Question 3

Whih direct acting cholinergic agonists are esters?

Answer 3

ACh (Miochol)
carbachol (Isoptocarbachol)
methacholine (Provocholine)
bethanechol (Urecholine)

Question 4

Describe the signal transduction pathway for an M2 receptor.

Answer 4

G protein actiation results in activation go K+ channel and hyperpolarization, slowing HR

Question 5

Which stereochemistry trans/cis of ACh is preferred by nicotinic receptors?

Answer 5

trans

Question 6

What are important structural features of muscarine and its analogs?

Answer 6

methyl to the back.

positive amine up.

Question 7

What are important structure features of nicotine?

Answer 7

dibasic
two rings
these receptors are less stereoselective.

Question 8

What are the direct-acting cholinergic receptor agonists that are alkalois and synthetic analogs?

Answer 8

(+) Muscarine
Nicotine (Nicorett)
pilocarpine (Isptocarpine)

Question 9

Describe the molecular actions of ACh at muscarinic receptors?

Answer 9

amine interacts with aspartic acid
aromatic AAs-pi cation interaction
ester portion hydrogen bonds with N, W

substle changes in receptor structure cause signalling

Question 10

What is the actin of Chantix? What are ADRs?

Answer 10

alpha4beta2 nicotinic receptor partial agonist
-act nic R less than nicotine; blocks nicotine from binding

well tolerated
SE: GI (N/V, constipation, gas), altered dreams

Question 11

What receptors do ACh and activate and what is its clinical use?
What other drug has the same activity?
Which drug is sensitive to cholinesterase?

Answer 11

M,N
intraocular use for miosis during surgery

carbachol, also used in glaucoma

ACh

Question 12

What receptors does pilocrpine activate and what is its clinical use?

Answer 12

M

glaucoma

Question 13

What receptors does bethanecholactivate and what is its clinical use?

Answer 13

M

urinary retention, post-op ileus

Question 14

What receptors does vareniciline activate and what is its clinical use?

Answer 14

N

smoking cessation

Question 15

Why are antimuscarinic drugs contraindicated in glaucoma?

Answer 15

will prevent reduction in intraocular pressure by paralyzing the ciliary muscle

Question 16

S/A: modifications of trimethylammonium head for cholinergic agonists

Answer 16

inverse relationship btw size and activity. amine most active.

Question 17

S/A: modifications to choline chain of cholinergic agonists

Answer 17

• 5 atoms ideal for binding pocket
• alpha methyl-more nicotinic selective
• beta methyl-more muscarinic selective and more resistant to metabolism by AChE

Question 18

S/A modifications to acetyl group of cholinergic agonists

Answer 18

• choline esters with larger alkyl groups–incr nicotinicc selectivity
• carbamyl group (O-CO-NH2) –> non-sel but decr metabolism by AChE
• replace C=O with P=0(OCH3)2 –> potent nicR ag