Muscurinic Agonists and Antagonists part 1

Question 1

What are the two receptor types that Ach can bind to?

Answer 1

Muscarinic and Nicotinic

Question 2

What kind of receptors are muscarinic receptors?

Answer 2

G-protein coupled receptors

Question 3

What kind of receptors are nicotinic receptors?

Answer 3

Ligand Gated Sodium Channels

Question 4

What is AChE and what does it do? Where is it located?

Answer 4

This is a serine hydrolase enzyme located in the synapse that rapidly hydrolyzes ACh. It is called Acetylcholinesterase

Question 5

What is BuChE? Where is it located and what does it do?

Answer 5

this is an esterase that is located in the plasma and can also rapidly hydrolyze ACh

Question 6

What is the MOA and reason we use AChE inhibitors?

Answer 6

They bind to the AChE enzyme and prevent it from breaking down acetylcholine, which ultimately increases Ach in the synapse and causes increased muscle contraction and parasympathetic nervous system effects

Question 7

What happens to ACh release when M2 and alpha2 receptors are activated?

Answer 7

The ACh release decreases which decreases parasympathetic and skeletal muscle action

Question 8

Which receptors of M1-M5 are involved in Alzheimer’s?

Answer 8

M1, because they are located in the CNS AND on the enteric nerves which are the nerves that have low ACh release in Alzheimer’s

Question 9

What kind of muscarinic drug would you use in Alzheimer’s and why?

Answer 9

and M1 agonist because those are the receptor type that is located in the brain and Alzheimer’s is primarily associated with loss of acetylcholine secreting neurons so we want to promote ACh capabilities as much as possible.

Question 10

What kind of muscarinic drug can we use to treat Parkinson’s and why?

Answer 10

an M1 antagonist because when you decrease ACh you automatically increase Dopamine which is what you want to do in Parkinson’s because you overall have low dopamine levels and high ACh in the patient. They have ACh to spare.

Question 11

What neurotransmitter do muscarinic agonists primarily resemble?

Answer 11

Acetylcholine

Question 12

What three things are necessary for muscarinic agonists? These are the classic SAR requirements for muscarinic agonists.

Answer 12

1) an ammonium group that is either tertiary or quaternary
2) an ethylene bridge (has to only be two carbon groups)
3) an acyloxy group (-OOCH3), ether, or simply a keytone! you just need some type of oxygen over there

Question 13

What is Ing’s rule of 5?

Answer 13

between the nitrogen and the hydrogen on the acyloxy group there can only be 5 molecules! no more and no less because it has to be a particular spacing

Question 14

Can the branches off of the Nitrogen be bigger than a methyl group? like an ethyl?

Answer 14

no, they should stay methyls because the bigger they get the more your activity decreases and they no longer become agonists

Question 15

What happens when you add a methyl to the Beta carbon on a muscarinic agonist?

Answer 15

2 things: it becomes more selective for muscarinic receptors than nicotinic receptors AND it slows down the metabolism by AChE

Question 16

What is a carbamate? what does it go to activity? google picture

Answer 16

this is a functional group on the muscarinic agonists which increases the half life of the drug because it makes it harder for AChE to break it down and hydrolyze it

Question 17

what are two muscarinic agonists that do not fit the normal muscarinic agonist mold?

Answer 17

pilocarpine and cevimeline

Question 18

What is special about bethanicol and methocholine?

Answer 18

they have a methyl group on the beta carbon which causes them to be more selective for muscarinics over nicotinics and also increases their half live slightly because it makes them harder to break down.

Question 19

What are some diseases that muscarinic agonists can treat? (6)

Answer 19

• non-obstructive urinary retention
• can stop the muscarinic side effects of antidepressants
• help diagnose bronchial hyper-reactivity in subjects who do not have obvious asthma
• lowering intraocular pressure in glaucoma
• constriction of the pupil (miosis) after an eye exam
• dry mouth

Question 20

What drug treats non-obstructive urinary retention?

Answer 20

bethanachol

Question 21

what drug treats muscarinic side effects of antidepressants?

Answer 21

bethanachol

Question 22

what drugs treat the intra ocular pressure of glaucoma?

Answer 22

pilocarpine and carbachol

Question 23

what drugs treat dry mouth?

Answer 23

pilocarpine and cevemiline

Question 24

what drug is used in the diagnosis of hyper-sensitivity in patients with boarder line asthma?

Answer 24

methacholine

Question 25

what drug helps cause miosis in patients after their eyes have been dilated from an eye exam?

Answer 25

pilocarpine

Question 26

can a patient take a muscarinic agonist if they have IDS-D?

Answer 26

no, because it will cause them to poop even more

Question 27

can someone take these drugs if they are braycardic?

Answer 27

no, it will slow down their heart rate even more

Question 28

can someone take these drugs if they have asthma or COPD?

Answer 28

no because it will cause bronchoconstriction which is so bad for them

Question 29

do more muscarinic agonists or antagonist have selectivity?

Answer 29

usually antagonist have selectivity but agonists do not

Question 30

do many or few drugs contain muscarinic antagonist activity? why?

Answer 30

many, because the SAR requirements are simple for this indication and many drug molecules have it

Question 31

are there any OTC products with muscarinic antagonist activity?

Answer 31

yes, thats why it is so important for us to know about them

Question 32

what are the SAR requirements for muscarinic antagonists?

Answer 32

• the nitrogen must be a tertiary amine or quaternary amine
• the R1 and R2 group on the opposite side than the nitrogen atom are big benzenes or are part of the same ring. (they cant be too big tho because then it will not fit in the receptor)
• the R3 subsituent is either an OH or just hydrogen atom. It can also be apart of the R1 and R2 ring systems
• usually there is an aster linkage, but that doesnt have to be there. it can also be an ether or not there at all
• the length between the carbon with the rings attached is 2 to 4 molecules away from the nitrogen

Question 33

is a muscarinic agonist with 4 molecules in between the carbon bearing the rings and nitrogen going to be more of less potent than a muscarinic antagonist that has 2 molecules in between the carbon bearing the rings and the nitrogen?

Answer 33

less, the fewer molecules are in between, the more potent the antagonist is