Cholinergics

Question 1

Stimulation of muscarinic M1, M3, and M5 receptors results in what?

Answer 1

Activation of the IP3, diacylglycerol cascade to increase intracellular Ca++

Question 2

Where are muscarinic receptors located?

Answer 2

All parasympathetic end organs and sweat glands and many CNS neurons

Question 3

Where are nicotinic receptors located?

Answer 3

Skeletal muscle, autonomic ganglia, adrenal medulla

Question 4

What are the effects of direct-acting muscarinic agonists?

Answer 4

Negative chronotropy/inotropy, release of NO in vessels (vasodilation and subsequent decreased BP), miosis (constriction of iris), bronchoconstriction, increased secretions, increased sweat, increased GI motility and secretion, relaxation of bladder sphincter

*remember these are all parasympathetic

Question 5

Stimulation of muscarinic M2 and M4 receptors results in what?

Answer 5

Inhibition of cAMP production and/or activation of voltage-gated K+ channels (results in hyperpolarization in SA node and atrial cells)

Question 6

Name the direct muscarinic agonists

Answer 6

ABC - acetylcholine, bethanechol, and carbachol

*bethanechol is badass because it doesn’t give a fuck about nicotinic receptors (the other two are also nicotinic agonists at high doses)

Question 7

What are some general clinical uses for direct-acting cholinergic agonists?

Answer 7

Overcoming post-op paralytic ileus, urinary retention, and glaucoma

Question 8

What are the contraindications to using direct-acting cholinergic agonists?

Answer 8

Asthma, heart conditions, peptic ulcer, GI/urinary tract obstruction, and hyperthyroidism (could get A fib)

Question 9

What is the primary clinical use for carbachol?

Answer 9

Used in eyedrops as miotics for wide-angle type glaucoma treatment

Question 10

Describe the mechanism of action of nicotine and its clinical relevance.

Answer 10

A potent nicotinic receptor agonist that is uncharged so it readily passes the BBB. It is used clinically for smoking cessation.

Question 11

Why is nicotine addictive?

Answer 11

Because it activates the midbrain reward pathway increasing the release of dopamine particularly in the nucleus accumbens –> pleasure

Question 12

Describe the side effects associated with nicotine.

Answer 12

Nausea/vomiting, CNS excitation, enhancement of short-term memory from increased attention, addiction and cravings, increased GI tone/activity, and increased HR/BP

Question 13

Describe the mechanism of action and clinical use of varenicline.

Answer 13

It is a partial agonist at a4B2 nicotinic receptors, binding and activating them to lesser degree than nicotine. Used for smoking cessation. Don’t give to depressed/suicidal patients!

*If you wanna get clean from nicotine, you’ve gotta do your part(ial agonist)

Question 14

Name and describe the general mechanism of action of indirect-acting cholinergic agonists.

Answer 14

Neostigmine, physostigmine, donepezil, and sarin.

They are all anticholinesterases, blocking metabolism of ACh to increase levels. *Sarin is a poison

Question 15

What is the main clinical use of physostigmine?

Answer 15

A miotic agent to treat glaucoma.

*Can cross BBB

Question 16

What is the main clinical use of donepezil?

Answer 16

Treatment for Alzheimer’s
*Crosses BBB

Increased ACh levels improve memory/cognition (effects are modest) and can cause insomnia (think of all the confused old people who don’t ever sleep)

Question 17

What are the clinical uses of neostigmine?

Answer 17

Used for myasthenia gravis, paralytic ileus, and reverses vecuronium

*You won’t be paralyzed after I sting you with neostigmine

Question 18

What are the effects of sarin?

Answer 18

SLUDGE

salivation
lacrimation
urination
defecation
GI distress
emesis

(+the usual, pulm edema, twitching, resp paralysis, ataxia, confusion, convulsions, coma)

Question 19

Describe the mechanism of action and clinical use of botulinum toxin.

Answer 19

Protein neurotoxin that blocks ACh release by cleaving SNAP-25 (the protein required to release ACh from vesicles) used for wrinkle reduction and muscle relaxation.

*SNAP you look 25 again!

Question 20

Name the muscarinic antagonists and their clinical uses.

Answer 20

Atropine- preanesthetic medication (reduce secretions, relax bronchi), antispasmodic, antidiarrheal, treats sarin poisoning, and tx for bradycardia

Ipratropium- bronchodilation

Question 21

Name the nicotinic antagonists.

Answer 21

SVT - succinylcholine, vecuronium, trimethaphan

*SVT? no nicotine for me!

Question 22

Describe the mechanism of action and clinical use of trimethaphan.

Answer 22

It is the only clinically available ganglionic (a3) blocker. Used for acute dissecting aortic aneurysm to rapidly control BP and block reflexes

Question 23

Describe the physiological effects of trimethaphan.

Answer 23

Vasodilation –> hypotension, venous dilation –> decreased CO, tachycardia, mydriasis (etc)

Big things to remember are listed because it treats acute dissecting aortic aneurysm so you don’t want high BP

Question 24

Describe the mechanism of action and clinical use of vecuronium.

Answer 24

It is a competitive antagonist that binds to ACh recognition sites blocking ACh access. Used for muscle paralysis (lasts 1-1.5 hours) and can cause hypotension and histamine release

Question 25

How can you reverse the effects of vecuronium?

Answer 25

Give neostigmine (often with atropine) which increases ACh levels at the NMJ eventually overcoming the blockade.

Question 26

Describe the adverse effects associated with succinylcholine and thus what patients to avoid using it on.

Answer 26

Can cause malignant hyperthermia from Ca++ release (give dantrolene to block release from sarcoplasmic reticulum in skeletal muscle) and also increases K+ release which can cause hyerkalemia and arrhythmias. Thus avoid in renal failure, burn patients, patients w/ large areas of denervated muscle

Question 27

How is succinylcholine metabolized and why is it relevant?

Answer 27

It is metabolized by cholinesterase. This is relevant because you DO NOT reverse it with neostigmine (remember that’s an anticholinesterase)

Question 28

Describe the mechanism of action and clinical use of pralidoxime.

Answer 28

It can reactivate acetylcholinesterase and is used with atropine to treat sarin exposure.

Question 29

What is the focus of Alzheimer’s treatment?

Answer 29

Focus is on anticholinesterases – mechanisms to increase ACh levels at CNS synapse.