Cholinomimetic Agents

Question 1

Define cholinomimetic agent

Answer 1

Nonaceytlcholine compounds that mimic actions of acetylcholine.

Question 2

How do cholinomimetic agents act on the body?

Answer 2

1. As stimulants (DIRECT AGONIST): Directly binding to ACh receptors
2. As cholinesterase inhibitors (indirect agonist):
   Indirect cholinergic action by preventing breakdown of ACh
   or-if ACh doesn’t get broken down, stays around longer in synapse and allows it to continue to produce cholinergic actions.

Question 3

What are the two groups of direct acting cholinomimetics?

Answer 3

1. Esters of choline (acetylcholine)

2. Alkaloids (muscarine and nicotine)

Question 4

T/F Quarternary Ammoniums are Hydrophobic?

Answer 4

F. Quarternary Ammoniums aka choline esters are Hydrophillic and poorly penetrate into CNS

Question 5

What are Quaternary ammonium hydrolyzed by?

Answer 5

Acetylcholinesterase (AChE). The variance of the rate of hydrolysis effects the half-life of the drug.

Question 6

What do variations in chemical structure alter in regards to quaternary ammoniums?

Answer 6

Potency, and susceptiblity to hydrolysis by AChE

Question 7

What are 4 examples of cholinomimetic alkaloids

Answer 7

1. Muscarine
2. Pilocarpine
3. Nicotine
4. Lobeline

Question 8

T/F cholinomimetic alkaloids are poorly absorbed after oral administrations?

Answer 8

F. cholinomimetic alkaloids are well absorbed after oral administration.

Question 9

T/F cholinomimetic alkaloids have a large volume of distribution?

Answer 9

T. The lipid soluble characteristic of alkaloids allow for a large volume of distribution (typically the structure is tertiary amine-but can be quaternary as well)

Question 10

T/F cholinomimetic alkaloids are able to cross the blood brain barrier into CNS

Answer 10

T The lipid soluble characteristic of alkaloids allows it to cross the blood-brain barrier into the CNS (including muscarine)

Question 11

T/F cholinomimetic alkaloids are susceptible to AChE

Answer 11

F cholinomimetic alkaloids are not susceptible to AChE-they rely on other mechanisms of metabolism

Question 12

What is the indirect action of cholinomimetics?

Answer 12

Normally the action of ACh is terminated by AChE. Indirect cholinomimetics inhibit AChE therefore prolonging the presence and actions of ACh at all ACh receptors (M,N,NMJ and brain)

Question 13

What are the 3 chemical groups of AChE inhibitors? (continuum)

Answer 13

1. Simple alcohols-bind weakly and reversibly to AChE (shorter half life <10 minutes)
2. Carbamate esters-Bind reversibly but tighter (extends 1/2 life 30 min to 6 hours)
3. Organophosphates-Covalent binding is extremely stable (nearly irreversible) creates a very long half-life of hundreds of hours.

Question 14

What organs do cholinomimetics effect regardless of direct or indirect status?

Answer 14

Eye
Respiratory system
GI tract
GU tract

Question 15

How do cholinomimetics effect the eye?

Answer 15

1. miosis-pupillary constriction

2. accommodation

Question 16

What role do muscarinic agonists and AChE inhibitors play in intra-ocular pressure?

Answer 16

Muscarinic agonists and AChE inhibitors REDUCE intra-ocular pressure in narrow and wide angle glaucoma by allowing the the outflow of aqueous humor. (drugs: pilocarpine, physostigmine)

Question 17

What effect do cholinomimetics have on the respiratory system?

Answer 17

Cause contraction of smooth muscle in bronchial tree, and stimulates secretions form tracheobronchieal mucosa (obviously we wouldn’t WANT to do this).

Question 18

What are the cholinomimetic effects on the GI tract?

Answer 18

Increased secretory and motor activity in the gut (fight or flight).
stims-salivary,gastric glands, pancreas, and small intestine
increases peristalsis
relaxes most GI sphincters

Question 19

What are cholinomimets used to achieve in GI disorders

Answer 19

Agents can be used to correct depressed smooth muscle activity and increase motility: Post operative ileus, and congenital megacolon. (neostigmine)

Question 20

What effect do cholinomimetics have on the GU tract?

Answer 20

Trigger voiding of the bladder.

Question 21

What are the clinical uses for cholinomimetics?

Answer 21

Tx. urinary retention (meds bethenacol, neostigmine)

Question 22

What organs are effected differently dependent on Direct or indirect action of cholinomimetics?

Answer 22

CV systems
Secretory Glands
CNS
Peripheral NS
Neuromuscular Junction

Question 23

T/F We often use direct cholinomimetics as a heart medication

Answer 23

F. This drug increases and decreases the heart rate by reducing peripheral vascular resistance. When the drop in BP occurs as a result of vasodilation the heart compensates by increasing the HR- Because this med also decreases the heart rate by decreasing the firing at the sinoatrial node the patient will result in bradycardia and reduce cardiac output! it is unpredictable so we don’t use it as a heart medication.

Question 24

T/F ACh agonist are used in cardiovascular medicine because there aren’t any other drugs that do this well.

Answer 24

False there are drugs that work better and more predictably and are used in CV med instead of ACh agonists.

Question 25

What is the role of indirect cholinomimetics in the CV system?

Answer 25

Bradychardia and drop in cardiac output. AChE inhibitors allow for the parasympathetic side to overcome what happens on the sympathetic side (there are more ACh receptors on the parasymp side). this results in a modest DROP in BP

Question 26

What are signs of toxicity in Muscarinic Agonists? What do you tx with?

Answer 26

SLUD-salivation, lacrimation, urination, defecation. TX with atropine, an anticholinergic

Question 27

What are signs of toxicity of direct nicotinic agonists? What do you tx with?

Answer 27

CNS stim-convulsions, coma, respiratory arrest, skeletal muscle depolarization leading to blockate and resp paralysis, and HTN and cardiac arrhythmias. TX is supportive until drug is metabolized

Question 28

What are signs of cholinesterase inhibitor toxicity? What is the TX?

Answer 28

Often related to organophosphates-DUMBBELLS- diarrhea, urination, mitosis, bradycardia, bronchoconstriction, emesis, lacrimation, salivation, sweating. TX includes

1. monitor VS
2. Decontaminate if possible (vomitting)
3. Antidote with parenteral atropine or pralidoxime (2-PAM) which reactivated inhibited AChE before the full covalent bond forms through “aging”