6 - Cholinomimetics

Question 1

What is a cholinomimetic

Answer 1

A drug that stimulates the action of ACh and thus the parasympathetic nervous system

Question 2

What happens to acetate produced by ACh metabolism?

Answer 2

It is transported away and buffered in the blood

Question 3

What is a muscarinic effect?

Answer 3

An effect that can be replicated by muscarine and abolished by atropine.

Question 4

How can stimulation similar to nicotine be achieved using atropine?

Answer 4

Atropine blockade of muscarinic actions

Large dose of ACh

Question 5

Briefly outline structure of muscarinic receptors

Answer 5

type 2, metabotropic

intracellular loop with coupled G protein

there are 7 TM segments

Question 6

Outline the types and locations of muscarinic receptors

Answer 6

M4 and M5 in CNS

M1 - Salivary glands, stomach, CNS
M2 - Heart
M3 - Salivary glands, bronchial visceral smooth muscle, sweat glands, eye

Question 7

Categorize the muscarinic receptors in terms of whether they are stimulatory or inhibitory

Answer 7

M1, M3 Generally excitatory
M2 Inhibitory {Heart}

M1, M3, M5 Gq, IP3 DAG (stimulatory G protein)
M2, M4 Gi, cAMP (inhibitory G protein) - inhibits adenylyl cyclase

Question 8

Outline the structure of nicotinic receptors

Answer 8

They are ligand gated ion channels - they have 5 subunits a b d y e; the combination of subunits determines ligand properties of the receptor

Muscle 2a bde
Ganglionic 2a 3b

Question 9

What is the relative strength of ACh on nicotinic receptors?

Answer 9

It is relatively weak

Question 10

List the muscarinic targets

Answer 10

Eye

Heart
Vasculature

Lung
Gut
Bladder

Exocrine Glands

Question 11

Outline muscarinic effects in the eye

Answer 11

Eye - contraction of ciliary muscle - near vision

    - contraction of sphincter pupillae (circular muscle of the iris); miosis (pupil constriction), increased drainage of intraocular fluid*
    - lacrimation * via canals of Schlemm; in glaucoma, iris is ruffled and angle is reduced, cholinomimetic drug flattens iris back against the lens

Question 12

Outline muscarinic effects in the heart and vasculature that work in dropping BP

Answer 12

Heart (in nodes and atria) - decrease in cAMP; decreased cardiac output [negative inotropic], decreased HR [negative chronotropic]

Vasculature (have muscarinic receptors but no direct parasympathetic innervation) - vascular endothelial cells [M3, on endothelial cells, not muscle] produce NO which relaxes smooth muscle and decreases Total Peripheral Resistance

Question 13

Outline muscarinic effects in other areas of smooth muscle

Answer 13

Lung - Bronchoconstriction

Gut - Increased peristalsis (motility)

Bladder - Increased bladder emptying

Question 14

Outline muscarinic effects in the exocrine glands

Answer 14

• salivation
• bronchial secretions
• GI secretions
• increased sweating (via sympathetic nervous system)

Question 15

Summarise the systemic muscarinic effects of all organs symptomatically

Answer 15

Decreased HR

Decreased BP

Increased sweating

Difficulty breathing

Bladder contraction

GI pain

Increased salivation and tears

Question 16

What are the two types of muscarinic receptor agonists?

Answer 16

1. Direct - target receptor, bind and have efficacy; choline esters and alkaloids
2. Indirect - anticholinesterases (target one of 2), indirectly increase [ACh] by preventing breakdown, reversible or irreversible

Question 17

Outline the properties of choline esters with an example

Answer 17

Bethanechol (or new Cevimeline - greater M3 selectivity)

M3 selective
Resistant to cholinesterases
Oral
Limited access to brain
t1/2 3-4hrs

Given post-operatively to kickstart bladder emptying and gastric motility
Side effects: bradycardia, hypotension, respiratory difficulty

Question 18

What is the structure of bethanechol?

Answer 18

See structure

Question 19

Outline the properties of alkaloids with an example

Answer 19

Pilocarpine

Muscarinic selective but not for subtypes
t1/2 3-4 hrs, lipid soluble

Local treatment (eye drops) for closed angle glaucoma
Side effects: hypotension, respiratory distress

Question 20

What are the two types of cholinesterases that anticholinesterases can act on

Answer 20

Vary in distribution, substrate specificity and function

1. Acetylcholinesterase (true/specific) - ACh specific, fast acting, found at all cholinergic synapses, has a serine residue with OH group
2. Butyrylcholinesterase (pseudo) - broad specificity e.g. suxamethonium, found in plasma + other tissues, genetic variation, responsible for low plasma ACh

Question 21

Outline the mechanism of action for the two types of anticholinesterases

Answer 21

Reversible - PHYSOSTIGMINE, neostigmine, donepezil ‘Aricept’; donate a carbamyl group, slow hydrolysis (mins), surmountable

Irreversible - ECOTHIOPATE, dyflos, sarin; organophosphates, require new enzymes to be produced (days/weeks), insurmountable

Question 22

What are the general effects of anticholinesterases by dosage level?

Answer 22

At low doses - enhance muscarinic activity

At medium doses - they further enhance muscarinic activity and increase transmission at autonomic ganglia

At high doses - they are toxic due to depolarising block at autonomic ganglia and NMJ

Question 23

What is a depolarising block?

Answer 23

There are two phases to the depolarizing block. During phase I (depolarizing phase), depolarising blocking agents cause muscular fasciculations (muscle twitches) while they are depolarizing the muscle fibers. Eventually, after sufficient depolarization has occurred, phase II (desensitizing phase) sets in and the muscle is no longer responsive to acetylcholine released by the motoneurons.
At this point, full neuromuscular block has been achieved.

The prototypical depolarizing blocking drug is succinylcholine (suxamethonium). It is the only such drug used clinically.

Question 24

Outline the properties of reversible anticholinesterases with an example

Answer 24

Physostigmine

Primarily acts at the post-ganglionic parasympathetic synapse
t1/2 30mins

Used for treating glaucoma and atropine poisoning in children (atropa belladonna - deadly nightshade); in latter is given via IV shot, surmounts the atropine block

Question 25

Outline the properties of irreversible anticholinesterases with an example

Answer 25

Ecothiopate

Slow reactivation of the enzyme takes several days

Used as a prolonged treatment for glaucoma

Question 26

Why are organophosphates used a pesticides?

Answer 26

Insects are more sensitive to low doses

Question 27

What are the effects of anticholinesterases on the CNS?

Answer 27

Non-polar drugs (e.g. physostigmine, nerve agents) can cross the blood brain barrier

• cause excitations and convulsions
• can cause unconsciousness and respiratory depression resulting in death

Question 28

What is respiratory depression?

Answer 28

slow and ineffective breathing

Question 29

What are the effects and treatment of high level organophosphate exposure?

Answer 29

Severe toxicity (increased muscarinic activity, CNS excitation, depolarising NM block)

e.g. novichok, sarin (lipid soluble through skin)

Atropine (IV), artificial respiration, pralidoxime (IV)*

*N.B. phosphorylated enzyme ages within a few hours so it must be taken before then, it reactivates AChE