Cholinomimetics

Question 1

What are muscarinic effects

Answer 1

Those that can be replicated by muscarine and demolished by low doses of the antagonist atropine
Corresponds to parasympathetic stimualtion

Question 2

What occurs after atropine blockade

Answer 2

Larger doses of acetylcholine can induce effects similar to those caused by nicotine

Question 3

What are the 3 main muscarinic receptor subtypes

Answer 3

M1 - salivary glands, stomach, CNS
M2 - Heart
M3 - Salivary glands, bronchial/visceral SM, sweat, eye

Question 4

Describe nicotinic receptors

Answer 4

Ligand gated ion channels
subunits: α β γ δ ε
Subunit combo determines ligand binding properties of the receptor 
Muscle type: 2α β δ ε 
Ganglion type: 2α 3β  (CNS - similar)
Effects of ACh relatively weak

Question 5

What are the muscarinic cholinergic target systems

Answer 5

Eye
Salivary glands
Sweat glands 
Lung 
Heart 
Gut 
Bladder
Vasculature

Question 6

What are the muscarinic effects on the eye

Answer 6

Contraction of the ciliary muscle (near vision)
Contraction of the sphincter papillae (iris circular muscle) - contracts pupil (miosis) and improves drainage of intraocular fluid
Lacrimation (tears)

Question 7

How does the parasympathetic system act to alleviate glaucoma

Answer 7

Contraction of sphincter pupillae opens pathway for aqueous humour, allowing drainage via the canals of Schlemm and reducing intra-ocular pressure

Question 8

Explain how muscarinic receptor activation affects heart rate

Answer 8

1. ACh binds to M2 AChR in atria and nodes
2. Decrease cAMP
3. Decreased Ca2+ entry to decrease CO
4. Increased K+ efflux to decrease HR

Question 9

Explain how muscarinic receptor activation affects vasculature

Answer 9

1. Acts on vascular endothelial cells to stimulate NO release via M3 AChR (no parasympathetic innervation)
2. NO induces VSMC relaxation
3. Decrease in TPR

Question 10

What are the second messengers for the muscarinic receptors

Answer 10

M1,M3,M5 - IP3, DAG (Gq)

M2, M4 - cAMP (Gi)

Question 11

What are the muscarinic effects on non-vascular smooth muscle

Answer 11

Contraction
Lung - bronchoconstriciton
Gut - increases peristalsis
Bladder - increased bladder emptying

Question 12

What are the muscarinic effects on exocrine glands

Answer 12

Salivation
Increased bronchial secretions
Increased GI secretions (including HCl)
Increased sweating (SNS-mediated)

Question 13

What are some typical agonists at muscarinic receptors

Answer 13

Choline esters e.g. bethanechol

Alkaloids e.g. pilocarpine

Question 14

Describe pilocarpine

Answer 14

From pilocarpus
Non-selective muscarinic agonist 
Half-life = 3-4hrs
Has good lipid solubility 
Used for glaucoma

Question 15

What are the side effects for pilocarpine

Answer 15

Blurred vision
Sweating
GI disturbance and pain
Hypotension
Resp. diseases

Question 16

What are the main muscarinic effects

Answer 16

Decreased heart rate
Decreased blood pressure
Increased sweating
Difficulty breathing
Bladder contraction
Gastrointestinal pain
Increased salivation and tears

Question 17

Describe bethanechol

Answer 17

Modification of acetylcholine to produce an M3 ‘selective’ agonist
Resistant to degradation, orally active, limited access to the brain
Half-life = 3-4hrs
Used to assist bladder emptying and enhance gastric motility

Question 18

What are the side effects of bethanechol

Answer 18

Sweating
Impaired vision 
Bradycardia
Hypotension
Respiratory difficulty

Question 19

What do indirectly acting cholinomimetic drugs do

Answer 19

Increase the effect of normal parasympathetic nerve stimulation by targeting the enzymes that break down the NT

Question 20

What are some examples of reversible anticholinesterases

Answer 20

physostigmine, neostigmine, donepezil (‘Aricept’)

Question 21

What are some examples of irreversible anticholinesterases

Answer 21

ecothiopate, dyflos, sarin

Question 22

What are the two types of cholinesterase enzymes

Answer 22

Acetylcholinesterase (true of specific)

Butyrylcholinesterase (pseudocholinesterase)

Question 23

What do cholinesterase enzymes metabolise acetylcholine to

Answer 23

Choline and acetate

Question 24

Describe acetylcholinesterase

Answer 24

Found in all cholinergic synapses
very rapid hydrolysis reaction (>10,000 reactions/sec)
Highly selective for acetylcholine

Question 25

Describe butyrylcholinesterase

Answer 25

Found in plasma and most tissues, but not localised in cholinergic synapses
Broad substrate specificity (can hydrolyse other esters)
Causes low plasma acetylcholine
Genetic variation

Question 26

How does increasing the dose of cholinesterase inhibitors change the effect

Answer 26

Low - enhanced muscarinic activity
Moderate - further enhancement, increased transmission at all autonomic ganglia
High - depolarising block at autonomic ganglia and NMJ

Question 27

How do reversible anticholinesterases work

Answer 27

Competitive inhibitor
Donates a carbamyl group to the enzyme, blocking the active site
This group is then removed by slow hydrolysis (mins)

Question 28

Describe physostigmine

Answer 28

Naturally occurring tertiary amine from calabar beans
Acts at the postganglionic parasympathetic synapse
Half life = 30mins
Used for glaucoma, aids intraocular fluid drainage
Used to treat atropine poisoning

Question 29

How do irreversible anticholinesterases work

Answer 29

Rapidly react with the enzymes active site to leave a large blocking group
This is stable and resistant to hydrolysis, new enzymes must be produced
(Organophosphates compounds)

Question 30

Describe ecothiopate

Answer 30

Potent inhibitor
Slow reactivation of the enzyme takes several days
Used as eye drops for glaucoma for prolonged drainage of intraocular fluid

Question 31

What are the side effects of ecothiopate

Answer 31

Sweating
Blurred vision 
GI pain
Bradycardia
Hypotension
Respiratory difficulty

Question 32

How do anti cholinesterase drugs affect the CNS

Answer 32

non-polar drugs (e.g. physostigmine, nerve agents) can cross the blood brain barrier
low - excitation, maybe convlusions
high - unconsciousness, respiratory depression and death

Question 33

What are the treatments for organophosphate poisoning

Answer 33

Atropine, pralidoxime via IV

Artificial respiration