Cholinomimetics

Question 1

What are the 5 muscarinic receptor subtypes?

Answer 1

M1 - Salivary glands, stomach, CNS
M2 - Heart
M3 - Salivary and sweat glands, bronchial/visceral SM, Eye
M4, M5 - CNS

Question 2

How can muscarinic affects be abolished?

Answer 2

Using low doses of the antagonist atropine

Question 3

What do larger doses of ACh do to the body after an atropine blockade of muscarinic receptors?

Answer 3

Induce effects similar to those caused by nicotine

Question 4

Where do nicotine receptors exist?

Answer 4

On all post ganglionic neuronal cell bodies

Question 5

Where do all ACh receptors exist?

Answer 5

On all post ganglionic neuronal cell bodies in ANS

Question 6

What are nicotinic receptors?

Answer 6

FASTER ligand gated ion channels

Question 7

What are the 5 subunits of nicotinic receptors?

Answer 7

alpha beta, gamma, delta, epsilion

Question 8

What are the muscle types of subunits of nicotinic receptors?

Answer 8

2alpha, beta, delta, epsilion

Question 9

What are the ganglion types of subunits of nicotinic receptors?

Answer 9

2alpha, 3beta

Question 10

What does the subunit combination determine?

Answer 10

Ligand binding properties of the receptor

Question 11

What are the effects of ACh like on nicotinic receptors?

Answer 11

Relatively weak

Question 12

What does cholinergic innervation mediate in the eye?

Answer 12

1. ciliary muscle contraction - near vision
2. sphincter pupillae contraction - miosis and drainage of intra-ocular fluid
3. lacrimation - tears

Question 13

What is impeded in a glaucoma?

Answer 13

Contraction of the sphincter pupillae opens a pathway for aqueous humour, allowing drainage via the Canals of Schlemm thus reducing IOP

Question 14

Where are the muscarinic receptors mainly located in the heart?

Answer 14

M2 AChR are located mainly in the atria and the nodes

Question 15

What effects do the muscarinic receptors have on the cardiovascular system?

Answer 15

Decreased HR, CO, vasodilation
Depresses the heart by:
- Reduction of cAMP
- Decrease Ca2+ entry leading to lower CO
- Increase K+ efflux therefore decreasing HR

Question 16

What does ACh act on in the vasculature?

Answer 16

Acts on vascular endothelial cells to stimulate NO release via M3 AChR

Question 17

What is PNS innervation like in the vasculature?

Answer 17

Most blood vessels don’t have PNS innervation

Question 18

What are the muscarinic effects on non vascular SM?

Answer 18

SM with PNS innervation contracts instead of relaxes so:
Lungs - bronchoconstriction
Gut - Increased peristalsis (can lead to GI pain)
Bladder - increased bladder emptying

Question 19

What are the muscarinic effects on exocrine glands?

Answer 19

Salivation
Increased bronchial and GI secretions
Increased sweating

Question 20

What are 2 examples of directly acting cholinomimetic drugs?

Answer 20

Bethanechol - choline ester

Pilocarpine - alkaloid

Question 21

What is bethanechol?

Answer 21

A choline ester - M2 AChR selective antagonist that is resistant to degradation, orally active and has limited access to the brain. Half life is 3-4 hrs.

Question 22

What is bethanechol used for?

Answer 22

Aid bladder emptying and enhance GI motility

Question 23

What is philocarpine?

Answer 23

A non-selective muscarinic agonist with good lipid solubility - attaches to any subtype of muscarinic receptor

Question 24

What is philocarpine used to treat?

Answer 24

Glaucoma

Question 25

What are indirectly acting cholinomimetic drugs used for?

Answer 25

Increasing the effect of normal PNS stimulation

Question 26

What are the two types of cholinesterase enzymes that are used to metabolise ACh to choline and acetate?

Answer 26

Acetylcholinesterase | Butyrylcholinesterase

Question 27

What are the properties of acetylcholinesterase? (3)

Answer 27

Found in synapses Rapid Highly selective for ACh

Question 28

Where is butyrylcholinesterase found?

Answer 28

in plasma and most tissues but not in synapses

Question 29

What is the specificity of butyrylcholinesterase?

Answer 29

Broad substrate specificity?

Question 30

What are the effects of cholinesterase inhibitors?

Answer 30

Low dose - causes enhanced muscarinic activity Moderate dose - further enhancement, increased transmission of all ANS ganglia (inc nAChRs) High dose TOXIC - depolarising block at ANS ganglia and NMJ

Question 31

What are examples of reversible antocholinesterases?

Answer 31

Physostigmine, neostigmine, donepezil

Question 32

What do reversible anticholinesterases do?

Answer 32

Donate a carbamyl gropu to the enzyme active site, blocking the active site - competitive

Question 33

What is physostigmine?

Answer 33

Tertiary amine that acts at post ganglionic PNS synapse

Question 34

What is physostigmine used to treat

Answer 34

Glaucoma (aids IOP reduction) | Atropine poisoning

Question 35

What are examples of irreversible anticholinesterases?

Answer 35

Ecothiopate, dyflos, sarin (all organophosphate compounds)

Question 36

What do irreversible anticholinesterases do?

Answer 36

Rapidly react to enzyme active site and leave a large blocking group - stable and resistant to hydrolysis

Question 37

What is ecothiopate?

Answer 37

A potent inhibitor of anticholinesterase?

Question 38

What is ecothiopate used to treat?

Answer 38

Glaucoma (eye drops) but it has a prolonged duration of action

Question 39

What are the side effects of ecothiopate?

Answer 39

Sweating, blurred vision, GI pain, bradycardia, hypotension, respiratory difficulty

Question 40

What is special about non- polar anticholinesterases and needs to be considered when giving doses?

Answer 40

They can cross the blood brain barrier therefore lose doses can cause excitation with possibility of convulsions and high doses can lead to unconsiousness, respiratory depression and death

Question 41

What drugs are used to treat alzheimers?

Answer 41

Donepezil and Tacrine

Question 42

How do the drugs that are used to teat alzheimers help?

Answer 42

They potentiate the central cholinergic transmission, relieving AD symptoms but does not affect degeration

Question 43

What is organophosphate poisoning?

Answer 43

Accidental exposure to organophosphates in insecticides or deliverate use as nerve agents can cause servere toxicity causing increase in muscarinic activity, CNS excitation and depolarising NM block

Question 44

What is the treatment for organophosphate poisoning?

Answer 44

Atropine in IV Artificial respiration Pralidoxime in IV