Pharmacology: Block 2: Neuroeffector Systems 4, Nicotinic/cholinergic Receptor Agonists/antagonists

Front 1

What is the effect of prolonged exposure to nicotinic receptor agonists?

Back 1

Blockage of signal transduction.

Front 2

What are the effects of nicotinic receptor agonists at the ganglionic nicotinic receptor?

Back 2

Agonists stimulate ganglionic transmission at low doses and block transmission at high doses.

Front 3

What is the effect of prolonged exposure to nicotinic receptor agonists?

Back 3

Blockage of signal transduction.

Front 4

What are the effects of nicotinic receptor agonists at the ganglionic nicotinic receptor?

Back 4

Agonists stimulate ganglionic transmission at low doses and block transmission at high doses.

Front 5

Competitive antagonists of the nicotinic receptor are what type of neuromuscular blockers?

Back 5

They are non-depolarizing blockers.

Vecuronium
Pancuronium
Turbocurarine (South American arrow poison)

Front 6

Nicotinic receptor agonists are what type of neuromuscular blocker?

Back 6

They are depolarizing neuromuscular blockers.

Succinylcholine

Front 7

True or false: Nicotinic receptor antagonists not are susceptible to AChE.

Back 7

False. Most are susceptible, with the exception of mivacurium.

Front 8

True or false: Nicotinic receptor agonists are susceptible to AChE.

Back 8

False. Less sensitive to AChE than ACh. Still sensitive to psuedocholinesterase, however.

Front 9

What are some chemical properties that both nicotinic receptor agonists/antagonists share?

Back 9

Both are quaternary amines that provide electrostatic binding to the nicotinic receptor, and also limit lipid solubility and CNS entry.

Front 10

(extra credit)

What is the basic structure of succinylcholine?

Back 10

Two acetylcholines, tail-to-tail.

Front 11

Both nicotinic receptor agonists and antagonists are used as ________ _________.

Back 11

Both nicotinic receptor agonists and antagonists are used as MUSCLE RELAXANTS.

Front 12

How does a nicotinic receptor antagonist cause a nerve block?

Back 12

It binds to the nicotinic receptor and does not allow ACh to bind.

Front 13

Describe the two phases involved with a neuromuscular block caused by a nicotinic receptor agonist.

Back 13

Phase I: Binding of the agonist causes fasciculations, but eventually a flaccid paralysis develops. This is a phase I block.

Phase II: Eventually the membrane repolarizes DESPITE the agonist being bound. This creates a situation that looks a lot like when a nicotinic receptor antagonist is bound (i.e. a non-depolarizing block).

Front 14

What effect does a AChE inhibitor have on the phases of nicotinic receptor agonists?

Back 14

In phase I, the agonist is bound and the ion channels are open, so giving an AChE inhibitor will allow more ACh to be around --> this will prolong the phase I response.

In phase II, the agonist is bound to the REPOLARIZED membrane. Here it is acting much like a competitive antagonist, so by giving an AChE inhibitor, you are increasing the amount of ACh present, and you are "competing off" the (competitive) agonist that is bound to the receptor.

Front 15

In general, what does an AChE do to the level of ACh?

Back 15

It increases the amount of ACh that is available.

Front 16

What adverse effect does tubocurarine have at high doses?

Back 16

(nicotinic receptor antagonist)

Causes a fall in blood pressure due to histamine release and ganglionic blockade.

Front 17

Adverse effect of pancuronium?

Back 17

(nicotinic receptor agonist)Increased heart rate due to antimuscarinic action.

Front 18

Adverse effects of succinylcholine?

Back 18

(nicotinic receptor agonist)

Has effects on PSNS (lowered heart rate) and S ganglia(increased heart rate, elevated blood pressure)

Also has effects on cardiac muscarinic receptors (lowered heart rate)

Succinylcholine releases K from muscle cells --> may lead to cardiac arrest, particularly in denervated muscle (b/c of increased number of AChR)

Succinylcholine also enhances Ca release from the SR --> muscle rigidity and heat production.

Also causes increased intraocular pressure, increased intragastric pressure, and muscle pain.

Front 19

What is a generalized statement about the effects of neuromuscular blockers on small muscles?

Back 19

The smaller muscles are the first to go and the first to recover.

Front 20

What are the three main theraputic uses of neuromuscular blocking agents?

Back 20

1. Adjunct to surgical anesthesia

2. For orthopedic procedures

3. To facilitate endotracheal intubation.

Front 21

Will the PSNS or the SNS be affected by nicotinic receptor antagonists/agonists?

Back 21

Both will be affected.

Front 22

What determines the effect of a ganglionic nicotinic receptor antagonist?

Back 22

The amount of S vs PS nervous tone at the target organ.

Front 23

What are the effects of nicotine on the adrenal medulla?

Back 23

Low doses --> high release of catecholamines

High doses --> low release of catecholamines

Front 24

Nicotine stimulates the receptors in the carotid and aortic bodies and causes what?

Back 24

1. Vasoconstriction
2. Increased HR
3. Increased BP

Front 25

What are the theraputic uses of ganglionic blocking agents?

Back 25

1. To control blood pressure in patients with acute dissecting aneurysms

2. To produce controlled hypotension during surgery.

3. To control autonomic hyperreflexia or reflex sympathetic dystrophy.

Front 26

What are the effects of AChE inhibitors at:

1. Peripheral neuroeffector junctions

2. Autonomic ganglia

3. Neuromuscular junction

4. CNS

Back 26

What are the effects of AChE inhibitors at:

1. Peripheral neuroeffector junctions: enhanced muscarinic transmission

2. Autonomic ganglia: Initial stimulation followed by depolarizing block.

3. Neuromuscular junction: Initial facilitation followed by a depolarizing block.

4. CNS: Initial stimulation followed by depression

Largely parasympathomimetic

Front 27

What are the two mechanisms of action of AChE inhibitors?

Back 27

1. Non-covalent competitive inhibition.

2. Covalent inactivation of AChE

Front 28

What are some examples of non-covalent competitive AChE inhibitors?

What is the action of these agents?

Back 28

Edrophonium
Ambenonium
(+ many others)

These inhibitors compete for the active site with ACh.

Front 29

What are some examples of covalent AChE inhibitors?

What is the action of these agents?

Back 29

Cabamoylate AChE:
Physostigmine
Neostigmine

Phosphorylate AChE:
Echothiophate
Isoflurophate
+ many insecticides

Front 30

Edrophonium

Back 30

(Tensilon®)

Non-covalent competitive AChE inhibitor
2-10 min block
Used to distinguish between myasthenic vs. cholinergic crisis.

Front 31

Ambenonium

Back 31

(Mytelase®)

May have mixed non-covalent/covalent activity
4-8 hr block (Uniquely long among non-covalent AChE inhibitors)
Used to treat myasthenia gravis

Front 32

Echothiphate

Back 32

(Phospholine®)

Covalent AChE inhibitor
Inactivates AChE via phosphorylation.
100+ hour block
Quaternary amine
Used to treat glaucoma (topical)

Front 33

Isoflurophate

Back 33

(Floropryl®)

Covalent AChE inhibitor
Creates a phosphorylated AChE intermediate
100+ hour block
Recovery probably comes from the synthesis of more AChE
Highly lipid soluble
Used to treat glaucoma (topical)
Used as an insecticide

Front 34

What are the basic steps of the interactions between ACh and AChE?

Back 34

1. ACh binds
2. ACh forms an intermediate covalent complex with ChE.
3. ACh-ChE complex collapses --> makes choline + acetylated ChE.
4. The acetylated ChE then undergoes rapid hydrolysis to yield acetate and the active enzyme.