By Duy Thai, 1997 Pharmacology Semester 1 page 1 of 4

CHOLINERGIC PHARMACOLOGY II

Muscarinic receptors
• Location of muscarinic receptors:
• On tissues innervated by postganglionic parasympathetic nerve fibres:
• Heart
• GIT smooth muscle
• Bronchi
• Eye
• Glands
• On tissues innervated by postganglionic cholinergic sympathetic nerve fibres:
• Sweat glands on the skin

Muscarinic effects on tissues

Organ Effect M receptor

Heart Bradycardia M2 (decrease in cAMP)
Blood vessels Vasodilation M3 (increase IP3 à Ca2+)
Lung Constriction M3
GIT Constriction M3
Glands Secretion M3
Stomach Acid secretion M1
Eye Pupil constriction M3
(constrict circular muscle)

• All the effects on smooth muscle are mediated by M3 receptors which act to increase the levels of intracellular Ca
via IP3. This generally causes constriction.
• The exception is in the blood vessels. Why?
• The blood vessels are lined by a layer of endothelium, with the smooth muscle located
underneath. When an agonist binds to the M3 receptor on the endothelial cells, it stimulates the
release of NO by these cells. NO diffuses down to the smooth muscle cells where it causes
relaxation of the smooth muscle, and hence vasodilation. If the endothelium were removed,
agonists acting directly on the smooth muscle M3 receptor would cause vasoconstriction.
• Hence, the vasodilation is a result of the indirect action of an M3 agonist.
• Note that blood vessels do not receive parasympathetic innervation and so vasodilation caused
by muscarnic receptors only occurs as a result of circulating muscarinic agonists. (Not due to
Ach released from nerve terminals)

Examples of muscarinic agonists

• Naturally occurring
• Anecholine (found in beetle nut)
• Pilocarpine (M agonist used in eye drops)
• Muscarine (found in mushroom, used experimentally)
• McNA343 (experimental, only selective M1 drug)
• Oxotremorine (centrally acting)
• Synthetic:
• Methacholine
• Similar in structure to Ach but with a methyl substitution, thus making it M selective.
• Acts on the heart, blood vessels
• Bethanechol
• Resistance to cholinesterase action, therefore has a longer life.
• Acts in the GIT
• Furthrethonium
• Acts in the bladder
By Duy Thai, 1997 Pharmacology Semester 1 page 2 of 4

Therapeutic uses of M agonists

• Not many uses, M antagonists are better.
1. Atrial tachycardia
• M agonists slow the heart, but have other effects since they are not M2 selective. It would be nice to have
a M2 selective agonist.
2. Reynauds disease (peripheral vasoconstriction)
• M agonists will cause vasodilation (M3 à NO à smooth muscle).
• Other effects as well sue to non specificity.
3. Paralytic ileus
• One of the good, effective uses of M agonists
• After an abdominal operation, the natural rhythms of the gut do not restart.
• Bethanechol is given to activate M3 receptors to cause gut motility.
4. Glaucoma
• Increase in intraocular pressure
• Give pilocarpine as eye drops which improves drainage of ocular fluid in the canal of Schlemm. It is
given because it gets across the membrane barrier of the eye more easily.
• Pilocarpine causes pupil constriction, which opens the canal of Schlemm. (pupil dilation blocks the canal
of Schelmm)
• Ach cannot be given because:
• It is too highly charged to pass through the membrane easily
• It is rapidly degraded
5. Alzheimers disease
• Found to have a development of cholinergic deficits.
• Oxotremorine has been developed as a M agonist which is able to pass through the blood brain barrier
and act centrally. It is not available for clinical use yet.

Muscarinic antagonists
• The prototype compound is atropine
• Others:
• Scopolamine
• Able to pass through BBB
• Homatropine
• Much shorter action than atropine
• It is the drug of choice when doing investigations of the eye, since it dilates the pupil for a short
time only.

*** IMPORTANT CONCEPT!

• A quaternary derivative of atropine can be produced by placing an extra methyl group on the N atom. A
quaternary N is produced which is now positively charged. This derivative is atropine metanitrate.
• It has the same effect as atropine, but acts locally because it cannot be absorbed.
• If given locally, it is not absorbed by the gut and so its activity is confined to the gut.
• It is often used as an antispasmodic to treat babies with colic.
• If injected, the effects will be purely confined to the periphery (No CNS effects)
• The concept is: if a quaternary derivative is produced, it will be poorly absorbed.

Subtype selective M antagonists

Pirenzepine M1
Methoctramine M2 Not important
HHSiD M3
By Duy Thai, 1997 Pharmacology Semester 1 page 3 of 4

Effects of blocking M receptors

Organ Effect M receptor

Heart Tachycardia M2
Blood vessels Vasodilation M3
Lung Dilation M3
GIT Relaxation M3
Glands Decrease secretions M3
Stomach Decrease acid M1
Eye Dilate pupil M3

• An antagonist binds to the same site as an agonist but has no effect of its own. Therefore, to see the effects of an
agonist, you need to have the effects of the agonist present first.
• e.g. The hear has resting vagal tone. This means that at rest, the vagus nerve is controlling the heart via
Ach. If, while at rest, atropine is given, it will block the M2 receptor so that Ach cannot work and so you
get a faster heart rate than it was initially. (The atropine did not cause the tachycardia directly).
• Say that the resting heart has go no nervous input. If atropine is given, it will block the M2 receptor but
we would not see any effect because three was no agonist activity to start off with.
• Analogy:
• Say you are riding a bike and you put on the brakes (antagonist). The brakes will cause the bike
to stop, so you say that the antagonist stops the bike. However, you can only see this effect if the
bike is in motion. If the bike is not moving and you put on the brakes, what will hhappen? How
do you know what effect the brakes had on the bike?

• Blood vessels have no parasympathetic innervation from the adventitia, it is only sympathetic. Hence, the resting
tone of blood vessels is not mediated by Ach. If atropine is given, it will block the M3 receptor but will not remove
endogenous tone. A side effect of atropine is that it will stimulate the release of histamine, which causes
vasodilation.

Therapeutic uses of muscarinic antagonists

• There is a much wider range than for angonists
1. Premedication
• Atropine
• Given before operations to prevent unwanted M stimulation.
• Want to eliminate bronchial secretions (don't want the patient to choke on their own secretions)
• Want to block vagal stimulation to the heart and lungs (want to keep airways open)
• During induction of anesthesia, there may be excessive vagal stimulation, which we want to
eliminate.
2. Antispasmodic
• Hyoscine N butyl Bromide
• A quaternary derivative
• Treats colic
3. Bronchodilator (asthma)
• Ipratropium
• A quaternary derivative
• Given by inhalation, get a local effect
4. Treatment of peptic ulcers
• Pirenzepine
• Selective M1 antagonist
• Not as good as H2 antagonists (e.g. cimetidine) or proton pump inhibitors (e.g. omeprazole)
5. Anticholinesterase toxicity
• Anticholinesterases inhibit the activity of ACE, which breaks down acetylcholine. Hence, Ach activity is
prolonged (the action of Ach is potentiated every time it is released) which causes excessive stimulation of
both N and M receptors. It is the M receptors in the brain which cause the lethal effects. Excessive
stimulation of the brain M receptors results in respiratory depression.
• Atropine is used to treat this condition by blocking all M receptors.
By Duy Thai, 1997 Pharmacology Semester 1 page 4 of 4

6. Parkinson's disease
• Benztropine
7. Motion sickness
• Hyoscine
8. Eye examination
• Homatropine
• Favoured because it passes through the conjunctiva easily and has a brief duration of action.

Nicotinic receptors
• Found in 2 major areas:
1. In autonomic ganglia
2. At skeletal NMJ
• Both types of receptors are clearly related, but they are different enough to be recognised by different drugs.
• The receptors are part of an ion channel.
• The ion channel is made up of α, β, γ, δ subunits, which form a pore.
• The 2 α subunits are the nicotinic receptor portion of the channel which bind Ach.
• A whole variety of α, β, γ and δ subunits have been discovered. Therefore, there may be a whole variety of N
receptors based on different combinations of these subunits.

Nicotinic agonists
• None of therapeutic use
• Nicotine
• Stimulate particularly ganglionic N receptors (also NMJ to some extent)
• Lobeline
• Similar to nicotine.
• Given to smokers in an attempt to stop smoking (by replacing nicotine addiction with lobeline addiction)
• Dimethyl phenylpipenzinium (DMPP)
• Selective for ganglionic N receptors

Nicotinic antagonists at the ganglion

• Hexamethonium
• First effective antihypertensive (not used any more)
• By altering the central carbon chain from 6 carbons to 10 (decamethonium), it changes the drug from
being ganglionic selective to NMJ selective.
• Poorly absorbed due to the presence of 2 highly charged N atoms, hence it is administered intravenously.
• Lots of side effects since it blocks all ganglia. You effectively shut off the whole autonomic nervous
system.
• Can develop tolerance. After a few weeks, the drug becomes less effective.
• Trimethaphan Only marginal improvement - better absorbed than hexamethonium but has the same
• Mecamylamine side effects -

The hexamethonium man - what happens if no ANS?

• Pink Vasodilation
No α1 constriction
• Postural hypotension Loss of sympathetic tone (α1 constriction)
• Handshake warm and dry Vasodilation (warm)
No M3 secretion of sweat glands
• Relaxed No flight or fight response (lack of β1 effects- increase heart rate and α1 effects)
• Cant cry No M3 secretion of lacrimal glands
• Can't blush Loss of vasomotor control
• Dry mouth and throat Loss of M3 secretions of salivary glands
• Long sighted Can't adjust pupil (M3-constriction and α1-dilation effect)
• Blinded by bright light Cant constrict the pupil (M3 effect)
• Cold Loss of heat through continual vasodilation, can’t vasocontrict to
• Thin No β2 effects in liver (gluconeogenesis, glycogenolysis)
• No appetite pains No M3 GIT contractions
• Constipated
• Retention of urine No α1 contraction of ureter and bladder
• Impotent No α1 contraction of vas