CHOLINERGIC AGONISTS

Dr. Muhammad Adil Rasheed

Cholinergic agonists can be defined as drugs which
produce actions similar to that of acetylcholine either by

1. Directly interacting with cholinergic receptors

2. By increasing availability of acetylcholine at its receptor

sites

2
 CLASSIFICATION
I. DIRECT ACTING CHOLINOMIMETICS
1.Cholinomimetic esters e.g. acetylcholine, carbachol
2.Cholinomimetic alkaloids e.g. pilocarpine, muscarine and
nicotine
3.Miscellaneous agents e.g. cevimeline, aceclidine

II.INDIRECT ACTING CHOLINOMIMETICS OR

CHOLINESTERASE ENZYME INHIBITORS
1.Reversible cholinesterase enzyme inhibitors e.g.
neostigmine, physostigmine
2.Irreversible cholinesterase enzyme inhibitors e.g.
dichlorvos, malathion
3
 I. DIRECT ACTING CHOLINOMIMETICS

• Direct acting cholinomimetics are drugs which interact

directly with cholinergic receptors and activate them
to produce pharmacological response.

4
 1. ACETYLCHOLINE
• Acetylcholine (ACh) act on all cholinergic nerves and is
the stimulant of both muscarinic and nicotinic receptors.

5
 MUSCARINIC ACTIONS
• These are exerted primarily on the cardiovascular system,
smooth muscles and exocrine glands, where muscarinic
receptors are predominantly present.
•

• Acetylcholine does not differentiate between the various

subtypes of muscarinic receptors (M 1 through M5) and
bind to all.
• The muscarinic effects are produced at somewhat lower
concentration and generally predominate over nicotinic
effects.

6
 Cardiovascular System
• BLOOD VESSELS: Acetylcholine produces dilatation of all
vascular beds including the coronary and pulmonary vessels
due to presence of M3 subtypes of muscarinic receptors
located on the endothelial cells of the vasculature.
• BLOOD PRESSURE: IV administration of a small dose
produces a rapid fall in blood pressure owing to
generalized vasodilatation.
• Large doses produce increase in blood pressure by
stimulation of nicotinic receptors located on adrenal
medulla, which causes release of catecholamines in
circulation.
• HEART: The actions of acetylcholine on the heart mimic
effects of vagal stimulation. When given IV produces
decrease in heart rate and force of cardiac contraction.
7
 Non-vascular Smooth Muscles
• GASTROINTESTINAL TRACT: Causes contraction of all
non-vascular smooth muscles including Gl tract. It
produces increase in tone, amplitude of contractions
and peripheral activity of stomach and intestine.
•

• OTHER SMOOTH MUSCLES: Increases motility and

contraction of uterus, urinary bladder, gall bladder
and bronchiolar smooth muscles.

Other Effects
• EXOCRINE GLANDS: It stimulates all glands causing
enhanced salivation, lachrymation, sweating,
tracheobronchial secretion and gastric secretion.
8
 NICOTINIC ACTIONS
• These are exerted at the skeletal neuromuscular
junction, autonomic ganglia, adrenal medulla and
CNS.
• SKELETAL MUSCLE: Intra-arterial injection produces
skeletal muscle fasciculation due to stimulation of
the nicotinic receptors.
• ADRENAL MEDULLA AND AUTONOMIC GANGLIA: It
stimulates nicotinic receptors of adrenal medullary
chromaffin cells to cause release of epinephrine and
norepinephrine into circulation.

9
 CENTRAL NERVOUS SYSTEM

• Acetylcholine injected IV does not penetrate blood

brain barrier due to lipophobic nature.

• However, direct injection of ACh into the brain

produces a complex pattern of stimulation followed
by depression.

10
 CLINICAL USES
• Acetylcholine has no systemic use because of its
multiplicity of actions and rapid inactivation by both
acetylcholinesterase and plasma cholinesterase.
• However, acetylcholine chloride (I %) in combination with
mannitol is used as an ophthalmic solution for
production of miosis during corneal grafting.
• Direct application of acetylcholine to the iris causes rapid
miosis of short duration.

11
 2. CARBACHOL

• Carbachol is a potent synthetic choline ester.

• It is active on both muscarinic and nicotinic

receptors.

12
 PHARMACOLOGICAL EFFECTS
• Pharmacological properties similar to acetylcholine.
• It exerts both muscarinic and nicotinic effects, but
the muscarinic actions usually predominate.
• It produces effects on cardiovascular system and GI
tract because of its potent actions on both
muscarinic receptors in heart and GI tract and
nicotinic receptors in autonomic ganglia and adrenal
medulla.
• Locally instilled into eye, it mimics the effects of
acetylcholine causing miosis.

13
 CLINICAL USES

• Occasionally used for treatment of colic in horses

or ruminal stasis in cattle.
• It may also be used to treat post-operative
intestinal atony, retention of urine or uterine
disorders.
• It is primarily used locally in the eye as a miotic
agent to cause contraction of pupil and decrease
in intraocular pressure.

14
 SIDE EFFECTS/ADVERSE EFFECTS
• Extremely potent. Its systemic use cause salivation,
sweating and abdominal pain.
• Also causes hypotension, bronchoconstriction,
purgation, urination and tremors.
• It can cause rupture of intestine if intussusception or
other mechanical obstructions are present in the gut.

TREATMENT
• Atropine and epinephrine are effective antidotes to
overdose toxicity or severe side effects from
carbachol.
15
 3. PILOCARPINE

• Pilocarpine is obtained
from the Pilocarpus plants.
• It is a non-selective
muscarinic receptor
agonist, widely used in the
treatment of glaucoma for
over 100 years.

16
 MECHANISM OF ACTION

• It stimulates muscarinic receptors at the post-

ganglionic neuro effector junction directly, with very
minimal nicotinic effects.

• Although it is a non-selective muscarinic receptor

agonist in the parasympathetic nervous system, but
its actions are more significant on M3-receptor.

17
 PHARMACOLOGICAL EFFECTS
• It stimulates mainly muscarinic receptors with a more
selective action on exocrine glands than other tissues.

• Exocrine glands: It stimulates flow of secretions from

exocrine glands including salivary, sweat, mucous, gastric
and pancreatic secretions.
• It is one of most potent stimulators of secretions like
sweat, tears and saliva.

• OTHER EFFECTS: Pilocarpine augments gastrointestinal

motility and also enhances tone and motility of uterus,
urinary bladder, gall bladder and biliary ducts.

18
• EYE: Pilocarpine produces a rapid miosis and contraction
of the ciliary muscle when it is applied topically to the
cornea.
• It produces a rise in intraocular pressure.

• CARDIOVASCULAR SYSTEM: The effects of pilocarpine

are complex.
• Small doses generally cause a fall in blood pressure
(muscarinic).
• This response is prevented by atropine

19
 CLINICAL USES
• Pilocarpine is primarily used in ophthalmology
mainly in the treatment of glaucoma.

• Pilocarpine is considered the drug of choice in

emergency lowering of intraocular pressure and
glaucoma.

• Reduction of intraocular pressure occurs within a few

minutes and lasts 4 to 8 hours.

• Pilocarpine may also be used topically in eye to

control mydriasis produced by atropine.

20
 SIDE EFFECTS/ADVERSE EFFECT
• High doses of pilocarpine may evoke severe
muscarinic signs like colic, diarrhoea, sweating,
salivation, bronchoconstriction, hypotension and
bradycardia.

• Local irritation may occur after its topical application

in eye.

• TREATMENT: Atropine is a specific antidote to

pilocarpine toxicity.

21
 II. INDIRECT ACTING CHOLINOMIMETICS

• These are agents which inactivate or inhibit the

enzyme acetylcholinesterase, thereby preventing
it from hydrolyzing acetylcholine.

• Thus inhibitors of acetylcholinesterase indirectly

provide a cholinergic action by prolonging the
lifetime of acetylcholine produced endogenously
at the cholinergic nerve endings.

22
• The accumulated acetylcholine at synaptic and
neuro-effector junctional sites provoke a response at
all cholinoceptors in the body, throughout the central
and peripheral nervous systems.
•

• Therefore, indirectly acting cholinomimetics are

commonly called anticholinesterase agents or
cholinesterase enzyme inhibitors.

• These agents are important both as therapeutic

agents and potent toxicants.

23
According to stability of the complexes formed with
acetylcholinesterase enzyme, the anticholinesterase
agents are divided into two groups:

1. Reversible anticholinesterase agents (reversible

cholinesterase inhibitors)
2. Irreversible anticholinesterase agents (irreversible
cholinesterase inhibitors).

24
 REVERSIBLE ANTICHOLINESTERASE
AGENTS
They form reversible complex with acetylcholinesterase
enzyme leading to temporary inhibition of enzyme and
accumulation of ACh at cholinergic sites.

25
A. CARBAMATES
1. Quaternary ammonium compounds e.g. neostigmine,
demecarium.
2. Tertiary/ Secondary amines e.g. physostigmine.
3. Carbamate insecticides e.g. carbaril and propoxur.

B. NON-CARBAMATES
1. Quaternary ammonium compounds e.g. edrophonium
2. Acridine derivatives e.g. tacrine.
3. Miscellaneous agents e.g. galantamine

26
 IRREVERSIBLE ANTICHOLINESTERASE
AGENTS
• Irreversible anticholinesterase agents (Irreversible
cholinesterase inhibitors) are compounds which
have capacity to bind covalently to
acetylcholinesterase enzyme resulting in its
irreversible inhibition and causing the long lasting
accumulation of acetylcholine at all cholinergic
sites.

27
A. Phosphates and pyrophosphates
Tetraethyl pyrophosphate (TEPP), dichlorvos
B. Phosphorothioates
Parathion, fenthion
C. Phosphoramidates
Phospholan, mephospholan
D. Phosphonates
Metrifonate
E. Phosphorothiolates
Echothipate
F. Phosphorohalides
Diisopropyl-fluorophosphate (DFP)
G. Phosphorocyanides
28
Tabun
• Irreversible cholinesterase inhibitors include organic
esters of phosphorus called ORGANOPHOSPHORUS (OP)
compounds.
• These compounds were developed initially as chemical
warfare during World War II, but presently they are used
mainly as insecticides in agricultural and veterinary
practices.
• Organophosphorus compounds are highly lipophilic and
some are non-polar and have prominent action on both
peripheral and central nervous systems.
• Many of these agents are extremely toxic and potent
compounds.
• The organophosphorus insecticides have a very limited
therapeutic application.
• Nerve agents, also referred to as nerve gases are
extremely potent organophosphates used primarily as
weapons of mass destruction.
29