CHOLINERGIC AGONIST

(DIRECT ACTING)

BY
Dr. Sarwat Jahan
Assistant Professor
Pharmacology
2017
 LEARNING OBJECTIVES
• CLASSIFICATION OF CHOLINOMIMETICS
• ESTERS OF CHOLINE
• BASIC PHARMACOLOGY OF THE DIRECT-
ACTING CHOLINOCEPTOR STIMULANTS
 ACETYLECHOLINE
 PILOCARPINE
 Absorption, Distribution, and
Metabolism
• Choline esters are poorly absorbed and poorly distributed into the
central nervous system
• All are hydrolyzed in the gastrointestinal tract
• Acetylcholine is very rapidly hydrolyzed
• Methacholine and the carbamic acid esters (carbachol and
bethanechol) are still more resistant to hydrolysis by cholinesterase
• Tertiary alkaloids are well absorbed from most sites of
administration.
• Nicotine, is sufficiently lipid-soluble to be absorbed across the skin.
• Muscarine, a quaternary amine, is less completely absorbed from
the gastrointestinal tract than the tertiary amines
Properties of choline esters
 PHARMACODYNAMICS
A. Mechanism of Action
• Activation of the parasympathetic nervous system modifies
organ function by two major mechanisms.
1. First, acetylcholine released from parasympathetic nerves
activates muscarinic receptors on effector cells to alter organ
function directly.
2. Second, acetylcholine released from parasympathetic nerves
interacts with muscarinic receptors on nerve terminals to
inhibit the release of their neurotransmitter.
• Muscarinic agonist binding to M1, M3, and M5 receptors activates
the inositol trisphosphate (IP3), diacylglycerol (DAG) cascade.
• DAG in the opening of smooth muscle calcium channels;
• IP3 releases calcium from endoplasmic and sarcoplasmic reticulum.
• M2 and M4 muscarinic receptors inhibits adenylyl cyclase activity in
tissues (eg, heart, intestine).
• Activation of muscarinic receptors also increases potassium flux
across cardiac cell membranes and decreases it in ganglion and
smooth muscle cells.
• These muscarinic effects on cAMP generation reduce the
physiologic response of the organ to stimulatory hormones.
 ACETYLCHOLINE
• Quaternary ammonium compound that cannot penetrate
membranes.
• Lacks therapeutic importance because of its multiplicity of
actions (leading to diffuse effects) and its rapid inactivation
by the cholinesterases.
• ACh has both muscarinic and nicotinic activity
 MECHANISM OF ACTION
MUSCARINIC EFFECTS:
o Stimulation of phospholipase C.
o Activation of muscarinic
receptors also increase K+ flux
across cell membranes.
NICOTINIC EFFECTS:
o Acetylcholine after binding to
nicotinic receptors opens the
ionic channels, which in turn
regulate the depolarization and
repolarization processes.
 PHARMACOLOGICAL
ACTIONS
MUSCARINIC EFFECTS:
EYE CVS
LUNGS GIT
URINARY BLADDER GLANDS
NICOTINIC EFFECTS:
AUTONOMIC GANGLIA
SKELETAL MUSCLES
 MUSCARINIC ACTIONS
EYE:
o Constriction of pupil (Miosis)
o Contraction of ciliary muscle
o Spasm of accommodation
o Lacrimation
o Reduction of intraocular pressure
CVS:
o Reduces heart rate
o Reduces force of contraction
o Decreases conduction through
AV node
o Produces vasodilatation
o Reduces blood pressure
RESPIRATION:
o Produces bronchoconstriction
o Increases bronchial secretions
 Decrease in blood
pressure:
• ACh activates M3 receptors found on endothelial cells lining the
smooth muscles of blood vessels, results in the production of
nitric oxide from arginine.
• Nitric oxide then diffuses to vascular smooth muscle cells to
stimulate protein kinase G production, leading to
hyperpolarization and smooth muscle relaxation via
phosphodiesterase-3 inhibition.
• Atropine blocks these muscarinic receptors and prevents ACh
from producing vasodilation.
GIT:
o Increases G.I.T motility
o Decreases sphincter tone
o Increase the GIT secretions
GENITOURINARY TRACT:
o Stimulates detrusor
o Relaxes trigonal muscles of urinary
bladder
GLANDS:
o Increases secretion of exocrine glands
 NICOTINIC ACTIONS
AUTONOMIC GANGLIA:
o Stimulates release of neurotransmitters
• Nicotine action is the same on both parasympathetic and
sympathetic ganglia.
• Sympathomimetic in the case of the cardiovascular system, .
• Dramatic hypertension is produced by parenteral injection of
nicotine; sympathetic tachycardia may alternate with a
bradycardia mediated by vagal discharge.
• In the gastrointestinal and urinary tracts, the effects are
largely parasympathomimetic: nausea, vomiting, diarrhea,
and voiding of urine are commonly observed.
• Prolonged exposure may result in depolarizing blockade of the
ganglia
• ADRENAL MEDULLA:
o Acetylcholine causes the release of adrenaline by adrenal
medulla.

NEUROMUSCULAR JUNCTION:
o Acetylcholine causes the skeletal muscle contraction
 THERAPEUTIC USES

Acetylcholine has no therapeutic

utility as a drug as exogenous
acetylcholine is rapidly destroyed
in the body.
 PILOCARPINE
• Alkaloid PILOCARPINE is a tertiary amine and Stable to
hydrolysis by Ach E
• Compared with ACh and its derivatives, it is far less potent
but is uncharged and can penetrate the CNS at therapeutic
doses.
• Pilocarpine exhibits muscarinic activity and is used primarily
in ophthalmology.
 Actions:
• Applied topically to the eye, pilocarpine
produces rapid miosis and contraction of the
ciliary muscle.
• When the eye undergoes this miosis, it
experiences a spasm of accommodation.
• Pilocarpine is one of the most potent
stimulators of secretions but its use for
producing these effects has been limited
due to its lack of selectivity.
• The drug is beneficial in patients with
xerostomia resulting from irradiation of the
head and neck.
• Sjögren syndrome, is treated with oral
pilocarpine tablets
 Therapeutic use in
glaucoma:
• Pilocarpine is used to treat glaucoma and is the drug of
choice for emergency lowering of intraocular pressure of
both open-angle and angle-closure glaucoma.
• Pilocarpine is extremely effective in opening the trabecular
meshwork around the Schlemm canal, causing an immediate
drop in intraocular pressure as a result of the increased
drainage of aqueous humor.
• This action occurs within a few minutes, lasts 4 to 8 hours,
and can be repeated.
• The miotic action of pilocarpine is also useful in reversing
mydriasis due to atropine
 Adverse effects:
• Blurred vision, night blindness, and brow ache.
• Poisoning with this agent is characterized by exaggeration of
various parasympathetic effects, including profuse sweating
(diaphoresis) and salivation.
• The effects are similar to those produced by consumption of
mushrooms
• Parenteral atropine, at doses that can cross the blood–brain
barrier, is administered to counteract the toxicity of
pilocarpine.
 BETHANECHOL
• An unsubstituted carbamoyl ester, structurally related to
ACh.
• Not hydrolyzed by AChE due to the esterification of carbamic
acid, although it is inactivated through hydrolysis by other
esterases.
• It lacks nicotinic actions (due to the addition of the methyl
group) but does have strong muscarinic activity.
• Its major actions are on the smooth musculature of the
bladder and GI tract.
• About a 1-hour duration of action.
 Actions:
• Bethanechol directly stimulates muscarinic receptors, causing
increased intestinal motility and tone.
• It also stimulates the detrusor muscle of the bladder, whereas the
trigone and sphincter muscles are relaxed.
• These effects produce urination.
Therapeutic applications:
• In urologic treatment, bethanechol is used to stimulate the atonic
bladder, particularly in postpartum or postoperative, non
obstructive urinary retention.
• Bethanechol may also be used to treat neurogenic atony as well as
megacolon.
 Adverse effects:
Generalized cholinergic stimulation include
sweating, salivation, flushing, decreased
blood pressure, nausea, abdominal pain,
diarrhea, and bronchospasm.
• Atropine sulfate may be administered to
overcome severe cardiovascular or
bronchoconstrictor responses to this
agent.
 CARBACHOL
• Has both muscarinic and nicotinic actions.
• Like bethanechol, carbachol is an ester of carbamic acid and a poor
substrate for AChE.
• It is biotransformed by other esterases, but at a much slower rate.

Actions:
• Carbachol has profound effects on both the cardiovascular and GI
systems
• It can cause release of epinephrine from the adrenal medulla by its
nicotinic action.
• Locally instilled into the eye, it mimics the effects of ACh, causing
miosis and a spasm of accommodation in which the ciliary muscle
of the eye remains in a constant state of contraction.
 Therapeutic uses:
Because of its high potency, receptor nonselectivity, and
relatively long duration of action, carbachol is rarely used
therapeutically except in the eye as a miotic agent to treat
glaucoma by causing pupillary contraction and a decrease in
intraocular pressure.
Adverse effects:
• At doses used ophthalmologically, little or no side effects occur
due to lack of systemic penetration (quaternary amine).