•Red : important

•Black : in male / female slides

•Pink : in female’s slides only
•Blue : in male’s slides only 
•Green : Dr’s notes
•Grey: Extra information, explanation
Editing File

LECTURE 3:
DIRECT ACTING
CHOLINERGIC DRUGS
OBJECTIVES:

By the end of this lecture students should be able to:

✓ Mention different types, locations,
and actions of cholinergic receptors

✓ Identify the mechanism of action of

direct acting cholinomimetics

✓ Describe the pharmacokinetics of

cholinergic drugs

✓ Identify pharmacological actions

and uses of cholinomimetics
 this slide is just for good understanding
Nervous System:
Central Nervous System peripheral Nervous System

● Brain ● Afferent (Sensory) ● Efferent (Motor):

● Spinal cord Somatic; skeletal muscles
Autonomic; Smooth
muscles: Sympathetic
Parasympathetic Enteric

Autonomic peripheral Nervous System

Parasympathetic
Parasympathetic Sympathetic Enteric
(Cholinergic)
(Cholinergic) (Adrenergic) (For GIT)
“The drugs of this lecture”

Preganglionic neurons: Postganglionic neurons:

-Long Synapses with -Short Synapses on the
postganglionic at or organ.
near organ. -Acetylcholine is
-Acetylcholine is neurotransmitter.
neurotransmitter. -Muscarinic receptor on
-Nicotinic receptor on the organ.
postganglionic neuron *Cholinergic Fibers:
or adrenal medulla. Fibers release Ach in ANS or
Somatic Nervous System
* ANS: Autonomic Nervous System

Found in Male’s slides only

Botox is Botulinum toxin that’s produced

by clostridium botulinum.
 Cholinomimetics
Drugs that produce actions similar to stimulation of
M.O.A parasympathetic system or similar to Acetylcholine.

Class Direct Cholinomimetics Indirect Cholinomimetics

Cause direct stimulation of cholinergic
Acts indirectly by inhibiting
receptors. Each receptor will give different
Acetyl cholinesterase thus preventing
effect depending on the receptor and the
Action drug/neurotransmitter.
the hydrolysis of Ach.
They are called Cholinesterase
inhibitors or anticholinesterases
Cholinergic drugs act upon two types of receptors:
Site of ● Nicotinic receptors
Action ● Muscarinic receptors

Cholinergic or Parasympathetic receptors

Nicotinic receptors (N) Muscarinic receptors (M)
“Central Receptors” “Peripheral Receptors”
Type I receptors: *when stimulation happens, Type II receptors:
channels open. G-protein linked receptors
Ion channel linked receptors (Ligand gated ion channels) Located at:
Located in:
● Skeletal muscles (Neuromuscular junction) (Nm) ● All target organs that are innervated
● Autonomic ganglia (Sympathetic and by parasympathetic fibers (Heart,
parasympathetic ganglia) (Nn)
● Adrenal Medulla (Nn)
CVS, Eye, Bladder, etc).Internal organs
● CNS (Nn) except ventricles
Subclasses: Subclasses:
● Nm: A class of nicotinic receptors found in skeletal
muscles.
● M1,M3,M5 are excitatory or
● Nn: A class of nicotinic receptors found in stimulatory in function. ‫اﻻﻋداد اﻟﻔردﯾﺔ‬
autonomic ganglia (sympathetic and ● M2,M4 are inhibitory in function. ‫اﻻﻋداد‬
parasympathetic) , CNS, and adrenal medulla.
Nn —> nerve to nerve Nm—> Nerve to muscle
‫اﻟزوﺟﯾﺔ‬

Nicotinic Receptors VS Muscarinic

Nicotinic receptors Muscarinic receptors
“Central cholinoceptors” “Peripheral cholinoceptors”

Almost excitatory Excitatory or inhibitory

Autonomic ganglia Nn
On all peripheral organs innervated by
sympathetic & parasympathetic
postganglionic parasympathetic fibers
stimulation

Adrenal medulla Nn Heart (bradycardia, M2)

release of catecholamines exocrine glands (secretion,M3)
(adrenaline & noradrenaline)

Skeletal muscles Nm contraction Smooth muscles (contraction, M3)

(GIT, urinary tract, bronchial muscles,
uterus)
 Direct Acting cholinergic drugs:
Actions that are similar to the effects of parasympathetic system activation.
Pharmacolo
gical Action

And are classified according to the type of receptor acting on into

Nicotinic Action Muscarinic Action

*Contraction of circular muscle of iris (also
called iris sphincter muscle or constrictor

Eye (M3)
pupillae)(miosis)
. Low concentration (Therapeutic *Contraction of ciliary muscles for near vision
dose) of Nicotine : When these 2 contractions happen , a
Muscle Contraction decrease in intraocular pressure happens.
Skeletal muscle

. High concentration (Toxic dose) (IOP) So we use drugs that have muscarinic
of Nicotine: actions to treat glaucoma.
Persistent depolarization and
-Bradycardia (decrease in heart rate) M2
endotheli

relaxation (Blocking of
Heart

-Release of Nitric oxide(NO) (EDRF)

um

depolarization). Constant
contraction of muscle means there which causes Vasodilation M3
is no repolarization which is
essential for muscle relaxation
Lung (M3)

leading to muscle paralysis. Constriction of bronchial smooth

Succinylcholine has similar effect. muscles and increase bronchial
secretion. Contraindication: Asthma

-Increase in motility(peristalsis) over

stimulation leads to diarrhea.
GIT

-Gastric acid secretion M1

Autonomic ganglia

-Relaxation of sphincter causing

By stimulating it. defecation M3
This happens by both
sympathetic and Urinary bladder:
muscles (M3)

parasympathetic stimulation. Contraction of muscles

Smooth

Secretion of Relaxation of sphincter leading

Neurotransmitters to urination.
Smooth muscle:
Contraction. Uterus is not sensitive
to muscarinic agonists
Exocrine glands

Increase in exocrine glands

release of Catecholamine
medulla
Adrenal

secretions (exocrine glands are glands

(Adrenaline and
(M3)

that secretes through ducts)

Noradrenaline). Over
which are:
stimulation leads Adrenergic
Sweat, Saliva, Lacrimal,
crisis
Bronchial, intestinal secretion.

___ -CNS excitation M1

-Memory, arousal, attention and

CNS

____ analgesia M4+M5

 Parasympathetic Actions on Eye
● It innervates the constrictor pupillae (circular muscle of iris)
which is important for adjusting the pupil in response to
change in light intensity and regulating the intraocular
pressure.
● Aqueous humor secreted by ciliary body is removed
continuously by drainage into the canal of schlemm.
● Normal intraocular pressure: 10-15 mmHg above
atmospheric pressure. Abnormal raised pressure (glaucoma)
leads to retinal detachment. if the ciliary body is contracted
the canal of schlemm will
● Cholinergic drugs leads to Miosis which decreases the open allowing the drainage of
intraocular pressure in glaucoma by increasing the filtration fluid
Ciliary muscle is contracted
angle. Suspensory ligament is
● When the ciliary muscle contracts, the lens bulges more. relaxed.
This parasympathetic reflex is essential to accommodate (Opposite action)

for near vision.

Direct Acting Cholinergic Drugs

Drug Type Natural Alkaloids Synthetic Choline Esters

● Are lipid soluble nitrogen ● Polar (contains N ion)

nonpolar compound found in quaternary ammonium
nature compounds
Features
● Tertiary amines ● muscarinic quaternary amine less
● Common suffix (-ine) which completely absorbed from the GIT
but still toxic when ingested in
means natural and basic
mushroom.
Nicotine & lobeline has ● Acetylcholine
● Pilocarpine Mnemonic:
an alerting action on ● Carbachol Always Care
● Nicotine the CNS
Bethanechol.
Examples ● Before Calling
● Lobeline and high levels of
● Cevimeline
nicotine leads to
convulsions and coma ● Methacholine 3X more resistant to hydrolysis

● Non-polar, lipid soluble ● Poor distribution

● Well absorbed by the skin. ● Cannot cross BBB so no CNS
effects
Pharmaco ● Not metabolized by
kinetics cholinesterase EXCEPT Ach
● all of them have longer
duration of action than Ach
● Never given I.V. or I.M. BUT
S.C.
● Bronchial asthma (because asthmatics are already hyperresponsive to cholinergic agonist, giving
cholinergic drugs may cause unwanted bronchoconstriction which leads to increased narrowing of airways).
● Peptic ulcer (M1 muscarinic agonists can stimulate gastric acid secretion from gastric parietal cells,
thus intensifying the acidity and ulceration)
● Angina pectoris (Chest pain, mostly related to a coronary artery disease, muscarinic receptors are
Contra- found on the SA node of the heart and slows heart rate when activated which can decrease the heart flow
indications further than it already is)
● Urinary incontinence (inability to hold in urine, spontaneous urination)
● Intestinal obstruction (the treatment for intestinal obstruction is providing rest for its activities,
muscarinic agonist increase its GIT motility and irritate the GIT even more in this case)
 Natural Alkaloids

Drug Pilocarpine

● Direct muscarinic agonist

M.O.A ● Acts mainly on eye and secretion

● Non-polar (lipophilic) tertiary amine

● Well absorbed, good distribution
● Cross BBB, so has CNS effects
P.K ● Cross placenta
● Not metabolized by cholinesterase
because basic drugs
● Long duration of action are best excreted in
● Excretion is enhanced by acidification of urine acidic medium

● Xerostomia (dry mouth)

Uses ● Drug of choice in emergency glaucoma (applied as eye drops)

● Profuse sweating
● Salivation
Side
● Bronchoconstriction
Effects
● Diarrhea
● CNS effects

Synthetic Choline Esters

Drug Acetylcholine Carbachol Bethanechol Cevimeline

(Carbamoylcholine) (Carbamoyl-β-methylcholine)

Muscarinic and -Muscarinic action - Prominent muscarinic Direct acting

nicotinic agonist on the eyes, GIT, actions on GI, UT. muscarinic agonist
M.O.A UT. - No nicotinic actions (M3)
due to the presence of a methyl
-Has nicotinic group which reduces its potency
actions (side effects) at nicotinic junctions.

- -Resistant to
hydrolysis by
-Resistant to hydrolysis
by acetylcholinesterase -
P.K acetylcholinestera -Longer duration than
se Acetylcholine
-Longer duration
than Ach
Not used clinically. Drug of choice in: treatment of the
(Why?) -Paralytic ileus it’s a dry mouth
-not as selective as
post-operative side effect of the symptom
anesthesia
it acts on both -Treatment of associated with
-Urinary retention in
glaucoma as eye Sjogren’s
muscarinic and case of postoperative
drops only syndrome
Uses nicotinic receptors. atony and neurogenic
Sjogren’s
-Has short duration bladder.
syndrome:
of action. Why? Due autoimmune disease
characterized by
to rapid metabolism formation of antibodies
by leading to dryness of
mouth (xerostomia) and
acetylcholinesterase eye.

Side
effects - Nicotinic side
effects - -
 Found in Male’s slides only

TOXICITY

muscarinic Nicotinic
stimulants stimulants

CNS: Skeletal muscle CVS:

-convulsions endplate Hypertension -Nausea
-coma depolarization: and -vomiting
-respiratory arrest depolarization block Cardiac -diarrhea
respiratory paralysis arrhythmias -salivation
-cutaneous vasodilation
-bronchial constriction

TREATMENT:

● Muscarinic excess → atropine

● CNS stimulation → central anticonvulsants e.g.
Diazepam
● Neuromuscular block → mechanical respiration

Chronic Nicotine toxicity:

● 30% of deaths due to cancer and coronary heart
disease are due to smoking.

● Nicotine contributes to risk of vascular diseases,

sudden coronary death and ulcers.
 Summary
Drug Acetylcholine Carbachol Bethanechol Pilocarpine
(Carbamoylcholine) (Carbamoyl-β-methylcholine)

quaternary quaternary quaternary tertiary

Polar Polar Polar non Polar
chemistry

NOT better absorbed than Ach complete

absorption

metabolised by Not metabolised by cholinesterase

cholinesterase
metabolism

very short longer (++)

duration

I.V eye drops oral, eye drops oral, S.C oral, eye drops
administrati S.C
on

direct Cholinomimetic
Drug Acetylcholine Carbachol Bethanechol Pilocarpine Cevimeline

muscarinic muscarinic muscarinic muscarinic muscarinic

recepto nicotinic nicotinic
rs

+++
muscari
nic

NOT eyes, GIT, GIT, more on exocrine

selectiv urinary urinary eyes, glands
ity bladder bladder exocrine
glands

nicotini +++ NO
c

NO Glaucoma paralytic ileus, Glaucoma sjogren’s

uses urinary xerostomia syndrome
retention
QUIZ
 QUIZ

1. Nicotinic receptor - Muscarinic receptors

2.Increase in motility(peristalsis)-Increase in secretion Postsurgical

-Relaxation of sphincter causes defecation.

3.Because they are not metabolized by Cholinesterase

4.Pilocarpine

5.eye drops

6. Is not selective as it acts on both nicotinic and muscarinic

receptors-Has short duration of actin.

7. 2 acetylcholine molecules

8.For dry mouth symptom associated with Sjogren’s syndrome

9.Bethanechol

10.No, it has quaternary structure that makes it polar. Thus can't cross
the BBB.

11.Diarrhea,Bradycardia,Sweating & Salivation,Broncho-constriction

 GOOD LUCK

Team Leaders:
Nouf Alshammari Zyad Aldosari

Team Members:
Deana Awartani
Reema Alserhani
Najla Alkilani
Njoud Almutairi
Noura Almazrou
Shahad alsahil
Reema Almutawa
Sources:
Team 435 Shahad Althaqeb
Team 437