Pharmacology 1:

4. Cholinergic agonists and

antagonists

Dr. Sarah Alanazi

shdalenzi@ju.edu.sa
Office number: G02
Office hours: Sunday 12:00 – 16:00
 Learning outcomes

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

• Describe the types of cholinergic receptors.
• Explain the mechanism of action and uses of cholinergic agonists.

• Explain the mechanism of action and uses of anticholinergic agents.

• Discuss the role of direct and indirect-acting cholinergic agents.

 Introduction to the Parasympathetic
Nervous System (PNS)

1. Overview of the Autonomic Nervous System (ANS):

• Composed of the Sympathetic and Parasympathetic divisions
• The PNS is responsible for maintaining “rest-and-digest” activities.

2. Key functions of the PNS:

• Conserves energy by lowering heart rate and promoting digestion.
• Controls:
• Smooth muscle (e.g., GI tract, bladder).
• Exocrine glands (e.g., salivary and sweat glands).
• Cardiac muscle.
 Introduction to the Parasympathetic
Nervous System (PNS)

3. Primary Neurotransmitter:
• Acetylcholine (Ach) is the key neurotransmitter.

4. Key Targets for Drug Action:

• Cholinergic Receptors:
• Muscarinic receptors (M1-M5) in smooth muscle, glands, and the heart.
• Nicotinic receptors in autonomic ganglia and skeletal muscle.
5. Clinical Relevance:
• Drugs targeting the PNS have applications in treating: Glaucoma,
Alzheimer’s disease, urinary retention, COPD and asthma.
 Cholinergic Receptors

• Two families: Muscarinic and

Nicotinic

• Distinguished from each other

based on their different affinities
for agents that mimic the action of
acetylcholine.
 1. Muscarinic Receptors

• Recognizes acetylcholine and muscarine (alkaloid from

mushrooms).

• Subclasses: M1, M2, M3 (functionally characterized). M4 & M5

identified but not functionally characterized.

• Locations:
• M1: Ganglia of the PNS.
• M2: Autonomic effector organs (e.g., cardiac cells, smooth
muscle, brain and exocrine glands).
• M3: Bladder, exocrine glands, smooth muscle.
 1. Muscarinic Receptors

• Muscarinic receptors are

G-protein coupled receptors
(GPCRs).
• M1 & M3: coupled to
IP3/DAG pathway.
• M2 & M4: cAMP pathway.
 2. Nicotinic Receptors

• Linked to ion channels.

• Locations:
• CNS, adrenal medulla, autonomic ganglia, neuromuscular
junction (NM/NN differentiation).

• Ganglionic receptors: Specifically blocked by hexamethonium.

• Neuromuscular receptors: Specifically blocked by tubocurarine.
 Cholinergic Agents

• Drugs that stimulate the PNS.

• Also known as cholinergic agonists/parasympathomimetic.
• Mimic Acetylcholine effects.

• Mechanisms:
• Direct-acting (Cholinergic agonists): Bind to cholinergic receptors.
• Indirect-acting (anticholinesterase): inhibit cholinesterase ->
increase Ach availability for the receptor.
• Reversible vs. irreversible.
 Effects of Cholinergic Agents

• Vasodilation (blood vessels), decreased HR (cardiac muscle), increased

GI motility, salivation, bladder contraction, bronchoconstriction, pupil
constriction.
• Dose-dependent effects:
• Low doses: Muscarinic stimulation (desired effects).
• High doses: Nicotinic stimulation (undesirable effects).
 Drug Effects of Cholinergic Agents

RESPONSE LOCATION
Vasodilation Blood vessels
Decreased contractility Cardiac muscle CVS
Decreased heart rate Node
Increased motility Muscles
Increased secretion / Increased Sphincters GI
salivation
-Contraction -Bladder
Genitourinary
-Dilation (increased frequency) -Sphincter
Bronchoconstriction Bronchial muscle Lung
Constriction / Decreased intraocular Pupil
pressure Eye
 Direct-Acting Cholinergic Agonists
1. Acetylcholine:
• Cardiovascular: Heart Rate Cardiac output Blood pressure.
• GIT: Stimulates intestinal smooth muscles.
• Bronchi: Secretions.
• Urinary: Detrusor muscle tone Urination.
• Eye: Miosis via circular muscle contraction.

Therapeutic use: Limited due to its multiplicity of actions and its rapid
inactivation by cholinesterases.
 Direct-Acting Cholinergic Agonists
2. Bethanechol:
• Directly stimulates muscarinic receptors.
• Increases intestinal motility and tone.
• Stimulates detrusor muscles of the bladder (while trigone and
sphincter are relaxed 🡪 Urination.

• Uses: Atonic bladder (postpartum/postoperative,

non-obstructive urinary retention), Neurogenic atony and
megacolon.
 Direct-Acting Cholinergic Agonists
3. Carbachol:
• Profound cardiovascular and GI effects.
• Stimulates adrenal medulla 🡪 Epinephrine release.
• Eye: Miosis and accommodation spasm (ciliary muscle of the eye
remains in a constant state of contraction).

• Uses: Miotic agent for glaucoma (pupillary contraction &

reduced intraocular pressure). Rarely used because it is
highly potent, non-selective and has a relatively long duration
of action.
 Indirect-Acting Cholinergic Agents
Cholinesterase inhibitors: Reversible vs. Irreversible
• Reversible (bind to cholinesterase for a period of minutes to hours):
• Short-acting (15mins): Edrophonium
• Intermediate-acting (3-6hrs): Physostigmine.
• Long-acting (6-8hrs): Carbamates.
• Newer & longer-acting: Donepazil
• Irreversible (bind to cholinesterase and form a permanent bond &
forces the body to make new cholinesterase):

• Extreme long-acting (e.g., Echothiophate).

• Permanent cholinesterase inhibition 🡪 Generalized cholinergic
stimulation.
 Reversible Cholinergic Agonist
• Physostigmine
• Mechanism of action: stimulates muscarinic and nicotinic receptors
(including nicotinic receptors of the neuromuscular junction).
• Intermediate action: duration of action is 2-4 hours.
• Uses:
• Intestinal and bladder atony.
• Glaucoma treatment (topical, produces miosis and spasm of
accommodation and reduction of intraocular pressure). Pilocarpine is
more effective
• Antidote for atropine, phenothiazines & tricyclic antidepressants.
• Adverse effects:
• Convulsions (high dose), bradycardia, reduced cardiac output.
 Reversible Cholinergic Agonist

• Neostigmine.
• Pyridostigmine.
• Demecarium.
• Tacrine.
• Donepazil. Lipid-soluble substances that cross the
• Rivastigmine. blood-brain-barrier & used for Alzheimers
disease treatment.
• Galantamine.
 Irreversible Anticholinesterases
• Echothiophate
• Mechanism of action: Generalized cholinergic stimulation.
Paralysis of motor function (causing breathing difficulties), and
convulsions. It produces intense miosis and thus, has therapeutic
use.
• Uses:
• Open-angle glaucoma (up to 1-week duration with single
administration).
• Not first-line due to cataract risk.
 Anticholinergic Agents
• Agents that block/inhibit the actions of acetylcholine (ACh) in the PNS.

• Also known as: parasympatholytic & cholinergic antagonists.

• Mechanism of action:
• Block acetylcholine action at cholinergic receptors.
• Competitive antagonists.
• Prevent cholinergic effects on: cardiovascular, GI, respiratory,
urinary, CNS, and ocular systems
• Types of anticholinergics:
1. Antimuscarinic agents: Majority of anticholinergic drugs.
2. Antinicotinic agents: Skeletal neuromuscular blockers.
 RESPONSE LOCATION
Small doses: decrease heart rate AV/ SA Node CVS
Large doses: increase heart rate

Decreased motility Muscles GI

Decreased secretion / Decreased salivation Sphincters
Constriction (retention) Bladder Genitourinary
sphincter

Bronchodilation /Decreased bronchial secretions Bronchial Lung

muscle
Dilation Pupil Eye

Small doses: decrease muscle rigidity & tremors CNS

Large doses: drowsiness, hallucinations
 Therapeutic uses of antimuscarinics

1. Atropine:
• SA node dysfunction, bradycardia, pre-surgery secretions, 2nd degree heart
block, antispasmodic (stomach, intestines & other organs) & eye drop for
examination and surgeries.
2. Scopolamine:
• Nausea and vomiting, motion sickness (applied as a transdermal patch behind
the ear), Gastrointestinal, renal or biliary spasms, Irritable bowel disease,
“truth drug” in combination with other drugs.
3. Dicyclomine:
• IBD, peptic ulcers, hypersecretory state.
 Therapeutic uses of antimuscarinics

4. Ipratropium
• Bronchodilation, reduces secretions from nose, pharynx and
bronchi, chronic bronchitis, asthma, chronic obstructive
pulmonary disease.

5. Benztropine
• Parkinson’s disease (reduces muscle rigidity/muscle tremors).
 Side effects of antimuscarinics

1. Cardiovascular: increased heart rate & dysrhythmias

2. Central nervous system: Hallucinations & drowsiness.
3. Eye: Dilated pupils, increased intraocular pressure.
4. Gastrointestinal: Reduced salivation, gastric secretions and motility.
5. Genitourinary: Urinary retention.
 Therapeutic uses of antinicotinic
neuromuscular blockers
1. Tubocurarine:
• First used neuromuscular blocker, but now rarely used because safer
alternatives.
2. Atracurium:
• Onset of action: 90 seconds.
• Duration of action: 30 minutes.
• Widely used.
• Should be refrigerated.

Used for:
(1) Producing complete muscle relaxation with anesthetics during surgeries or
mechanical ventilation (2) Facilitating intubation.
 Side effects of antinicotinic
neuromuscular blockers

• These drugs may cause paralysis of the diaphragm and bronchospasm.

• May facilitate histamine release, which causes hypotension, flushing,
and tachycardia.
• Some drugs may trigger a transient release of large amounts of
potassium from muscle fibers.
• This puts the patients at risk for life-threatening complications, such
as hyperkalemia and cardiac arrhythmias.