Batch 2025

PHARMACOLOGY
LECTURE | DR. CLARION
[TRANS] CHOLINOMIMETICS AND CHOLINOCEPTER BLOCKING DRUGS
Topic Outline CHOLINERGIC TRANSMISSION
● Brief Review on Cholinergic Receptors & Transmission
o Nicotinic Acetylcholine Receptors
o Muscarinic Acetylcholine Receptors
● Cholinomimetics (& Major Groups of Cholinomimetic Drugs)
● Direct Acting
o Muscarinic Receptor Agonists
o Nicotinic Receptor Agonists
● Indirect Acting
o Anticholinesterase Agents
● Muscarinic Receptor Antagonists
● Nicotinic Receptor Antagonists

BRIEF REVIEW ON CHOLINERGIC RECEPTORS AND

TRANSMISSION

CHOLINERGIC RECEPTORS

TRISH 1
 [PHARMACOLOGY] CHOLINOMIMETICS AND CHOLINOCEPTOR BLOCKING DRUGS
CHARACTERISTICS OF SUBTYPES OF CHOLINOMIMETICS
NICOTINIC ACETYLCHOLINE RECEPTORS § Drugs that mimic the action of acetylcholine stimulating the
nicotinic receptor (ionotropic), or muscarinic receptor
(metabotropic), or both
MAJOR GROUPS OF CHOLINERGIC DRUGS

CHARACTERISTICS OF SUBTYPES OF
MUSCARINIC ACETYLCHOLINE RECEPTORS

DIRECT ACTING
§ Directly binds to cholinergic receptors mimicking the effect
of Acetylcholine

1. Choline Esters
§ Acetylcholine, Methacholine
§ Carbachol, Bethanechol

2. Natural Alkaloids
§ Muscarine, Pilocarpine
§ Nicotine, Lobeline

INDIRECT ACTING
§ Amplify the effect of endogenous acetylcholine by inhibiting
acetylcholinesterase

1. Irreversible
a. Organophosphates
§ Parathion
§ Malathion
§ Echothiopate
b. Nerve Gases
§ Sarin, Tabun

2. Reversible
a. Lipid Soluble
§ Physostigmine, Tacrine,
Galantamine, Donepezil,
Rivastigmine

b. Water Solution
§ Neostigmine,
Pyridostigmine,
Edrophonium

TRISH 2
 [PHARMACOLOGY] CHOLINOMIMETICS AND CHOLINOCEPTOR BLOCKING DRUGS
DIRECT ACTING
o Nicotinic Receptors
MUSCARINIC RECEPTOR AGONISTS § Muscle: If activated → CONTRACTION
• Structure § Nerve cells or Neuromuscular end plate:
o Choline Esters If activated → EXCITATION
§ Permanently charged quaternary
ammonium group renders them relatively
lipid insoluble
• Absorption, Distribution, and Metabolism
o Choline Esters
§ Hydrophilic → poorly absorbed and
poorly distributed into the CNS
§ Hydrolyzed by GIT → less active if taken
per orem § Prolonged agonist occupancy →
o Acetylcholine is rapidly hydrolyzed 5-20 seconds abolishment of effector response
§ IV route needs large amount to infuse - Relaxation of skeletal muscle
§ IM or subcutaneous routes produced - Postganglionic neuron stops
local effects firing
o Methacholine, Carbachol and Bethanechol
§ More resistant to hydrolysis, therefore, → DEPOLARIZING BLOCKADE
relatively longer duration of action return of membrane
o B-methyl group of methacholine and bethanechol voltage to resting level
§ Reduced potency to nicotinic receptor
o Alkaloids Pilocarpine, Nicotine, Lobeline → Desensitized to agonist →
§ Well-absorbed from most sites of REFRACTORY TO REVERSAL to
administration any agonist
§ Excreted by kidneys – clearance is
• Organ System Effects: Muscarinic Agonists
accelerated by urine acidification
o Eye (M3)
• Pharmacodynamics § Contraction of the pupillary sphincter
muscle/ smooth muscle of the iris
sphincter causing pulling away of the iris
from the angle of the anterior chamber →
MIOSIS
§ Contraction of the ciliary muscle (for near
vision) causing opening of the trabecular
meshwork at the base →
ACCOMMODATION
§ Both facilitate aqueous humor outflow
into the canal of Schlemm draining the
o Muscarinic Receptors
anterior chamber
§ M1, M3, M5 receptors activates the IP3,
o Cardiovascular System
DAG cascade – EXCITATORY
§ Vasodilation (M3)
§ M2, M4 receptors inhibits adenylyl
§ Decrease in heart rate (negative
cyclase activity – INHIBITORY
chronotropic effect) (M2)
§ Decrease in conduction velocity in the AV
node (negative dromotropic effect)
§ Decrease in the force of cardiac
contraction (negative inotropic effect)
o Respiratory System (M3)
§ Bronchoconstriction, increased
tracheobronchial secretion, stimulation of
the chemoreceptors of the carotid and
aortic bodies

TRISH 3
 [PHARMACOLOGY] CHOLINOMIMETICS AND CHOLINOCEPTOR BLOCKING DRUGS

o Urinary Tract (M3, M2)

§ Detrusor muscle contraction, increased
voiding pressure, and ureteral peristalsis
o GI Tract (M3, M2)
§ Increase tone, amplitude of contraction,
and secretory activity of the stomach and
intestine
o Secretory Effects (M3)
§ Stimulate secretions from lacrimal,
nasopharyngeal, salivary, and sweat
glands
o CNS Effects (M1, M2, M3, M4, M5)
§ Cortical arousal o Contraindications
§ Cognitive function, motor control, § Asthma, COPD, Urinary and GIT
appetite regulation, nociception obstruction, Acid Peptic Disease, Cardiac
disease with Bradycardia, Hypotension,
Hyperthyroidism (muscarinic agonists
may trigger AF in hyperthyroid)
o Adverse Effects
§ Diaphoresis, diarrhea, abdominal cramps,
nausea/ vomiting, sensation of tightness
in the urinary bladder, difficulty in visual
accommodation, hypotension
o Limited concerns if administered topically.

NICOTINIC RECEPTOR AGONISTS

• Nicotine
§ Present in tobacco
§ Propensity for conferring dependence on
its users
• Effects on Physiological Systems
o PNS
§ Transient stimulation, then more
persistent depression
§ NMJ: stimulation then neuromuscular
blockade
o CNS
§ Stimulant to the CNS, excitation of
respiration
§ Induce vomiting
§ Low dose: weak analgesic
§ High dose: tremors
o CVS: Sympathetic response
§ Vasoconstriction, tachycardia, elevated
blood pressure
o GIT
§ Nausea, vomiting, diarrhea (if not
previously exposed to nicotine)
o Exocrine Glands
§ Salivary and bronchial secretions
followed by inhibition

TRISH 4
 [PHARMACOLOGY] CHOLINOMIMETICS AND CHOLINOCEPTOR BLOCKING DRUGS

• Absorption, Distribution, Metabolism, & Excretion (ADME) • Therapeutic Uses

§ Readily absorbed from the respiratory
tract, buccal membranes, skin
§ Limited absorption in the stomach
o Chewed nicotine:
§ absorbed slowly than inhaled
o Cotinine:
§ major metabolite once metabolized by the
liver
§ excreted by the kidney
§ excreted in the milk
INDIRECT ACTING
• Acute Adverse Effects
§ Ingestion of nicotine-containing ANTICHOLINESTERASE AGENTS
insecticide sprays
• Structure
§ 60mg: acutely fatal (1 cigarette: 6-11 mg
o Noncovalent Reversible Inhibitors
→ delivers 1-3 mg nicotine)
§ Edrophonium, Tacrine, Donepezil,
§ Symptoms: Nausea, salivation, abdominal
Propidium, Fasciculin, Galantamine
pain, vomiting, diarrhea, cold sweat,
o Reversible Carbamate Inhibitors
headache, dizziness, disturbed hearing
§ Physostigmine, Neostigmine,
and vision, mental confusion, marked
Pyridostigmine, Ambenonium,
weakness
Rivastigmine
• Treatment of Acute Adverse Effects o Carbamate Insecticides
1. Induce vomiting or gastric lavage § Carbaryl, Propoxur, Aldicarb
2. Activated charcoal o Organophosphates
3. Alkaline solutions should be avoided § Echothiopate, Nerve Agents, Pesticides
4. Treatment of shock
• Pharmacological Effects of Anti-ChE Agents
• Nicotine addiction and smoking cessation § Stimulation of muscarinic receptor
o Goals responses at autonomic effector organs
§ Reduction of the craving for nicotine § Stimulation, followed by depression or
§ Inhibition of the reinforcing effects of paralysis, of all autonomic ganglia and
smoking skeletal muscle (nicotinic actions)
o Drug Regimens § Stimulation, with occasional subsequent
§ NRT depression, or pre- and postsynaptic
§ Bupropion cholinergic receptor sites in the CNS
§ Varenicline
• Effects on Physiological Systems
o Nicotine Replacement Therapy
o Eye
§ Nicotine gum or lozenge
§ Conjunctival hyperemia
§ Nicotine patch
§ Constriction of the pupillary sphincter
§ Nicotine nasal spray or Vapor inhaler
muscle (Miosis)
• Varenicline § Constriction of ciliary muscle (block of
§ Interacts with Nicotinic Ach receptors accommodation reflex)
§ Partial agonists at a4b2 receptor → o GI Tract
nicotinic receptor subtype in nicotine § Gastric contractions and gastric acid
addiction secretion (Neostigmine)
§ Black Box Warning: mood and behavioral § Contraction of lower portion of
changes; increased cardiovascular risk esophagus (Neostigmine as treatment for
Achalasia)
§ Increase intestinal motility (effect of the
Ganglion cells of Auerbach plexus and
smooth muscle contraction)

TRISH 5
 [PHARMACOLOGY] CHOLINOMIMETICS AND CHOLINOCEPTOR BLOCKING DRUGS
• Acute Intoxication
o NMJ
§ Muscarinic and nicotinic signs and
§ Prolongation of decay time of the end-
symptoms
plate potential
o CNS
§ Anti-ChE agents will reverse the
antagonism caused by competitive § Confusion, ataxia, slurred speech, loss of
reflexes, Cheyne-Stokes respiration,
neuromuscular blocking agents
seizure, coma, central respiratory
- Neostigmine is not effective
paralysis
against muscle paralysis caused
o Ocular
by succinylcholine
§ Miosis, ocular pain, conjunctival
- Neostigmine enhances
congestion, diminished vision, ciliary
depolarization → BLOCKADE spams, brow ache
o Cardiopulmonary System o Respiratory
§ Heart: Predominantly Bradycardia → § Rhinorrhea, chest tightness and
decrease CO wheezing due to bronchoconstriction and
§ Edrophonium: Formerly a drug to treat increase bronchial secretions
paroxysmal SVT o CVS
o Actions at Other Sites § Bradycardia, hypotension, arrhythmia
§ Increase glandular secretions – bronchial, from hypoxemia
lacrimal, sweat, salivary, gastric, o GIT
intestinal, and pancreatic acinar glands § Anorexia, nausea, vomiting, abdominal
cramps, salivation, diarrhea, involuntary
• ADME defecation
o Physostigmine o Skin and Muscle
§ Absorbed readily from the GIT § Diaphoresis, muscle fasciculations,
§ Absorbed from the nasal mucosa – put eventual paralysis (nicotinic receptors)
pressure on the inner canthus when § Others: Penile Erection
instilling to the conjunctiva
§ IV administration – readily destroyed
within 2-3 hours by plasma esterase
o Neostigmine and Pyridostigmine
§ Poorly absorbed after oral administration
§ Destroyed by plasma esterase
o Organophosphates
§ Highest risk of toxicity
§ Highly lipid soluble
§ Absorbed through the skin
§ Absorbed by the GIT after ingestion
§ Excretion almost entirely in the urine
§ Hydrolyzed by carboxylesterases and
paraoxonases
• Toxicology
o Accidental and Non-Accidental oral intake of
agricultural insecticides
§ Homicidal or suicidal purposes • Diagnosis and Treatment
o Occupation exposure § History of exposure, and signs and
§ Dermal and pulmonary routes symptoms
o Atropine
§ Antagonizes the actions at muscarinic
receptors sites
§ Addresses the salivation,
bronchoconstriction, bradycardia,
hyperperistalsis, miosis
§ No effect against peripheral
neuromuscular compromise

TRISH 6
 [PHARMACOLOGY] CHOLINOMIMETICS AND CHOLINOCEPTOR BLOCKING DRUGS

o Pralidoxime
§ Cholinesterase reactivator
§ Can reverse peripheral neuromuscular
compromise
§ Early administration is the rule;
administer before the organophosphates
undergo “aging” – resistant to
reactivators
o Other measures
1. Termination of exposure, by removal
of the patient or application of a gas
mask if the atmosphere remains MUSCARINIC RECEPTOR ANTAGONISTS
contaminated, removal and • Naturally occurring alkaloids atropine and scopolamine
destruction of contaminated • Semisynthetic derivatives of these alkaloids, which primarily
clothing, copious washing of differ from the parent compounds in their disposition in the
contaminated skin or mucous
body or their duration of action
membranes with water, or gastric
• Synthetic derivatives, some of which show a limited degree
lavage
2. Maintenance of a patent airway, of selectivity for certain muscarinic receptor subtypes
including endobronchial aspiration • Special Mention
3. Artificial respiration: Administration o Quaternary Amines
of O2, if required § Methscopolamine, ipratropium,
4. Alleviation of persistent convulsions tioproprium, aclidinium, umeclidinium
with diazepam (5-10 mg IV); and o Pirenzepine: M1 receptor-preferring antagonist
5. Treatment of shock o Darifenacin and Solifenacin: M3 receptor-
• Therapeutic Uses preferring antagonist
• Pharmacological Effects
o Atropine
§ Prototypical muscarinic antagonist

TRISH 7
 [PHARMACOLOGY] CHOLINOMIMETICS AND CHOLINOCEPTOR BLOCKING DRUGS

o CVS o Other Smooth Muscle

§ Heart: § Urinary Tract
- Tachycardia (M2 blockade) with - Decreased normal tone and
initial transient modest amplitude of contractions of the
bradycardia (M1 blockade) ureter and bladder
§ Circulation: - Biliary Tract: Anti-spasmodic on
- Little effect to BP the gallbladder and bile ducts –
- Dilate cutaneous blood vessels not enough to prevent marked
especially in blush area spasm
(atropine flush) • ADME
o Respiratory § Rapidly absorbed from the GIT
§ Bronchodilation § Good mucosal absorption
§ Decrease tracheobronchial secretion § Partial absorption in intact skin
§ Inhibits secretions of the nose, mouth, - Efficient absorption in the
pharynx, and bronchi – Dry mouth postauricular region
§ Ipratropium and tiotropium § Ipratropium and Tiotropium:
- Minimal inhibitory effect on - Inhalational route
mucociliary clearance
o Eye • Therapeutic Uses
§ Mydriasis → photophobia
§ Cycloplegia (paralysis of
accommodation)
§ Danger: Angle-closure glaucoma in
predisposed individuals
§ Pilocarpine and carbachol – reverse the
ocular effects of atropine
o GIT
§ Motility: Reduction in tone and amplitude
of peristaltic contractions
§ Gastric acid secretion: Partially inhibits
gastric acid secretory responses
§ Secretions: Inhibition of salivation →
difficulty in swallowing and talking
o Sweat glands and temperature
§ Inhibit activity of sweat glands
- Dry and Hot
o CNS
§ Atropine has little CNS effects at TD
- High dose: Restlessness,
irritability, disorientation,
hallucinations, delirium
- Higher dose: Circulatory
collapse, respiratory failure,
paralysis, coma
§ Scopolamine
- Prominent central effects: CNS
depression, amnesia, fatigue,
dreamless sleep
- Effective for motion sickness –
blocking the neutral pathways
from the vestibular apparatus in
the inner ear to the emetic
center in the brainstem

TRISH 8
 [PHARMACOLOGY] CHOLINOMIMETICS AND CHOLINOCEPTOR BLOCKING DRUGS
NICOTINIC RECEPTOR ANTAGONISTS
• Structure
§ With five (5) subunits of the nicotinic Ach
receptor
§ Highly permeable to Na+, K+, and in some
cases Ca++

• Neuromuscular Blocking Agents

• Neuromuscular Blocking Agents

o Succinylcholine
§ Only depolarizing neuromuscular
blocking agent
§ Use to endotracheal intubation and to
relax the muscle during surgery
§ Competitively block the binding of Ach →
persist more in the NMJ because of • ADME
resistance to Acetylcholinesterase § Tubocurarine: unable to cross the BBB
§ Poor GIT absorption
§ Intramuscularly: absorption is adequate

TRISH 9
 [PHARMACOLOGY] CHOLINOMIMETICS AND CHOLINOCEPTOR BLOCKING DRUGS

• Therapeutic Uses REFERENCES:

Þ Cholinomimetics and Cholinoceptor Blocking Drugs: PPT

Lecture by Dr. Clarion

TRISH 10