Muscarinic agonist and antagonist

MUSCARINIC RECEPTOR
AGONIST AND ANTAGONIST
BY GAJENDRA CHOUDHARY
1

Ach and its Muscarinic Receptor Target
 Found primarily on autonomic effector
cells innervated by postganglionic
parasympathetic nerves.
 Also present in autonomic ganglia and on
some cells (e.g., vascular endothelial
cells)
 Within the CNS, the hippocampus, cortex
and thalamus have high densities of
muscarinic receptors.
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LOCATION

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• Acetylcholine the naturally
occurring neurotransmitter for
these receptors.
• No systemic therapeutic
applications
• Because its actions are diffuse ,
and its hydrolysis is catalyzed by
both AChE and plasma
butyrylcholinestrase, is rapid.

Properties and subtypes of Muscarinic
Receptors
 Initially was characterized by analysis of the responses of cells and organ
systems in the periphery and the CNS.
 Bethanechol and McN-A-343, on the tone of lower oesophageal sphincter
led to initial designation of muscarinic receptors as M1 (ganglionic) and M2
(effector cell).
 Molecular cloning identified 5 distinct gene products now designated as M1-
M5.
 All are GPCR.
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EC Loops
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α
β γ
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α
GTP
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PIP2
ER
Ca+2
Ca+2 Ca+2
Ca+2
Ca+2
Ca+2
Ryanodin
receptor
Calcium
mediated
responses
M1, M3, M5

Gi
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7
IC Loops
EC Loops
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2
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β γ
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GTP
Gi
α
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A
C
cAM
P
M2, M4
Decrease in
biological
responses

X-Ray Crystallographic studies
 Demonstrated the classical (orthosteric) binding site for muscarinic agonist and
antagonist , highly conserved among muscarinic receptor subtypes.
 Consists of cleft (deeply buried in the membrane), formed by conserved amino
acid chains located on several of the receptors seven TM helices.
 A feature unique to muscarinic receptors is hydrogen bond interaction between
the orthosteric ligand and a TM6 asparagine residue.
 Agonist binding to receptor leads to considerable contraction of the ligand-binding
pocket, reflecting the relatively small size of muscarinic agonist, as compared to
muscarinic antagonist.
 Residues that line the orthosteric binding site are highly conserved among all
muscarinic receptors. So, DEVELOPING MUSCARINIC LIGANDS WITH A HIGH
DEGREE OF RECEPTOR SUBTYPE HAS PROVEN DIFFICULT.
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Pharmacological effects of ACh
 CARDIOVASCULAR SYSTEM
Vasodilation
Decrease in heart rate (negative chronotropic
effect)
Decrease in conduction velocity in AV node
(negative dromotropic effect)
Decrease in the force of cardiac contraction
(negative ionotropic effect)
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RESPIRATORY TRACT
• M3, bronchial and tracheal
smooth muscle
• Plays a major role in regulating
branchiomotor tone.
• Bronchoconstriction
• Increased tracheobronchial
secretion
• Stimulation of the
chemoreceptors of carotid and
aortic bodies.
URINARY TRACT
• M3 –detrusor muscle
contraction, increased voiding
pressure, and ureteral
peristalsis
• M2- inhibit adrenergic
receptor- cAMP-mediated
relaxation of the bladder

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GASTROINTESTINAL TRACT
• M3, M2
• Increases tone
• Increases amplitude of
contractions
• Increases secretory activity of the
stomach and intestine
• Responses are inconsistently
seen with administered ACh
MISCELLANEOUS PERIPHERAL
EFFECTS
• Stimulates secretion from glands
(M3)
• Lacrimal, nasopharyngeal,
salivary (M1) and sweat glands
• Eye (M3)
• Miosis by contracting the
pupillary sphincter muscle
• Accommodation for near vision
by contracting the ciliary muscle
• Other subtypes may contribute to
the ocular effects of cholinergic
stimulation

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CNS EFFECTS
• Systemically administered Ach has limited
CNS penetration, muscarinic agonists that
can cross BBB evoke a characteristic
cortical arousal or activation response.
• Similar to that produced by injection of
cholinesterase inhibitors or
• By electrical stimulation of the brainstem
reticular formation
• M1-M5
• Muscarinic receptor-regulated
pathways may have an
important role in cognitive
function, motor control,
appetite regulation,
nociception and other
processes.

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MUSCARINIC RECEPTOR
AGONIST

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• Carbamoyl ester related to
acetylcholine
• Resistant to hydrolysis by AChE: long
duration of action
• Choline is methylated: No nicotinic
action
• Half life is longer
• Non obstructive urinary
retention/stimulate atonic bladder
in postoperative conditions.
• Oral: 10-50 mg
TDS/QID
BETHANECHOL
Uses

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Thursday, February 25, 2021
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• Carbamoyl ester related to
acetylcholine
• Resistant to hydrolysis by AChE: long
duration of action
• Lacks methyl group of bethanechol:
both muscarinic and nicotinic action
• Half life is longer
• Mitotic agent to treat glaucoma
• Ophthalmic surgery: instilled into
anterior chamber for miosis.
CARBACHOL
Uses

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• Beta methyl analog of Ach
• Largely resistant to hydrolysis by
AChE: Long duration of action.
• Shows muscarinic action with minor
nicotinic action.
• Do not cross BBB and poor
absorption from GIT
• Diagnosis of bronchial hyperactivity.
• Bronchial challenge test: subjects are exposed to methacholine
aerosols which leads to bronchoconstriction.
• Rarely performed.
METHACHOLINE
Uses

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• Quinuclidine derivative of
acetylcholine.
• Muscarinic agonist with high affinity
to M3 receptors on lacrimal and
salivary glands.
• Xerostomia: Sjogren’s syndrome
CEVIMELINE
Uses
Oral:30 mg TDS

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• Chief alkaloid obtained from shrubs
of genus Pilocarpus
• Shows only muscarinic action, no
nicotinic action
• Tertiary amine: can cross BBB
• Narrow angle glaucoma: used to lower IOP and
removing pupillary block
• Open angled glaucoma: used as last resort
• Reversing mydriasis due to atropine
• Xerostomia: Radiation induced and Sjogren’s
syndrome
PILOCARPINE
Uses
• 1-4% ophthalimic
solution applied
every 6 hours or as
directed.
• Oral for Xerostomia:
5-10 mg TDS/QID

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• Obtained from poisonous mushroom
Amanita muscaria.
• Shows only muscarinic action.
• No therapeutic use; only toxicological
significance.
MUSCARINE
Uses

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• Chief alkaloid of Areca catechu and
betel nuts.
• Has muscarinic as well as nicotinic
action.
• Tertiary amine: can cross BBB.
• Acts on Nm type of receptors also
• Used for recreation; no therapeutic
use.
ARECOLINE

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• Synthetic quaternary amine: does
not enter CNS.
• Intermediate duration of action: 30
min-2 hours
• Poor oral bioavailability (1-2%)
NEOSTIGMINE
Uses
• Myasthenia gravis:
symptomatic treatment and
diagnosis.
• Reversal of non depolarising
neuromuscular blockers.
• Myasthenia treatment- Acute 0.5-
2.5 mg IM/SC
• Maintenance 15-375 mg/day Oral
in divided doses.
• Myasthenia diagnosis – 0.022
mg/kg along with atropine
• Reversal of nondepolarizing
neuromuscular blockers – 0.03-
0.07 mg/kg IV

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• Natural tertiary amine: enters CNS
• Intermediate duration of action: 2-4
hours
• Instilled in eyes: penetrates cornea
and causes miosis and decrease in
IOP.
PHYSOSTIGMINE
Uses
• Glaucoma
• Antidote for drugs having
anticholinergic activity:
atropine, phenothiazine,
tricyclic antidepressants
• 0.1-1% eye drops.
• 0.5-2 mg slow IV as antidote.

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• Attaches reversibly to choline
substitute and inhibits AChE.
• Does not react with AChE enzyme.
• Rapid renal elimination: due to
quaternary amine
• Short duration of action 10-20 mins
EDROPHONIUM
Uses
• Diagnosis of Myasthenia gravis
• Differentiating cholinergic crisis from myasthenia crisis:
Cholinergic crisis improves risky and infrequently indicated
• Reversal of non depolarizing neuromuscular blockers
• Paroxysmal atrial tachycardia.
• Myasthenia gravis
diagnosis: 2 mg IV
• Antidote: 10 mg IV

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• Synthetic quaternary amine:
does not enter CNS
• Intermediate duration of action:
3-6 hours
PYRIDOSTIGMINE
Uses
• Myasthenia treatment
• Reversal of non depolarising
neuromuscular blockers
• Myasthenia gravis treatment:
600 mg/day Oral in 3 divided
doses
• Antidote: 0.1-0.25 mg/kg/dose
IV

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• Synthetic quaternary amine:
does not enter CNS
• Intermediate duration of action:
4-8 hours
AMBENONIUM
Uses
• Myasthenia treatment
• Oral:5-50 mg TDS-QID

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• Centrally acting cholinesterase
inhibitor
• Poorly absorbed from oral route
• Bioavailability – 36%
RIVASTIGMINE
Uses
• Mild to moderate Alzheimer’s
Disease
• Oral 1.5 -6 mg BD
• Transdermal patch: 4.6- 13.3
mg/24 hrs

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DONEPEZIL
Uses
• Mild to moderate and moderate
to severe Alzheimer’s Disease
• Oral initial 5 mg HS
• Maximum 23 mg/day
inhibitor
• Reversibly binds to active site of
AChE with high affinity
• Does not react with AChE enzyme
• Well absorbed from oral route
• Bioavailability- 100%

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GALANTAMINE
Uses
• Mild to moderate Alzheimer’s
Disease
• Oral 4mg BD or 8 mg OD
inhibitor
• Reversibly binds to active site of
AChE with high affinity
• Does not react with AChE enzyme
• Well absorbed from oral route
• Bioavailability- 90%

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TACRINE
• Centrally acting cholinesterase inhibitor.
• Attaches reversibly to choline substitute and
inhibits AChE
• Was used for the treatment of Alzheimer’s
disease
• Hepatotoxic is a major adverse effects.
Discontinued due to safety concerns in most
of the countries.

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PROPOXUR
• Non systemic insecticide used for pest
control.
• Toxic to children
• Toxicological importance: Accidental and
suicidal consumption

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ECHOTHIOPHATE
• Possess long duration of
action
• Can cause lens opacites
Uses
• Open angled glaucoma 0.03% eye drops
instilled BD

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MALATHION
• Organophosphate insecticide:
low toxicity to humans
Uses
• Pediculosis capitis (head
lice) treatment 0.5% lotion applied to
dry hair

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DYFLOS SARIN
TABUN
DIAZINON
• Organophosphorus
insecticide
• Rarely used for
chronic glaucoma
treatment
• Organophosphorus
insecticide
• Fat soluble: more
careful handling
required
• Extremely toxic
• Used in
chemical
warfare.
• Extremely toxic
• Used in
chemical
warfare.
SOMAN
• Extremely toxic
• Used in chemical warfare

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Anticholinesterase overdose
• Available as insecticides
• Accidental or suicidal consumption is common
• Symptoms: Salivation, Lacrimation, urination, involuntary defecation, miosis,
increased respiratory secretions, hypotension, cardiac arrythmias, muscle
fasciculations, weakness and paralysis
• Death mainly due to respiratory paralysis.
Treatment
• Preventing further exposure: Gastric lavage, washing skin and mucous
membrane
• Maintaining patient airway
• Supportive measures like maintaining BP, hydration and ventilation
Antidotes
• Atropine
 Reverses muscarinic effects
 2 mg IV every 10 minutes is required
Pralidoxime
• Started as early as possible preferably
within 24 hours before aging sets in
• Useful only in organophosphate
poisoning and C/I in carbamate
insecticide poisoning

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Cholinesterase reactivators
PRALIDOXIME
• Approaches anionic site on AChE; displaces the
phosphate group of organophosphates; reactivation of
AChE enzyme
• Contraindicated in carbamate poisoning: anionic site is
occupied by carbamates, pralidoxime has weak anti
AChE activity that worsens the condition.
• Cannot penetrate into CNS: no reversal of central
effects
• No effect if given after the enzyme goes aging
• Usually used combination with atropine for
organophosphate poisoning
• 1-2 g IV over 15-30
mins repeat after 8-12
hours as required or
• 30 mg/kg over 20
minutes followed by 8
mg/kg/hour
• 600 mg 3 doses IM 15
minutes apart

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OBIDOXIME
• Cholinesterase reactivator similar to pralidoxime
• 0.25 g slow IV infusion followed by 0.75 g/24 hour
infusion

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MUSCARINIC RECEPTOR
ANTAGONIST

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ANTICHOLINERGICS
• Also referred as: cholinergic blockers, parasympatholytic, cholinergic
antagonist
• Muscarinic receptor antagonist/antimuscarinic agents
• Bind to muscarinic receptor but do not elicit any response
• Some muscarinic receptor antagonists can have minimal blocking action
on nicotinic receptors
• Nicotinic receptor antagonists of Nn type in sympathetic and
parasympathetic ganglia is classified as ganglionic blockers
• Nicotinic receptor antagonists of the Nm type is classified as
neuromuscular blocking agents

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ATROPINE
• Belladonna alkaloid: tertiary amine
• Blocks all type of muscarinic receptors
• Has both central and peripheral action
• Pharmacokinetics
 Rapidly absorbed
 50% metabolised and 50% excreted
unchanged
 Duration of action: 3-4 hours
 Ophthalmic
 Onset of action: dilation – 30 minutes;
cycloplegia 1-2 hours
 Duration of action: more than one day;
blurred vision for up to a week.

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• Gastrointestinal
 Visceral smooth muscles are relaxed
 Reduces acid secretion
• Cardiovascular system
 Initial bradycardia: inhibition of M1
receptors on prejunctional neurons.
 Followed by tachycardia: blockade of
M2 receptors on Sinu atrial node.
• CNS
 Stimulant action: vagal, respiratory,
vasomotor
 Depressant action: vestibular pathway
(useful in motion sickness)
• Secretions
 Atropine blocks glandular
secretions
 Reduces sweat, salivary
secretions, tracheobronchial
and lacrimal secretions.
• Eye –
 Mydriasis
 Abolition of light reflex
 Cycloplegia: paralysis of
accommodation
 Narrow angle glaucoma: IOP
can raise significantly

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ADVERSE EFFECTS
• Dry Mouth
• Blurred vision
• Dry, flushed and hot skin
• Excitement, delirium, psychotic
behaviour
• Urinary retention, constipation
• Increase body temperature: Atropine
fever in infants and children
USES
• Pylorospasm and other spastic
condition of GIT
• Anticholinesterase poisoning
• Sinus bradycardia
• Pre-anaesthetic medication: to
decrease secretions
Ophthalmic uses:
• Refraction testing: mydriasis and
fundoscopic examination:
cycloplegia
• Preferred for children (<5 years) as
they have high ciliary tone
• Iritis, Uveitis, iridocyclitis: decrease
the spasms

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DOSAGE
Ophthalmic
• 1% Solution 30 minutes before testing
• 1% solution applied QID for therapeutic effect
Spastic conditions
• 0.4 mg oral every 4-6 hours
Antidote
• 2 mg IV repeated as needed
Sinus bradycardia
• 0.5-1 mg IV
Preanesthetic medication
• 0.4-0.6 mg IV 30-60 minutes before procedure

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HYOSCINE/SCOPOLAMINE
• Plant alkaloid and a tertiary amine
• CNS effects are more marked than
atropine.
• Therapeutic doses: causes sedation
rather than excitation
• Route of administration: transdermal
patches, oral route, ophthalmic route
USES
• Prophylaxis of motion sickness and postoperative
nausea and vomiting
• Nausea and vomiting treatment
• GI tract spasm, irritable bowel syndrome treatment
• Ophthalmic: Refraction testing
Dosage:
• IV/IM/SC: 0.3-0.65 mg every 6-8 hours or as
required
• Oral: 10 mg TDS-20 mg QID
Motion sickness
• Transdermal patch delivering 1 mg/72 hours
• Apply 1 hour before travel; change every 3
days
• Apply night before surgery; remove after 1
day
Refractory testing
• 0.25% solution 1 hour before procedure

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HOMATROPINE
• Semisynthetic derivative of atropine
• Onset of action:45-60 mins
• Duration of action: 24-48 hours
• Less potent and having shorter duration of
action than atropine
Dosage:
1-2% 1 hour before
procedure
• Refraction testing
USES

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ATROPINE
METHONITRATE
• Quaternary ammonium salt of atropine
• Less lipid soluble compared to atropine: do not cross
BBB
• Used for abdominal spastic conditions
• Initially used for inhalational form for asthma
• Decreases ciliary clearance and reduces respiratory
secretion: formation of mucus plugs
• Also resulted in higher incidence of anticholinergic side
effects.

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HYOSCINE BUTYL BROMIDE
• Semisynthetic derivative of scopolamine
• Do not pass BBB hence no CNS effect
USES
• Gastrointestinal spastic conditions
• Renal colic

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MYDRIATICS
CYCLOPENTOLATE TROPICAMIDE
• Synthetic antimuscarinic
• Onset of action: 30-60 mins
• Duration of action: 24 hours
USES USES
• Refraction testing and
fundoscopic examination
Dosage: 0.5-1% solution 60 minutes before
examination
• Synthetic antimuscarinic
• Short and rapid acting mydriatic
• Onset of action: 20-40 mins
• Duration of action : 6-8 hours
• Refraction testing and
fundoscopic examination
Dosage: 0.5-1% 15-20 mins before
examination

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BRONCHODILATORS: QUATERNARY AMINES
IPRATROPIUM
• Short acting muscarinic antagonist
• Duration of action 4-6 hours
• Minimal effect of mucocilliary clearance,
volume or consistency of respiratory
secretions
• Blocks all subtypes of muscarinic receptors
• Blockade of presynaptic M2 receptors may
increase Ach release and counteract M3
receptor antagonism mediated inhibition of
bronchoconstriction
USES AND DOSAGE
COPD
• MDI: 2 puffs (34 mcg) every 6
hours
• Nebulisation: 500 mg every 6-
8 hours
Severe bronchospasm
treatment:
• Nebulisation: 500 mg repeated
as needed
• Perennial and seasonal
allergic rhinitis/ non-allergic
rhinitis: reduces rhinorrhoea
• Nasal spray (0.03%): 2 sprays
per nostril every 6-12 hours

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TIOTROPIUM BROMIDE
• Long acting muscarinic antagonist
• Minimal effect on mucocilliary clearance, volume
or consistency of respiratory secretions
• Duration of action: up to 24 hours
• Once daily dosing is sufficient
• More selective to M1 and M3 receptors
• Presynaptic effect on M2 receptors is nil/minimal
USES AND DOSAGE
COPD, acute bronchospasm prophylaxis
MDI: 2 puffs (10 mcg) OD

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UMECLIDINIUM
• Long acting muscarinic antagonist
• Dissociates slowly from M3 receptors
• Long duration of action: once daily dosing
is sufficient
USES AND DOSAGE
COPD maintenance therapy
Powder: single actuation (52.5 mcg) OD
ACLIDINIUM
• Long acting muscarinic
antagonist
• Has more selectivity to M3
receptors
USES AND DOSAGE
COPD maintenance therapy
MDI: 1 puff (400 mg) BD

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DICYCLOMIE
• Synthetic tertiary amine antimuscarinic
• Additive direct smooth muscle relaxation
USES
• Spasmodic conditions
• Antimotion sickness, antiemetic
• Dysmenorrhoea
• Irritable bowel syndrome
DOSAGE
• ORAL 20 mg QID
OXYBUTYNIN
• Synthetic tertiary amine
antimuscarinic
• Relatively selective for M1/M3
receptors
• CYP3A4 substrate
USES and DOSAGE
• Overactive bladder: reduces
intravesicular pressure, increases
bladder capacity, reduced bladder
contractions
• Oral 5 mg TDS/QID
• Transdermal patch 3.9 mg/day Apply twice weekly
• Gel sachet 10%: Apply 1 sachet (100mg/1 g) OD

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ANTISECRETORY ANTISPASMODICS : QUATERNARY AMINES
PROPANTHELINE GLYCOPYRROLATE
• Synthetic quaternary amine
antimuscarinic
• Used for reducing gastric
secretion in peptic ulcer
• Also used as an antispasmodic
DOSAGE
• 15 mg TDS administered 30-60
mins before food
• Synthetic quaternary amine anti
muscarinic
• Potent and rapidly acting
USES and DOSAGE
• Preoperative medication : to reduce
secretions
• Intraoperative: reduce cholinergic side
effects
• Preoperative: 4 mcg/kg IV/IM 30-60 mins
before surgery
• Intraoperative: 0.1 mg IV
• Reversal: 0.2 mg IV for 1 mg of neostigmine

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ANTIPARKINSONIAN DRUGS
BENZHEXOL/
TRIHEXYPHENIDYL
BIPERIDEN BENZTROPINE
• Central
anticholinergic
• Central
anticholinergic
• Central
anticholinergic
USES
Parkinsonism and Drug induced EPS

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REFERRENCES
1. Goodman & Gilman, The Pharmacological basis of Therapeutics,
13th edition
2. Classify Rx

Muscarinic agonist and antagonist

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