Pharmacology of Muscarinic Receptor
Blockade
Acetylcholine is an agonist at
both muscarinic and nicotinic
receptors
The nicotinic actions of
acetylcholine remain when
muscarinic receptors are
blocked
Muscarinic Receptor Blockade Does Not Affect
Ganglionic Transmission
X
Muscarinic receptor blockade prevents generation of the IPSP and the
sEPSP but not the fEPSP
X
X
Muscarinic receptor blockade does not interfere with transmission at
autonomic ganglionic sites, the adrenal medulla, or skeletal muscle fibers.
Sympathetic adrenergic functions are not affected.
In Dual Innervated Organs, Muscarinic Receptor
Blockade Allows Sympathetic Dominance
X
Atropine
Characteristics of Atropine
• Source
– Atropa belladonna
– Datura stramonium
• Known as Jamestown weed or jimsonweed
• Chemical nature
– An alkaloid
• Alternate name is d,l-hyoscyamine
• Nature of blockade
– Competitive
Response
Response to ACh in the Presence of Atropine
Log dose of acetylcholine
Atropine competitively inhibits muscarinic reponses to ACh
Actions of Atropine at Tissue Sites
• Eye
Accomodations 1 & 2
– Sphincter muscle of the iris: mydriasis
– Ciliary muscle: cycloplegia
Atropine limits
focusing to
distant objects
Accomodation
is blocked by
atropine
Ac c omoda tion (diopter s)
Pupil diameter (mm)
Changes in Accomodation and Pupillary Diameter after
Changes in Accomodation and Pupillary
Administration
of an Antimuscarinic Agent
Diameter after Administration of a Drug
10
pup il diameter
8
6
4
a cco modation
2
0
0
15
30
45
60
75
90
Time (minutes)
Reproduced from Basic and Clinical Pharmacology
Actions of Atropine At Smooth Muscles And Glands
•
•
•
•
•
•
•
•
•
•
Eye
Lacrimal glands
Mucus glands of the pharynx and nasal cavity
Bronchial smooth muscle
Gastric glands
Intestinal glands
Pancreas
Mucus glands of the respiratory tract
Lacrimal glands
Eccrine sweat glands
Cardiovascular Actions of Atropine
• Heart rate
– Low dose
– High dose
• Systemic blood vessels
• Peripheral resistance
• Cutaneous blood vessels
Response to Doses of Atropine
Reproduced from Basic and Clinical Pharmacology
M1Receptor Activation at Parasympathetic Nerve Terminals Exerts A
Small Negative Feedback Effect Upon ACh Release in Response to
Nerve Impulse Flow
postsynaptic
fiber
M1 ACh
ACh
ACh
M2
cardiac
muscle fiber
M1Receptor Blockade Eliminates the Negative Feedback Effect and
Increases ACh Release in Response to Nerve Impulse Flow
postsynaptic
fiber
x
M1 ACh
ACh
ACh
M2
Pirenzepine is an
M1 antagonist
ACh
cardiac
muscle fiber
i.v. infusion
Intravenous infusion of acetylcholine in high doses produces actions at numerous
sites. Bradycardia and hypotension are among the results. Such actions are
accentuated in the presence of inhibitors of AChE (they also block plasma
pseudocholinesterase).
x
x
x
i.v. infusion
Prior blockade of muscarinic receptors followed by intravenous infusion of a high
dose of ACh converts the bradycardiac and hypotensive responses to tachycardia
and hypertension, mediated through the nicotinic receptors.
Effect Of Atropine in Relation
to Dosage ...
Dose of Atropine
DOSE
0.5 mg
EFFECT
Slight decline in heart rate
Some dryness of mouth
Inhibition of sweating
Dose of Atropine
DOSE
1.0 mg
EFFECT
Definited dryness of mouth
Thirst
Inreased heart rate, sometimes
preceded by slowing
Mild dilatation of pupil
Dose of Atropine
DOSE
2.0 mg
EFFECT
Rapid heart rate
Palpitation
Marked dryness of mouth
Dilated pupils
Some blurring of near vision
Dose of Atropine
DOSE
5.0 mg
EFFECT
All the previous symptoms are
marked
Difficulty in speaking and swallowing
Restlessness and fatigue
Headache
Dry hot skin
Difficulty in micturition
Reduced intestinal peristalsis
Dose of Atropine
DOSE
10 mg
and more
EFFECT
Previous symtoms are more marked
Pulse, rapid and weak
Iris practically obliterated
Vision very blurred
Skin flushed, hot, dry, and scarlet
Ataxia
Restlessness and excitement
Hallucinations and delirium
Coma
The previous five slides are reproduced from
Goodman and Gilman’s
The Pharmacological Basis of Therapeutics
Scopolamine (1)
•
•
•
•
Source - Hyoscyamus niger (henbane)
Chemical nature of the molecule
Nature of blockade
Changes in the dose response curve of muscarinic
agonists in the presence of scopolamine
• Lower doses of scopolamine (0.1 - 0.2 mg) produce
greater cardiac slowing than an equivalent dose of
atropine. Higher doses produce tachycardia
• Low doses of scopolamine produce CNS effects that
are not seen with equivalent doses of atropine
Scopolamine (2)
• Therapeutic doses of scopolamine normally produce
CNS depression, manifested as drowsiness,
amnesia, fatigue, dreamless sleep, reduction in REM,
euphoria
• In the presence of pain, the same therapeutic dose
occasionally cause excitement, restlessness,
hallucinations, or delirium. Such excitement is always
seen with large doses, as is also seen with large
doses of atropine
• Therapeutic use - prophylaxis of motion sickness; an
adhesive preparation, the Transderm scop is used
Therapeutic Uses of Antimuscarinic Agents
Therapeutic Uses of Muscarinic Antagonists (1)
• Cardiovascular System - atropine is generally used
for the following cases
– Improper use of choline esters
– Sinus or nodal bradycardia in cases of excessive
vagal tone associated with myocardial infarct
– Hyperactive carotid sinus (syncope and severe
bradycardia)
– Second degree heart block
Therapeutic Uses of Muscarinic Antagonists (2)
• Gastrointestinal Tract
– Peptic ulcers
• In Europe, Japan, and Canada, M1 muscarinic
receptor antagonists such as pirenzepine and
telenzepine are used
• In the U.S. H2 histamine antagonists such as
cimetidine are used
– Spasticity of the g.i. tract
• M3 muscarinic antagonists are being investigated
– Excessive salivation associated with heavy metal
poisoning and parkinsonism
– Production of partial blockade of salivation in patients
unable to swallow
Therapeutic Uses of Muscarinic Antagonists (3)
• Urinary Bladder
– Reverse spasm of the ureteral smooth muscle
(renal colic)
– Increase bladder capacity in cases of enuresis
– Reduce urinary frequency in cases of hypertonic
bladder
Therapeutic Uses of Muscarinic Antagonists (4)
• Central Nervous System
– Parkinson’s disease
– Motion sickness
– Produce tranquilization and amnesia prior to
surgery and in certain cases such as labor (not a
prominent use anymore)
– Anesthesia, to inhibit salivation (not a prominent
use anymore)
– Prevent vagal reflexes induced by surgical
manipulation of organs
Therapeutic Uses of Muscarinic Antagonists (5)
• Posioning by inhibitors of acetylcholinesterase
• Mushroom poisoning due to muscarine
• In conjunction with inhibitors of acetylcholinesterase
when they are used to promote recovery from
neuromuscular blockade after surgery
• Injudicious use of choline esters
• Prevent vagal reflexes induced by surgical
manipulation of visceral organs
Atropine is used for the above
Toxicity of Atropine
Contraindications to the Use Of Antimuscarinic Agents
• Narrow Angle Glaucoma
Flow of Aqueous and Its Escape From the Eye
Contraindications to the Use of Antimuscarinic Agents
•
•
•
•
Narrow angle glaucoma
Hypertrophy of the prostate gland
Atony of the bladder
Atony of the G.I. Tract
Tertiary Muscarinic Antagonists and Their Uses
• Ophthalmic applications
– Cyclopentolate
– Tropicamide
– Homatropine
• Parkinson’s disease
– Benztropine
– Trihexphenidyl
Tertiary Muscarinic Antagonists and Their Uses
• Used for antispasmodic purposes
– Flavoxate - urinary bladder
– Oxybutynin - urinary bladder
– Tolterodine - urinary bladder
– Dicyclomine
– Oxyphencyclimine
In general, they are useful for spasms of the g.t. tract,
bile duct, ureters,
Tolterodine
• Therapeutic use - reduce urinary urgency
• Metabolism
– Cytochrome P450
– Active metabolite is DD-01
• Drug interactions
– Ketoconazole
– Erythromycin
Quaternary Ammonium Antagonists (1)
• General characteristics
• Pharmacology and therapeutic uses
• Distinct side effects with high and sometimes
therapeutic doses
Quaternary Ammonium Antagonists (2)
•
•
•
•
•
Methantheline (N+)
Propantheline (N +)
Methscopolamine (N +)
Homatropine methylbromide (N +)
Oxyphenonium (N +)
Quaternary Ammonium Antagonists (3)
•
•
•
•
•
Anisotropine (N+)
Glycopyrrolate (N+)
Isopropamide (N+)
Mepenzolate (N+)
Ipratropium (N+)
Ipratropium
• Uses
• Distinctiveness from atropine
M1 Muscarinic Receptor Antagonists
• Pirenzepine
– Blocks the M1 and the M4 receptor
– Its usefulness for peptic ulcer
• Telenzepine
– Blocks the M1 receptor
– Its usefulness for peptic ulcer
M2 Muscarinic Receptor Antagonists
• Tripitamine
– Blocks the M2 receptor
– Blocks the action of acetylcholine at cardiac
muscle fibers
• Gallamine
– Blocks M2 muscarinic and the NN nicotinic sites
M3 Muscarinic Receptor Antagonist
• Darifenacin
– Blocks the M3 receptor
– Blocks the actions of acetylcholine at smooth
muscles and glands
Drugs of Other Classes With Antimuscarinic Activity (1)
• Tricyclic antidepressants
– Imipramine
– Amitriptyline
– Protriptyline
– Others
Drugs of Other Classes With Antimuscarinic Activity (2)
• Phenothiazine Antipsychotic Agents
– Chlorpromazine
– Thioridazine
– Perphenazine
– Others
Drugs of Other Classes With Antimuscarinic Activity (3)
• Dibenzodiazepine antipsychotic agents
– Clozapine
– Olanzepine
• Dibenzoxazepine antipsychotic agents
– Loxapine
Drugs of Other Classes With Antimuscarinic Activity (4)
• H1 Histamine receptor blocking agents
– Diphenhydramine
–
–
–
–
–
–
–
–
–
Dimenhydrinate
Promethazine
Carbinoxamine
Dimenhydrinate
Pyrlamine
Tripelennamine
Brompheniramine
Chlorpheniramine
Cyproheptadine