Chapter 5

Cholinergic Antagonists
Prepared by : Sevan Mahmod
07512491694
‫معهد الفجر التدريسي‬
Overview

‫د‬ ‫ه‬‫ع‬‫م‬
• The cholinergic antagonists (also called cholinergic

‫ا فل‬
blockers, parasympatholytics or anticholinergic

‫ج‬
drugs) bind to cholinoceptors, but they do not trigger

‫ل‬ ‫ا‬ ‫ر‬

the usual receptor-mediated intracellular effects

‫د‬ ‫ت‬
• The most useful of these agents selectively block

‫س‬ ‫ي‬ ‫ر‬

muscarinic synapses of the parasympathetic nerves.

‫ي‬
• A second group of drugs, the ganglionic blockers,
show a preference for the nicotinic receptors of the
sympathetic and parasympathetic ganglia.
 ‫د‬ ‫ه‬‫ع‬‫م‬
• A third family of compounds, the neuromuscular

‫ا فل‬
blocking agents, interfere with transmission of

‫ج‬
‫ر‬
efferent impulses to skeletal muscles.

‫ت‬‫ل‬ ‫ا‬
• These agent are used as adjuvants in anesthesia

‫د‬
‫ي‬ ‫ر‬
during surgery

‫ي‬ ‫س‬
II. Antimuscarinic Agents

‫د‬ ‫ه‬‫ع‬‫م‬
• known as antimuscarinics, these agents (for example,

‫ا فل‬
atropine and scopolamine) block muscarinic receptors

‫ج‬
,causing inhibition of all muscarinic functions.

‫ل‬ ‫ا‬ ‫ر‬

• In addition, these drugs block the few exceptional

‫د‬ ‫ت‬
sympathetic neurons that are cholinergic, such as

‫ي‬ ‫ر‬
those innervating salivary and sweat glands.

‫س‬
‫ي‬
• Because they do not block nicotinic receptors, the
antimuscarinic drugs have little or no action at
skeletal neuromuscular junctions or autonomic
ganglia
 ‫د‬ ‫ه‬‫ع‬‫م‬
‫ج‬ ‫ا فل‬
‫د‬ ‫ت‬‫ل‬ ‫ا‬ ‫ر‬
‫س‬ ‫ي‬ ‫ر‬
‫ي‬
 ‫د‬ ‫ه‬‫ع‬‫م‬
‫ج‬ ‫ا فل‬
‫د‬ ‫ت‬‫ل‬ ‫ا‬ ‫ر‬
‫س‬ ‫ي‬ ‫ر‬
‫ي‬
A. Atropine

‫د‬ ‫ه‬‫ع‬‫م‬
• Atropine , a tertiary amine belladonna alkaloid,

‫ا فل‬
has a high affinity for muscarinic receptors,

‫ج‬
‫ر‬
where it binds competitively, preventing

‫ت‬‫ل‬ ‫ا‬
acetylcholine from binding to those sites

‫د‬
‫ر‬
• Atropine acts both centrally and peripherally. Its

‫ي‬ ‫س‬ ‫ي‬

general actions last about 4 hours except when
placed topically in the eye, where the action may
last for days.
• Actions:

‫م‬
• Eye: Atropine blocks all cholinergic activity on the

‫ه‬‫ع‬
eye, resulting in persistent mydriasis (dilation of the

‫د‬
‫ا فل‬
• pupil, unresponsiveness to light, and cycloplegia

‫ج‬
(inability to focus for near vision). In patients with

‫ا‬ ‫ر‬
narrow-angle glaucoma

‫د‬ ‫ت‬‫ل‬
• intraocular pressure may rise dangerously. Shorter-

‫ر‬
‫ي‬
acting agents, such as the antimuscarinic

‫ي‬ ‫س‬
tropicamide, or an α adrenergic drug, like
phenylephrine, are generally favored for producing
mydriasis in ophthalmic examinations.
• Gastrointestinal (GI): Atropine can be used as an
antispasmodic to reduce activity of the GI tract.

‫د‬ ‫ه‬‫ع‬‫م‬
Atropine and scopolamine are probably the most
potent drugs available that produce this effect.

‫ا فل‬
• Although gastric motility is reduced,

‫ج‬
‫ر‬
hydrochloric acid production is not significantly

‫د‬ ‫ت‬‫ل‬ ‫ا‬

affected. Thus, the drug is not effective in

‫ي‬ ‫ر‬
promoting healing of peptic ulcer.

‫ي‬ ‫س‬
• [Note: Pirenzepine an M1-muscarinic
antagonist, does reduce gastric acid secretion at
doses that do not antagonize other systems.]
• Urinary system: Atropine is also employed to

‫م‬
reduce hypermotility states of the urinary
bladder.

‫د‬ ‫ه‬‫ع‬
‫ا فل‬
• It is still occasionally used in enuresis

‫ج‬
(involuntary voiding of urine) among children,

‫ل‬ ‫ا‬ ‫ر‬

but alpha adrenergic agonists with fewer side

‫د‬ ‫ت‬
effects may be more effective

‫س‬ ‫ي‬ ‫ر‬

• Cardiovascular: Atropine produces divergent

‫ي‬
effects on the cardiovascular system, depending
on the dose.
• At low doses, the predominant effect is a
decreased cardiac rate (bradycardia).
• With higher doses of atropine, the M2 receptors

cardiac rate increases modestly.

‫د‬ ‫ه‬‫ع‬‫م‬
on the sinoatrial node are blocked, and the

‫ا فل‬
• Secretions: Atropine blocks the salivary glands,

‫ج‬
‫ر‬
producing a drying effect on the oral mucous

‫ت‬‫ل‬ ‫ا‬
membranes(xerostomia).

‫د‬
‫ي‬ ‫ر‬
• The salivary glands are exquisitely sensitive to

‫ي‬ ‫س‬
atropine. Sweat and lacrimal glands are also
affected.
• [Note: Inhibition of secretions by sweat glands
can cause elevated body temperature.]
 ‫د‬ ‫ه‬‫ع‬‫م‬
‫ج‬ ‫ا فل‬
‫د‬ ‫ت‬‫ل‬ ‫ا‬ ‫ر‬
‫س‬ ‫ي‬ ‫ر‬
‫ي‬
:Therapeutic uses

‫د‬ ‫ه‬‫ع‬‫م‬
• Ophthalmic: In the eye, topical atropine exerts

‫ا فل‬
both mydriatic and cycloplegic effects

‫ج‬
‫ر‬
• Shorter-acting antimuscarinics (cyclopentolante

‫ت‬‫ل‬ ‫ا‬
and tropicamide) have largely replaced atropine

‫د‬
‫ر‬
due to prolonged mydriasis observed with

‫ي‬ ‫س‬ ‫ي‬

atropine (7 to 14 days versus 6 , 24 hours with
other agents)
• Atropine may induce an acute attack of eye pain
due to sudden increases in eye pressure in
individuals with narrow-angle glaucoma
• Antispasmodic: Atropine is used as an
antispasmodic agent to relax b. the GI tract and

‫م‬
bladder

‫ه‬‫ع‬
• Antidote for cholinergic agonists: Atropine is

‫د‬
‫ا فل‬
used for the treatment of overdoses of

‫ج‬
cholinesterase inhibitor insecticides and some

‫ل‬ ‫ا‬ ‫ر‬

types of mushroom poisoning (certain

‫د‬ ‫ت‬
mushrooms contain cholinergic substances that

‫ي‬ ‫ر‬
block cholinesterases).

‫س‬
‫ي‬
• The drug also blocks the effects of excess

‫م‬
acetylcholine resulting from acetylcholinesterase
inhibitors, such as physostigmine

‫د‬ ‫ه‬‫ع‬
‫ج‬ ‫ا فل‬
• Antisecretory: The drug is sometimes used as an

‫ل‬ ‫ا‬ ‫ر‬

antisecretory agent to block secretions in the

‫د‬ ‫ت‬
upper and lower respiratory tracts prior to

‫س‬
surgery.
‫ي‬ ‫ر‬
‫ي‬
:Adverse effects

‫د‬ ‫ه‬‫ع‬‫م‬
• Depending on the dose, atropine may cause dry

‫ا فل‬
mouth, blurred vision, sandy eyes, tachycardia,

‫ج‬
‫ر‬
and constipation

‫ت‬‫ل‬ ‫ا‬
• Effects on the CNS include restlessness,

‫د‬
‫ر‬
confusion, hallucinations, and delirium, which

‫ي‬ ‫س‬ ‫ي‬

may progress to depression, collapse of the
circulatory and respiratory systems, and death.
• Low doses of cholinesterase inhibitors such as
physostigmine may be used to overcome atropine
toxicity
• In older individuals, the use of atropine to
induce mydriasis and cycloplegia is considered

‫د‬ ‫ه‬‫ع‬‫م‬
to be too risky, because it may exacerbate an
attack of glaucoma in someone with a latent
condition.

‫ج‬ ‫ا فل‬
‫ر‬
• In other older individuals, atropine may induce

‫ت‬‫ل‬ ‫ا‬
urinary retention that is troublesome.

‫د‬
‫ي‬ ‫ر‬
• Children are sensitive to effects of atropine in

‫ي‬ ‫س‬
particular, the rapid increases in body
temperature that it may elicit. This may be
dangerous in children.
B. Scopolamine

‫د‬ ‫ه‬‫ع‬‫م‬
• Scopolamine another tertiary amine belladonna

‫ا فل‬
alkaloid, produces peripheral effects similar to

‫ج‬
‫ر‬
• those of atropine. However, scopolamine has

‫ت‬‫ل‬ ‫ا‬
greater action on the CNS

‫د‬
‫ي‬ ‫ر‬
• (unlike with atropine, CNS effects are observed

‫ي‬ ‫س‬
at therapeutic doses)
• and a longer duration of action in comparison to
those of atropine
Actions:

‫د‬ ‫ه‬‫ع‬
• Scopolamine is one of the most effective
‫م‬
‫ا فل‬
antimotion sickness drugs available

‫ج‬
‫ر‬
• Scopolamine also has the unusual effect of

‫ت‬‫ل‬ ‫ا‬
blocking short-term memory.

‫د‬
‫ي‬ ‫ر‬
• In contrast to atropine, scopolamine produces

‫ي‬ ‫س‬
sedation, but at higher doses it can produce
excitement instead.
• Scopolamine may produce euphoria and is
subject to abuse.
:Therapeutic uses

‫د‬ ‫ه‬‫ع‬‫م‬
• Although similar to atropine, therapeutic use of

‫ا فل‬
scopolamine is limited to prevention of motion sickness

‫ج‬
(for which it is particularly effective) and to blocking

‫ل‬
short-term memory.

‫د‬ ‫ت‬ ‫ا‬ ‫ر‬

• [Note: As with all such drugs used for motion sickness, it

‫ي‬ ‫ر‬
is much more effective prophylactically than for treating

‫س‬
motion sickness once it occurs.

‫ي‬
• The amnesic action of scopolamine makes it an
important adjunct drug in anesthetic procedures.]
• Pharmacokinetics and adverse effects: These aspects are
similar to those of atropine.
Side effect of
cholinergic

‫د‬ ‫ه‬‫ع‬‫م‬
‫ا فل‬
antagonist

‫ل‬ ‫ا‬ ‫ر‬‫ج‬

‫ي‬ ‫ر‬‫د‬ ‫ت‬
‫ي‬ ‫س‬
C. Ipratropium

‫د‬ ‫ه‬‫ع‬‫م‬
• Inhaled ipratropium a quaternary derivative of

‫ا فل‬
atropine, is useful in treating asthma in patients

‫ج‬
‫ر‬
who are unable to take adrenergic agonists.

‫ت‬‫ل‬ ‫ا‬
• Ipratropium is also beneficial in th management

‫د‬
‫ي‬ ‫ر‬
of chronic obstructive pulmonary disease.

‫س‬
• It is inhaled for these conditions. Because of its

‫ي‬
positive charge, it does not enter the systemic
circulation or the CNS, isolating its effects to the
pulmonary system
D. Tropicamide and cyclopentolate

‫د‬ ‫ه‬‫ع‬‫م‬
• These agents are used as ophthalmic solutions

‫ا فل‬
for similar conditions as atropine (mydriasis and

‫ج‬
‫ر‬
cyclopegia).

‫ت‬‫ل‬ ‫ا‬
• Their duration of action is shorter than that of

‫د‬
‫ي‬ ‫ر‬
atropine; tropicamide produces mydriasis for 6

‫س‬
hours and cyclopentolate

‫ي‬
• for 24 hours.
III. Ganglionic Blockers

‫د‬ ‫ه‬‫ع‬‫م‬
• Ganglionic blockers specifically act on the

‫ا فل‬
nicotinic receptors of both parasympathetic and

‫ج‬
‫ر‬
sympathetic autonomic ganglia.

‫ت‬‫ل‬ ‫ا‬
• Some also block the ion channels of the

‫د‬
‫ي‬ ‫ر‬
autonomic ganglia.

‫س‬
• These drugs show no selectivity toward the

‫ي‬
parasympathetic or sympathetic ganglia and are
not effective as neuromuscular antagonists
• Thus, these drugs block the entire output of the
autonomic nervous system at the nicotinic
receptor.

‫د‬ ‫ه‬‫ع‬‫م‬
‫ا فل‬
• Except for nicotine, the other drugs mentioned in

‫ج‬
‫ر‬
this category are nondepolarizing, competitive
antagonists.

‫د‬ ‫ت‬‫ل‬ ‫ا‬

‫ر‬
• The responses observed are complex and

‫ي‬ ‫س‬ ‫ي‬

unpredictable, making it impossible to achieve
selective actions. Therefore, ganglionic blockade is
rarely used therapeutically.
• However, ganglionic blockers often serve as tools
in experimental pharmacology.
A. Nicotine

‫د‬ ‫ه‬‫ع‬‫م‬
• A component of cigarette smoke, nicotine is a

‫ا فل‬
poison with many undesirable actions. It is

‫ج‬
‫ر‬
without therapeutic benefit and is deleterious to
health.

‫د‬ ‫ت‬‫ل‬ ‫ا‬

‫ر‬
• [Note: Nicotine is available as patches, lozenges,

‫ي‬ ‫س‬ ‫ي‬

gums, and other forms. Patches are available for
application to the skin. The drug is absorbed and
is effective in reducing the craving for nicotine in
people who wish to stop smoking.]
• Depending on the dose, nicotine depolarizes
autonomic ganglia, resulting first in stimulation
and then in paralysis of all ganglia

‫د‬ ‫ه‬‫ع‬‫م‬
‫ا فل‬
• The effects include increased blood pressure and

‫ج‬
cardiac rate (due to release of transmitter from

‫د‬ ‫ت‬‫ل‬ ‫ا‬ ‫ر‬

adrenergic terminals and from the adrenal
medulla) and increased peristalsis and

‫ي‬
secretions.

‫س‬ ‫ر‬
‫ي‬
• At higher doses, the blood pressure falls because
of ganglionic blockade, and activity both in the
GI tract and bladder musculature ceases.
B. Mecamylamine

‫د‬ ‫ه‬‫ع‬‫م‬
• Mecamylamine produces a competitive nicotinic

‫ا فل‬
blockade of the ganglia. The duration of action is

‫ج‬
‫ر‬
about 10 hours after a single administration.

‫ت‬‫ل‬ ‫ا‬
• The uptake of the drug via oral absorption is

‫د‬
‫ي‬ ‫ر‬
good, in contrast

‫س‬
• to that of trimethaphan.

‫ي‬
• As with trimethaphan, it is primarily used to
lower blood pressure in emergency situations.
IV. Neuromuscular Blocking Drugs

‫د‬ ‫ه‬‫ع‬‫م‬
• These drugs block cholinergic transmission

‫ا فل‬
between motor nerve endings and the nicotinic

‫ج‬
‫ر‬
receptors on the neuromuscular end plate of

‫ت‬‫ل‬
skeletal muscle

‫د‬ ‫ا‬
‫ر‬
• Neuromuscular blockers are clinically useful

‫ي‬ ‫س‬ ‫ي‬

during surgery for producing complete muscle
relaxation, without having to employ higher
anesthetic doses to achieve comparable
muscular relaxation
A. Nondepolarizing (competitive) blockers

‫د‬ ‫ه‬‫ع‬‫م‬
• The first drug that was found to be capable of

‫ا فل‬
blocking the skeletal neuromuscular junction was

‫ج‬
‫ر‬
curare, which the native hunters of the Amazon in

‫ت‬‫ل‬ ‫ا‬
South America used to paralyze game

‫د‬
‫ر‬
• The drug tubocurarine was ultimately purified and

‫ي‬
1940s.
‫س‬ ‫ي‬
introduced into clinical practice in the early

• Although tubocurarine is considered to be the

prototype agent in this class, it has been largely
replaced by other agents due to side effects
• The neuromuscular blocking agents have

‫م‬
significantly increased the safety of anesthesia,

‫ه‬‫ع‬
because less anesthetic is required to produce

‫د‬
‫ا فل‬
muscle relaxation, allowing patients to recover

‫ج‬
quickly and completely after surgery.

‫د‬ ‫ت‬‫ل‬ ‫ا‬ ‫ر‬

• Note: Higher doses of anesthesia may produce
respiratory paralysis and cardiac depression,

‫ي‬ ‫ر‬
increasing recovery time after surgery.]

‫س‬
‫ي‬
Mechanism of action

‫د‬ ‫ه‬‫ع‬‫م‬
• At low doses: Nondepolarizing neuromuscular
blocking drugs interact with the nicotinic

‫ا فل‬
receptors to prevent the binding of acetylcholine

‫ج‬
‫ر‬
• These drugs thus prevent depolarization of the

‫ت‬‫ل‬ ‫ا‬
muscle cell membrane and inhibit muscular

‫د‬
‫ي‬ ‫ر‬
contraction

‫ي‬ ‫س‬
• Because these agents compete with acetylcholine
at the receptor without stimulating the receptor,
they are called competitive blockers
• Their action can be overcome by increasing the
concentration of acetylcholine in the synaptic

‫م‬
gap for example, by administration of

‫ه‬‫ع‬
cholinesterase inhibitors, such as neostigmine,

‫د‬
‫ا فل‬
pyridostigmine, or edrophonium.

‫ج‬
• Anesthesiologists often employ this strategy to

‫ل‬ ‫ا‬ ‫ر‬

shorten the duration of the neuromuscular
blockade
‫د‬ ‫ت‬
‫س‬ ‫ي‬ ‫ر‬
‫ي‬
• At high doses: Nondepolarizing blockers can

‫ه‬‫ع‬
block the ion channels of the end plate.

‫د‬ ‫م‬
‫ا فل‬
• This leads to further weakening of

‫ج‬
neuromuscular transmission, and it reduces the

‫د‬ ‫ت‬‫ل‬ ‫ا‬ ‫ر‬

ability of acetylcholinesterase inhibitors to
reverse the actions of nondepolarizing muscle

‫ي‬
relaxants.

‫س‬ ‫ر‬
‫ي‬
• Actions: Not all muscles are equally sensitive to
blockade by competitive blockers. Small, rapidly

‫د‬ ‫ه‬‫ع‬‫م‬
contracting muscles of the face and eye are most
susceptible and are paralyzed first, followed by

‫ا فل‬
the fingers. Thereafter, the limbs, neck, and

‫ج‬
‫ر‬
trunk muscles are paralyzed.

‫ت‬‫ل‬ ‫ا‬
• Then the intercostal muscles are affected, and

‫د‬
‫ي‬ ‫ر‬
lastly, the diaphragm muscles are paralyzed.

‫س‬
Those agents (for example, tubocurarine,

‫ي‬
mivacurium, and atracurium), which release
histamine, can produce a fall in blood pressure,
flushing, and bronchoconstriction.
• Therapeutic uses: These blockers are used

‫م‬
therapeutically as adjuvant drugs in anesthesia

‫ه‬‫ع‬
during surgery to relax skeletal muscle. These

‫د‬
‫ا فل‬
agents are also used to facilitate intubation as

‫ج‬
well as during orthopedic surgery.

‫ل‬ ‫ا‬ ‫ر‬

• Pharmacokinetics: All neuromuscular blocking

‫د‬ ‫ت‬
‫ر‬
agents are injected intravenously, because their

‫س‬ ‫ي‬
uptake via oral absorption is minimal

‫ي‬
• Many of the drugs are not metabolized; their

‫ه‬‫ع‬
actions are terminated by redistribution

‫د‬ ‫م‬
‫ا فل‬
• tubocurarine, pancuronium, mivacurium,

‫ج‬
metocurine, and doxacurium are excreted in the
urine unchanged.

‫د‬ ‫ت‬‫ل‬ ‫ا‬ ‫ر‬

• Atracurium is degraded spontaneously in the

‫ي‬ ‫ر‬
plasma and by ester hydrolysis

‫س‬
‫ي‬
• The aminosteroid drugs (vecuronium and
rocuronium) are deacetylated in the liver, and
their clearance may be prolonged in patients
with hepatic disease
• These drugs are also excreted
unchanged in the bile
The choice of an agent will

‫د‬ ‫ه‬‫ع‬‫م‬
‫ا فل‬
depend on how quickly

‫ج‬
muscle relaxation

‫د‬ ‫ت‬‫ل‬ ‫ا‬ ‫ر‬

is needed and on the
duration of the muscle

‫س‬ ‫ي‬
relaxation.
‫ر‬
‫ي‬
• Drug interactions:
• A. Cholinesterase inhibitors: Drugs such as

‫م‬
neostigmine, physostigmine, pyridostigmine, and
edrophonium

‫د‬ ‫ه‬‫ع‬
‫ا فل‬
• B. Halogenated hydrocarbon anesthetics: Drugs such

‫ج‬
as halothane

‫ا‬ ‫ر‬
• C. Aminoglycoside antibiotics: Drugs such as

‫د‬ ‫ت‬‫ل‬
gentamicin or tobramycin inhibit acetylcholine

‫ر‬
‫ي‬
release from cholinergic nerves by competing with

‫س‬
calcium ions

‫ي‬
• D. Calcium-channel blockers: These agents may
increase the neuromuscular block of tubocurarine
and other competitive blockers as well as
depolarizing blockers.
B. Depolarizing agents
• Mechanism of action: The depolarizing

‫د‬ ‫ه‬‫ع‬‫م‬
‫ا فل‬
neuromuscular blocking drug succinylcholine

‫ر‬‫ج‬
attaches to the nicotinic receptor and acts like

‫ل‬ ‫ا‬
‫ت‬
acetylcholine to depolarize the junction.

‫س‬ ‫ي‬ ‫ر‬‫د‬

• Unlike acetylcholine, which is instantly destroyed
by acetylcholinesterase, the depolarizing agent

‫ي‬
persists at high concentrations in the synaptic cleft,
remaining attached to the receptor for a relatively
• longer time and providing a constant stimulation
of the receptor
• [Note: The duration of action of

‫م‬
• succinylcholine is dependent on diffusion from the
motor end plate and hydrolysis by plasma

‫د‬ ‫ه‬‫ع‬
‫ا فل‬
cholinesterase.]

‫ج‬
• Therapeutic uses: Because of its rapid onset and

‫ر‬
short duration of action, succinylcholine is useful

‫د‬ ‫ت‬‫ل‬ ‫ا‬

when rapid endotracheal intubation is required

‫ي‬ ‫ر‬
during the induction of anesthesia

‫س‬
• Pharmacokinetics: Succinylcholine is injected

‫ي‬
intravenously. Its brief duration of action (several
minutes) results from redistribution and rapid
hydrolysis by plasma cholinesterase. It therefore is
usually given by continuous infusion
• Adverse effects:Hyperthermia ,Apnea
Hyperkalemia

‫د‬ ‫ه‬‫ع‬‫م‬
‫ج‬ ‫ا فل‬
‫د‬ ‫ت‬‫ل‬ ‫ا‬ ‫ر‬
‫س‬ ‫ي‬ ‫ر‬
‫ي‬