Lecture :9 pharmacology Dr. Dalia A.

Muhsin

The cholinergic antagonists

Cholinergic antagonist is a general term for agents that bind to cholinoceptors (muscarinic or nicotinic) and
prevent the effects of acetylcholine (ACh) and other cholinergic agonists.
cholinergic antagonists can be classified into :
1- Antimuscarinic agents
2- Ganglionic blockers
3- Neuromuscular blockers

Figure (1) : Sites of action of cholinergic antagonists.

I. ANTIMUSCARINIC AGENTS:
Commonly known as anticholinergic drugs, these agents block muscarinic receptors, causing inhibition of
all muscarinic functions. Because they do not block nicotinic receptors, the antimuscarinic drugs have little
or no action at skeletal neuromuscular junctions (NMJs) or autonomic ganglia.
A. Atropine
Atropine is a tertiary amine belladonna alkaloid with a high affinity for muscarinic receptors. It binds
competitively and prevents acetylcholine (ACh) from binding to those sites.
Atropine acts both centrally and peripherally. General actions last about 4 hours; however, effects of topical
administration in the eye may persist for days. The greatest inhibitory effects are seen in bronchial tissue,
salivary and sweat glands, and the heart.

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Actions:
a. Eye: Atropine blocks all cholinergic activity on the eye, resulting in persistent mydriasis (dilation of the
pupil), unresponsiveness to light, and cycloplegia (inability to focus for near vision). In patients with
narrow-angle glaucoma, intraocular pressure may rise dangerously.
b. Gastrointestinal (GI): Atropine can be used as an antispasmodic to reduce activity of the GI tract.
Although gastric motility is reduced, hydrochloric acid production is not significantly affected.
Thus, atropine is not effective for the treatment of ulcers. Doses of atropine that reduce spasms also reduce
saliva secretion, ocular accommodation, and urination. These effects decrease compliance with atropine.
d. Cardiovascular: Atropine produces divergent effects on the cardiovascular system, depending on the
dose.
At low doses, the predominant effect is a slight decrease in heart rate. This effect results from blockade of
M1 receptors on the inhibitory prejunctional (or presynaptic) neurons, thus permitting increased ACh
release.
Higher doses of atropine cause a progressive increase in heart rate by blocking M2 receptors on the
sinoatrial node.
e. Secretions: Atropine blocks muscarinic receptors in the salivary glands, producing a drying effect on the
oral mucous membranes (xerostomia).
The salivary glands are exquisitely sensitive to atropine. Sweat and lacrimal glands are similarly affected.
[Note: Inhibition of secretions of sweat glands can cause elevated body temperature, which can be
dangerous in children and the elderly.]

Therapeutic uses:
a. Ophthalmic: In the eye, topical atropine exerts both mydriatic and cycloplegic effects, and it permits
the measurement of refractive errors without interference by the accommodative capacity of the eye.

b. Antispasmodic: Atropine is used as an antispasmodic agent to relax the GI tract and bladder.
c. Cardiovascular: Injectable atropine is used to treat bradycardia of varying etiologies.

d. Antidote for cholinergic agonists:

Atropine is used for the treatment of:

 organophosphate (insecticides, nerve gases) poisoning,
 overdose of clinically used anticholinesterases such as physostigmine,
 some types of mushroom poisoning (certain mushrooms contain cholinergic substances that
block cholinesterases).

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 Massive doses of injectable atropine may be required over a long period to counteract the poisons.
The ability of atropine to enter the central nervous system (CNS) is of particular importance in
treating central toxic effects of anticholinesterases.

d. Antisecretory: The drug is sometimes used as an antisecretory agent to block secretions in the
respiratory tracts prior to surgery.

Adverse effects:
Depending on the dose, atropine may cause dry mouth, blurred vision, “sandy eyes,” tachycardia,
urinary retention, and constipation. Effects on the CNS include restlessness, confusion, hallucinations,
and delirium, which 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.

C. Ipratropium
is quaternary derivatives of atropine. It is classified as a short-acting muscarinic antagonist and it is
approved as bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive
pulmonary disease (COPD), it is usually delivered via inhalation.

II. GANGLIONIC BLOCKERS

Ganglionic blockers specifically act on the nicotinic receptors of both parasympathetic and sympathetic
autonomic ganglia. These drugs show no selectivity toward the 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. Except for nicotine, the other drugs in this category are
nondepolarizing, competitive antagonists. The responses of the nondepolarizing blockers are complex,
Therefore, ganglionic blockade is rarely used therapeutically, but often serves as a tool in experimental
pharmacology.

III. NEUROMUSCULAR BLOCKING DRUGS

These drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors
on skeletal muscle (Figure 1).
They possess some chemical similarities to ACh and act either as antagonists (nondepolarizing)
or as agonists (depolarizing) at the receptors on the endplate of the NMJ.

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 Neuromuscular blockers (NMBs) are clinically useful to :
 facilitate rapid intubation when needed due to respiratory failure (rapid sequence intubation).
 During surgery, they are used to facilitate endotracheal intubation and provide complete
muscle relaxation at lower anesthetic doses. This increases the safety of anesthesia by allowing
patients to recover quickly and completely. NMBs should not substitute for inadequate
anesthesia.
 NMBs are also used in the intensive care unit (ICU) as adjuvant therapy to facilitate intubation
and mechanical ventilation in critically ill patients.

A. Nondepolarizing (competitive) blockers

The first drug that was found to be capable of blocking the skeletal NMJ was curare , which native South
American hunters of the Amazon region used to paralyze prey. The drug tubocurarine was ultimately
purified and introduced into clinical practice in the early 1940s. Although tubocurarine is considered to be
the prototype agent in this class, it has been largely replaced by other agents because of its adverse side
effects .
Mechanism of action: Nondepolarizing neuromuscular-blocking drugs interact with the nicotinic receptors
to prevent the binding of ACh . Thus, these drugs prevent depolarization of the muscle cell membrane and
inhibit muscular contraction.

Figure : Mechanism of action of competitive neuromuscular blocking drugs.

B. Depolarizing agents
Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to the
action of ACh. However, these agents are more resistant to degradation by AChE, and can thus more
persistently depolarize the muscle fibers. Succinylcholine is the only depolarizing muscle relaxant in use
today.
Mechanism of action: The depolarizing neuromuscular-blocking drug succinylcholine attaches to the
nicotinic receptor and acts like ACh to depolarize the junction . Unlike ACh, which is instantly destroyed by
AChE, the depolarizing agent persists at high concentrations in the synaptic cleft, remaining attached to the
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receptor for a relatively longer time and providing constant stimulation of the receptor .The depolarizing
agent first causes the opening of the sodium channel associated with the nicotinic receptors, which results in
depolarization of the receptor (Phase I). This leads to a transient twitching of the muscle (fasciculations).
Continued binding of the depolarizing agent renders the receptor incapable of transmitting further impulses.
With time, continuous depolarization gives way to gradual repolarization as the sodium channel closes or is
blocked. This causes a resistance to depolarization (Phase II) and flaccid paralysis .
Therapeutic uses: Because of its rapid onset and short duration of action, succinylcholine is useful when
rapid endotracheal intubation is required during the induction of anesthesia.

Figure: Mechanism of action of depolarizing neuromuscular blocking drugs.