Cholinergic Drugs

(Agonist&ANTAGONISTS)
Classification
1) Direct Acting 2) Indirect acting
(reversible)
1.Acetylcholine 1.Ambenonium
2.Bethanechol 2.Donepezil
3.Carbachol 3.Galantamine
4.Cevimeline 4.Neostigmine
5.Pilocarpine 5.Physostigmine
6.Pyridostigmine
7.Rivastigmine
8.Tacrine
3) Indirect acting(Irreversible)

Echothiophate

Reactivation of acetylcholinesterase

Pralidoxime
Synthesis and release of acetylcholine from the cholinergic neuron .
Bethanechol
 Its major actions are on the smooth musculature of the bladder,
and gastrointestinal tract.
 It has a duration of action of about 1 hour.
Pharmacological Actions: Bethanechol directly
stimulates muscarinic receptors, causing increased intestinal
motility and tone.
 It also stimulates the detrusor muscles of the bladder whereas
the trigone and sphincter are relaxed, causing expulsion of urine.
 Therapeutic applications:
 In urologic treatment, bethanechol is used to stimulate the
atonic bladder, particularly in postpartum or postoperative,
nonobstructive urinary retention.
 Bethanechol may also be used to treat neurogenic atony as well
as megacolon.
Pilocarpine
Pharmacological Actions:
Applied topically to the cornea,
pilocarpine produces a rapid miosis and
contraction of the ciliary muscle.

The eye undergoes miosis and a spasm of

accommodation; the vision is fixed at some
particular distance, making it impossible to focus .
Edrophonium
 Has a short duration of action of 10 to 20 minutes.
Prevent the hydrolysis of Ach.
 used in the diagnosis of myasthenia gravis.
Intravenous injection of edrophonium leads to a rapid increase in
muscle strength.
Care must be taken, because excess drug may provoke a cholinergic
crisis. Atropine is the antidote.
Echothiophate
Mechanism of action:
Echothiophate is an organophosphate that covalently
binds via its phosphate group to the serine-OH
group at the active site of acetylcholinesterase .
Once this occurs, the enzyme is permanently
inactivated, and restoration of acetylcholinesterase
activity requires the synthesis of new enzyme molecules.
the phosphorylated enzyme slowly releases one of its ethyl
groups . The loss of an alkyl group, which is called aging ,

makes it impossible for chemical reactivators, such as

pralidoxime, to break the bond between the remaining drug
and the enzyme.
ANTIMUSCARINIC DRUGS
 The cholinergic antagonists: (also called cholinergic
blockers, parasympatholytics, or anticholinergic drugs).
 CLASSIFICATION:
 1. Natural compounds:
Atropine
Hyosine (Scopolamine)
 2)Synthetic compounds
Tropicamide
Pirenzepine, Telenzepine
Propenthaline
Benzetamide
Ipratropium
 Atropine (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).
Gastrointestinal (GI):Atropine can be used as an
antispasmodic to reduce activity of the GI tract.
Although gastric motility is reduced.
Secretions:Atropine blocks 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.
 Cardiovascular:
Atropine produces divergent
effects on the cardiovascular
system, depending on the
dose.
At low doses, the
predominant effect is a
decreased cardiac rate
(bradycardia).
Therapeutic uses:
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.
Antispasmodic: Atropine is used as an
antispasmodic agent to relax the GI tract and
bladder
Antisecretory: The drug is sometimes used as
an ant secretory agent to block secretions in the
upper and lower respiratory tracts prior to
surgery
Pharmacokinetics:
Atropine is readily absorbed, partially
metabolized by the liver, and eliminated
primarily in urine. It has a half-life of about 4
hours.
Adverse effects:
Depending on the dose, atropine may
cause
dry mouth, blurred vision, “sandy eyes,”
tachycardia, urinary retention, and
constipation.
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
Scopolamine:
Therapeutic uses:
therapeutic use of scopolamine is limited to
prevention of motion sickness and
to blocking short-term memory.
NEUROMUSCULAR BLOCKING DRUGS..
These drugs block cholinergic transmission
between motor nerve endings and nicotinic
receptors on neuromuscular endplate of
skeleton muscle.
They are structural analogue of ACh
They act either as
1. antagonist (NONDEPOLARIZING TYPE)
2. Agonist (DEPOLARIZING TYPE) at nicotinic
receptor on NMJ.
NEUROMUSCULAR BLOCKING DRUS
Non depolarizing blockers.
Mechanism of action.
AT LOW DOSES :
They interact with nicotinic receptors to
prevent binding of Ach and compete with Ach
at receptor so called competitive blockers.

Thus they prevent depolarization of muscle cell

membrane and inhibit muscular contraction.

There action can be over come by increasing

Ach concentration in synaptic gap e.g. by
administration of cholinesterase inhibitors
neostigmine,edrophonium,pyridostigmine.
 AT HIGH DOSES:

They block the ion channels of endplate.

This lead to further weakening of

neuromuscular transmission ,thereby
reducing the ability of Ach inhibitors to
reverse the action of non depolarizing muscle
relaxants.
Actions.
Not all muscles are equally sensitive to blockade by
competitive blockers.

Small rapidly contracting muscles of face and eye

are most susceptible and are paralyzed
first ,followed by fingers. Thereafter limbs ,neck, and
trunk muscles are paralyzed. next intercoastal
muscles are affected ,lastly diaphragm muscles are
paralyzed.

The muscles recover in a reverse manner diaphragm

muscles recover first then contracting muscles of
the face and eye recovering last.

Those agents that produce histamine e.g. atracurium

can produce a fall in BP and bronchoconstriction
Therapeutic uses.
As an adjuvant drug in anesthesia during
surgery to relax the skeleton muscle.
paralyze the vocal cords, thus facilitates
intubation .( is the placement of a flexible
plastic tube into the trachea (windpipe) to
open airway)
Pharmacokinetics
All neuromuscular-blocking agents are
injected intravenously because their uptake
via oral absorption is minimal. These agents
possess two or more quaternary amines in
their bulky ring structure, making them orally
ineffective.

 They penetrate membranes very poorly and

do not enter cells or cross the blood-brain
barrier.
Adverse effects
In general, agents are safe with minimal side
effects e.g. hyperkalemia,increased intra
ocular pressure and postoperative muscular
pain.
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
drugs 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 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

(fasciculation).

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.
(an abnormal condition characterized by the weakening or
the loss of muscle)
 Actions:
The sequence of paralysis may be slightly
different, but, as with the competitive
blockers, the respiratory muscles are
paralyzed last.

Succinylcholine initially produces brief

muscle fasciculation and a ganglionic block
except at high doses.
 Normally, the duration of action
of succinylcholine is extremely short, because
this drug is rapidly broken down by plasma
pseudocholinesterase.
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 .

It is also used during electroconvulsive shock

treatment.( is a
standard psychiatric treatment in
which seizures are electrically induced in
patients to provide relief from psychiatric
illnesses)
Pharmacokinetics
Succinylcholine is injected intravenously.
Its brief duration of action (several minutes)
results from redistribution and rapid
hydrolysis by plasma pseudocholinesterase.
Therefore, it is sometimes given by
continuous infusion to maintain a longer
duration of effect.
Drug effects rapidly disappear upon
discontinuation.
Adverse effects
Hyperthermia:
When halothane is used as an anesthetic,
administration of succinylcholine has
occasionally caused malignant hyperthermia
(with muscular rigidity, metabolic acidosis,
tachycardia, and hyperpyrexia) .
Apnea:
Administration of succinylcholine to a
patient who is genetically deficient in plasma
cholinesterase or who has an atypical for

Sleep apnea is a common disorder

in which you have one or more
pauses in breathing or shallow
breaths while you sleep.

Hyperkalemia: Succinylcholine
increases potassium release from
intracellular stores.