Cholinergic blockers

Cholinergic Antagonists
• The cholinergic antagonists (also called cholinergic
blockers, parasympatholytics or anticholinergic drugs)
– bind to cholinoceptors, but
– they do not trigger the usual receptor-mediated
intracellular effects

• Drugs in this class block the effects of the

parasympathetic nervous system.

• Thus, the actions of sympathetic stimulation are

left unopposed
Cholinergic Antagonists
• Drugs which bind to cholinergic receptor but do not activate it
• Prevent acetylcholine from binding
• Opposite clinical effect to agonists - lower activity of
acetylcholine

Postsynaptic Postsynaptic
nerve nerve

Ach
Ach Ach

Antagonist
 Antimuscarinic Agents
• example, atropine and scopolamine
• block muscarinic receptors
• antimuscarinic drugs have little or no action at
skeletal NMJ or autonomic ganglia
• The structure of atropine (oxygen [red] at [1] is
missing) or scopolamine (oxygen present). In
homatropine, the
hydroxymethyl at [2] is replaced by a hydroxyl
group, and the oxygen
at [1] is absent
 Muscarinic Antagonists
ATROPINE

SCOPOLAMINE Attropa belladona

- Atropine and Scopolamine are belladona alkaloids

(competitive inhibitors)

-Drugs differ in their CNS effects, scopolamine permeates the BBB

-At therapeutic doses atropine has negligible effects upon the CNS,
scopolamine even at low doses has prominent CNS effects.
 Atropine
• Protoype
• a tertiary amine belladonna alkaloid,
• Selective for muscarinic receptors (blocks all subtypes)
– But at high dose selectivity lost
• Atropine acts both centrally and peripherally.
• Its general actions last about 4 hours except when placed
topically in the eye, where the action may last for days.

Me Me
Me
N N N NMe3

H CH2 CH2
H H
CH2 OH O CH2 OH CH2 OH
O CH3
O CH H O CH O C CH
C * C * C
H
O
O O O
• Pharmacological Actions:
– Eye: Atropine blocks all cholinergic activity on the eye, causes
paralysis of the sphincter muscle of the iris and ciliary muscle of
the lens resulting in mydriasis (dilation of the pupil) 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, hydrochloric acid production is not significantly
affected. Thus, the drug is not effective in promoting healing of
peptic ulcer. [Note: Pirenzepine, an M1-muscarinic antagonist,
does reduce gastric acid secretion
– Urinary system: bladder wall relaxation.
– Cardiovascular: depend on the dose: low doses, bradycardia
(blockade of M1 receptors on the inhibitory presynaptic
neurons). With higher doses of atropine, the M2 receptors on
the sinoatrial node are blocked, and the cardiac rate increases
modestly
– Secretions: Atropine blocks the salivary glands, producing a
drying effect on the oral mucous membranes (xerostomia).
Sweat and lacrimal glands are also affected
 ????
• Bp
• Bronchi
• Body temprature

• BP: Since cholinergic impulses are not involved in maintenance

of vascular tone, atropine does not have any consistent or
marked effect on BP.
• Tachycardia and vasomotor centre stimulation tend to raise BP
• Atropine blocks vasodepressor action of cholinergic agonists.
• Therapeutic uses:
– Ophthalmic: In the eye, topical atropine exerts both
mydriatic and cycloplegic effects, and it permits eye
examination
– Antispasmodic: Atropine is used as an antispasmodic agent
to relax the GI tract and bladder.
– Antidote for cholinergic agonists: Atropine is used for the
treatment of overdoses of cholinesterase inhibitor
insecticides and some types of mushroom poisoning
(certain mushrooms contain cholinergic substances that
block cholinesterases). The ability of atropine to enter the
central nervous system (CNS) is of particular importance.
The drug also blocks the effects of excess acetylcholine
resulting from acetylcholinesterase inhibitors, such as
physostigmine.
– Antisecretory: The drug is sometimes used as an
antisecretory agent to block secretions in the upper and
lower respiratory tracts prior to surgery
 Scopolamine
• Another tertiary amine belladonna alkaloid,
produces peripheral effects similar to those of
atropine.
• However, scopolamine has greater action on
the CNS
• Although similar to atropine, therapeutic use
of scopolamine is limited to prevention of
motion sickness
 Ipratropium
• A quaternary derivative of atropine,
• Is useful in treating asthma in patients who are unable to take
adrenergic agonists.
• Ipratropium is also beneficial in the management of chronic
obstructive pulmonary disease.
• It is inhaled for these conditions.

•No effect on volume and consistency of Br CH(CH3) 2

H 3C N
bronchial secretions
•But acts selectively on bronchial muscles H
CH2 OH

Gradual onset and late peak (60-90 min) O

C
CH

Not for rapid symptomatic relief O

rather for regular prophylactic use
Ipratropium
(bronchodilator & anti-asthmatic)
12. Cholinergic Antagonists (Muscarinic receptor)
12.5 Simplified Analogues
Me
N
N Me2N
H
O
CH2CH3 CH
O
CH
N O
OH
CH

O
CH2OH

Tropicamide Cyclopentolate Benztropine

(opthalmics) (opthalmics) (Parkinsons disease)
O

HN C

N
N
N C O

CH2
CH
Benzhexol N
Pirenzepine
(Parkinsons disease) (anti-ulcer)
N

Me
16
Fig ...Summary of cholinergic antagonists. *Contraindicated in narrow-angle
glaucoma. GI = gastrointestinal
 Ganglionic Blockers
• These drugs block the entire output of the ANS at
the nicotinic receptor (N)
• Except for nicotine, the other drugs mentioned in
this category are nondepolarizing, competitive
antagonists
• The responses observed are complex and
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.
19
 Nicotine
• Depending on the dose, nicotine depolarizes
autonomic ganglia, resulting first in stimulation and
then in paralysis of all ganglia.

• The stimulatory effects are complex due to effects on

both sympathetic and parasympathetic ganglia

• No therapeutic value
 Mecamylamine

• produces a competitive nicotinic blockade of

the ganglia.
• As with trimethaphan, it is primarily used to
lower blood pressure in emergency situations.
 QQQQQ
• 50-year-old male farm worker is brought to the
emergency room. He was found confused in the
orchard and since then has lost consciousness. His
heart rate is 45, and his blood pressure is 80/40 mm
Hg. He is sweating and salivating profusely. Which of
the following treatments is indicated?
• A. Physostigmine.
• B. Norepinephrine.
• C. Trimethaphan.
• D. Atropine.
• E. Edrophonium.
 Drugs acting at the
neuromuscular junction (NMJ)
• Drugs that affect skeletal muscle function include
two different therapeutic groups:
– Neuromuscular blockers
• Interfere with transmission at the neuromuscular end
plate and lack CNS activity (non-depolarizing vs depolarizing)
• Atracurium, Mivacurium, Tubocurarine, Pancuronium,
Rocuronium, Vecuronium, Succinylcholine
– Spasmolytics
• Those used to reduce spasticity in a variety of painful
conditions (centerally acting vs direct acting)
• Baclofen, Diazepam, Tizanidine, Dantrolene
 Normal Neuromuscular Function
• The binding of two Ach molecules to
receptors on the α-β and δ-α subunits
causes opening of the channel.
• The subsequent movement of Na+ and K+
through the channel is associated with a
depolarization of the end plate
membrane.
• This change in voltage is termed the
motor end plate potential (EPP).
• If the EPP is large, the adjacent muscle
membrane is depolarized, and an action
potential will be propagated along the
entire muscle fiber.
• Muscle contraction is then initiated by
excitation-contraction coupling.
 Neuromuscular blockers
(NMBs)
Chemistry
• All of the available NMBs bear a
structural resemblance to Ach.
• For example, succinylcholine is two
Ach molecules linked end-to-end
• The nondepolarizing agents (eg,
pancuronium) conceal the
“double-acetylcholine” structure in
one of two types of bulky, semirigid
ring systems
O O

C C
Me3NCH2CH2 O CH2 CH2 O CH2 CH2NMe3

Suxamethonium
 Chemistry
• Examples of the two major families of nondepolarizing
blocking drugs—the isoquinoline and steroid derivatives—are
shown in Figures

• Another feature common to all currently used neuromuscular

blockers is the presence of one or two quaternary nitrogens,
which makes them poorly lipid soluble and limits entry into
the CNS
 MeO

Me
N
HO Me
H CH2
O

CH2
H
Me
O
H N OH

OMe

Tubocurarine

MeO OMe
O O
Me H
N C C N
MeO CH 2 CH 2 O (CH 2)5 O CH 2 CH 2 OMe

OMe MeO
OMe OMe

Atracurium

• Structures of two isoquinoline neuromuscular blocking

drugs. These agents are nondepolarizing muscle relaxants.
• Structures of steroid neuromuscular blocking drugs (steroid
nucleus in color). These agents are all nondepolarizing muscle
relaxants.
 Pks of NMB Drugs
• All of the NMB drugs are highly polar compounds and inactive
orally;
– they must be administered parenterally.

• NMB drugs are highly ionized,

– do not readily cross cell membranes, and are not strongly bound in
peripheral tissues.

– Therefore, their volume of distribution (80–140 mL/kg) is only

slightly larger than the blood volume.

• The extremely short duration of action of succinylcholine (5–10

minutes) is due to its rapid hydrolysis by butyrylcholinesterase
and pseudocholinesterase in the liver and plasma, respectively
 Neuromuscular blocking drugs
• Used by anaesthetists to relax skeletal muscles
during surgical operations
• Competitive antagonists
– Compete with Ach for the receptor but do not initiate
ion channel opening
• Depolarizing blockers
– Also act on Ach receptors, but trigger the opening of
the ion channels
– They are not reversed by anticholinesterases
– Suxamethonium is the only drug of this type used
clinically
Examples of competitive/depolarizing drugs

Competitive

Tubocurarine Mivacurium

Depolarizing

AchE
Butyrylcholinesterase
Sensitive sites

Succinylcholine
 Competitive NM blocking drugs
• In general, they are bulky, rigid molecules

• Most have two quaternary N atoms

• Given by IV injections

• The choice of a particular drug is often

determined by the side-effects produced.
– These include: histamine release, vagal
blockade, ganglion blockade and
sympathomimetic actions
 Tubocurarine
• During the 16th century, Natives in the Amazon Basin of South
America were using curare, an arrow poison that produced
skeletal muscle paralysis, to kill animals.

• The active compound, d-tubocurarine, and its modern

synthetic derivatives have had a major influence on the
practice of anesthesia and surgery
• Tubocurarine
– Was introduced in 1942 but is no longer used
– it has been largely replaced by other agents due to
side effects MeO

Me
N
HO Me
H CH2
O

Tubocurarine
CH2
H
Me
O
H N OH

• Gallamine OMe

– Does not block ganglia or release histamine but

causes undesirable tachycardia by blocking the M2
muscarinic receptor
– It is rarely used (obsolete)
• Pancuronium
– Is an aminosteroid NMB drug with a relatively long
duration of action
– It does not block ganglia or cause histamine
release.
– However, it has dose related atropine like effect
on the heart that can produce tachycardiaO

O Me
Me

Me H N
Pancuronium (R=Me) N
Me
H H
Vecuronium (R=H)
O
H

O Me
• Vecuronium and Atracurium
– These are commonly used agents
– Vecuronium has no cardiovascular effects
• It depends on hepatic inactivation
• Recovery can occur within 20-30 minutes, making it an
attractive drug for short procedures
• Atracurium has a duration of action of 15-30 minutes
– It is only stable when kept cold and at low PH
– At body PH and temperature it decomposes spontaneously
(Hofmann elimination) in plasma and therefore does not
depend on renal or hepatic function for its elimination
– It is the drug of choice in patients with sever renal or
hepatic diseases
– Atracurium may cause histamine release with flushing and
hypotension
MeO OMe
O O
Me H
N C C N
MeO CH 2 CH 2 O (CH 2)5 O CH 2 CH 2 OMe

OMe MeO
OMe OMe
• Rocuronium
– Has an intermediate duration of action of about 30
minutes but with rapid onset of action (1-2 minutes)
comparable to that of suxamethonium (1-1.5 minutes).

– The least potent nondepolarizing relaxants

• Because succinylcholine is not metabolized effectively at the
synapse, the
depolarized membranes remain depolarized and unresponsive to
subsequent impulses (ie, a state of depolarizing blockade).
Furthermore, because excitation-contraction coupling requires
end plate repolarization (“repriming”) and repetitive firing to
maintain muscle tension, a flaccid paralysis results.

• In contrast to
the nondepolarizing drugs, this so-called phase I (depolarizing)
block is augmented, not reversed, by cholinesterase inhibitors.
 Depolarizing NM blocking drugs
• Suxamethonium (succinylcholine)
– Is used because of its rapid onset and very short
duration of action (3-7 minutes)
– The drug is normally hydrolysed rapidly by plasma
pseudocholinesterase
• But a few people inherit an atypical form of the enzyme
and in such individuals Nmblock may last for hours
– Suxamethonium depolarizes the endplate and,
because the drug does not dissociate rapidly from
the receptors, a prolonged receptor activation is
produced
• The resulting endplate depolarization initially
causes a brief train of muscle action potentials
and muscle-fibre twitches
• Neuromuscular block then occurs as a result
of several factors which include:
i. Inactivation of the voltage sensitive Na+
channels in the surrounding muscle-fibre
membrane, so that action potentials are no
longer generated
ii. Transformation of the activated receptors to a
‘desensitized’ state, unresponsive to Ach
• Succinylcholine initially produces short-lasting
muscle fasciculations, followed by paralysis
• The main disadvantage of suxamethonium is that
the initial asynchronous muscle-fibre twitches cause
damage, which often results in muscle pains the
next day
• The damage also causes potassium release
• Repeated doses of suxamethonium may cause
bradycardia in the absence of atropine (a muscarinic
effect)
 NM blockers
• Sequence of paralysis : Eye muscles, Jaw,
Larynx, limbs and trunk, intercostal muscles
and the dyaphragm
• Antidote : Neostigmine/Ephodronium to
increase Ach, and atropine to block Ach
muscarinic stimulation.
 Spasmolytics
• Diazepam---Central muscle relaxants---used to
control spastic muscle tone
• Dantrolene---interfer with the release of calcium
from the sarcoplasmic reticulum... For malignant
hyperthermia

• Baclofen is an agonist at GABAB receptors.

• Activation of these receptors by baclofen results
in hyperpolarization, probably by increased K+
conductance
 Clinical uses of NM blockers
• Adjuvant use in surgical anesthesia (muscular relaxation)

• Advantage – much lighter levels of anesthesia required

• Other uses: muscular relaxation for orthopedics (correction of

dislocation/alignment of fractures)

• (short duration) – facilitate intubation, laryngoscopy,

bronchoscopy, esophagoscopy

• Control of muscular spasms, strabism, hemifacial spasms,

oromandibular and cervical dystonia, spasms of the lower
esophageal sphincter

• Cosmetic – Bottox (Botulinum toxin A)

– Treatment of wrinkles
 Quiz
• Hunters in Amazon (south America) shoot
animals using arrows immersed in curare
extract (arrow poison). The animals get
paralysed. But, when the people eat the meat
contaminated with curare, they are not
affected. justify
 qqqq
1. Which one of the following drugs may cause
closure of the canal of schlemm?
A. Atropine
B. Pilocarpine
C. Carbachol
D. Acetylcholine
2. Aministration of cholinesterase inhibitors has no
value when there is over dose of which one of
the following?
A. Atracurium
B. Vecuronium
C. Suxamethonium
D. Tubocurarine