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
Thus, the actions of sympathetic stimulation are
left unopposed
12. 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
 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 narrowangle
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
 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
 MeO O O
Me
N C C
HO Me
CH2
Me3NCH2CH2 O CH2 CH2 O CH2 CH2NMe3
O H

H
CH2 Suxamethonium
Me

H N
O
Tubocurarine
OH

OMe O

O Me
Me
MeO
OMe
Me O
N O Me H N
MeO O N N
O
H3C
OMe Pancuronium (R=Me) Me
H H

OMe
Vecuronium (R=H) O
H
MeO
OMe
OMe O Me

Mivacurium

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 Atracurium MeO

OMe OMe
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
Was introduced in 1942 but is no longer used
it has been largely replaced by other agents due to
side effects
Gallamine
Does not block ganglia or release histamine but
causes undesirable tachycardia by blocking the M2
muscarinic receptor MeO

Me

It is rarely used (obsolete) HO

N

CH2
Me
O H

CH2
H
Me
O
H N OH
Tubocurarine
OMe
 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
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).
 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.
others---
Diazepam---Central muscle relaxants---used to control
spastic muscle tone
Dantrolene---interfer with the release of calcium from
the sarcoplasmic reticulum... For malignant
hyperthermia
 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)

Paralytic action on skeletal muscle

 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