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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
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
-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
O
CH2OH
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.
• No therapeutic value
Mecamylamine
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
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
Competitive
Tubocurarine Mivacurium
Depolarizing
AchE
Butyrylcholinesterase
Sensitive sites
Succinylcholine
Competitive NM blocking drugs
• In general, they are bulky, rigid molecules
• Given by IV injections
Me
N
HO Me
H CH2
O
Tubocurarine
CH2
H
Me
O
H N OH
• Gallamine OMe
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).
• 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
– 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