An anticholinergic agent is a
substance that blocks the neurotransmitter
acetylcholine in the central and the
peripheral nervous system
they inhibit parasympathetic nerve
impulses by selectively blocking the binding
of the neurotransmitter acetylcholine to its
receptor in nerve cells
Atropine is a product resulted from esterification
of tropic and tropine base
In scopolamine, there is an oxygen bridging
In homatropine, hydroxymethyl of atropine is
replaced by an OH-radical (tertiary)
distribution is wide
absorption from gut and across conjunctiva is good
absorption across skin in suitable vehicle is good.
Significant concentration is reached within 0.5-1h (eg.
not very lipid soluble
distribution is confined to peripheral tissues (no central
absorption from the site of application is poor
1/2 is metabolized by hepatic esterase (atropinase)
1/3 is excreted unchanged in the urine
80% excreted in the urine with an half-life of 2h
the effects on the eye persist 40-72h
Interaction with muscarinic receptors: reversible,
Atropine: -selective for muscarinic receptors
non-selective for muscarinic receptor subtypes
But, pirenzepine a selective antagonist for m1-
receptors(stomach parietal cells)
not very selective for muscarinic receptors
can also antagonize Nicotinic-receptors in autonomic
Tissues more sensitive to:
Atropine: salivary, sweat and bronchial glands
Pirenzepine (telenzepine, more effective): acid
secretion from parietal cells (stomach)
Scopolamine: more effective on vestibular
disturbances (eg. Motion sickness)
- From Atropa belladonnea
Occurs as l-form, not stable
racemizes to dl-form rapidly
commercial products contain dl-form
l-form is 100-times as potent as d- or dl-forms
From Hyosciamus niger
Occurs as l-form
its l- form is stable
Muscarinic antagonists prevent the effects of ACh
by blocking its binding to muscarinic receptors on
effector cells at parasympathetic neuroeffector
junctions, in peripheral ganglia, and in the CNS.
In general, muscarinic antagonists cause little
blockade of nicotinic receptors.
The quaternary ammonium antagonists generally
exhibit a greater degree of nicotinic blocking activity
and therefore are more likely to interfere with
ganglionic or neuromuscular transmission.
Most clinically available muscarinic antagonists are
nonselective and their actions differ little from those
of atropine, the prototype of the group.
No subtypeselective antagonist, including
pirenzepine, is completely selective
An intact ester of tropine and tropic acid is
essential for antimuscarinic action,
The presence of a free OH group in the acyl portion
of the ester also is important for activity.
When given parenterally, quaternary ammonium
derivatives more potent than their parent
compounds in both muscarinic and ganglionic
(nicotinic) blocking activities.
The quaternary derivatives, when given orally, are
poorly and unreliably absorbed.
MECHANISM OF ACTION.
Atropine and related compounds compete with
ACh and other muscarinic agonists for a
common binding site on the muscarinic
Since antagonism by atropine is competitive, it can
be overcome if the concentration of ACh at
muscarinic receptors of the effector organ is
Muscarinic receptor antagonists inhibit responses
to postganglionic cholinergic nerve stimulation less
effectively than they inhibit responses to injected
PHARMACOLOGICAL EFFECTS OF
In clinical dose:
- With atropine:
- a long lasting sedation with slow onset
- stimulation of vagal nuclei in the brain stem
- sedative effect is more powerful (drowsiness, amnesia)
In toxic dose: (both atropine and scopolamine)
Paralysis of ciliary muscle (cycloplegia):
Loss of accommodation
Adjustment of eye for far vision
Lasts for 7-10 days
Acute glaucoma attack in patient with narrow irido-
corneal angle due to impairment of drainage
Reduction of lacrimal secretion leading dry sandy
Low dose central vagal stimulation
followed by tachycardia resulting from peripheral
anticholinergic efffec and thus unopposed sympathetic
Moderate dose tachycardia due to unopposed
accelereted due to unopposed sympathetic activity
PR shortening in ECG
in toxic doses, conduction block
At toxic doses:
suppression of thermoregulatory sweating
cutaneous vasodilatation at Release of hiatamine
by blush areas (face, neck, ear)
The net CV effects:
Slight elevation in blood pressure due to vasomotor
Inhibition of bronchial secretion
Premedication in anaesthesiology: Used before
inhalant anesthetics to reduce
-risk of airway obstructions
Inhibition of saliva secretion → Dry mouth
Blocked to lesser extent by atropine.
But, is blocked by pirenzepine and telenzepine
Volume of secretion and amount of acid, pepsin and
mucine are all reduced
Large doses of atropine are necessary to reduce gastric
Motility of gut is more powerfully depressed by
atropine than gastrointestinal secretions
Smooth musles of gut wall are paralysed
Propulsive movements are diminished
Sphincter muscles are not able to relax,constipation
Gastric emptying time prolonged
Intestinal transit time is lengthened
Some antimuscarinics have direct spasmolytic effect
Smooth muscles of ureter and bladder wall are
This is useful in the treatment of spastic pain due to
mild urinary inflammations
Sphincter muscles of bladder become unable to
may be hazardous in elder with prostate
Helpful in increasing bladder capacity
Controls detrusor hypereflexia in neurogenic
EFFECTS ON SWEAT GLAND
Thermoregulatory sweating is depressed by
In adults, large doses of atropine can increase body
In infants and children, even ordinary doses may
cause atropine fever
Markedly decreases salivary,lacrimal and
Decrease secretion of acid,pepsin and mucus of
Mild local anaesthetic action on cornea
Most of semisynthgetic belladona alkaloid
derivatives and synthetic compounds are atropine
Differs only slightly from atropine
Ipratropium and tiotropium .
Used in Asthma and COPD
These agents often are used with inhaled long-acting
β2 adrenergic receptor agonists,
Ipratropium is administered four times daily via a
metered-dose inhaler ornebulizer;
tiotropium is administered once daily via a dry powder
Ipratropium also is FDA-approved for use in nasal
inhalers for the treatment of the rhinorrhea associated
with the common cold or with allergic or
Overactive urinary bladder can be successfully treated with
muscarinic receptor antagonists.
These agents can lower intravesicular pressure, increase
capacity, and reduce the frequency of contractions by
antagonizing parasympathetic control of the bladder; they also
may alter bladder sensation during filling
Muscarinic antagonists can be used to treat enuresis in
In overactive bladder
Solifenacin , and
The most important adverse reactions are
consequences of muscarinic receptor blockade and
include xerostomia, blurred vision, and GI side effects
such as constipation and dyspepsia.
CNS-related antimuscarinic effects, including
drowsiness, dizziness, and confusion, can occur and are
particularly problematic in elderly patients.
CNS effects appear to be less likely with trospium, a
quaternary amine, and with darifenacin and solifenacin;
The latter agents are relatively selective for M3
receptors and therefore have minimal effects on M1
receptors in the CNS, which appear to play an important
role in memory and cognition
In Peptic ulcer.
In reducing spasticity or motility of the GI tract (e.g.,
atropine,hyoscyamine and scopolamine) alone or in
combination with sedatives or antianxiety
Reduce tone and motility
M3-selective antagonists might achieve more selectivity
Glycopyrrolate also is used to reduce GI tone and
Diarrhea associated with irritation of the lower
bowel, may respond to atropine-like drugs, an effect
that likely involves actions on ion transport as well
Dicyclomine is a weak muscarinic receptor
antagonist that also has nonspecific direct
spasmolytic effects on smooth muscle of the GI
It is occasionally used in the treatment of diarrhea-
predominant irritable bowel syndrome.
Produce mydriasis and cycloplegia.
For breaking or preventing the development of
adhesions between the iris and the lens.
Complete cycloplegia may be necessary in the
treatment of iridocyclitis and choroiditis and for
accurate measurement of refractive errors.
Atropine may be considered in the initial treatment of patients
with acute myocardial infarction in whom excessive vagal tone
causes sinus bradycardia or AV nodal block.
Doses that are too low can cause a paradoxical bradycardia ,
while excessive doses will cause tachycardia that may extend the
infarct by increasing the demand for oxygen.
It has little effect on most ventricular rhythms.
Eliminate premature ventricular contractions associated with a
very slow atrial rate.
Reduce the degree of AV block when increased vagal tone is
a major factor in the conduction defect, such as the second-
degree AV block that can be produced by digitalis.
Selective M2 receptor antagonists would be of potential utility
in blocking ACh-mediated bradycardia or AV block.
CENTRAL NERVOUS SYSTEM.
In prevention of motion sickness.
Scopolamine is the most effective agent
A transdermal preparation of scopolamine is used
prophylactically for the prevention of motion sickness.
In the treatment of Parkinson disease.
Selective M1 and M4 muscarinic antagonists may be
efficacious for the treatment of Parkinson disease
While selective M3 antagonists may be useful in the
treatment of obesity and associated metabolic
Uses in Anesthesia.
Atropine commonly is given to block responses to
vagal reflexes induced by surgical manipulation of
Atropine or glycopyrrolate is used with neostigmine
to block its parasympathomimetic effects
Serious cardiac arrhythmias have occasionally
occurred, perhaps because of the initial bradycardia
produced by atropine combined with the
cholinomimetic effects of neostigmine.
Atropine is not an actual antidote for organophosphate
By blocking the action of acetylcholine at Muscarinic
receptors, atropine also serves as a treatment for
poisoning by organophosphate insecticides
Atropine is often used in conjunction with oximes
Atropine is given as a treatment for SLUDGE
syndrome (salivation, lacrimation, urination, diaphoresi
s, gastrointestinal motility, emesis) symptoms caused
by organophosphate poisoning.
Other Therapeutic Uses of Muscarinic
Methscopolamine –In temporary relief of symptoms
of allergic rhinitis, sinusitis, and the common cold.
Homatropine potent as a ganglionic blocking
agent,primarily used with hydrocodone as an
I) Intoxications with rapid onset (eg. within 2
II) Intoxications with slow onset (eg. within 2 to 6
Rapid acting mushroom intoxications
1. -Mushrooms: Inocybe, Clitocybe
-posses high amount of muscarine
-cause severe parasympathomimetic effects
-onset of intoxication symptoms: within 15-30mins
2. -Mushrooms: Psilocibe, Copelandin, Pancoulus,
-posses psychoactive alkaloids such as psilocybin and
-cause delirium, euphoria, hallucination
-induce no sleep
- symptoms last 2-4 hours
-Treatment: Diazepam, phenothiazines
3. -Mushrooms: A. muscaria, A. pantherina, A.
cothurnate, A. gemmata
-posses GABA antagonists such as ibotenic acid and
-cause delirium, euphoria, hallucination
-but do induce sleep and coma
-symptoms resemble those of atropine, but not responsive
-symptoms last 2-9 hours
- no antidote available
4. -Mushroom: Coprinus atramentarius
-contain coprin which inhibits aldehyde dehydrogenase
-cause disulfiram-like effects (aldehyde reaction!)
-toxic effects appear, when alcohol is drunken 2-3h after
ingestion of mushrooms
Slow acting mushroom intoxications
Amanita phalloides group
-Mushrooms: A. phalloides, A. verna, A. virosa
-Toxins: Phalloidin and α-Amanitin
α-Amanitin Inhibition of Depression of mRNA RNA-
polymerase-II protein synthesis
- hepatotoxicity Tissue necrosis
- CNS toxicity
Intoxications have 3 phases
- resembles muscarine intoxication
- symptoms appear 8-12h after mushroom ingestion
- symptoms in the first phase lessen and disappear within 24-
- patient becomes asymptomatic in appearance
- but, biochemical hepatic changes continue developing
eg. - increase in transaminase activity
- elevation of biliuribin levels
- prolongation of prothrombin time
- lasts 2-6 days
-the patient may be discharged from the hospital considering
- begins abruptly with signs and symptoms of
hepatotoxicity and nephrotoxicity: -
- acute renal insufficiency
1/3th of patients die within a week or so
In overdoses, atropine is poisonous.
Atropine is incapacitating at doses of 10 to 20 mg per
Its LD50 is estimated to be 453 mg per person
The antidote to atropine is physostigmine or
These associations reflect the specific changes of
warm, dry skin from decreased sweating, blurry vision,
decreased sweating/lacrimation, vasodilation
This set of symptoms is known as anticholinergic
"hot as a hare, blind as a bat, dry as a bone, red
as a beet, and mad as a hatter".
ADVERSE EFFECTS OF ANTIMUSCARINICS
-Mydriasis and cycloplegia, when used against gut
-Blockade of all parasympathetic functions:
-dry mouth, sandy eye
-tachycardia, hot and flushed skin
-agitation, delirium, hallucination
-elevation of body temperature (children)
-Treatment of adverse effects:
-due to overdose of atropine and its tertiary
- 1-4mg, iv. in adults
- 0.5-1mg iv. in children
- Severe hyperthermia: - cooling blanket
- Seizures: -iv. diazepam
Central antimuscarinics used against
Ganglion-blocking agents competitively block the action of
acetylcholine and similar agonists at nicotinic (Nn)
receptors of both parasympathetic and sympathetic
Hexamethonium : acts mainly by channel blocker
Quaternary -Tetraethyl ammonium:
very short acting
Mechanism of ganglionic block:
1) Depolarizing block, eg. by sustained
depolarization: Ach, nicotine, carbamoylcholine
2) Nondepolarizing competitive antagonism of Ni
3) Channel block: Hexamethonium
Results of ganglion blockade
- Quaternary group is devoid of such effects
- Secondary group readily enters CNS: sedation, tremor,
choreiform movements,mental disturbances
- Moderate mydriasis (since p.sympathetic influence on
iris is dominant)
- Cycloplegia with loss of accommodation
- Sympathetic CV reflexes are depressed
- Sympathetic influence on arteriols and veins are
diminished, PVR and venous return are reduced,
vasodilatation, hypotension (orthostatic), tachycardia
- Secretions and motility are inhibited
- Some degree of constipation
- Urination is blocked
- Urine retention in a man with prostate hypertrophy
Thermoregulatory sweating is blocked.
- rapid tolerance development and orthostatic
-now more effective agents are available
2) Acute hypertensive crisis in a patient with
dissecting aortic aneurism.
Trimetaphan: 0.5-3mg/min by iv infusion
Disadvantage: tolerance development within 48h
3) Production of controlled hypotension to minimize
haemorrhage at the operative field.
Trimetaphan: 1-4mg/min by iv infusion
4) Autonomic hyperreflexia (or reflex sympathetic
The most serious one is orthostatic
Block synaptic transmission at the neuromuscular
Affect synaptic transmission only at skeletal muscle
Does not affect nerve transmission, action potential
Act at nicotinic acetylcholine receptor NM
MECHANISM OF ACTION
• Block transmission by causing prolonged depolarization
of endplate at neuromuscular junction.
• Manifestation by initial series of muscle twitches
(fasciculation) followed by flaccid paralysis.
• It immediately metabolize in plasma by Pseudo-
cholinesterase which is synthesized by liver so to prevent
its metabolism in plasma it should be given at faster rate.
Cardiovascular: Produces muscarinic effects as
acetylcholine , therefore causes bradycardia ( but when
given high doses causes tachycardia because of
stimulation of nicotinic receptors at sympathetic
Hyperkalemia: Occurs due to excessive muscle
fasciculations. Ventricular fibrillation can occur due to
CNS: Increases intracranial tension ( due to contraction
of neck vessels)
Eye: Increases intraocular pressure.
GIT: Increases intra-gastric pressure , salivation, peristalsis.
Muscle pains ( myalgia): This is a very common problem in
post operative period. These are due to excessive muscle
Masseter Spasm : Sch can cause masseter spasm
especially in children & patients susceptible for malignant
Doesnot require reversal rather cholinesterase inhibitors
(neostigmine) can prolong the depolarizing block (because
these agents also inhibits the pseudocholinesterase)
Mechanism of action:
• It blocks nicotinic receptors competitively resulting
in inhibition of sodium channels and excitatory post-
• It binds at the same site at which acetylcholine
• All NDMR are quarternary ammonium compounds
& highly water soluble i.e. hydrophilic. So, they do
not cross blood brain barrier & placenta except
These are broadly divided into steroidal compounds
and benzylisoquinoline (BZIQ) compunds.
STEROIDAL COMPOUNS: (vagolytic properties)
It includes PANCURONIUM,VECURONIUM ,
BZIQ(Benzylisoquinoline): (hystamine realease)
It includes d-Tubocurare, Metocurine, Doxacurium,
Atracurium, Mivacurium, Cisatracurium
OTHERS includes Gallamine, Alcuronium
DIFFERENCES BETWEEN DEPOLARIZING & NON-
Also called Phase I block -
Block preceded by muscle
Depolarizing blocking drugs are called
Does not require reversal rather
cholinesterase inhibitors (Neostigmine)
can prolong the depolarizing block (
because these agents also inhibit the
Reversed by cholinesterase
inhibitors like Neostigmine.
NDMR ARE USED IN ANAESTHESIA FOR:
Maintenance of anaesthesia.
For intubation where succinylcholine is contraindicated (
Rocuronium is of choice)
For precurarization to prevent postoperative myalgias by
Very commonly used as it is inexpensive.
It releases noradrenaline & can cause tachycardia & hypertension.
Because of this there are increased chances of arrhythmia with
It is a pancuronium derivative with no vagolytic activity, so cardiovascular
stable, slightly more potent
It is very commonly used now a days. It is cardiovascular stable. Shorter
duration of action.
It is the muscle relaxant of choice in cardiac patient.
8 times more potent than vecuronium and it also has earlier onset of
Because of onset comparable to succinylcholine it is suitable for rapid
sequence intubation as an alternative to succinylcholine.
It is named so because it was carried in bamboo tubes &
used as arrow poison for hunting by Amazon people.
It has highest propensity to release histamine
It causes maximum ganglion blockade. Because of
ganglion blocking & histamine releasing property it can
produce severe hypotension.
Due to histamine release it can produce severe
REVERSAL OF BLOCK
Drugs used for reversal of block are cholinesterase inhibitors
Reversal should be given only after some evidence of
spontaneous recovery appear.
Mechanism of Action
It inactivate the enzyme acetylcholinesterase which is
responsible for break down of actetylcholine, thus increasing
the amount of acetylcholine available for competition with non
depolarizing agent thereby re-establishing neuromuscular
Anticholinesterases used for reversal are:
FACTORS PROLONGING THE NEUROMUSCULAR
Hepatic disease (both depolarizer & NMDR)
Renal disease ( only NDMR)
Inhalational agents : Prolong the block by both
depolarizers & NDMR. Inhalational agents decrease the
requirement of relaxant .The maximum relaxation is by
ether followed by desflurane
Antibiotics: Both depolarizers & NMDR
Local Anaesthetics : Except procaine local anaesthetics
prolong the action by stabilizing post synaptic membrane.
Hypothermia : Decreases metabolism of muscle relaxants.
Hypocalcemia: Calcium is required for producing action
potential. Action of NDMR is enhanced.
Hypokalemia : NMDR block is enhanced.
Acid base imbalances especially acidosis.
Calcium channel blockers
DRUGS WHICH ANTAGONISE
They reverse the block by NDMR only
An agent for reversal of neuromuscular blockade by
the agent rocuronium in general anaesthesia.
It is the first selective relaxant binding
agent (SRBA) .
Sugammadex is a modified γ-cyclodextrin
The rocuronium molecule bound within
sugammadex's lipophilic core, is rendered
unavailable to bind to the acetylcholine receptor at
the neuromuscular junction.
No need to rely on anticholinesterase
An anticholinergic drug approved for use in
combination with vilanterol (as umeclidinium
bromide/vilanterol) for the treatment of COPD
An anticholinergic for the long-term management of
chronic obstructive pulmonary disease (COPD). It
has a much higher propensity to bind to muscarinic
receptors than nicotinic receptors.
FDA approved on July 24, 2012.
Darifenacin is a medication used to treat urinary
Darifenacin works by blocking the M3 muscarinic
acetylcholine receptor, which is primarily
responsible for bladder muscle contractions.
It thereby decreases the urgency to urinate. It
should not be used in people with urinary retention.
98% bound to plasma proteins
Hepatic metabolism. Primarily mediated by the
cytochrome P450 enzymes CYP2D6 and CYP3A4.
Solifenacin is a competitive cholinergic
The binding of acetylcholine to these receptors,
particularly the M3 receptor subtype, plays a critical role
in the contraction of smooth muscle.
By preventing the binding of acetylcholine to these
receptors, solifenacin reduces smooth muscle tone in
the bladder, allowing the bladder to retain larger
volumes of urine and reducing the number of micturition,
urgency and incontinence episodes.
Because of a long elimination half life, a once-a-day
dose can offer 24 hour control of the urinary
bladder smooth muscle tone.