Dr.Ch.

Shanmukha Sai Raghav

CHOLINERGIC ANTAGONISTS
 The Cholinergic Antagonists are also called cholinergic blockers
or anticholinergic drugs or Parasympatholytics usually binds to
cholinoceptors but they do not trigger the release of
acetylcholine instead it will block the receptor.
 Particularly and selectively block the muscarinic receptors of the
parasympathetic nerves and actions of sympathetic stimulation
are not affected.
 The Cholinergic antagonist drugs have three families of
compounds. They are: 1. Antimuscarinic Agents 2. Ganglionic
Blockers 3. Neuromuscular Blockers.
 1. Antimuscarinic Agents: Atropine, Benztropine,
Cyclopentolate, Darifenacin, Fesoterodine, Ipratropium,
Oxybutynin, Scopolamine, Tiotropium,Tolterodine,
Trihexyphenidyl, Tropicamide, Trospium chloride.
 2. Ganglionic Blockers: Mecamylamine, Nicotine.
 These ganglionic blockers will block the nicotinic receptors of
sympathetic and parasympathetic ganglia and it is clinically less
important.
 3. Neuromuscular Blockers: Atracurium, Cisatracurium,
Pancuronium, Rocuronium, Succinylchoine, & Vecuronium.
 These neuromuscular blockers are interfering with transmission
of efferent impulses to skeletal muscles. These agents are used
as skeletal muscle relaxants in anesthesia during surgery,
intubation and various orthopaedic procedures.
ANTIMUSCARINIC AGENTS
 Common called antimuscarinics, these drugs cause inhibition of
all muscarinic functions and also block few exceptional
 sympathetic neurons that are cholinergic such as those
innervating salivary glands and sweat glands.
 Cholinergic agonists have limited therapeutic uses in other hand
Cholinergic antagonists have huge variety of benefits
therapeutically because they do not block nicotinic receptors
and also they have no or little action at skeletal NMJs.
 Atropine: It has high affinity for muscarinic receptors and binds
competitively and prevents acetylcholine to bind to those sites.
 It acts both centrally and peripherally and general action
duration is about 4 hrs except when placed topically on eye it
may lasts for days.
 Neuroeffector organs have varying sensitivity to atropine. The
greatest inhibitory effects are on bronchial tissue and the
secretion of sweat and saliva.
 Dose-Dependent effects of atropine: 0.5mg-2.0mg; slight
cardiac slowing, some dryness of the mouth, inhibition of
sweat. 5.0mg; rapid heart rate, palpitation, marked dryness of
the mouth, dilation of pupil, some blurring of near vision.
>10mg; Hallucinations and delirium (an acute disturbance of
state of mind), Coma.
 Actions: I. Eye: Atropine blocks all cholinergic activity on the
eye and produce persistent Mydriasis means dilation of the
pupil, unresponsiveness of light and unable to focus on near
vision (Cycloplegia) atropine can be used in patients with
narrow-angle glaucoma, intraocular pressure will increase
dangerously. In ophthalmic examination, shorter acting drugs
like tropicamide or α-adrenergic drug like Phenylephrine are
generally favoured for producing Mydriasis.
 II. Gastrointestinal: Atropine can be used as an antispasmodic to
reduce activity of GI tract particularly patients with dyspepsia
or irritable bowel syndrome.
 Atropine & Scopolamine are most potent drugs available that
produce this effect. Gastric motility reduced but HCl production
is not significantly affected.
 In addition, doses of an atropine that reduce spasms also reduce
saliva secretion, ocular accommodation and urination.
 III. Urinary system: This drug is used to reduce hypermotility
states of urinary bladder. It is used occasionally in enuresis
(involuntary urination especially in children at nights) but α-
adrenergic agonists are used to treat this condition because it is
more effective and have fewer side effects.
 IV. Cardiovascular: Atropine provides vast different effects on
cardiovascular system depend on dosage. At low doses, the
predominant effect is the decreased cardiac rate
(bachycardia).With higher doses of atropine, which block the
M2 receptor on SA node which increase the cardiac rate. To
increase cardiac rate generally requires 1mg or more. Arterial
blood pressure is unaffected but at toxic levels atropine dilates
the cutaneous vasculature.
 V. Secretion: Atropine blocks the salivary glands causing
dryness in mouth/oral membranes. The salivary glands are
extremely sensitive to atropine, lacrimal and sweat glands are
similarly affected.
 Therapeutic Uses: I. Ophthalmic: Atropine exerts both
mydriatic and cycloplegic effects and it s permits the
measurement of refractive errors. Phenylephrine & similar α-
adrenergic drugs are used to produce mydriatic effect if
cycloplegic effect is not required.
 In ophthalmic examination, shorter acting drugs like
tropicamide & cyclopentolate or α-adrenergic drug like
Phenylephrine are generally favoured for producing Mydriasis
and atropine is replaced because of the prolonged effect on eye.
 Atropine may induce an attack of pain in eye due to sudden
increase in intraocular pressure in patients with narrow-angles
glaucoma.
 II.Antispasmodic: Atropine is used as an antispasmodic agent to
relax the GI tract and bladder.
 III. Antidote for Cholinergic agonists: This drug is used for the
treatment of overdoses of cholineresterases inhibitor and some
types of mushrooms which contain cholinergic substances and
block cholinesterase.
 Large amounts of doses are required for over a period of time to
counteract the poisons.
 The drug also blocks the effects of excess Ach resulting from
AChE inhibitors such as Physostigmine.
 IV. Antisecretory: It is used as Antisecretory agent to block the
secretions in the upper and lower respiratory tract before to
surgery.
 Atropine is readily absorbed and partially metabolized in liver
and eliminated through urine and half life is 4 hrs.
 Adverse Effects: Depending on doses, it can cause dryness,
blurred vision, sandy eyes, tachycardia, urinary retention, and
constipation.
 Effects on CNS are restlessness, confusion, hallucinations,
delirium and can leads to depression, respiratory and circulatory
failure and death.
 Low doses of cholinesterase inhibitors like Physostigmine can
overcome the toxicity.
 Patient with latent condition of glaucoma and older individuals,
the use of atropine to induce Mydriasis and Cycloplegia is
consider to be risky because of aggravation of an attack of
glaucoma due to an increase of intraocular pressure.
 It is also gives adverse effects in children because they are
sensitive to its effects particularly to the rapid increases in body
temperature.
 Note: Adverse effects commonly observed in cholinergic
antagonists are: Blurred Vision, Confusion, Mydriasis,
Constipation, Urinary retention.
 Scopolamine: It is another tertiary amine, plant alkaloid,
produces peripheral effects similar to atropine. It has greater
 action in CNS than atropine and longer duration. It also has
special actions.
 I. Actions: Scopolamine is one of the most effective anti motion
sickness drugs and it has unusual effect of blocking short-term
memory.
 In contrast of atropine, it produces sedation effect but at higher
doses it can produce excitement and euphoria, susceptible to
abuse.
 II. Therapeutic Uses: Scopolamine is similar to atropine hut its
therapeutic uses are limited to prevention of motion sickness
and it is pretty effective, it can block short term memory.
 It has more effective prophylactically than for treating motion
sickness once it occurs,
 Scopolamine can block the short term memory so it can produce
amnesic action and it makes an important supplement drug in
anesthetic procedures.
 It has similar adverse effects and pharmacokinetic properties.
 Ipratropium & tiotropium:
 These both are quaternary derivatives of atropine and they are
administered through inhalation.
 It is approved as bronchodilators for the treatment of
bronchospasm associated with COPD, for chronic bronchitis
and emphysema.
 These agents are pending for approval of treating asthma in
patients who are unable to take adrengic agonists.
 Because of positive charges, they can’t enter into systemic
circulation or the CNS, isolating to the pulmonary system.
 Tiotropium is administered only once daily than Ipratropium
which requires 4 doses.
 Tropicamide & Cyclopentolate: Are similar to atropine as
ophthalmic solutions for producing Mydriasis and Cycloplegia.
The duration is shorter than atropine 6 hrs and 24 hrs
respectively.
  Benztropine & trihexyphenidyl: These drugs are centrally
acting antimuscarinic agents and they are used to treat
Parkinson disease for a long time after the arrival of other drugs
like levodopa/carbidopa they have been replaced.
 But these drugs are used as supplement for other
antiparkinsonian agents to treat all types of Parkinsonian
syndromes.
 These drugs are used to treat geriatric patients who do not
tolerate stimulants.
 Darifenacin, fesoterodine, Oxybutynin, Solifenacin,
Tolterodine, Trospium: These drugs are synthetic atropine like
drugs and they are used to treat overactive urinary bladder
disease.
 Drugs will block the muscarinic receptors in urinary bladder
thus increase the capacity of bladder and frequency of urination
is decreased.
 Side effects are blurred vision, constipation, and dry mouth.
 Oxybutynin are available in transdermal and it is better tolerant
than oral, most of patients has greater acceptance.
GANGLIONIC BLOCKERS
 Ganglionic blockers specially act on the nicotinic receptors of
both parasympathetic and sympathetic autonomic ganglia.(AG)
 Some can also block the ion channels of autonomic ganglia.
 They neither sensitive towards parasympathetic and sympathetic
AG nor effective as neuromuscular antagonists.
 These drugs are categorized: Non-depolarizing and competitive
antagonists. Non-depolarizing drugs are complex.
 Eg: In the presence of non- depolarizing drug, the arterioles will
vasodiltate due to arterioles are innervated with sympathetic
AG.
 These drugs have no therapeutic use and it is used in
experimental pharmacology.
  Nicotine: Frome cigarette smoke, is a posion with many
undesirable action and it will detiorate the system. Depending
on dose, it will depolarizes the autonomic ganglia at first and
then paralyze all ganglia.
 Neurochemical effects of nicotine:

 Mecamylamine produces a competitive nicotinic blockage of

ganglia and has fewer side effects.
NEUROMUSCULAR BLOCKING DRUGS
 These drugs block the cholinergic transmission between motor
nerve endplate and nicotinic receptor of NMJ.
 These neuromuscular blockers are structurally similar to Ach
and they can act as either non depolarizing type or depolarizing
type at the endplate of NMJ.
 These are clinically useful during surgery for producing
complete muscle relaxation, without having higher dose of
anesthetic and it also used in orthopaedic surgery and in
facilitating tracheal intubation.
 Central muscle relaxants are used to control spastic muscle tone.
These include Diazepam which binds to GABA; Dantrolene,
which directly binds on muscle by interfering with the release of
calcium from SR.
 Non depolarizing blockers:
 The first drug is Tubocurarine introduced into clinical practice
in early 1940 and it is capable of blocking skeletal NMJ, but
because of its adverse effect it has been replaced with other
drugs.
 The neuromuscular blocking agents have increased the safety of
anesthesia because less anesthetic dose is required to produce
muscle relaxation and it will allow the patient recovery fast after
surgery.
 Higher anesthetic doses may produce respiratory paralysis and
cardiac depression increasing recovery time.
 Neuromuscular blockers should not be used to substitute for
inadequate depth of anesthesia.
 I. Mechanism of action: At low doses; non depolarizing
neuromuscular blocking drugs interact with skeletal NMJ to
prevent the binding of Ach.
 Thus, these drugs prevent depolarization of muscle membrane
and prevent muscle contraction and they compete with Ach to
bind to receptors, they are called competitive blockers.
 This action can be overcome by giving cholineresterase
inhibitors such as Neostigmine, Physostigmine etc..,
 At low doses, the muscle will respond to electrical stimulation
from a peripheral nerve stimulator to varying degrees.
 At high doses; They can block ion channels of the endplate and
leads to further weakening of neuromuscular transmission and
also reducing the ability of AChE inhibitors to reverse the
action.
 II. Action: All muscles are not equally sensitive to blockade by
competitive blockers. Muscles will relax as follows: Muscles of
 face and eyes fingers muscles of limbs, neck, trunk
intercostals muscles diaphragm.
The recovery is reverse pattern.

 III. Therapeutic uses: These drugs are useful in anesthesia

during surgery, it will used as supplement. They are also used to
facilitate intubation as well as orthopaedic surgery.
 IV. Pharmacokinetics: All neuromuscular blockers are injected
via IV because their uptake through oral administration is
minimal.
 These agents possess two or more quaternary amines in their
ring structure making them through oral it is less effective.
 They can’t penetrate through membrane and they don’t enter
into cell or cross through BBB.
 Many of these drugs not metabolized and their actions are
terminated through redistribution.
 Pancuronium is excreted unchanged in urine, Atracurium is
degraded in plasma and by ester hydrolysis.
 Atracurium releases histamine and metabolized to laudanosine
which can provoke seizures.
 Cisatracurium is the isomer, which has same pharmacokinetic
properties but less effective.
 Vecuronium & rocuronium are aminosteriod drugs and are
deacteylated in the liver and these drugs are also excreted
unchanged in bile.
 V. Drug interaction:
 Cholinesterase inhibitors: Drugs like Physostigmine,
Neostigmine, pyridostigmine & edrophonium can overcome the
action of nondepolarizing neuromuscular blockers, but with
higher dose it can induce depolarizing block as result Ach
concentration is elevated at endplate.
 If neuromuscular blockers have entered into ion channel,
cholinesterase inhibitors cannot overcome the blockade.
 Drugs such as halothane act to enhance neuromuscular blockade
by exerting a stabilizing action at the NMJ.
 Drugs such as gentamicin & tobramycin inhibit the ACH release
from cholinergic nerves by competing with calcium ions and
these drugs enhance the neuromuscular blockade.
 Calicum-channel blockers, are may increase the neuromuscular
block of competitive blockers as well as depolarizing blockers.
 Depolarizing agents: These agents work by depolarizing the
plasma membrane of the muscle fibers similar action of Ach,
but these agents are more resistant to degradation by AChE and
they can continuously depolarize the muscle fibers.
 Succinylcholine is the only depolarizing muscle relaxant in
use today.
 I. Mechanism of action: This drug attaches to nicotinic receptor
and acts like Ach and depolarize the membrane. Unlike Ach
which can degrade by AChE instantly, this depolarizing agent
remains attached to the receptor for a long time and continue to
stimulate the receptor.
 The depolarizing agent first causes to opening of the sodium
channel associated with nicotinic receptors which results in
depolarization of the receptor.
 Leads to twitching of muscle, continue binding of the
depolarizing agent makes the receptor incapable of transmitting
further impulses.
 For a long time of depolarization the sodium channels will close
or is blocked, causes a resistance of depolarization and flaccid
paralysis.
 II. Actions: The sequence of paralysis may be slightly different
but with competitive blockers, the respiratory muscles are
paralyzed last.
 Succinylcholine initially produces muscle fasciculations and a
ganglionic block except at higher dose.
 Administering a small dose of non-depolarizing neuromuscular
blockers before succinylcholine helps decrease or prevent the
fasciculation which can cause muscle soreness.
 The duration of action is extremely short because this drug is
broken down by plasma pseudocholinesterase, and it is not
metabolized AChE at NMJ thus allowing the agent to bind to
nicotinic receptors and redistribution to plasma in necessary to
metabolism.
 Genetic variants in which plasma pseudocholinesterases levels
are low or absent leads to prolonged neuromuscular paralysis.
 III. Therapeutic uses: Because of rapid onset and short duration
of action, it is useful when rapid endotracheal intubation is
required during the induction of anesthesia.
 A rapid action is required if aspiration of gastric contents is too
avoided during intubation.
 It is also used during electroconvulsive shock treatment (ECT):it
is a procedure done under general anesthesia in which small
electric currents are passed through brain intentionally triggering
a brief seizure.
 IV. Pharmacokinetics: It is injected intravenously and short
duration of action results from redistribution and rapid
hydrolysis by plasma pseudocholinesterase.
 Therefore, it is sometimes given by continuous infusion to
maintain a longer duration of effect.
 V. Adverse Effects: 1. Hyperthermia: When halothane is used
as an anesthetic administration of succinylcholine has
occasionally cause malignant hyperthermia (abnormally high
body temp.) with muscle rigidity, tachycardia or sometimes
bradycardia, metabolic acidosis, in genetically susceptible
people.
 This can be treated with rapid cooling of patient and
administration of dantrolene which blocks the release of Ca+2
ions from SR of muscle cells and reducing heat production and
relaxing of muscle tone.
 2. Apnea: The patient who has genetically deficient in plasma
pseudocholinesterase or who has atypical form of an enzyme
can lead to prolonged apnea (temporary breathing cessation
especially during sleep) due to paralysis of diaphragm.
 The rapid release of K+ ions may also contribute apnea in
patients with electrolyte imbalances who receive drug.
 Patients with electrolyte imbalance who are also receiving
digoxin or diuretics should use succinylcholine cautiously or not
at all.
 3. Hyperkalemia: This drug increase potassium release from
intracellular stores.
 This may be dangerous in burn patients and patients with
massive tissue damage in which potassium has been lost from
within cells.
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