ANTICHOLINERGIC DRUGS,

GANGLION BLOCKING AGENTS AND

NEUROMUSCULAR BLOCKING AGENTS
• Parasympathetic Nervous System plays an important Role
in physiologic and pathophysiologic responses – “Rest
and Digest”
• Drugs that block Cholinoreceptors have important clinical
effects, some of which are of great clinical value
• Cholinoceptor antagonists are – Muscarinic and
Nicotinic
• Antinicotinic – ganglion blockers and NM junction
blockers
• Muscarinic blockers
– Atropine is the prototype – many synthetic and semi
synthetics are available now
– All are competitive blockers
 ANTICHOLINERGIC DRUGS
(Muscarinic Receptor Antagonist,
Parasympatholytics, Cholinolytics
Atropine-like Drugs)
Atropine, the prototype drug of this class,
is a nonselective blocking agent for pre
and postmuscarinic receptors, some
of its synthetic derivatives have significant
nicotinic blocking property as well.
 (-)
Atropine

Presynaptic receptors in adrenergic synapse

and their role in the regulative negative and
positive feedback
Atropine

(-)
 Atropine blocks ACh

M-effects of ACh
A 1 min B C D
200
Blood pressure [mm Hg]

150

100

50 M- M- N-
effect effect effect
ACh ACh Atropine ACh ACh
2 mcg i.v. 50 mcg 2 mg i.v. 50 mcg 5 mg
Tropane alkaloids

•Atropine

•Scopolamine (Hyoscine) Atropa belladonna

•Solanine (in potatoes) (Deadly night shade)
Jimson Henbane
weed

Datura stramonium Hyoscyamus niger

Atropine (hyoscyamine) is found in
the plant Atropa belladonna, or
deadly nightshade
Also in Datura stramonium, also
known as jimsonweed (Jamestown
weed) or thorn apple
Atropa belladona
Scopolamine (hyoscine) occurs in
Hyoscyamus niger
Many drugs: Histamine, Serotonin,
Ergots alkaloids, Antipsychotic Hyoscyamus niger
Agents, Lithium and antidepressant
drugs have similar structures and,
predictably, significant
antimuscarinic effects Datura stramonium
 Atropine – Mechanism
• Atropine causes reversible (surmountable)
blockade of cholinomimetic actions at
muscarinic receptors
– blockade by a small dose of atropine can be
overcome by a larger concentration of acetylcholine
or equivalent muscarinic agonist
• Atropine is highly selective for muscarinic
receptors
• Does not distinguish between the M 1, M2 and M3
• Some quaternary amine antimuscarinic agents
have significant ganglion-blocking actions
Action of atropine
CNS. Atropine has an overall stimulant action. Its sti-
mulant effects are not appreciable at low doses which
produce peripheral effects because of restricted entry
into the brain. Scopolamine (hyoscine) produces
central depressant effects even at low doses.
•Atropine stimulates many medullar centers –
vagal, respiratory, and vasоmotor.
•By blocking the relative cholinergic overactivity in
basal ganglia, it suppresses tremor and rigidity
in parkinsonism.
•High doses cause cortical excitation, rest-
lessness, disorientation, hallucinations, and delirium
followed by respiratory depression and coma.
CVS. Atropine causes tachycardia, due to blockade of
M2-receptors on SA node through which vagal tone
decreases HR. The tachycardia is more marked in
young adults than in children and the elderly. Atropine
shortens the refractory period of AV conduction,
especially if it has been depressed by high vagal tone.
Atropine does not influence BP. It blocks the
vasodepressor action of cholinergic agonists.
Eye. Topical instillation of atropine (0.1%) causes
mydriasis, abolition of light reflex, and cycloplegia,
lasting 7-10 days. This results in photophobia and
blurring of near vision. The intraocular tension rises,
specially in narrow angle glaucoma, but conventional
systemic doses produce minor ocular effects.
Autonomic
control
of pupil (A)
and site
of action of
mydriatics (B)
and
miotics (C)
Smooth muscles. All visceral smooth muscles with
parasympathetic innervation are relaxed (M3-blokade).
Tone and amplitude of GIT are reduced. Spasm may be reduced,
constipation may occur. Peristalsis is only incompletely suppressed
because it is primarily regulated by local reflexes and other
neurotransmitters (serotonin, encephalin, etc.).
Atropine causes bronchodilation and reduced airway resistance,
especially in asthma patients. Inflammatory mediators (histamine,
PGs, and kinins) increase vagal activity in addition to their direct
action on bronchial muscle and glands. Atropine attenuates their
action by antagonizing the reflex vagal component. It has a relaxant
action on the ureter and urinary bladder.
Urinary retention can occur in older men with prostatic hyperplasia.
Glands. Atropine decreases sweat, salivary, tracheo-
bronchial, and lacrimal secretion (M3-blockade). Skin
and eyes become dry, talking, and swallowing my be
very difficult.
Atropine decreases less the secretion of acid and pep-
sin and more of the mucus in the stomach.
Body temperature. Rise in body temperature occurs at
higher doses, and is due to both inhibition of sweating as
well as stimulation of the temperature regulating centre in
the hypothalamus. Children are highly susceptible.
Local anaesthetic action. Atropine has a mild
anaesthetic action on the cornea.

The sensitivity of different organs and tissues

to atropine varies and can be graded as:

saliva, sweat, bronchial secretion > eye >

bronchial muscles > heart > intestinal and
bladder smooth muscles > gastric glands
and gastric smooth muscles
 Anticholinergics – Ophthalmic uses
Mydriatic and Cycloplegic
• Used as eye drop or ointment:
– Diagnostic:
• Atropine 1% ointment is used
– Measurement of refractive error
– Ophthalmic examination of retina – fundoscopy
– Preferred ones: Homatropine, Tropicamide and
Cyclopentolate – shorter action
– Therapeutic Uses:
• For resting eye: Iritis, iridocyclitis, keratitis, corneal
ulcer, after surgical operations etc.
 Uses Anticholinergics
Antisecretory:
1. Preanaesthetic medication:
• To reduce secretions
• To prevent laryngospasm
2. Peptic ulcer
3. Pulmonary embolism
4. Hyperhidrosis
Antispasmodic:
– Intestinal and renal colic – not in biliary colic
– Diarrhoea (nervous and drug induced)
– Pylorospasm, gastric hypermotility, gastritis, nervous
dyspepsia etc.
 Uses Anticholinergics
– Parkinsonism: Mild cases of parkinsonism (early
cases), Drug induced Parkinsonism and adjunct to
Levodopa
– Motion sickness:
• Hyoscine (scopolamine) is the drug used – Oral,
injection and transdermal patch
• 0.2 mg orally given as prophylaxis before journey
• Not effective in other type of vomiting
– Twilight sleep: sedation and amnesia
– To antagonize Muscarinic effects of Drugs
and Poisons: Anti-ChE, Mushroom poisoning, and to
block Muscarinic effects of Neostigmine, Cobra
envenomation
 Uses Anticholinergics
CVS:
– Bradiarrhythmias
– Vagolytic – Marked reflex vagal discharge in
myocardial infarction – depression of SA or AV
node function to impair cardiac output –
Parenteral atropine or a similar antimuscarinic
drug
– Hyperactive carotid sinus reflexes
Respiratory:
– In COPD and chronic bronchitis
• Improves mucociliary clearance and
bronchodilatation
 Atropine – Pharmacokinetics
Absorption:
– The natural alkaloids and most tertiary antimuscarinic drugs are
well absorbed from the gut and conjunctival membranes – some
even over the skin (scopolamine)
– Quaternary ones – only upto 30%
Distribution:
– Atropine and the other tertiary agents are widely distributed in the
body. Passage across BBB is somewhat restricted.
– Scopolamine is rapidly and fully distributed into the central nervous
system where it has greater effects than most other antimuscarinic
drugs.
– Quaternary derivatives are poorly taken up by the brain
Metabolism:
– Atropine is metabolized in liver by conjugation and 60% excretes
unchanged in urine. It has t1/2 3-4 h.
– Effects disappear quickly within 2 Hrs except eye.
Unwanted effects:
Dry mouth, difficulty in swallowing and talking;
dry, flushed, and hot skin (especially over the face and
neck); fever; difficulty in micturition; a scarlet rash
may appear; dilated pupils, photophobia, blurring of
near vision; palpitation; excitement, psychotic behavior,
ataxia, delirium, hallucinations; hypotension, weak and
rapid pulse, cardiovascular collapse with respiratory
depression; convulsion and coma (in very high doses).
Diagnosis: 1 mg neostigmine s.c. fails to induce
typical M-effects.
Treatment: Gastric lavage with tannic acid (KMnO4 is
ineffective in oxidation of atropine). The patient must
be kept in a dark quiet room. Galantamine or physo-
stigmine (1-3 mg s.c./i.v.), diazepam against convulsion.
 ANTICHOLINERGIC DRUGS
1.Natural alkaloids: Atropine (spasmolytic, mydriatic),
Hyoscine (Scopolamine), Scopoderm® TTS (antiemetic)
2. Semisynthetic derivatives
• Mydriatics: Homatropine
• GI spasmolytics: Hyoscine butyl bromide (Buscolysin®)
3. Synthetic compounds
• GI spasmolytics: Oxyphenonium
• Antiulcus drugs: Pirenzepine (M1-blockers)
• Antiasthmatics: Ipratropium and Tiotropium
• Antidisurics: Flavoxate, Oxybutynyne, Trospium
• Mydriatics: Tropicamide
• Antiparkinsonian (central M-cholinolytics):
Benztropine, Biperiden, Trihexyphenidyl
Central
М-cholinolytics:
•Biperiden
•Trihexyphenidyl
Indications:
•Drug induced
(e.g. neuroleptics)
parkinsonism
•Spastic paralysis

They remove tremor and hypersa-

livation. Atropine-like side effects!
CNS

Parkinson's
disease
M receptors

dopamine

acetylcholine

Therapeutic use:
Antiparkinsonic drugs
Antiemetic drugs (motion disease)
HEART

Atropine

M2 receptors have inhibitory role – inhibition leads to

BRADYCARDIA

Therapeutic use: treatment of bradyarrhytmias

Homatropine
Tropicamide
EYE

Effects: mydriasis, cycloplegia, increase of intraocular

pressure, dry mucous membranes.
Therapeutic use: ophthalmoscopy of retina, measurement of
refractive errors, prevention of synechia during eye
inflammation and surgery.

Drug Concentration Duration of

action
atropine 0,5-1% 7-10 days
scopolamine 0,1- 0,25% 24 hours

homatropine 1-5% 24 hours

tropicamide 0,5-1% 3 hours

MYDRUM,
UNITROPIC
Cyclopentolate 1% 6-24 hours
CYCLOPENT
NONSELECTIVE QUARTERNARY PARASYMPATHOLYTICS
GIT

Hyoscine butyl
bromide
Trospium
Oxyphenonium

Therapeutic use: cholelithiasis, diarrhoea,

painful spasm and dyskinesia
NONSELECTIVE QUARTERNARY PARASYMPATHOLYTICS

AMINES WITH EFFECTS ON

RESPIRATORY ORGANS
Ipratropium t ½ 0.5/4 h
Thiotropium t ½ 1.5/24 h

Therapeutic use:
COPD, bronchial asthma
 Anticholinergics
in asthma
•Ipratropium

•Tiotropium
Primarily, the site of bronchodilation action of inhaled β2-adrenergic
agonists is mainly the bronchiolar smooth muscle. Atropinic drugs
cause bronchodilation by blocking cholinergic constrictor tone,
act primarily in large airways.
NONSELECTIVE QUARTERNARY PARASYMPATHOLYTICS
UGT

Oxybutynyne
Tolterodine
Trospium
Flavoxate

Therapeutic use:
Treatment of bladder spasms (inflammation, surgery),
oveactive bladder diseases (detrusor instability, spastic
neurogenic bladder, children enuresis)
SELECTIVE QUARTERNARY PARASYMPATHOLYTICS

Antagonists of enterochromaffin-like cells M1 receptors

Pirenzepine, telenzepine

Therapeutic use: decrease of gastric acid

secretion (peptic ulcer, GERD, ZE syndrome)

pirenzepine
 ATROPINE AS ANTIDOTE – CHOLINERGIC POISONING
Irreversible
inhibitors of ACHE
• Sarin (GB), Soman (GD), Tabun
Atropine 2 mg i. v., every
(GA), Vi-gases 5 -15 min.
• Organophosphates (malathion, TMB4 – pralidoxime +
parathion) atropine
• !!! Skin, mucous membrane
penetrability

Muscarine poisoning autoinjectors

 Anticholinergic –
Contraindications

• Glaucoma – Narrow angle (Precipitation

of angle closure)
• Benign prostatic hyperplasia – urinary
retention
Main interactions of anticholinergic drugs
•Absorption of more drugs is slowed because atropine
delays gastric emptying. As a result the dose of
levodopa, needed to control parkinsonism may have to
be increased. But the extent of digoxin, and
tetracyclines absorption may be increased.
•Antacids interfere with the absorption of anticholinergics.
•Antihistaminics, tricyclic antidepressants, pheno-
thiazines, pethidine, etc. have anticholinergic property:
additive side effects with atropinic drugs are possible.
•MAO inhibitors interfere with the metabolism of central
antiparkinsonian drugs (biperiden and others):
delirium may occur.
Ganglion
blocking
agents
- many side effects
- out of date
Were used in the 1950s for hypertension and peptic ulcer, but
have been totally replaced now because they produce a number or
intolerable side effects.
Relative autonomic tone and effects of
ganglionic blockade on organ function
NEUROMUSCULAR BLOCKING AGENTS

Skeletal muscle relaxants act peripherally

at neuromuscular junction. According to
their action they are divided into the
following groups.

•Nondepolarizing (competitive) agents

or curare-like drugs
•Depolarizing (hyperdepolarazing) agents
NEUROMUSCULAR BLOCKING AGENTS
(1) Nondepolarizing
(competitive) agents
Long acting: d-Tubocurarine, Pancuronium,
Doxacurium, Pipecuronium
Intermediate acting: Atracurium, Vecuronium
Short acting: Mivacurium
(2) Depolarizing agents
Suxamethonium (Succinylcholine)
Decamethonium (C-10)
Competitive
(curare-like)
blocking
agents
N+ (14 Å) N+

GI resorption
BBB
Curare is plant extract from
Chondrodendron tomentosum,
Strychnos toxifera etc. It is
used by South America tribals
as arrow poison for game
hunting. The animals got pa-
ralyzed even if not killed by
the arrow. Muscle paralyzing
active principles of curare
are alkaloids tubocurarine,
toxiferine etc.
 The South Americam lianas

Chondrodendron Strychnos toxifera

tomentosum
The competitive blockers have affinity for the nicotinic
(NM) cholinoceptors at the muscle end-plate, but no
intrinsic activity.
The NM-receptor
is a macroprotein with
5 subunits, which are
arranged like a rosette
surrounding the Na+
channel. The two alpha
subunits carry two ACh
binding sites with nega-
tively charged groups
which combine with the
cationic group of ACh
and open Na+ channel.
Competitive (nondepolarizing) block
Most of the competitive blockers have two or more
quarternary N+ atoms which provide the necessary
attraction to the same site, but the bulk of the
antagonist molecule does not allow conformational
changes in the subunits needed for opening
the channel. Competitive blockers generally have
thick bulky molecules and were termed
Pachycurare by Bovet (1951). ACh esterase released
from motor nerve endings is not able to combine with
its NM-receptors to generate end-plate potential (EPP).
MECHANISM OF ACTION:
competitive inhibition of
•Acetylcholine on NM
receptors
•Sodium ion channels
N+:
quarter-
nary
N-atom
Depolarizing block
Succinylcholine (SCh) and decamethonium have affinity
as well as submaximal intrinsic activity at the
NM-cholinoceptors. They depolarize muscle end-
plates by opening Na+ channels (just as ACh does)
and initially produce twitching and fascilations. These
drugs do not dissociate rapidly from the receptor,
induce prolonged partial depolarization of the region
around muscle end-plate, and inactivation of Na+
channels.
Depolarizing agents also have two quaternary N+
atoms but their molecule is long, slender, and flexible.
They are termed Leptocurare by Bovet (1951).
Depolarizing agents produce dual
mechanism neuromuscular
blockade which can be divided in
two phases:
Phase I block. It is rapid in onset,
results from persistent
depolarization of muscular end-
plate and has features of
depolarization blockade.
Phase II block. It is slow in onset
and results from desensitation of
the NM-receptor to ACh. It
superficially resembles block
produced by tubocurarine.
Depolarizing agents
and acetilcholine

(doubled acetylcholine molecule)

Action of
succinylcholine
(suxamethonium)

Toxicity
•Cardiac arrhythmias
•Prolonged apnoea
•Malignant hyperthermia
– idiosyncrasy
(1:20000) (which needs
treatment with directly
acting muscle relaxant
Dantrolene i.v.)
Effects of neuromuscular blocking drugs
Skeletal muscles. Intravenous injection of competitive
blockers rapidly produces muscle weakness, followed
by flaccid paralysis. Small fast response muscles
(fingers, extraocular) are affected first. Paralysis
spreads to hands, feet, arm, leg, neck, face, trunk,
intercostal muscles, diaphragm, and respiration stops.
Recovery occurs in the
reverse sequence:
diaphragmatic
contractions resume first.
Depolarizing agents produce fasciculations, lasting few
seconds before inducing flaccid paralysis, but
fasciculations are not prominent in well anaesthetized
patients.
The action of SCh develops very rapidly.
Apnoea occurs within 45-90 sec, but lasts only 2-5 min
and recovery is rapid.
Autonomic ganglia. Competitive blockers can produce
some degree of ganglionic blockade. SCh as an agonist
of N-receptors may cause ganglionic stimulation.
Histamine release with hypotension and bronchospasm
can cause tubocurarine from the mast cells.
This does not involve the immune system.
CVS. Tubocurarine produces significant fall in BP
and sometimes – tachycardia (due to vagal
ganglionic blockade or blockade of M2 receptors).
SCh initially produces bradycardia due to
activation of vagal ganglia, followed by
tachycardia and rise in BP, due to stimulation of
sympathetic ganglia.

GIT. The ganglion blocking action of competitive

Agents may enhance postoperative paralytic
ileus after abdominal operations.
Pharmacokinetics
All neuromuscular blockers are quaternary compounds.
They are not absorbed in GIT, do not cross placental,
and BBB. The unchanged drug is excreted in urine,
and bile.
SCh is rapidly hydrolyzed by plasma
pseudocholinesterase to succinylmonocholine and then
to succinic acid and choline (the action lasts 3-5 min).
Some patients (idiosyncrasy 1:3000) have genetically
determined abnormality (deficiency of
pseudocholinesterase). In these patients SCh causes
Dominant phase II blockade, resulting in muscle
paralysis and apnoea, lasting 6-8 hours. In this case the
Intubation of the patient must be continuous until
full recovery.
Indications
The most important use of neuromuscular blockers is as adjuvant
drugs to general anaesthesia. Surgical procedures are
performed more safely and rapidly.
The competitive neuromuscular blockers are particularly helpful in
abdominal and thoracic surgery, intubation and endoscopies,
orthopedic procedures.
SCh is employed for brief procedures, e.g. endotracheal intubation,
laryngoscopy, bronchoscopy, esophagoscopy, reduction of
fractures, and dislocations.
SCh is mostly used to avoid convulsions and trauma from
electroconvulsive therapy.
In severe cases of tetanus and status epilepticus, which are not
controlled by diazepam or other anticonvulsive drugs, competitive
neuromuscular blockers are used.
Main drug interactions
•There is in vitro incompatibility between SCh
and thiopental (thiopentone).
•General anaestetics, aminoglysides (gentamicin, etc.) and
hypokalemic diuretics potentiate competitive blockers.
•Anti-ChEs (galantamine, neostigmine) and amino-
pyridine (Pymadine®) reverse the action of
competitive neuromuscular blockers.
•SCh potentiates malignant hyperthermia, produced
by halothane. SCh has not any antagonists.
•Calcium channel blockers potentiate both depolarizing
and nondepolarizing neuromuscular blockers.
•Sympathomimetics (adrenaine, etc.) reduce the competitive
block by increasing ACh release.
Dantrolene

Different from neuromuscular blockers

MOA – Ryanodine receptors (RyR) calcium channels –
prevents depolarization – no intracellular release of Ca++
Absorbed orally, penetrates brain and produces sedation,
metabolized in liver, excreted in kidney.
T1/2 8-12 hrs.
Dose: 25-100 mg 4 times daily
Uses: UMN (upper motor neurons) disorders – paraplegia,
hemiplegia, cerebral palsy and malignant hyperthermia (drug
of choice 2.5 – 4 mg/kg))
Adverse effects – Sedation, malaise, light headedness,
muscular weakness, diarrhoea and hepatotoxicity