CHOLINERGIC ANTAGONISTS

ANTICHOLINERGIC DRUGS
(PARASYMPATHOLYTICS)

PHARMACOLOGY I/ ANS, LECTURE 4

DR. HIWA K. SAAED, HD, MSC. PHD
PHARMACOLOGY & TOXICOLOGY

Cholinergic antagonists
Drugs that block cholinergic
receptors (M and/or N).
The actions of sympathetic
stimulation are left
unopposed.

3/16/15

Cholinergic antagonists
They are classified to two subclasses:
1. Muscarinic (M1-M5) receptor

antagonists: the most useful clinically.

2. Nicotinic receptor antagonists:
further subdivided to:
NMJ Blocking agents: inhibit the efferent

impulses to skeletal muscle via the (NM)

receptor
Ganglionic Blocking agents: inhibit the
nicotinic neuronal receptor (NN) of both
parasympathetic and sympathetic ganglia
3

3/16/15

Sites of action of cholinergic antagonists

3/16/15

Muscarinic antagonists:
Atropine (prototype): comes from the plant

Atropa belladonna and is known as a belladonna

alkaloid. Belladonna in Latin means pretty lady.
Inhibit all M functions.
Scopolamine (hyoscine): Rx of motion sickness ;
natural occurring alkaloid
Propantheline, Dicyclomine: Rx of peptic
disease, hypermotility
Clidinium (Librax), isopropamide (stelabid),
Mebeverine (Duspataline)
Homatropine:Cyclopentolate, Tropicamide:
mydriasis and cycloplegia
Pirenzepine & telenzipine: Selective M1 blocker.
Rx of Gastric ulcer
Oxybutinin: somewhat selective for M3 receptors
5

3/16/15

Muscarinic antagonists:
Trospium: nonselective comparable in

efficacy and SE with oxybutinin

Darifenacin and Solifenacin: selective M3
blocker
Tolterodine: selective M3 blocker Rx of
urinary incontinence
Flavoxate: also indicated for overactive
bladder
Benztropine: Rx of Parkinsonism
Ipratropium, Tiotropium: Rx of Asthma
*Imipramine a TCA with strong
6

antimuscarinic actions, has long been

used to reduce incontinence in3/16/15
elderly

Atropine (hyoscyamine) Mechanism of action:

It causes reversible, nonselective blockade of

muscarinic receptors.
Therefore, High concentration of Ach or an
equivalent muscarinic agonists can be used to
counteract the effects of atropine

3/16/15

Pharmacologic actions of atropine

CNS: at toxic doses can cause
restlessness,
hallucinations,
and delusions.
CVS:

At low doses, atropine reduces heart

rate through central stimulation of the
vagus nucleus.
At high doses, atropine blocks
heart and
8 muscarinic receptors of the 3/16/15

Pharmacologic actions of atropine

GIT: reduces salivary gland secretion and

GI motility.
Pulmonary system: reduces bronchial
secretions and stimulates
bronchodilation.
Urinary system: blocks muscarinic
receptors in the bladder wall, which
results in bladder wall relaxation.
Eye: causes paralysis of the sphincter
muscle of the iris and ciliary muscle of
the lens, resulting in mydriasis and
cycloplegia
3/16/15
Sweat glands: Suppresses sweating,

Atropine effects in order of increasing dose

Decreased secretions

(Salivary, bronchiolar, sweat)

Mydriasis and cycloplegia
Hyperthermia (vasodilation)
Tachycardia
Sedation
Urinary retention and
constipation
Behavioral excitation and
hallucinations
10

3/16/15

Therapeutic uses of atropine

Bradycardia
Mydriasis and cycloplegia- beneficial when a

thorough fundus examination or an accurate

refraction is required.
NB: atropine contraindicated in a patients who
has narrow-angle glaucoma, because this may
result in acute crisis due to closure of the canal
of Schlemm
GIT and bladder spasms:
organophosphate poisoning.
11

3/16/15

Pharmacokinetics
Atropine as a tertiary amine, it is well

absorbed from the GIT and conjunctival

membrane.
It is excreted through both hepatic
metabolism and renal function.
Atropines duration of action is ~ 4 hrs,
except when it is placed in the eye,
where it usually lasts about 14 days

12

3/16/15

Adverse effects
Dry mouth (dry as bone)
Inhibition of sweating especially in

young children (hot as a hare)

Tachycardia and coetaneous
vasodilation (red as beet)
Blurring of vision (blind as a bat)
Hallucinations and delirium (mad as
a hatter)
Urine
retention
13

3/16/15

Scopolamine
Like atropine, this drug is a

belladonna alkaloid.
But it has a longer duration of
action and more potent CNS Others:
Homatropine,
effect
cyclopentolate &
Nonselective competitive
Tropicamide: In
blockade of muscarinic
ophthalmology, they
receptors
are given topically for
Therapeutic uses: Prevention
mydriasis and
of motion sickness
cycloplegia.
Adverse effects: similar to
Pirenzepine:
those of atropine
a selective M1
muscarinic
inhibitor,
3/16/15
14
used for treating

15

3/16/15

2. Neuromuscular blocking agents

16

3/16/15

17

3/16/15

NM blockers

I. Nondepolarizing blocking agents

(antagonists)
1. Tubocurarine (prototype)
2. Pancuronium: longer duration of action
3. Atracurium
4. Vecuronium
II. Depolarizing blocking agents (agonists):
5. Succinylcholine
3-6 minutes if given as a single dose.
Metabolized by plasma cholinesterase
18

3/16/15

I. Nondepolarizing NM blockers
Mechanism of action:
At low dose: these drugs competitively
block cholinergic transmission at the
nicotinic receptors by preventing the
binding of Ach to its receptor.
Their action can be reversed with
edrophonium or neostigmine ????
At high dose: block the ion
channels of the end plate.
This action can not be
reversed by CE inhibitors.
19

3/16/15

I. Nondepolarizing NM blockers
All NM junction blockers must be given I.V

because oral absorption is poor.

Therapeutic use: They are used as adjuvant
drugs for anesthesiathey promote muscle relaxation; the muscle
of the eye and face are affected first, whereas
the respiratory muscles are affected last.

20

3/16/15

Sequence of Paralysis
Fingers, orbit (small muscles)

limbs

Trunk

Diaphragm

21

Recovery in Reverse

neck

Intercostals

3/16/15

II. Depolarizing NM junction

blockers

22

Succinylcholine:
Mech. of action:
Phase I- opens the Na
channels-membrane
depolarization-transient
fasciculations. Flaccid
paralysis will follow in a few
minutes
Phase II: the membrane
partially repolarize.
However, these receptors
are now desensitized to Ach,
Thus preventing the
formation of further action
potentials. In other words, is
now acting in a manner

3/16/15

Therapeutic Use
As an adjuvant to GA to facilitate
rapid intubation.
2. Orthopedic procedures for alignment
of fractures.
3. In electroshock treatment of
psychiatric disorders.
1.

23

3/16/15

Drug Interaction
Cholinesterase inhibitors: can overcome the action

of nondepolarizing neuromuscular blockers

Halogenated hydrocarbon anesthetics: Drugs such
as halothane sensitize the neuromusclular junction
to the effects of neuromuscular blockers.
Aminoglycoside antibiotics: inhibit Ach release
from cholinergic nerves by competing with calcium
ions. (Synergistic)
Calcium-channel blockers: These agents may
increase the neuromuscular block of tubocurarine
and other competitive blockers as well as
depolarizing blockers.
24

3/16/15

25

3/16/15

26

3/16/15

Adverse effects of NM blockers:

Bronchoconstriction caused by histamine
release
2. Decreased tone and motility in GI tract
3. Depolarizing agents can cause increased K+
efflux in patients with burns, trauma, or
denervation and lead to hyperkalemia
4. Hypotension
5. Arrhythmias
6. Apnea due to respiratory paralysis (check for
psudocholinesterase genetic polymorphism)
7. Malignant hyperthermia
(succinylcholine+halothane especially);
Rx by dantroline. It blocks the release of Ca+2 from
the sarcoplasmic reticulum which subsequently
reduces skeletal muscle contraction.
3/16/15 autonomic
Q. Do NM junction blocking agents block
ganglia as well???
1.

27

Classification of Blockers
Agent

Pharmacological
Properties

Onset time
(min)

Duration
(min)

1-1.5

6-8

4-6

80-120

Elimination

Succinylcholine

Ultra-short acting;
Depolarizing

D-tubocurarine

Long duration;
Competitive

Atracurium

Intermediate
duration;
Competitive

2-4

30-40

Plasma
cholinesterase

Mivacurium

Short duration;
Competitive

2-4

12-18

Plasma
cholinesterase

Pancuronium

Long duration;
Competitive

Rocuronium

Intermediate
duration;
competitive

28

4-6
1-2

4-6
1-2

3/16/15

Plasma
cholinesterase
Renal and liver

Renal and liver

Renal and liver

3. Ganglionic blockers

29

Nicotine, Hexamethonium, Mecamylamine,

Trimethaphan
Ganglionic blockers compete with Ach to
bind with nicotine receptors of both
Parasympathetic and Sympathetic
ganglia
Ganglionic blockers divided into two
groups:
1. Drugs such as nicotine, which initially
stimulate the ganglia and then block
them because of a persistent
3/16/15
depolarization

3. Ganglionic blockers
The physiologic effects of ganglionic blockers
can be predicted depending on which
division of the ANS exercises dominant
control of the organ in question:
Heart: tachycardia results because the

parasympathetic system is normally

dominant on the heart.
Arterioles and veins: vasodilation,
increased peripheral blood (sympathetic
normally dominant)
30

3/16/15

3. Ganglionic blockers
Eye: cycloplegia, mydriasis

(parasympathetic normally dominant)

GIT: reduced motility; diminished gastric
and pancreatic secretions
(parasympathetic normally dominant)
Urinary system: urinary retention
(parasympathetic normally dominant)
Sweat glands: reduced sweating
(sympathetic normally dominant)
31

3/16/15

3. Ganglionic blockers
Therapeutic use
Because they lack the selectivity, the ganglionic
blockers very rarely used clinically.
In the past, these drugs were used in
hypertensive emergencies.

32

3/16/15