PARASYMPATHOMIMETIC DRUGS

OR
CHOLINERGIC DRUGS
OR
CHOLINOMIMETIC DRUGS

DEFINITION
These are the group of drugs which produce
effects resembling those produced by the
stimulation of parasympathetic autonomic
nervous system on the target organs

Communication
between nerve cells,
and between nerve
cells
and
effector
organs, occurs through
the release of specific
chemical signals, called
neurotransmitters,
from
the
nerve
terminals
in
the
synapse.
The
neurotransmitters
rapidly diffuse across
the synaptic cleft and
combine with specific
receptors
on
the
postsynaptic
(target)
cell.

CHOLINOCEPTOR - ACTIVATING AND

CHOLINESTERASE - INHIBITING DRUGS

Drugs with acetylcholine-like effects

(cholinomimetics) consist of 2 major
subgroups on the basis of their mode of
action:
they act directly at the acetylcholine
receptor or
indirectly
through
inhibition
of
cholinesterase
(the
enzyme
that
terminates the action of endogenous
acetylcholine)
So, cholinomimetic effect is achieved
by
either
activating
of
cholinoceptors or the inhibition of
disintegrate of acetylcholine!

Two types of activities

Muscarinic
Nicotinic

Parasympathetic Ganglionic Synapse

Ca 2+

Acetylcholinesterase

Na+

ACH
Action Potential

Na
Preganglionic neuron

Nicotinic
Receptor

Postganglionic neuron

Parasympathetic Organ Synapse

Acetylcholinesterase

Ca 2+
Effector
Organ

Na+

K+

G
Action Potential

ACH
Muscarinic
Receptor

Postganglionic neuron

MECHANISM OF
ACTION
G protein linked (Muscarinic)
Ion channel (Nicotinic)

PHOSPHO INOSITOL SYSTEM

BINDING OF DRUG WITH RECEPTOR

(ALPHA-1 ADRENDERGIC, MUSCARINIC CHOLINERGIC. M1, M3)

ACTIVATION OF PHOSPHOLIP
PHOSPHATIDYL INOSITOL 4-5 BIPHOSPHATE

DIACYL GLYCEROL
(CONFINED TO MEMBRANE)

INOSITOL 1.4.5 TRIPHOSPHATE

(DIFFUSES INTO CYTOSOL)

ACTIVATION OF PROTEIN KINASE C

INTRACELLULAR
ENTRY OF Ca++ THROUGH THE CA++

RELEASE OF Ca++ FROM

SOURCES
FORMATION OF Ca++ CALMODULIN
COMPLEX

CHANNEL
ALTERATION IN THE ACTIVITY OF Ca++
DEPENDENT ENZYMES
EFFECT

In contrast, activation of the M2

subtype on the cardiac muscle
stimulates a G protein, designated Gi,
which inhibits adenylyl cyclase2 and
increases K+ conductance
The heart responds with a decrease in
rate and force of contraction.

13

CHOLINERGIC RECEPTORS
Muscarinic
M1 = Nerves, Stomach, Brain
Antagonist:

Pirenzepine

M2 = Heart, Nerves, Smooth Muscle.

Antagonist:

Gallamine

M3 = Glands, Endothelium, Smooth Muscle.

M4 and M5 newly discovered, role not yet known

Nicotinic
Neuromuscular Junction
Agonist: Phenyl Trimethyl Ammonium
Antagonist: Tubocurarine
Autonomic Ganglia, Adrenal Medulla
Agonist:

Dimethyl phenyl piperazinium

Antagonist: Hexamethonium

CLASSICIFICATION
A. Directly Acting
B. Indirectly Acting

Directacting
cholinomimetic
agonists
This class comprises

a c e t y l c h o l i
n e,
methacholine,
Muscarine,
pilocarpine,
nicotine,
lobeline.

A. Directly Acting Cholinergic

Drugs :
I. Choline Esters
Acetylcholine
Carbachol
Methacholine
Bethanechol

II. Cholinomimetic Alkaloids

a. Mainly Muscarinic Agonists
Natural Alkaloids:
Muscarine
Pilocarpine
Arecholine
Synthetic Alkaloid:
Oxotramorine
b. Mainly Nicotinic Agonists
Natural Alkaloids:
Nicotine
Lobeline
Synthetic Alkaloids:
Dimethylphenylpiperazinium(DMPP)

Tissue and major organ systems

effects

Effects of cholinomimetics include:

CNS complex stimulatory effects, for

example, nicotine (elevation of mood, altering,
addiction), excessive concentrations may
cause coma.
Eye contraction of the pupillae sphincter
muscle of iris (miosis). Cyclospasm marked
contraction of the ciliary muscle; maximum
accommodation for close (near) vision.
[Ach (1% solution) is instilled into the
anterior chamber of the eye to produce
miosis during ophthalmic surgery].

Heart decrease in rate (negative

chronotropy) and cardiac output,
decrease in contractile force (negative
inotropy), decrease in conduction
velocity
(negative
dromotropy),
decrease in blood pressure.
Blood vessels dilation (via release
of relaxing factor nitric oxide from
epithelium).

Bronchi contraction (bronchoconstriction)

Gastrointestinal tract increase in
smooth muscle contraction, peristalsis;
decrease in
tone or relaxation of sphincters.
Urinary bladder increase in contraction
of detrusor and
relaxation of sphincter;
voiding.
Skeletal muscle contraction
Glands (exocrine) increased secretion
(thermoregulatory sweating, lacrimation,
salivation,
bronchial
secretion,
gastrointestinal glands, accept lactation).

Clinical use
Several clinical conditions benefit
cholinergic activity, including

from

an

increase

in

Glaucoma;
[Note: Carbonic anhydrase inhibitors, such as acetazolamide,
as well as the -adrenergic blocker timolol, are effective in
treating chronic glaucoma but are not used for emergency
lowering of intraocular pressure. Pilocarpin - the direct
acting cholinomimetic drug - is used for emergency
conditions.]

Sjorgrens syndrome
[Sjogrens syndrome, which is characterized by dry mouth
and lack of tears, is treated with oral pilocarpine tablets
which increases salivation];

Loss of normal PANS activity in

the bowel and bladder;
Smoking cessation (direct-acting
nicotinic agonists nicotine);
Skeletal muscle paralysis.

Toxicity of cholinomimetics
These effects include:

CNS stimulation,
miosis, spasm of
accommodation,
bronchoconstriction,
excessive gastrointestinal and
genitourinary smooth muscle
activity,
increased secretory activity,
vasodilation, bradycardia.

Indirect acting agonists

Include 2 major classes:
Carbamates neostigmine,
rivastigmine,
pyridostigmine,
endrophonium,
physostigmine, and
Organophosphates

zarin,
tabun, others and insecticides.
Many of these drugs are
extremely toxic and were
developed by the military as
nerve agents.

EFFECTS
By
inhibiting
cholinesterase,
these
agents
cause
an
increase
in
the
concentration, half-life,
and
actions
of
acetylcholine
in
synapses where acetylcholine
is
released
physiologically
(thus
amplifying
acetylcholine effects).

B. Indirectly Acting Cholinergic Drugs

(Anticholinesterases)

I- Reversible
a. Carbamates
b. Alcohols
II- Irreversible

I- Reversible
a. Carbamates
Tertiary amines
Physostigmine
Quaternary Ammonium compounds
Neostigmine
Pyridostigmine
Distigmine
Ambenonium
Demecarium

b. Alcohols
Edrophonium

c. Miscellaneous
Tacrine
Donepezil
Galantamine
Rivastigmine

II. Irreversible Anticholinesterases

(Organophosphorus Compounds)
1) Therapeutically useful:
Ecothiophate

2)

War Gases:
Sarin
Tuban,
Soman

3)

Insecticides:Parathion
Malathion
Diisopropyl Flurophosphate (DFP)
Tetramethyl Pyrophosphate (TMPP)
Octamethyl Pyrophosphotetraamide (OMPA)

Clinical use

Carbamates are used

far more commonly
in therapeutics than
are
organophosphates:

glaucoma
(physostigmine, but
pilocarpine is more
effective);
treatment of

myasthenia
gravis (has

important
autoimmune
aspects, treatment
may also include
thymectomy and
immunosuppressant drugs);

Myasthenia gravis improvement

after intravenous administration
of
edrophonium (indirect agonist)

Alzheimers
galanthamine,
(obsolete).

disease
(rivastigmine
donepezil,
tacrine

Note: Patients with Alzheimer disease have a significant

loss of cholinergic neurons in the temporal lobe and
entorhinal cortex. Most of the drugs available to treat
this disease are acetylcholinesterase (AchE) inhibitors.
But nowadays it is considered, that these drugs
are ineffective.

Reversal of severe atropine poisoning (i/v

physostimine). Physostigmine is also used in the
treatment of overdoses of drugs with anticholinergic
actions, phenothiazines, and tricyclic antidepressants;
As an antidote for tubocurarine and other
competitive
neuromuscular
blocking
agents
(neostigmine).

TOXICITY

In addition to their
therapeutic uses, some
indirect acting agents
(especially
organophosphates)
have
clinical
importance
because
organo- phosphates are
long-acting drugs, they
form an extremely stable
phosphate complex with
the
enzyme
Acetylcholinesterase. These
drugs can be rapidly fatal if
exposure
is
not
immediately
recognized
and treated.

The antidote of first choise in this

instance is the
1. antimuscarinic agent atropine;
2. Diazepam is also administered to
reduce the persistent convulsion
caused by these agents;
3. General supportive measures, such
as maintenance of patient airway,
oxygen
supply,
and
artificial
respiration, may be necessary as
well.

The signs and symptoms

poisoning with organophosphates
the same as those described for
direct-acting agents:
vasodilation;
bradycardia;
CNS stimulation (convulsion);
respiratory and cardiovascular
depression.

of
are
the

The spectrum of toxicity can be

remembered with the aid of the
mnemonic DUMBBELSS:
diarrhea;
urination;
miosis;
bronchoconstriction;
bradycardia;
excitation (skeletal muscle and CNS);
lacrimation;
salivation;
sweating.

ACETYLCHOLINE
NOT USED AS A DRUG

Parasympathetic
O
CH3

CH3
O

CH2

CH2

CH3

CH3

Acetylcholine

HO
CH3
H 3C

CH2

Muscarine
N

CH3

CH3

CH3
N

Nicotine

PHARMACOKINETICS

Acetylcholine & other Choline esters have a

permanently charged quaternary ammonium group
in their structure
All are hydrolysed in the GIT
The tertiary natural cholinomimetic alkaloids
(pilocarpine, nicotine, lobeline) are well absorbed from
most sites of adm. Muscarine, a quaternary amine is
less completely absorbed from the GIT and is toxic too.
Excretion mainly by the kidneys

Pharmacological Actions/ 0rgan

system effects:
Muscarinic Actions
Nicotinic Actions

EYE:

Miosis (constriction of pupil).

Spasm of accommodation
Decrease in intraocular pressure.
Conjunctival hyperaemia
Lacrimation

CVS (Heart & B.V)

Respiratory system
Gastro intestinal tract
Urinary bladder
Exocrine glands
Central Nervous System
Peripheral nervous system
N.M .Junction

CARBACHOL

Ester of carbamic acid

Has both muscarinic and nicotinic actions
Muscarinic actions are prominent on eye, GIT &
urinary bladder
DOA more than 30 min
Therapeutic uses:
Glaucoma

METHACHOLINE

Has methyl group in its structure

Has both muscarinic and nicotinic actions
(very mild nicotinic actions )
Muscarinic actions are prominent on CVS
Longer DOA as compared to ACh
Therapeutic uses: given SC for the relief
of paroxysmal atrial tachycardia

BETHANECHOL

Structure related to Ach, acetate is replaced by

carbamate & choline is methylated
Has no nicotinic actions
Muscarinic actions are prominent on eye, GIT &
urinary bladder
Prolonged DOA
Therapeutic uses:

Post operative Gastric distension

Paralytic ileus
Bladder atonia

MUSCARINE

Quaternary amine (Amanita muscaria)

Less complete absorption from the GIT
Very toxic & can even enter the brain
Rx : Atropine

PILOCARPINE

Tertiary amine (Pilocarpus jaborandi leaves)

Has muscarinic actions
Therapeutic uses:

Glaucoma
To reduce the effect of mydriatics
To break adhesions

Not used for systemic diseases

increased
tracheobronchial secretions leading to
pulmonary oedema

NICOTINE & LOBELINE

Plant derivatives
Actions are mainly on nicotinic receptors (CNS,
PNS, NMJ)
CNS, have important effects on brainstem and
cortex.
PNS autonomic ganglia.
NMJ, immediate depolarization of the end plate
increase in permeability to Na and K ions.

Rivastigmine, galantamine,
donepezil

Carbachol

Neostigmine

Echothiophate

Prevents postoperative
abdominal
distention and urinary retention
Used in treatment of myasthenia
gravis
Used as an antidote for
tubocurarine
Has long duration of action (2 to 4
hrs)

Pilocarpine

Edrophonium

For diagnosis of myasthenia

gravis
As antidote for tubocurarine
Has short duration of action (10 to
20 min)

Acetylcholine
Has no therapeutic uses

Bethanechol
Used in treatment of urinary
retention
Binds preferentially at muscarinic
receptors

Produces miosis during ocular

surgery
Used topically to reduce
intraocular
pressure in open-angle or narrowangle
glaucoma, particularly in patients
who
have become tolerant to pilocarpine
Reduces intraocular pressure in
openangle
and narrow-angle glaucoma
Binds preferentially at muscarinic
receptors
Uncharged, tertiary amine that
can penetrate the CNS

Physostigmine
Increases intestinal and bladder
motility
Reduces intraocular pressure in
glaucoma
Reverses CNS and cardiac eects of
tricyclic antidepressants
Reverses CNS eects of atropine
Uncharged, tertiary amine that
can penetrate the CNS

Used as rst-line treatments for

Azheimer disease, though confers
modest benet
Have not been shown to reduce
healthcare costs or delay
institutionalization
Can be used with memantine
(N-methyl-D-aspartate antagonist)
with moderate to severe disease

Used in treatment of open-angle

glaucoma
Has long duration of action (1
week)