AUTONOMIC PHARMACOLOGY:

General considerations
Elmer P. Cayaban

Drugs affecting the ANS either stimulate or inhibit

the cholinergic (parasympathetic)nor
adrenergic (sympathetic) component.
o Both sympa. and parasympa. divisions innervate
most organs in which they usually have
antagonistic effect.
Ex. -Tachycardia ( HR) caused by sympa.
stimulation.
-Bradycardia ( HR) by parasym. stimulation.
o In some organs such as salivary glands, they are
both excitatory.
-Sympa. stimulation causes secretion of scant,
thick and mucoid saliva.
-Parasym. stimulation causes secretion of
profuse, thin and enzyme- rich saliva.

state of balanced antagonism exists in most

organ system.
Exceptions: State of tonus- predominance of
one division over the other.
Example: Sympa. Tone- maintains systemic
blood pressure.
Parasympa. Tone- maintains gut
motility.

NEUROCHEMICAL
ORGANIZATION OF THE ANS
o

2 major neurochemical transmitters are realeased

at the synapse and at the neuroeffertor
junctions.

NOREPINEPHRINE(noradrenaline)- major
neurotransmitter at the terminals of
postganglionic fibers in the neuroeffector
junction in the sympathetic division.
Postganglionic fibers are called adrenergic
fibers.

 Exception:

those innervating sweat glands and

blood vessel in the skeletal muscles which
anatomically part of sympathetic division but
secretes acetylcholine.
Chromaffin cells in adrenal medulla are actually
modified adrenergic nerve cells. When
stimulated, the splanchnic nerve, which
supplies the adrenal medulla, causes the release
of epinephrine(adrenaline) from the
chromaffin ceells into the blood circulation.
Tyrosine hyroxylase- rate limiting enzyme.

 ACETYLCHOLINE(Ach)-

transmitter realeased at
the peripheral motor portions of ANS which
include:
o
o
o
o

postganglionic parasympa. fibers at the

neuroeffector junction
preganglionic parasympa. fibers
splancnic nerve terminal in the adrenal medulla
sympa. Postganglionic neurons which innervate
sweat gland and vessels in the skeletal muscles

These

fibers called cholinergic fibers.

TYPES OF RECEPTORS IN THE ANS

1. CHOLINERGIC RECEPTORS
Muscarinic receptors- stimulated by
muscarine, poisonous substance in certain
species of mushroom. Stimulation of these
receptors produces so called muscarinic
effect which include effects of acetylcholine
on:
-glands(increased secretion)
-smooth muscles(generally enhanced
contraction
-cardiac muscle(depressed activity)

 Nicotinic

receptors- stimulated by nicotine,

substance derived from tobacco. Nicotinic effect
which include the action of Ach on:
-parasympa. and sympa.
ganglia(overstimulation of both parasympa. and
sympa. postganglionic nerve fiber)
-neuroeffector junctions(increased skeletal
muscle contraction)

2. ADRENERGIC RECEPTORS
Alpha adrenergic (1 and 2)
Beta adrenergic (1 and 2)
Dopaminergic
-all these receptors can be stimulated by the
different adrenergic transmitters (catecholamines)
but produce varying degrees of response.

CHOLINERGIC AND
CHOLINERGIC BLOCKING
DRUGS
ELMER P. CAYABAN

ACETYLCHOLINE(Ach) cholinergic NT, acts on

five sites in the PNS, interacting with either
muscarinic or nicotinic cholinergic receptors.
Hydrolysis by cholinesterase (ChE) into choline
and acetate is the principal means of terminating
acetylcholine (Ach) action.
- Choline is taken back into the presynaptic
fiber by active transport, and is used again in the
synthesis of new Ach molecule.
- Acetate is abundantly supplied by
mitochondria.

Acetylcholine is not used in clinical

therapeutics because:
- following its administration, it causes to
generated but transient effect.
- it is so readily hydrolyzed by plasma
cholinesterases that it cannot be detected in the
plasma following absorption.
o

PHYSIOLOGICAL AND
PHARMACOLOGICAL EFFECT
OF ACETYLCHOLINE
o

The muscarinic and nicotinic effects of

acetylcholine on selected effector organs or
tissues are outlined at the next slide.

NICOTINIC EFFECTS
o mediated at the autonomic ganglia, adrenal,
medulla, and motor-end plate.
o to demonstrate the nicotinic effect of Ach on
blood pressure, two requirements must be
satisfied:
- blockade of the muscarinic neuroeffector sites
with atropine in order to eliminate the influence
of muscarinic effects on blood pressure, and
- administration of large dose of acetylcholine.

Acetylcholine produces a hypertensive effect by

acting on the sympathetic ganglia and at adrenal
medulla to discharge norepinephrine then
increase blood pressure by introducing
vasoconstriction and elevating cardiac output.
Acetylcholine also acts on the cholinergic
(nicotinic) receptors at the motor-end plate to
cause muscle contraction, tremors and
fasciculation. Sustained stimulation can cause
muscle fatigue and paralysis.

DRUG ACTING ON THE

CHOLINERGIC DOMAIN
o

Drug acting on the cholinergic domain of the

peripheral nervous system may be divided into
categories as follows:
CHOLINERGICS
(PARASYMPATHOMIMETICS)

Directly acting (binds directly to receptors)

- Ester: e.g methacholine, carbachol,

betanechol
- Alkaloids: e.g muscarine, pilocapine,
arecoline

Indirect-acting (cholinesterase inhibitors)

- Natural Alkaloids: e.g physostigmine
- Synthetic alkaloids: e.g neostigmine,
edrophonium, ambernonium,
pyridostigmine.
- Organophosphates
- Carbamate pesticides: e.g carbaryl,
propoxur

 ANTICHOLINERGICS

(PARASYMPATHOLYTICS)

Examples:
- atropine
- scopolamine
- glycopyrrolate
GANGLIONIC BLOCKERS
- e.g hexamethonium not used clinically
NEUROMUSCULAR BLOCKERS
- used as muscle relaxants: e.g dtuborcurarine, gallamine, pancuronium,
succinylcholine

 ACETYLCHOLINE

SYNTHESIS INHIBITOR
- e.g hemicholinium not used clinically
ACETYLCHOLINE RELEASE INHIBITORS
- of toxicological importance only: e.g
botulinus toxin, aminoglycoside antibiotics

CHOLINERGIC OR
CHOLINOMIMETIC DRUGS
Cholinergic drugs come in three categories: choline
esters, natural alkaloids, cholinesterase inhibitors.
CHOLINE ESTERS derivatives of acetylcholine.
Act directly on muscarinic receptors in glands,
smooth muscle and cardiac muscle.

Methacholine(acetyl--methyl-choline)
-resists degration by cholinesterase and
therefore has more prolonged action than Ach

-having no action on nicotinic

receptors, produces typical
muscarinic
effects such increased
glandular secretion,
bbradycardia,
hypotension.
Carbachol(known as carbamycholine)
-has an amine group instead of methyl in
the esteratic end of the Ach molecules,
which makes its resistant to cholinesterase.
-has most marked effect on urinary bladder
and gut.
-used clinically in treatment of gut
hypomotility and bladder parlysis; also for
glaucoma as opthalmic solution.

Bethanicol
-almost totally resistant to
cholinesterase with action
lasting for
several hours.
-used clinally in such cases as
neurogenic urinary bladder paralyssis and
post- surgical treatment of esophageal
achalasia.
NATURAL CHOLINERGIC ALKALOIDS- includes
alkaloids of plant origin.
Muscarine- active principle of poisonous
mushroom including genera Amanita and
Clitocybe. Toxicological importance only
and not used in therapeutics. Clinical sign of
poisoning: profuse salivation, lacrimation,
dyspnea, colic, diarrhea and cardiovascular

Pilocrine- derived from leaves of Pilocarpus

jaborandi, most marked effects on muscarinic
receptors in eye and exocrine glands. Causes
pupillary constriction and may used aternately with
pupillary dilator(epinephrine and atropine). Used in
treatment of glaucoma ( intra-ocular pressure).
Used in the treatment of gut impaction in large
animals but it is a dangerous practice and is not
recommended.

Arecholine derived from fruit of Areca catechu

(betel nut). Has both muscarinic and nicotinic
effects. Used to eradicate tapeworms by its
purgative effect but may cause toxic reation in the
host.

CHOLINESTERASE INHIBITORS- enzymes that

catalyze the breaking down of Ach into acetate and
choline
SUBSTRATE

LOCATION

Acetylcholinesteras
e
(True
cholinesterase)

Ach

Nerve terminals;
neuromuscular
junction; CNS
gray matter;
erythrocytes

Butyrylcholinesteras
e
(Pseudocholinestera
se)

Ach; other esters

of choline; some
local of
anesthetics

Plasma
CNS whit emater

Both types can hydrolyze Ach but only

Pseudocholinesterase can hydrolyze other
esters.
Cholinesterase (ChE) like cholinergic receptors,
has ionic binding site and an esteratic binding
site.
Acetylcholinesterase- most important faactor
terminating the action of Ach at receptor site.

 Starts

when Ach binds with the cholinesterase. The

ester bond betweeen choline and acetate breaks. The
inactive metabolites (choline and acetate) move away
from the enzyme, restoring its hydrolytic activity.

 When

the cholinesterase action is blocked by a

chemical inhibitor, Ach will accumulate in the
receptor sites and will cause exaggerated or
prolonged cholinergic effect.
Clinical signs of cholinesterase inhibition,
therefore, include both:
Muscarinic signs(colic, diarrhea, dyspnea,
hypotension, miosis and
Nicotinic signs(muscles tremors then
paralysis, convulsions, mania (CNS excitation)
then coma.

 Generally

a cholinesterase may be inhibited by

acetylation(with acetylcholine), carbamylation(with
carbamates) and phosphorylation(with
organophosphates) of the esteratic binding site of
enzymes.

 Inhibition

by acetylation is readily revversible(in

seconds) and does nnot cause clinical problems.
Carbamylated enzyme takes longer time (hours)
to restore activity and may cause signs of
poisoning in patients.
Phosphorylation generally cause irreversible
inhibition of cholinesterase.

IRREVERSIBLE
CHOLINESTERASE INHIBITORS
Group includes organophosphate (OP)
compounds used commonly as
insecticides/acaricides, anthelmintics and
agricultural pesticides to which domestics
animals may be exposed.
Examples which can cause poisoning in animals
and humans are:
Malathion
Ruelene
Dichlorvos
Coumaphous

 Some

deadly war gases are Ops including:

diisopropyl- flourophosphates (DFP)
OPs are highly lipid soluble, well absorbed and
widely distributed.
Some are so volatile that they can be absorbed
through the lungs and skin.
OP can be:

Directly- acting OPs-can inhibit cholinesterase without

prior metabolism(ex. Phosphonates)
Indirectly acting- need to be metabolized first to
phosphonates before they can inhibit cholinesterase
(ex. Phosphothionates)
OPs are mainly excreted in urine as inactive
metabolites

STAGES OF CHOLINESTERASE
INHIBITION BY ORGANOPHOSPHATES
Stage

I: Phosphorylation of enzyme- forms a

strong covalent linkage between OP and
cholinesterase. Binding s more or less
permanent depending on the nature of specific
OP compoinds.
Stage II: Spontaneous recovery or
dephosphorylation of the enyme

OPs with more complex R groups, takes long er

time to recover.
Dephosphorylation of enzyme can be induce
sometimes with drugs such as hydroxylamine
and pralidoxime.

- Hydroxylamine- very toxic and is not used

clinicallly for this purpose. Acts directly on OP
attached to esteratic site of the enyme.
- Pralidoxine- nontoxic and used clinically to
counteract OP toxicosis at early stage. Reacts first to
anionic site and then attacks the phosphates bound
to the esteratic state.
Stage III. Aging- enzyme cannot be reactivated
Stage IV. Biosynthesis of new cholinesterasetakes weeks or months to restor the normal level of
cholinesterase in the body. Patient may die before
this sstage is reached

PHARMACOLOGICAL EFFECTS
OF ORGANOPHOSPAHTE
Effects

of OP compounds are attributable to

excessive stimulation of muscarinic and nicotinic
cholinergic receptors by unhibited endogenous
Ach.
CNS effects include excitation and mania
progressing to convulsion and coma.
Usual cause of death in OP poisoning is
respiratory failure.

TREATMENT OF OP POISONING
Atropine-

most important antidote to the effeect

of OP.
Blocks muscarinic effects but not nicotinic.
Given IV to effect
Beware of toxic signs of atropine overdosge
which consist of hyperthermia and CNS
stimulation. Can be counteracted with
pentobarbatil, a sedative- hypnotic drug.
Pralidoxime- clinically useful only during the
early stages of poisoning.

REVERSIBLE CHOLINESTERASE
INHIBITORS
Drugs under this category inhibit cholinesterase for a few hours
only.
Physostigmine(eserine)
Tertiary ammine alkaloid derived from Calabar bean or
ordeal bean Physostigma venenosum.
Bind to esteratic site of cholinesterase. Bond
spotaneously breaks off to leave a fully active enzyme.
Effect mainly muscarinic, such as increased gut motility,
mild bradycardia, miosis and stimulation of gravid uterus.
Little inhibition of enzyme at nicotinic site.
Almost exclusively used in ophthalmology to relieve
glaucoma. Applied topically on eye as ophthalmic
solution, duration of action short.

Neostigmine
synthetic quaternary amine analogue of
physostigmine and has dual action.
-inhibits cholinesterase and directly
stimulates the
cholinergic receptor.
Has potent anticurare action
Clinical uses:
-treatment of gut motility
-urinary bladder paralysis
-myasthenia gravis
Edrophonium
Similar Neostigmine but shorther duartion of
action
Use to differentiate bet muscle weakness due to
myasthenia gravis and muscle weakness caused
by overstimulation of cholinergic receptors

Muscle weakness worsens with

edrophhonium- overstimulation or
cholinergic crisis
Muscle weakness improves- myasthenia
gravis
Ambenomium and Pyridostigmine
Similar neostigmine but moderately longeracting
Carbamate incesticide
Used to control external parasites.

ANTICHOLINERGIC DRUGS
Or paraysmpatholytics- antagonist of Ach
specifically at the muscarinic receptors. Very little
nor no action on nicotinic sites.
Atropine
Racemixture of D- and L- hyocyamine,
prototype of parasympatholytic drugs.
Important therapeutically as well as
toxicologically. Active poison in deadly
nightshade(Atropa belladona), Jimson
weed(Datura stramonium) and
henbane(Hyocayamus niger).

Most animal species metabolize atropine.

-goats rabbits: resistant to effect of atropine
because of presence in them of high concentration
of atropinase, an esterase that breaks down
atropine.
Pharmacoligic effect: opposite of Ach.

Used clinically as pre- anesthetic agent in most

patients to decrease salivary and respiratory
secretions and prevent heart block which may
occur during induction of anesthesia.
-Preanesthetic administration of anti- cholinergics are
not required in horses unless absolutely necessary.
-Anticholinergics may cause ileus.

In opthalmology, atropine used to produce

mydriasis for eye examination. Because pipillary
dilation may last 7-14 days.

Other atropine- like drugs are:

o

o
o
o
o

Scopolamine- natural congener of atropine, more

CNS effects than atropine. Used in women to produce
twilight sleep during childbirth. Not used in animals.
Homatropine- shorter duration of action than
atropine, has only 10% of atropines potency.
Eucatropine- shorter duration of action than atropine
and produces mydriasis with little cycloplegia.
Hyocine- produces greater CNS depression, has
unique antiemetic in dog.
Glycopyrrolate- used as preanesthetic
anticholinergic and 5 times more potent than atropine
as sialogogue, lacks iniital decrease in heart rate
usually observed with atropine. Less CNS effects than
atropine.
Propantheline- synthetic atropine substitute, has
ratio of ganglionic blocking to antimuscarinic activity.
Used as gastrointestinal antispasmodic agent.

GANGLIONIC BLOCKING AGENTS

Agents block cholinergic receptors in autonomic ganglia
in both parasympa. and sympa divisions.
Classified as:
1. Nondepolarizing blockers- no intinsic activity,
compete with Ach for receptor sites in the ganglia and
adrenal medulla. Pharma effects: fall in blood pressure
(blockage of sympathetic tone), decreased gut
motility and constipation.
Ex. tetrathylammonium (TEA)
-hexamethonium
-pentolinium
-mecamylaamine

2. Depolarizing blockers- cause powerful and

persistent stimulation of cholinergic receptors
leading to receptor blockage and fatigue. Effect is
biphasic- initial stimulation and then inhibition.
Ex. Nicotine- used as wildlife capture drug(very
dangerous) and as insecticide(as 40% nicotine
sulfate). Absorbed from all routes of
administration.
Poisoning: hypertension, and tachycardia followed
by drying of mouth; CNS stimulation followed by
coma; muscular hyperactivity followed by
weakness and paralysis.