Autonomic system and Autonomic Pharmacology

Autonomic Nervous
System
&
“Autonomic
Pharmacology”
By
Reza Heidari
Pharm. D & Toxicology PhD

Goal
To Learn about the drugs
affecting the autonomic
nervous system

The autonomic nervous system
maintains the internal
environment of the body – clled
HOMEOSTASIS
Role of ANS in homeostasis
links to target organs -
(Cardivascular System , smooth
muscle of GI and glands)

NERVOUS
SYSTEM
CENTRAL
NERVOUS
SYSTEM
PERIPHERAL
NERVOUS
SYSTEM
BRAIN
SPINAL
CORD
AUTONOMIC
N.S.
SOMATIC N.S.
Sympathetic
N.S.
Parasympathetic
N.S.

NEUROTRANSMITTER
S:
• Sympathetic: ADRENERGIC
 Central: EPINEPHRINE
 Peripheral:
NOREPINEPHRINE
 Parasympathetic: CHOLINERGICParasympathetic: CHOLINERGIC
 AcetylcholineAcetylcholine

+
Drug A decreases
activity of
organ Y
Autonomic Pharmacology
Nerves to organ Y
release neurotransmitter X,
and X increases
the activity of organ Y
A Drug Mimic or Block transmitters
Drug A blocks
receptors for
neurotransmitter
X

+
Atropine blocks muscarinic
receptors
and decreases intestinal
motility
Atropine blocks
muscarinic
cholinergic
receptors
that respond to
ACh
Parasympathetic
nerves
release ACh
and increase
intestinal motility
Understanding actions of drugs that influence
the autonomic nervous system allows
prediction of their effects!

Autonomic Drugs are
very much Clinically
Relevant

Autonomic drugs are used for the
treatment of Angina

treatment of Heart Failure

treatment of High Blood
Pressure
• Autonomic drugs also used for
treatment of
- Anaphylactic shock
- Septic shock
- Benign prostatic hypertroph
- Alzheimer’s disease
- Asthma

Skeletal
Muscle
Peripheral Nervous System
Somatic Nervous
System
Autonomic Nervous
System
Parasympathetic
Nervous System
Sympathetic
Nervous System
Glands, Smooth Muscle
& Cardiac Muscle

AUTONOMIC NERVOUS
SYSTEM
• SYMPATHETIC
• Fight or Flight
• PARASYMPATHETIC
• Rest and Digest

Parasympathetic Nervous System (Craniosacral Outflow)
Genitalia
Bladder
Large Intestines
Kidney
Bile Ducts
Gallbladder
Small Intestines
Stomach
Bronchi/Bronchial
Glands
SA & AV Node
Sphincter Muscle of Iris
Ciliary Muscle
Lacrimal Gland
Submaxillary &
Sublingual
Glands
Parotid Gland

Radial Muscle of Iris
Ciliary Muscle
SA & AV Nodes
His-Purkinje System
Myocardium
Bronchi/Bronchial
Glands
Stomach
Kidneys
Intestines
Bladder//Genitalia
Sublingual/Submaxillary
& Parotid Gland
Pilomotor Muscles
Sweat Glands
Blood Vessels
Sympathetic Nervous System
(Thoracolumbar Outflow)
Paravertebral Ganglia
Prevertebral Ganglia

Epinephrine
(+) Fatty Acid Release (-) Intestinal Motility
(+) Glycogenolysis
(+) ACTH & TSH
(+) Mental Alertness
(+) Muscle Contraction & Efficiency
(+) Dilates Airways
(+) Cardiac Output
ADRENAL
MEDULLA
Chromaffin Cells

What is a synapse?
A synapse is a junction between two neurones across
which electrical signals pass. The human body contains up
to 500 trillion synapses.
presynaptic
cell
postsynaptic
cell

Release of
neurotransmittersWhen a nerve impulse arrives at the end of one neurone it triggers the
release of neurotransmitter molecules from synaptic vesicles.
synaptic
vesicle
neurotransmitter
molecules

Continuing the impulse
The neurotransmitters diffuse across the synaptic cleft and
bind with receptors on the next neurone, triggering another
impulse.
nerve
impulse
receptor
synaptic
cleft

Cholinergic and
Adrenergic System
• Accordingly:
• Cholinergic Drugs, i.e., they act
by releasing acetylcholine
• But also utilize nitric oxide (NO) or
peptides for transmission
• Noradrenergic (commonly
called "adrenergic") Drugs -
act by releasing norepinephrine
(NA)

Cholinergic receptors
– Muscarinic (M) and Nicotinic (N)
• Nicotinic receptors:
• nicotinic actions of ACh are those
that can be reproduced by the
injection of Nicotine
• and also can be blocked by
tubocurarine and hexamethonium
• ligand-gated ion channels
• activation results in a rapid increase
in cellular permeability to Na+ and
Ca++
• results in depolarization and initiation
of action potential

Muscarinic (M)
Receptors
Amanita
muscaria

Acetylcholine (cholinergic
receptors)
– Muscarinic Receptors
• Selectively stimulated by Muscarine nd
blocked by Atropine
• G-protein coupled receptors
• Primarily located in heart, blood vessels,
eye, smooth muscles and glands of GIT
• Subsidiary M receptors are also present in
ganglia for modulation
• Autoreceptors (M type) are present in
prejunctional cholinergic Nerve endings

Acetylcholine (cholinergic
receptors)
– Muscarinic Receptors
• Selectively stimulated by
Muscarine and blocked by
Atropine
M1 M2 M3
Ganglia Heart Glands and SM

Cholinergic Drugs or
Cholinomimetic or
Parasympathomimetics
Drugs producing actions similar
to Ach – by interacting with
Cholinergic receptors or by
increasing availability of Ach at
these sites.

Classifiction - Direct-
acting (receptor
agonists )
• Choline Esters
• Natural: Acetylcholine
• Synthetic: Methacholine,
Carbachol and Bethanechol.
• Alkaloids: pilocarpine,
muscarine, arecholine
• Synthetic: Oxotremorine

Cholinergic Drugs –
Indirect acting
• Cholinesterase inhibitors or
reversible anticholinesterases:
• Natural: Physostigmine
• Synthetic: neostigmine, pyridostigmine, distigmine,
rivastigmine, donepezil, gallantamine, edrophonium,
ambenonium, demecarium
• Irreversible anticholinesterases:
• Organophosphorous Compounds (OPC) –
Diisopropyl fluorophosphate (DFP), Ecothiophate,
Parathion, malathion, diazinon (insecticides and
pesticides)
• Tabun, sarin, soman (nerve gases in war)
• Carbamate Esters Carbaryl and Propoxur (Baygon)

Ach actions - Muscarinic
1. Heart: M2
• Hyperpolarization of SA node, reuction in impulse
generation and Bradycardia
• Slowing of AV conduction and His-purkinje fibres –
partial or complete block
• Atrial fibrillation and flutter – nonuniform vagal
innervations
• Decrease in ventricular contractility
1. Blood Vessels: M3
• Cholinergic innervations is limited – skin of face and
neck
• But, M3 present in all type blood vessel –
Vasodilatation by Nitric oxide (NO) release
• Penile erection

Muscarinic action –
contd.
3. Smooth Muscles: M3
• Abdominal cramps, diarrhoea – due to
increased peristalsis and relaxed sphincters
• Voiding of Bladder
• Bronchial SM contraction – dyspnoea, attack
of asthma etc.
4. Glands: M3
• Increased secretions: sweating, salivation,
lacrimation, tracheobronchial tree and gastric
glands
5. Eye: M3
• Contraction of circular fibres of Iris – miosis
• Contraction of Ciliary muscles – spasm of
accommodation, increased outflow and
reduction in IOP

Pilocarpine
• Alkaloid from leaves of Pilocarpus
microphyllus
• Prominent muscarinic actions
• Profuse salivation, lacrimation, sweating
• Dilates blood vessels, causes hypotension
• On Eyes it produces miosis and spasm of
accommodation
• Lowers intraocular pressure (IOP) in
Glaucoma when applied as eye drops
• Too toxic for systemic use

Pilocarpine – contd.
• Used as eye drops in treatment of narrow
angle and wide angle glaucoma to reduce
IOP
• Used to reverse mydriatic effect of
atropine
• To break adhesion between iris and
cornea/lens alternated with mydriatic
• Pilocarpine nitrate eye drops ( 1 to 4% )
• CNS toxicity after systemic use
• Atropine used as antidote in acute
pilocarpine poisoning ( 1-2 mg IV 8hrly )

Pilocarpine –
Mechanism in Eye
Causes opening up
of trabecular pores
and increased
drainage

Muscarine
• Alkaloid from mushroom Amanita
muscaria
• Only muscarinic actions
• No clinical use
• Cause mushroom poisoning due to
ingestion of poisonous mushroom
= Early onset mushroom poisoning
= Late onset mushroom poisoning
(neurogenic)

Early Onset Mushroom
Poisoning
• Occurs ½ to 1 hour.
• Muscaria cause mild cholinergic symptoms like
nausea, vomiting, salivation, lacrimation, headache,
bronchospasm, diarrhoea
• ntidote is Atropine sulphate (0.5-I mg IM twice
daily)
• Inocybe or Clitocybe – severe cholinergic symptoms
like bradycardia, dyspnoea, hypotension,
weakness, cardiovascular collapse, convulsions
and coma
• Antidote is Atropine sulphate ( 2-3 mg IM hrly till
• improvement )
Volvariella volvacea

Late Onset Mushroom
Poisoning
• Occurs within 6-15 hours
• Amanita phylloides – irritability,
restlessness, nausea, vomiting, ataxia,
hallucination, delirium, sedation,
drowsiness and sleep.
• Maintain blood pressure, respiration
• Inj. Diazepam 5 mg IM
• Atropine contraindicated as it may cause
convulsions and death
• Gastric lavage and activated charcoal

Cholinesterase inhibitors:
• Reversible anticholinesterases
(Carbamates):
• Natural: Physostigmine
• Synthetic: Neostigmine, pyridostigmine,
distigmine, rivastigmine, donepezil,
gallantamine, edrophonium, ambenonium,
demecarium
• Irreversible anticholinesterases:
• Organophosphorous Compounds (OPC) –
Diisopropyl fluorophosphate (DFP), Ecothiophate,
Parathion, malathion, diazinon (insecticides and
pesticides)
• Tabun, sarin, soman (nerve gases in war)
• Carbamate: Carbaryl and Propoxur (Baygon)

Anti-ChEs (MOA) –
contd.
• Anticholinesterases also react with the enzyme ChEs in
similar fashion like Acetylcholine
• Carbamates – carbamylates the active site of the enzyme
• Phosphates – Phosphorylates the enzyme
• Carbamylated (reversible inhibitors) reacts with water
slowly and the esteratic site is freed and ready for action
– 30 minutes (less than synthesis of fresh enzyme)
• But, Phosphorylated (irreversible) reacts extremely
slowly or not at all – takes more time than synthesis of
fresh enzyme
• Sometimes phosphorylated enzyme losses one alkyl group
and become resistant to hydrolysis – aging
• Edrophonium and tacrine reacts only at anionic
site while Organophosphates reacts only at
esteratic site

Anticholinesterases –
Individual Drugs
• 2 (two) important clinically used
drugs –
• Physostigmine – lipid soluble,
ganglion acting and less action in
skeletal muscle
• Also organophosphates
• Neostigmine – lipid insoluble,
skeletal muscle acting

Physostigmine
• Alkaloid from dried ripe seed (Calabar bean) of African
plant Physostigma venenosum
• Tertiary amine, lipid soluble, well absorbed orally and
crosses BBB
• Hydrolyzed in liver and plasma by esterases.
• Long lasting action (4-8 hours)
• Reversible anticholinesterase drug
• It indirectly prevents destruction of acetylcholine
released from cholinergic nerve endings and causes ACh
accumulation
• Muscarinic action on eye causing miosis and spasm of
accommodation on local application
• Antagonises mydriasis and cycloplegia produced by
atropine and anticholinergic drugs
• Salivation, lacrimation, sweating and increased
tracheobronchial secretions.
• Increased heart rate & causes hypotension

Physostigmine - uses
1. Used as miotic drops to decrease IOP in
Glaucoma
2. To antagonise mydriatic effect of atropine
3. To break adhesions between iris and
cornea alternating with mydriatic drops
4. Belladonna poisoning, TCAs &
Phenothiazine poisoning
5. Alzheimer’s disease- pre-senile or senile
dementia.
6. Atropine is antidote in physostigmine
poisoning.
7. ADRs – CNS stimulation followed by
depression.

Neostigmine
• Synthetic reversible anticholinesterase drug.
• Quaternary ammonium compound and lipid soluble.
• Cannot cross BBB
• Hydrolysed by esterases in liver & plasma
• Short duration of action (3-5 hours)
• Direct action on nicotinic (NM) receptors present in
neuromuscular junction (motor end plate) of
skeletal muscle
• Antagonises (reverses) skeletal muscle relaxation
(paralysis) caused by tubocurarine and other
competitive neuromuscular blockers
• Stimulates autonomic ganglia in small doses
• Large doses block ganglionic transmission
• No CNS effects

Neostigmine – Uses and
ADRs
• Used in the treatment of Myasthenia
Gravis to increase muscle strength
• Post-operative reversal of neuromuscular
blockade
• Post-operative complications – gastric
atony paralytic ileus, urinary bladder atony
• Cobra snake bite
• Produces twitchings & fasciculations of
muscles leading to weakness
• Atropine is the antidote in acute
neostigmine poisoning

Physostigmine and
Neostigmine - Summary
Physostigmine Neostigmine
Source Natural Synthetic
Chemistry Tertiary amine Quaternary ammonium
compound
Oral absorption Good Poor
CNS action Present Absent
Eye Penetrates cornea Poor penetration
Effect Ganglia Muscle
Uses Miotic Mysthenia gravis
Dose 0.5-1 mg
oral/parenteral
0.1-1% eye drop
0.5-2.5 mg IM/SC
15-30 mg orally
Duration of
action
4-6 Hrs 3-4 Hrs

Therapeutic Uses –
cholinergic drugs
1. Myasthenia gravis: Edrophonium to
diagnose and Neostigmine,
Pyridostigmine & Distigmine to treat
2. To stimulate bladder & bowel after
surgery:
• Bethanechol, Carbachol, Distigmine.
1. To lower IOP in chronic simple glaucoma:
• Pilocarpine, Physostigmine
1. To improve cognitive function in
Alzheimer’s disease: Rivastigmine,
Gallantamine, Donepezil.
2. Physostigmine in Belladonna poisoning

Myasthenia gravis
• Autoimmune disorder affecting 1 in 10,000
population
• Causes: Development of antibodies directed to
Nicotinic receptors in muscle end plate – reduction
in number by 1/3rd
of NM receptors
• Structural damage to NM junction
• Symptoms: Weakness and easy fatigability
• Treatment:
• Neostigmine – 15 to 30 mg orally every 6 hrly
• Adjusted according to the response*
• Pyridostigmine – less frequency of dosing
• Other drugs: Corticosteroids (prednisolone 30-60
mg /day)
• Azathioprin and cyclosporin also
Plasmapheresis

Myasthenic crisis
• Acute weakness and respiratory
paralysis
• Tracheobronchial intubation and
mechnical ventilation
• Methylprednisolone IV with
withdrawal of AChE
• Gradual reintroduction of AChE
• Thymectomy

Snake venom Poisoning
• Asian Cobra Bite
• Symptoms are similar to
Myasthenia gravis
• Atropine sulfate 0.6 mg IV
slowly – to counteract
Muscarinic action
• Edrophonium chloride
(Tensilon) - 10 mg IV over 2
minutes – reversal of
occulomotor and respiratory

AChE Poisoning
(Organophopsphorous Poisoning)
• Poisoning may be –
Occupational, accidental,
Suicidal
• Symptoms:
• Fall in BP, bradycardia or tachycardia,
cardiac arrhythmia and vascular
collapse
• Irrittion of Eye, lacrimation, salivation,
colic, involuntary defection,
breathlessness, blurring of vision
• Muscular fasciculations and weakness
• Death due to respiratory paralysis –

Principles of Treatment
• Remove soiled clothes
• Wash soiled skin and eyes
• Prone Positioning and clear mouth
and throat
• Intubation of airway
• Gastric lavage
• Atropine: All cases of AChE
poisoning, 2mg IV every `10 minutes
– continue till atropinization occurs
• Cholinesterase reactivators: Oximes

Cholinesterase
Reactivators - Oximes
• Pralidoxime (2-PAM), Obidoxime Diacetyl
monoxime (DAM)
• Oximes have generic formula R-CH=N-OH
• Provides reactive group OH to the enzymes
to reactivate the phosphorylated enzymes
• PAM:
• Quaternary Nitrogen of PAM gets attaches to
Anionic site of the enzyme and reacts with
Phosphorous atom at esteratic site
• Forms Oxime-phosphonate complex making
esteratic site free
• Not effective in Carbamate poisoning
• Dose: 1-2 gm IV slowly

• Site and Mode of Action:
1. Direct Acting
- Epinephrine - Dobutamine
- Phenylephrine - Norepinephrine
- Isoproterenol - Clonidine
2. Indirect Acting
• Tyramine, Amphetamine, Cocaine
3. Mixed Acting Agonists
- Dopamine - Ephedrine
- Amphetamine - Metaraminol
- Phenylpropanolamine
SYMPATHETIC DRUGSSYMPATHETIC DRUGS

αα11 αα22 αα andand ββ ββ11 ββ22
αα11 andand αα22 ββ11 andand ββ22
Sympathetic
AgonistsAgonists
(Sympathomimetics)(Sympathomimetics)
EPINEPHRINE
NOREPINEPHRINE
DOPAMINE
IBOPAMINE
AMPHETAMINE
METHAMPHETAMINE
EPHEDRINE
PSEUDOEPHEDRINE
DOBUTAMINE
ISOPROTERENOL

AgonistsAgonists
(Sympathomimetics(Sympathomimetics
))
PHENYLEPHRINE
METHOXAMINE
MEPHENTERMINE
METARAMINOL
MITODRINE

Sympathetic
AgonistsAgonists
(Sympathomimetics(Sympathomimetics
))
METHYLDOPA
CLONIDINE
GUANABENZ
GUANFACINEGUANFACINE

SympatheticSympathetic
AgonistsAgonists
(Sympathomimeti(Sympathomimeti
cs)cs)
NAPHAZOLINE
TETRAHYDROZOLINE

AgonistsAgonists
(Sympathomimeti(Sympathomimeti
cs)cs)
NAPHAZOLINE
TETRAHYDROZOLINE
OXYMETAZOLINE
XYLOMETAZOLINE

αα11 andand αα22
ββ11 andand ββ22
AgonistsAgonists
(Sympathomimetic(Sympathomimetic
s)s)METAPROTERENOL
TERBUTALINE, ALBUTEROL
RITODRINE
ISOETHARINE, PILBUTEROL
BITOLTEROL, FENOTEROL
FORMOTEROL, SALMETEROL
PROCATEROL

Sympathetic
Antagonists
SYMPATHOLYTIC
S

1. Adrenergic Neuron Blockers
(ANB)
- Guanethedine, Reserpine
1. Adrenergic Receptor Blockers
(ARB)
 Reversible – Prazosin, Phentolamine,
Tolazoline, Labetalol,
Ergot alkaloids
 Irreversible – Phenoxybenzamine,
AntagonistsAntagonists
(Sympatholytics)(Sympatholytics)

αα11 andand αα22 ΒΒ11 andand ββ22
YOHIMBINE BUTOXAMINELABETALOL
CARVEDILOL

αα11 αα22
αα andand ββ ββ11 ββ22
ββ11 andand ββ22
αα11 andand αα22
PRAZOSIN, TERAZOSIN
DOXAZOSIN, TRIMAZOSIN
INDORAMIN, URADIPIL
KETANSERIN, ALFUZOSIN
BUNAZOSIN, TAMSULOSIN

αα11 αα22 αα andand
ββ
ββ11 ββ22
PHENOXYBENZAMINE
PHENTOLAMINE
ERGOT ALKALOIDS
NEUROLEPTIC DRUGS

METOPROLOL
ATENOLOL
ACEBUTOLOL
BETAXOLOL
CELIPROLOL
ESMOLOL

PROPRANOLOL
NADOLOL, TIMOLOL
PINDOLOL, LEVOBUNOLOL
CARTEOLOL, BISOPROLOL

QUIZQUIZ
1. Major neurotransmitter of the Sympathetic1. Major neurotransmitter of the Sympathetic
Nervous System?Nervous System?
2.Write A if Agonist or B if Antagonist:2.Write A if Agonist or B if Antagonist:
. Epinephrine. Epinephrine . Phentolamine. Phentolamine
. Labetalol. Labetalol . Cocaine. Cocaine
. Clonidine. Clonidine . Phenylephrine. Phenylephrine
. Prazosin. Prazosin . Ephedrine. Ephedrine
. Terbutaline. Terbutaline

Autonomic system and Autonomic Pharmacology

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