AUTONOMIC PHARMACOLOGY

by Dr. Khalid Niaz

Why study autonomic
pharmacology?
Autonomic Pharmacology
is Clinically Relevant
Autonomic drugs are used for the
treatment of Angina
 Autonomic drugs are used for the
treatment of Heart Failure
Autonomic drugs are used for the
treatment of
Alzheimer’s Disease
Autonomic drugs are used for
the treatment of
High Blood Pressure
 Autonomic drugs are used for the
treatment of

Benign Prostatic Hypertrophy

 Autonomic drugs are used for the

treatment of Anaphylactic Shock

 Autonomic drugs are used for the

treatment of Septic Shock

Autonomic drugs are used for the

treatment of Asthma
Anatomy of Peripheral
Nervous System
 Peripheral Nervous System
Autonomic Nervous
Somatic Nervous System
System

Parasympathetic Sympathetic
Nervous System ENS? NervousSystem

Selective
Diffuse
Activation
Skeletal GIT Activation
Muscle

Glands, Smooth Muscle

& Cardiac Muscle
 Peripheral Nervous System
Controls
Controls smooth &
skeletal cardiac
muscle muscle &
glands
Somatic
Nervous Autonomic
System Nervous
System

One Two
Neuron Neuron
Efferent Efferent
Limb Limb
 Somatic Motor Fiber Skeletal
Ach Muscle
Ganglion
Sympathetic Smooth
A N Muscle
ch E Cardiac Cells
Gland Cells
Sympathetic
A Sweat
Ach
ch Glands
Sympathetic
A EPI/NE
ch
Adrenal Gland
Para- Smooth
sympathetic Ac
Ach
Muscle
h Cardiac Cells
Gland Cells
 Radial Muscle of Iris
Sympathetic Nervous System Ciliary Muscle
(Thoracolumbar Outflow) Sublingual/Submaxillary
& Parotid Gland
SA & AV Nodes
Pilomotor Muscles His-Purkinje System
Sweat Glands Myocardium
Bronchi/Bronchial
Glands
Stomach

Kidneys
Blood Vessels

Intestines

Paravertebral Ganglia Bladder//Genitalia

Prevertebral Ganglia
 ADRENAL
MEDULLA

Chromaffin Cells

Epinephrine
(+) Dilates Airways (+) Mental Alertness

(+) ACTH & TSH

(+) Cardiac Output

(+) Muscle Contraction & Efficiency (+) Glycogenolysis

(+) Fatty Acid Release (-) Intestinal Motility

The basic anatomy of the parasympathetic and sympathetic nervous systems and t
Transmitters employed at specific junctions of the peripheral nervous system
Mechanism of neurotransmission
in the autonomic nervous system
Summary of Catecholamine Biosynthesis

Tyrosine

DOPA

Dopamine

SYMPATHETIC
Norepinephrine NERVE

ADRENAL
Epinephrine GLAND
 SUMMARY OF CHOLINERGIC NEUROTRANSMISSSION

Neuroeffector Junction

Parasympathetic/Sympathetic Parasympathetic or
Preganglionic Fibre or Sympathetic
Parasympathetic Postganglionic Fibre Postganglionic Fibre
or Effector Cell
AUTONOMIC RECEPTORS
Influence of Brain on Autonomic Functions
Parasympathetic
Sympathetic
AUTONOMIC RECEPTORS
 Adrenergic Receptors: Receptors Activated by EPI/NE

a- adrenergic receptors  - adrenergic receptors

(Epinephrine>Isoproterenol)
a (Isoproterenol>Epinephrine)

 1- adrenergic receptors
a1- adrenergicreceptors (EPI = NE)
(Phenylephrine>Clonidine)

 2- adrenergic receptors
(EPI>NE)

a 2- adrenergic receptors  3-adrenergic receptors

(Clonidine>Phenylephrine) (NE>EPI)
 Cholinergic Receptors: Receptors Activated by Ach

Muscarinic Receptors
(Activated by muscarine from Amanita muscaria)

Nicotinic Receptors
M1 (Activated by nicotine from tobacco)
(Nerve Cells)

M2
(Heart & SM)

M3 NM(Neuromuscular)
(Heart & SM)
(Blocked by
M4 Tubocurarine)
(SM & Glands)
NN (Autonomic ganglia,
Adrenal medulla &CNS)
M5 BV
CNS Neurons (Blocked by Trimethaphan)
Summary of Autonomic Receptors:

Cholinergic Receptors
– Muscarinic receptors
⚫ M1,, M2, M3, M4, M5
– Nicotinic receptors
⚫ Nn
⚫ Nm
α 1A
α 1B
Adrenergic Receptors Alpha-1
α 1D
(i) alpha adrenoceptor
α 2A
Alpha -2 α 2B
α 2C
Beta -1
(ii) beta adrenoceptor
Beta -2

Beta-3
(iii) Dopaminergic
Adrenergic Receptors:
Signal Transduction
AUTONOMIC RECEPTORS
AUTONOMIC RECEPTORS
⚫ RECEPTORS COUPLED TO ADENYLYL CYCLASE
⚫ ➢ Beta- adrenoceptors
⚫ ➢ Alpha-2 adrenoceptors

Adenylyl
ATP cyclase cAMP

PROTEIN PHOSPHORYLATION

INTRACELLULAR EFFECT
 As Ai

Adenylate
R1 Cyclase R2
Gs Gi

GTP GTP
GDP GDP
ATP
AMP
PDE cAMP

C
Protein
C
Reg Reg
C C

Protein Kinase A PKA

(PKA) Protein-P
Cholinergic Receptors:
Signal Transduction
 Muscarinic Receptors

Gq(M1, M3, M5 ) Gi (M2, M4 )

Activation of PLC a γ
subunit subunit

Formation Formation
of IP3 of DAG

Inhibition Opening of
Release of of Adenylyl Potassium
Activation
Intracellular Cyclase Channels
of PKC
calcium
 RECEPTORS COUPLED TO PHOSPHOLIPASE-C.

Cholinergic muscarinic receptor. ( M1, M3, M5 )

(Alpha-1 adrenoceptor )

DAG IP3

Protein phosphorylation & increase in intracellular Ca++

Intracellular effect
AUTONOMIC RECEPTORS
 Ca++
A

R PLC
Gq
DAG

PIP2 PKC

Protein
IP3 Protein-P

Endoplasmic Reticulum
Ca++
 Muscarinic M2 Receptors

Coupled to :

• Adenylyl cyclase pathway through GI

(a subunit inhibit adenylyl cyclase)

• Potassium channels
(g subnit opens K+ channels)
 Nicotinic Receptors

Nm Nn

Opening of Na+ Opening of Na+

channels channels
 RECEPTORS COUPLED TO AN ION CHANNEL

⚫ ➢ Cholinergic nicotinic receptors

Ions

Change in membrane potential or ionic

Concentration in cell.
Ions
 Ligand-gated Channels

⚫ Endogenous ligand –
drugs
(agonist/antagonists)

⚫ Nicotinic ACh-receptor
in skeletal muscle
– Blocked by tubocurarine
(muscle relaxant, during
surgery)
FUNCTIONS OF AUTONOMIC
RECEPTORS
Functions of Cholinergic Receptor
⚫ Nicotinic Nn (neuronal)
– Promote ganglianic transmission
– Promote release of epinephrine

⚫ Nicotinic Nm (muscle)
– Contraction of skeletal muscle
– Promote release of Ach at NMJ

⚫ Muscarinic
– Activate parasympathetic nervous system
Functions of Adrenergic Receptor
⚫ Alpha1
– Vasoconstriction
– Contraction of radial muscle of iris
– Contraction of bladder neck and prostate
– Contraction of sphincters of GIT
– Ejaculation
– Increased sweating (Apocrine….In stress)
⚫ Alpha2
– presynaptic …… Control release of NT.
– Aggregation of platelets
– Contraction of some vascular sm ms.
– Fat cells …… Inhibition of lipolysis.
Functions of Adrenergic Receptor
⚫ Beta1
⚫ Heart
– Increases
⚫ heart rate
⚫ force of contraction
⚫ velocity of conduction in AV node
⚫ Automaticity/Excitability

⚫ Kidney
– Renin release
Functions of Adrenergic Receptors
⚫ Beta2
– Bronchodilatation.
– Relaxation of uterine muscle.
– Vasodilation of BV of sk ms.
– Glycogenolysis in human liver.
– Increase K+ uptake in sk ms.
⚫ Beta3
– Lipolysis

⚫ Dopamine-1
– Dilates renal blood vessel
Dopamine-2
Modulate NT release from nerve endings
Most organs receive dual sympathetic
and parasympathetic innervation
BUT
SOME ORGANS RECIEVE ONLY SYMPATHETIC
INNERVATION

⚫ Adrenal Medulla
⚫ Kidney
⚫ Pilomotor muscles
⚫ Sweat glands
⚫ Most BV
⚫ Metabolic processes
⚫ Spleen
 Actions of autonomic nerves:
Adrenergic and cholinergic responses
 Effect of
Organ
Sympathetic Parasympathetic
Action Receptor Action Receptor

Eye
Iris
α1
-------- -------
Radial muscle Contracts
-------- ---------
Circular muscle Contracts M3

Cilliary muscle Relaxes β contract M3

Normal:
Ciliary Muscle Relaxed
Suspensory Ligaments Under Tension
Lens is Flattened
Focus on Distant Objects
Accommodation:
Ciliary Muscle Contracts
Reduced Tension on Suspensory Ligaments
Lens becomes Round
Focus on Near Objects
 Effect of
Organ Sympathetic Parasympathetic
Action Receptor Action Receptor
Heart
SA node Accelerate β1 Decelerates M2

β1
----------
Ectopic pacemaker Accelerate
Contractility Increases β1 Decreases M2
Vascular Sympathetic Parasympath
Smooth Muscle etic

……
Skin,
Splanchnic Contract
α -----

vessels
Skeletal Muscle Relaxes β2 --------- --------
vessels

Contract α --------- --------

Relaxes M3 --------- …….

Ach & Directly acting cholinergic
agonists (when given i/v

M EDRF (NO)
Bronchial smooth Relaxes β2 contracts M3
muscles
G.I.T

Walls Relaxes α 2, β2 Contracts M3

Sphincters Contracts α1 Relaxes M3

-------- -------
Secretion Increases M3

Myenteric plexus Activates M1

Genitourinary
System
Bladder wall Relaxes β2 Contracts M3

Sphincter Contracts α1 Relaxes M3

 β2
------- -------
Relaxes
Uterus, pregnant

α
------- --------
Contracts

Penis, Seminal
Vesicles
Ejaculation
α Erection M3

Skin
Pilomotor
smooth muscles
Contract
α ------- -------

Sweat glands
Thermoregualtory
Increases M

Apocrine (stress) Increases

α -------- --------
Metabolic Sympathetic Parasympat
hetic
Functions
β2 / α
-------- --------
Liver Gluconeo
genesis

β2 / α
-------- --------
Liver Glycogeno
lysis

Fat cells Lipolysis α 2/ -------- --------

β1/β3

β1
-------- --------
Kidney Renin
release
Opposing effects of parasympathetic and
sympathetic nerves.
Interaction of drugs with the
AutonomicNervous System
 SYMPATHOMIMETICS: Drugs that
facilitate or mimic some or all of the
actions of the sympathetic nervous system.

Direct Acting Indirect Acting

a-adrenergic agonists Drugs that facilitate NE release

 - adrenergic agonists Drugs that block NE uptake

AUTONOMIC RECEPTORS
 Ganglionic Centrally acting Drugs that
blocking sympatholytics inhibit NE
drugs synthesis

SYMPATHOLYTICS: Drugs that reduce

NE depleting or inhibit some or all of the actions of the
drugs sympathetic nervous system.

Adrenergic Neuron  -adrenergic a -adrenergic

blocking drugs antagonists antagonists
 PARASYMPATHOMIMETICS
(CHOLINOMIMETICS): Drugs that
facilitate or mimic some or all of the
actions of the parasympathetic nervous
system.

Directly acting drugs Indirectly acting drugs

Muscarinic Nicotinic
receptor receptor Anticholinesterases
agonists agonists
ANTICHOLINERGICS: Drugs that
reduce or inhibit some or all of the
actions of Cholinergic nerve stimulation

Antimuscarinics Antinicotinics

NM Ganglion
Blockers Blockers
 Predicting Responses of Drugs that
Interact with the Autonomic Nervous
System
Baroreceptor Reflex
 Baroreceptor Reflex
Phenylephrine Histamine

BP
(mmHg)

SNA
(Units)

PSNA
(Units)

HR
(bpm)

Time (minutes)
 Predicting Responses

1&2

 1,  2, a 1 & a 2

 1, a 1 & a 2
 Predicting Responses

1&2

 1,  2, a 1 & a 2

 1, a 1 & a 2
 Heart Rate Blood Pressure

ACH (2 mg)

ACH (50 mg)

(Atropine: Muscarinic Receptor Antagonist)

ACH (50 mg)

ACH (5 mg)

(Hexamethonium: Neuronal Nicotinic Receptor

Antagonist)
ACH (5 mg)