INTRODUCTION TO

AUTONOMIC NERVOUS SYSTEM (ANS)

PHARMACOLOGY

Basic Pharmacology - 2016

dr. Agung Nova Mahendra, M.Sc.

Department of Pharmacology
Faculty of Medicine, Udayana University
Curriculum Vitae
Full Name : Agung Nova Mahendra
P/DoB : Tabanan/November 14, 1986
Research Areas:
Antioxidant pharmacology
Experimental neuropsychopharmacology
Level of Education Alma mater Degree / Awards
Senior High School SMAN 1 Singaraja Silver Medal in National
Biology Olympiad - 2003
Undergraduate (S1) Fakultas Kedokteran dr.; S.Ked.
UNUD

Postgraduate (S2) in Fakultas Kedokteran M.Sc. / Certificate of

Pharmacology UGM Summa Cum laude

Postmaster Research Yakko Kaiseki Gaku, Certificate of Excellence

Fellowship Yakko Gakubu, in Neuropharmacology
Okayama Daigaku,
Okayama, Japan
The importance of comprehending
ANS pharmacology

ANS controls nearly all bodily functions

ANS pathophysiology is involved in many

disorders/diseases

Many drugs may affect ANS (therapeutic, side, & toxic

effect)

Serves as a basis for higher medical education

Basic Pharmacology - 2016

 List of Terms

Sympathomimetics/Adrenomimetics
Sympatholytics /Antiadrenergics or Adrenoceptor
antagonists
Cholinomimetics/Cholinergics
Cholinesterase regenerators
Parasympatholytics/Anticholinergics or Cholinoceptor
antagonists
Dopaminergics

Basic Pharmacology - 2016

 Anatomic aspect of the ANS
Spinal root of origin & ganglia location
Division Origin Ganglia Location
Parasympathetic Cranial nerve Lateral aspects of
ANS (PANS) nuclei III, VII, IX, & spinal collumn
X& (except
Sacral segments prevertebral
of spinal cord ganglia)

Sympathetic ANS Thoracic & lumbar Near the

(SANS) segments of spinal innervated organs
cords

Basic Pharmacology - 2016

Basic Pharmacology - 2016 (Mathias, 2003)
Creative thinking.

SANS: Flight or Fight Response

PANS: Rest & Digest (Spit-Pee-Shit)

Basic Pharmacology - 2016

Neurotransmitter aspects of the ANS

NOREPINEPHRINE:
primary transmitter of
SANS adrenoceptor &
noradrenergic
neuron/synapse

ACETYLCHOLINE:
COTRANSMITTERS:
primary transmitter of
ATP, VIP, NPY,
PANS cholinoceptor
substance P,
& cholinergic
somatostatin, etc.
neuron/synapse

Basic Pharmacology - 2016

Neurotransmitters involved in the ANS pathways

Basic Pharmacology - 2016 (Mathias, 2003)

Many drugs exert their effects by working at
different steps of autonomic transmission:

Synthesis

Uptake &
Storage
Metabolism

Receptor
Interaction Release
Basic Pharmacology - 2016
 Presynapse CHOLINERGIC NEURON

1.
Drugs affecting
Acetyl-CoA + Choline Choline
cholinergic activity:
1. Hemicholinium
2.
2. Vesamicol
ACh-containing 3. Botox
vesicle breakdown of SNAP25
Ca2+
+

3. Vesicle docking &

fusion;
ACh release
ACh
AChE
Cholinoceptor
Acetate & Choline
Postsynapse
Basic Pharmacology - 2016
 Presynapse NORADRENERGIC NEURON
Tyrosine Tyrosine
Mt TH 1.
(with DOPA
MAO)
AT II R
DA* Drugs affecting
2. M1 R noradrenergic
NE-containing activity:
2 R
vesicle
1. Metyrosine
++
Ca2+ 2. Reserpine
NE
uptake 3. Guanethidine,
3. Vesicle docking &
4. fusion; Amphetamine
NE *(& DA) 4. Cocaine, TCAs
NE release

Adrenoceptor

Diffusion & Metabolism

Postsynapse
Basic Pharmacology - 2016
Receptor characteristics
Cholinoceptors:
Muscarinic &
Nicotinic

Major ANS
Adrenoceptors:
receptor
Alpha & Beta
systems

Dopamine
receptors (D or
DA receptors)

Basic Pharmacology - 2016

 Cholinoceptors

Type Mechanism Location

M1 Gq increases IP3 & DAG Nerve endings

M2 Gi decreases cAMP, activates K+ Heart, some nerve

channels endings

M3 Gq Effector cells: SM,

glands, endothelium

NN Ion channel depolarization ANS ganglia

NM Ion channel depolarization NMJ

Basic Pharmacology - 2016

 Adrenoceptors & Dopaminergic Receptors
Type Mechanism Function Location

1 Gq Increases Ca2+ Effector tissues: SM,

contraction & secretion glands

2 Gi Reduces transmitter release Nerve endings &

contraction some SM

1 Gs Inotropic & chronotropic Cardiac muscle &

(+); increases renin release JGA

2 Gs Inotropic & chronotropic Heart, liver, & SM

(+); increases
glycogenolysis; relax SM

3 Gs Increases lipolysis Adipocytes

D1 Gs Relax renal vascular SM SM

Basic Pharmacology - 2016

Effects of autonomic nerves activation

E.g.: Pupil is both innervated

Each ANS division has
by SANS & PANS fibers (with
specific effects on organ
-adrenoceptors & M
systems
receptors, respectively)

Basic Pharmacology - 2016

Sympathetic innervation of the pupil: Example of autonomic
nerves activation

SANS
Pupil

1
receptor

Radial muscle of
the iris (m.
dilator pupillae)

Mydriasis

Basic Pharmacology - 2016

Parasympathetic innervation of the pupil: Example of autonomic
nerves activation

PANS Pupil

M receptor

Circular muscle of the

iris (m. constrictor
pupillae)

Miosis

Basic Pharmacology - 2016

 Sites of autonomic drug action
The sites include CNS
centers, ganglia,
There are many sites of drug postganglionic nerve
action (e.c. multistep nature terminals, effector cell
of ANS transmission) receptors, & steps of
autonomic transmission

Selectivity is mostly
achieved by drugs acting @
receptors with very specific
actions

Basic Pharmacology - 2016

Functional integration of the ANS
Mainly based on negative feedback
Two levels of integration

Modulatory pre- &

Local integration postsynaptic receptors
Autonomic
integration
Systemic Systemic homeostatic
reflexes
integration

Basic Pharmacology - 2016

 Systemic integration: symphony of
autonomic & hormonal feedback loop
Increased blood
pressure to normal
level
Increased
Decreased HR & CO
PANS
Vasomotor (vagal)
center tone &
Baroreceptors increased
increase firing SANS tone

Reduced blood
pressure RAAS
Increases renin release
AT II increases PVR; activation
aldosterone causes salt &
water retention

Basic Pharmacology - 2016

 Conclusions
The ANS (PANS & SANS) involves various types of
neurotransmitter to regulate bodily functions, with ACh & NE
as primary neurotransmitters

Cholinergic & Adrenergic systems mainly work to

counterbalance one another

Autonomic drugs exert their effects on various components of

autonomic transmission, from the CNS centers to
neurotransmitters reuptake or metabolism

Both local & systemic integration have important contribution

on the functional integrity of ANS

Basic Pharmacology - 2016

 References
Trevor AJ, Katzung BG, Masters SB. Katzung & Trevors
Pharmacology Examination & Board Review seventh edition. The
McGraw-Hill Companies. 2005: 43-53.
Mathias CJ. Autonomic Diseases: Clinical Features and
Laboratory Evaluation. J Neurol Neurosurg Psychiatry. 2003(74):
31-41.

Basic Pharmacology - 2016

ANS PHARMACOLOGY (2):
DRUGS ACTING ON PANS

dr. Agung Nova Mahendra, S.Ked., M.Sc.

Department of Pharmacology
Faculty of Medicine, Udayana University
2016
Postganglionic parasympathetic
neurotransmission

Decker, 2012
 Muscarinic (M) Receptor
Subtypes:
M1: brain, autonomic ganglia, presynaptic neuronal
endings

M2: heart (>>)

M3: glands (>>)

M4 & M5: CNS (>>)

Reminder

Decker, 2012
 CHOLINERGICS
CHOLINERGICS
Basic concepts of cholinergics

Most cases: cholinergics specificity for

muscarinic receptor > nicotinic receptor
hence the term MUSCARINICS

Cholinergic activity can be

stimulated at the cholinoceptors
CONCEPTS (direct action) or
: Increased by inhibiting AChE
(indirect action)
Clinical Uses

Cholinergics:
Pilocarpine: muscarinic agent used as miotics
(treatment of glaucoma) & as antixerostomia
Cevimeline: muscarinic agent (at M3) approved for
xerostomia
Clinical Uses

Cholinesterase inhibitors:
Pyridostigmine: for myasthenia gravis
Neostigmine: neuromuscular blockade reversal
Donepezil: for Alzheimer dementia
ANTICHOLINERGICS

ANTICHOLINERGICS
 Basic concepts of
anticholinergics

Anticholinergics: antagonists at M
receptors

Note: cholinergic synapses are prevalent

in brain (excitatoric effect)

Anticholinergics sedation, antiemetic,

worsening of dementias symptoms
Clinical uses

Atropine: mydriatic & antibradycardia

Scopolamine: antisialagogues (sedative &
psychotomimetic)
Glycopyrrolate: antisialagogues (water-
soluble does not cross BBB)
Trihexyphenidyl: antiparkinsonism
Benztropine: antiparkinsonism
 All drugs with anticholinergic
properties should be avoided in
patients with:
Constipation
Urinary retention
Alzheimers dementia
Other dementias
 Summary

Cholinergics mainly act at M receptors

Cholinergic activity can be stimulated through direct

action (cholinoceptors agonims) & indirect action
(AChE inhibition)

Anticholinergics act as antagonists at M receptors.

These agents are used to counteract disease- or drug-
induced PANS overactivity
 Reference

Becker, D.E., 2012. Basic and Clinical

Pharmacology of Autonomic Drugs. Anesth
Prog. 59: 159 169.
ANS PHARMACOLOGY (3):
DRUGS ACTING ON SANS

dr. Agung Nova Mahendra, S.Ked., M.Sc.

Department of Pharmacology
Faculty of Medicine, Udayana University
2016
Introduction

Korakuen, Okayama-shi, Okayama, Japan

 Sympathetic Neurotransmission
Very prominent roles in cardiovascular
system
Transmitters: NE (& E)
Inactivation: Reuptake mechanism >>
Receptors: &
 SYMPATHOMIMETICS

Tsush
ima C
ampu
s , Kita-
ku, O
kayam
a-shi,
Okaya
ma, Japan
SYMPATHOMIMETICS
Drugs that mimic the action of NE &/or E
(stimulate adrenergic activities)
Pharmacodynamics:
Direct : Adrenoceptor agonists of
effector cells
Indirect : Act in presynaptic neuron, dependent
on endogenous catecholamines release
Displace stored catecholamines
Inhibit catecholamines reuptake
Agonists of 1:

Phenylephrine: used intranasally

as decongestant
Midodrine: used PO as a prodrug to
treat orthostatic hypotension
Agonists of 2:
Clonidine: used PO as hypertension tx
-Methyldopa: safe choice for
hypertension in pregnancy
Agonist of 1:

Dobutamine: positive inotropic

effect (IV use to treat cardiogenic
shock & acute heart failure)
Agonist of 2:

Albuterol: dilates bronchi (for asthma)

with 4 6 hrs duration little 1
activity
SYMPATHETIC ANTAGONISTS

Fuyu sakura in Tsuyama-jo, Okayama, Japan

 Sympathetic
Antagonists
Drugs that block catecholamine receptors
activation
Antagonist of -adrenoceptors:
Phenoxybenzamine: irreversible
blocks of both subtype of -
adrenoceptors pheochromocytoma
tx.
Antagonist of 1-adrenoceptors:

Tamsulosin: HT & benign prostatic

hyperplasia (BPH) tx.
Antagonist of 2-adrenoceptors:

Yohimbine: 2 blockade increased

NE release; male erectile dysfunction
& hipotension tx.
Antagonist of -adrenoceptors:

Propranolol: 1 & 2 blockade; HT,

angina pectoris, arrhythmias,
migraine, hyperthyroidism tx.
 Summary
Drugs acting on SANS can be classified
as sympathomimetics & sympathetic
blockers

SANS neurotransmission modulation

(i.e., adrenoceptors activation) can be
established directly or indirectly
Reference
 THE END OF
PRESENTATION

Shikata Campus, Shikata-cho, Okayama-shi, Okayama, Japan

TERIMAKASIH

MATUR SUKSMA

MATUR NUWUN

THANK YOU

ARIGATOU
GOZAIMASU