PHARMACOLOGY

AUTONOMIC PHARMACOLOGY
Dr. Minerva P. Calimag, MD || August 30, 2019

▪ these signals are conveyed to the cranial and

OUTLINE spinal nerves
– Motor Division
1. Peripheral Nervous System
▪ Efferent Division
1.1. Somatic Nervous System ▪ contains pathways that go from the brain and
1.2. Autonomic Nervous System spinal cord to the lower motor neurons of the
2. Autonomic Nervous System cranial and spinal nerves
2.1. Sympathetic Nervous System ▪ stimulation causes voluntary contraction of the
2.2. Parasympathetic Nervous System skeletal muscles
2.3. Physiological Antagonism
3. Neurochemical Classification of Peripheral NS 1.2 AUTONOMIC NERVOUS SYSTEM
3.1. Acetylcholine ● Releases Ach
● Mediates control of vegetative or involuntary
3.2. Norepinephrine
functions
4. Autonomic Receptors ● Innervation of cardiac muscle, vascular and
4.1. Sympathetic Receptors nonvascular smooth muscle and exocrine glands
4.2. Parasympathetic Receptors ● Consist of 2 sequential neurons: preganglionic and
5. Autonomic Nervous System Drugs postganglionic neurons that synapse in autonomic
5.1. Sympathetic Drugs ganglia
5.2. Parasympathetic Drugs ● Consist of 2 divisions:
○ Sympathetic
○ Parasympathetic
I. PERIPHERAL NERVOUS SYSTEM

II. AUTONOMIC NERVOUS SYSTEM

2.1 SYMPATHETIC NERVOUS SYSTEM

1.1 SOMATIC NERVOUS SYSTEM
• Regulates activities under conscious control.
• Acetylcholine (Ach) is the neurotransmitter released
at the neuromuscular junction
• Consist of sensory and motor nerve divisions
– Sensory Division
▪ Afferent Division
▪ contains neurons and signals from the
tendons, joints, skin, skeletal muscles, eyes,
nose, and many other organs
• Catabolic
• Short preganglionic synapsing with several (one or
more) long postganglionic fibers in the sympathetic
ganglia
• preganglionic neurons exit the spinal cord at the
thoracolumbar level to synapse with postganglionic
nerves at the paravertebral ganglia to form the
sympathetic trunk
• all the paravertebral ganglia provide sympathetic
innervation to blood vessels in muscle and skin,
arrector pili muscles, and sweat glands
• Sympathetic trunk (22 pairs on each side of the spinal
cord)

A. AQUINO; C. BAUTISTA; M. CANO; J. BUENAVENTURA 1

 PHARMACOLOGY
AUTONOMIC PHARMACOLOGY
Dr. Minerva P. Calimag, MD || August 30, 2019

– Cervical 3 – Inferior Mesenteric Ganglion

▪ Superior Sympathetic Ganglion innervates ▪ innervates embryonic hindgut (descending
viscera of the head colon, sigmoid colon, rectum, urinary bladder,
▪ Middle Cervical Ganglion and Stellate and sexual organs)
Ganglion (Cervicothoracic Ganglion)
innervate viscera of the neck, thorax, and • discrete action: conservation and restoration of energy
upper limbs • localized control
– Thoracic 10 or 11 • typical response:
▪ innervate the trunk region – dec. HR
– Lumbar 4 – Dec. BP
– Sacral 4 – constriction of pupil
▪ Lumbar and sacral innervate the pelvic floor – emptying of bladder
and the lower limbs
– Coccygeal unpared
Keywords of responses
▪ called Ganglion Impar
• adrenal medulla is considered to be a modified
sympathetic ganglion Sympathetic Parasympathetic
– embryologically and anatomically homologous to
the sympathetic ganglia Eyes Mydriasis Miosis
• greater ramification of sympathetic fibers compared to
parasympathetic (ratio of pre- to postganglionic fibers = Glands secretion Inhibited Enhanced
1:20)
• Diffuse action: fight or flight response Smooth muscle Relax Contract
• normally active with the degree of activity varying from
moment to moment and organ to organ Blood vessels in Dilate Constrict
• adjust to changing environment, esp. during rage or muscle
fright
• typical response: Blood vessels in Constrict Dilate
– inc. HR (tachycardia) skin (except for
– shift blood flow to muscle bluish areas of
– Inc. in blood glucose level face and neck
– dilation of pupil
Hollow Organ: Retention Evacuation
2.2 PARASYMPATHETIC NERVOUS SYSTEM ● Longitudinal ● Relax ● Contract
Muscle
• CN 3,7,9,10 ● Sphincter ● Contract ● Relax
• anabolic
• Preganglionic neurons originate in cranial nerves and
sacral portion of spinal cord
• Long preganglionic fiber; short postganglionic fiber
• more circumscribed than sympathetic system (1:1 ratio
although not always) 2.3 PHYSIOLOGIC ANTAGONISM
• preganglionic neurons synapse with postganglionic • Sympathetic and Parasympathetic systems usually do
neurons in preaortic ganglia very close or in the organs not function independently; i.e. they are physiologically
innervated antagonists
• Preaortic or Prevertebral Ganglion lies on the • Often when one system inhibits a process, the other
anterior surface of the aorta which retain a pattern of system will augment the level of activity so that the total
innervation that originates in the embryo response depends on the influence of both systems,
– Celiac Ganglion although this is not always the case.
▪ innervates structure from embryonic foregut • the integration of these systems function below the level
including stomach,liver, pancreas, duodenum, of consciousness
and first part of the small intestine
– Superior Mesenteric Ganglion
▪ innervates small intestine (from embryonic
midgut)

A. AQUINO; C. BAUTISTA; M. CANO; J. BUENAVENTURA 2

 PHARMACOLOGY
AUTONOMIC PHARMACOLOGY
Dr. Minerva P. Calimag, MD || August 30, 2019

III. NEUROCHEMICAL CLASSIFICATION OF THE c. Dopamine receptors

PERIPHERAL NERVOUS SYSTEM d. Adenosine receptors
2. Ligand-gated ion channels
a. Acetylcholine nicotinic receptors
3.1 ACETYLCHOLINE
• synthesis: Receptors Affinity and Efficacy

• major means of inactivation: degradation by
• synapses:
– all preganglionic fibers outside CNS (sympathetic
and parasympathetic)
– all parasympathetic postganglionic nerve endings
– sympathetic postganglionic nerve endings of sweat
glands
– Somatic: motor neurons innervating skeletal muscle
3.2 NOREPINEPHRINE
• synthesis:
• Agonist
– binding to receptors trigger a pharmacologic
response (with affinity and intrinsic activity)
– Full Agonist produces maximum response
(intrinsic activity = 1)
– Partial Agonist cannot produce maximum
response (intrinsic activity < 1)
• Antagonist
– binding to receptors does not trigger a
pharmacologic response (with affinity, no intrinsic
activity) (intrinsic activity = 0)
– Competitive Antagonist block of receptor can be
overcome by increasing the concentration of the
agonist
– Noncompetitive Agonist bock of receptor cannot
be overcome by increasing the concentration of the
agonist
• Inverse Agonist
– ligand binding produces opposite effects to those of
an agonist
– not the same as antagonists which block the effects
of both agonist and inverse agonist.

Receptors with:
● subscript 1 or 3
○ excitatory
○ contraction, constriction, enhanced
secretion
● subscript 2
○ inhibitory
○ relaxation, dilatation, inhibited
secretion

4.1 SYMPATHETIC RECEPTORS

• major means of inactivation:
– reuptake back into the presynaptic neuron from
which it was released
• synapses:
– all postganglionic sympathetic fibers (except those
to sweat glands)
– adrenal medulla (norepinephrine and epinephrine)
IV. AUTONOMIC RECEPTORS
1. G-protein coupled receptors
a. Acetylcholine muscarinic receptors
b. Adrenergic receptors
Norepinephrine Receptors
• Alpha Receptors are found in smooth muscles and
glands
– Alpha₁ (postsynaptic receptors)
▪ vascular smooth muscle, genitourinary
smooth muscle, liver (contraction)
▪ intestinal smooth muscle (hyperpolarization,
relaxation)
▪ heart (inc. contractile force, arrhythmias)
– Alpha₂ (presynaptic receptors) cause feedback
inhibition on the release of NE
A. AQUINO; C. BAUTISTA; M. CANO; J. BUENAVENTURA 3
 PHARMACOLOGY
AUTONOMIC PHARMACOLOGY
Dr. Minerva P. Calimag, MD || August 30, 2019

▪ pancreas islets (b cells, dec. insulin secretion) V. THE ANS DRUGS

▪ platelets (aggregation)
▪ vascular smooth muscle (contraction)
5.1 SYMPATHETIC DRUGS
• Beta Receptors
– Beta₁ are excitatory to the heart and fat cells
▪ heart (inc. force and rate of contraction, AV Adrenergic Agonists (Sympathomimetic)
nodal conduction velocity)
▪ juxtaglomerular cells (inc. renin secretion) • Direct acting
– Beta₂ are inhibitory to smooth muscles and – Mixed alpha and beta (NE, EPI- 1 methyl →
glands catecholamine)
▪ smooth muscle (vascular, bronchial, – Alpha 2 selective (Clonidine)
gastrointestinal, genitourinary; relaxation) – Beta 2 selective (Terbutaline-3-methyl constituent at
▪ skeletal muscle (glycogenolysis; uptake of K+) amine, Isoproterenol)
▪ liver (glycogenolysis, gluconeogenesis) • Indirect acting- (Amphetamine, Cocaine)
• Dual-acting- (Ephedrine)
4.2 PARASYMPATHETIC RECEPTORS
Adrenergic Antagonists (Sympatholytic)
Acetylcholine (Cholinergic) Receptors) • Alpha blockers
– Nonselective(Phenoxybenzamine, Phentolamine)
• Nicotinic Receptors are ligand-gated ion channels – Selective alpha 1 (Prazosin)
– Nicotinic muscle-subtype are found in NM • Beta blockers
junction – Nonselective (Propanolol)
– Nicotinic neuronal-subtype are found in the – Selective beta 1 (Metoprolol- causes bradycardia)
autonomic ganglia
– classically a biphasic response (stimulation at low 5.2 STRUCTURE-ACTIVITY OF SYMPATHOMIMETIC DRUG
doses and inhibition at high doses)
– sympathetic and parasympathetic autonomic
ganglia, and adrenal medulla
▪ effects blocked with ganglionic blockers (e.g.
trimethaphan, hexamethonium)
– NM junction of skeletal muscle
▪ effects blocked with neuromuscular blockers
(e.g. curare)
• Muscarinic Receptors are G protein-coupled
receptors (5 subtypes)
– M1 are excitatory and found in the autonomic
ganglia and CNS
▪ causes depolarization of postganglionic
autonomic nerves
– M2 are found in the supraventricular parts of the
heart
– M3 are excitatory and found in smooth muscles,
glands, and on endothelial cells in the vasculature
Substitution of the Benzene Ring
▪ mediate contraction of smooth muscles and
increased secretion in glands (except for the • Substitution of hydroxyl groups at the 3- and 4-
effect of Ach on blood vessels which causes positions of the benzene ring converts benzene to
vasodilation and dec. blood pressure). this is catechol, and this the dihroxylated phenylethylamine
mediated by an effect of Ach on the endothelial compounds are known as catecholamines with
cells of the vasculature maximal a and b effects
– postganglionic parasympathetic fibers innervating – Catecholamines are subject to inactivation by
heart, smooth muscles and exocrine glands catechol-O-methyltranferase
– exception: postganglionic sympathetic fibers – i.e. Catechol, NE, Epinephrine, Isoproterenol,
innervation sweat glands Dopamine
▪ effects blocked by antimuscarinic agents
(e.g. atropine-blocks nerves to sweat glands)
A. AQUINO; C. BAUTISTA; M. CANO; J. BUENAVENTURA 4
 PHARMACOLOGY
AUTONOMIC PHARMACOLOGY
Dr. Minerva P. Calimag, MD || August 30, 2019

Substitution at the b-carbon

• Typical of direct-acting agonist

• Important for storage of sympathmimetic amines in
neural vesicles
• i.e. NE, Epinephrine, Isoproterenol, Phenlylephrine,
Ephedrine, Methoxamine
• Dopamine does not have

Substitution of the amide side chain

• Increasing the size (substitution of bulky structures) to

the catecholamine amino group:
– Increases b2 slectivity
– Decreases affinity for a-receptors
– Protects against metabolism by COMT
• i.e. - Norepinephrine (0 methyl substituent)
-Epinephrine (1 methyl substituent)
-Isoproterenol (2 methyl substituents)
-Terbutaline (3 methyl substituents)
• Absence of one or the other substituent particularly at
the 3-position causes marked diminution in potency.
– a effect is decreased about 100-fold and b effect is 5.3 PARASYMPATHETIC DRUGS
negligible (a-selective)
– i.e. Phenylephrine
Cholinergic Agonists (Parasympathomimetic)
• Substitution of hydroxyl groups at the 3- and 5-
positions of the benzene ring imparts b2 slectivity
• Direct acting
– i.e. Terbutaline
– Naturally occurring alkaloids (Muscarine, Arecoline,
Pilocarpine)
Unsubstituted Benzene Ring
– Synthetic alkaloids (Carbachol, Betanechol)
• Indirect-Acting Muscarinic (AChE inhibitors)
• Absence of one or both -OH groups of catecholamines
– Short acting (Edrophonium)
increases oral bioavailability and prolongs duration
– Medium acting (Neostigmine, Physostigmine)
of action because it is not anymore affected by COMT
– Long acting (Organophosphates)
• causes increased CNS effects
• Dual-Acting Nicotinic depolarizing NMB
• i.e. Ephedrine, Amphetamine
• Noncatechiolamines (aka sympathomimetic
Cholinergic Antagonists (Parasympatholytic)
amines) are primarily metabolized by Monoamine
Oxidase (MAO)
• Antimuscarinic- (Belladona alkaloids)
• Antinicotinic- (Nonpolarizing NMB & ganglionic
blockers)
Substitution at the a-carbon
Transcribed by: A. Aquino; C. Bautista
• Substitutions at the a-carbon block oxidation by MAO Edited by: M. Cano; J. Buenaventura
and prolongs duration of action Checked by: P. Alea
• Noncatecholamines that have a substituted a-carbon
have a longer duration of action because they are not
metabolized by MAO nor COMT
• i.e. Ephedrine, Amphetamine
• Some are also indirectly-acting sympathomimetics by
enhanced ability to displace catecholamines from
storage sites of noradrenergic nerves (i.e. Ephedrine)

A. AQUINO; C. BAUTISTA; M. CANO; J. BUENAVENTURA 5

 PHARMACOLOGY
AUTONOMIC PHARMACOLOGY
Dr. Minerva P. Calimag, MD || August 30, 2019

ADRENERGIC AGONISTS (SYMPATHOMIMETIC DRUGS)

Drug Mechanism of Action Indications

Epinephrine ● Direct Acting ● Used in asthma & other allergic

-Alpha diseases
-Beta ● Relaxes airways & reduces
swelling

Phenylephrine ● Alpha 1-Selective ● Used as treatment for rhinitis &

colds as decongestants

Clonidine ● Alpha 2-Selective ● Used for treatment of HPN

Terbutaline ● Beta 2-Selective ● Used as bronchodilator in asthma

● Tocolytic agent in premature labor

Dopexamine ● Dopamine Alpha 1 Agonist ● Used for Hemodynamic support in

● Beta 2 Agonist activity patients with low cardiac output as
in heart failure

Ephedrine ● Acts indirectly on both alpha & beta receptors ● Used a vasopressor
● Causes release of endogenous
catecholamines (i.e. NE)

Pseudoephedrine ● Causes release of NE ● Used as treatment for rhinitis &

colds as decongestant

Amphetamines ● Causes accumulation of NE at the synapses ● No longer used clinically

● Except for the treatment of
narcolepsy & attention deficiency
hyperkinesis

ADRENERGIC ANTAGONISTS (SYMPATHOLYTIC DRUGS)

Drug Mechanism of Action Indications

Reserpine ● Blocks synthesis & storage of NE ● Used in the management of some types of
HPN
● Adverse effect: Sedation

Phenoxybenzamine ● Noncompetitive Alpha Blocker ● Used in the management of malignant HPN

secondary to Pheochromocytoma (small
vascular tumor of the adrenal medulla, causing
irregular secretion of epinephrine and
norepinephrine)

Phentolamine ● Competitive Alpha Blocker ● Used in the management of HPN during

operations for Pheochromocytoma
 PHARMACOLOGY
AUTONOMIC PHARMACOLOGY
Dr. Minerva P. Calimag, MD || August 30, 2019

Prazosin ● Alpha 1-Selective Blocker ● Used in the management of some types of

HPN
● NO reflex tachycardia & postural HPN

Propanolol ● Beta Blocker ● Used in HPN, Angina, Migraine, Headaches,

and mitral valve prolapse

Metaprolol ● Beta 1-Selective Blocker ● Predominant effects are cardiac

Metoclopramide ● Dopamine 2-Selective Blocker ● Used as powerful antiemetic

○ Increases lower esophageal sphincter
pressure
○ Increases rate of gastric emptying

CHOLINERGIC AGONISTS (PARASYMPATHOMIMETIC DRUGS)

Muscarinic Sites

Drug Mechanism of Action Indications

Acetylcholine ● Direct Acting: Muscarinic R ● Used as eye drops in Ophthalmology to

constrict the iris of the eye

Pilocarpine ● Direct Acting: Muscarinic R ● Used as eye drops in Ophthalmology to

constrict the iris of the eye
● Treatment of acute angle closure glaucoma

Betanochol ● Direct Acting: Muscarinic R ● Used for the treatment of GI & bladder atony

CHOLINERGIC AGONISTS (PARASYMPATHOMIMETIC DRUGS)

Nicotinic Sites

Drug Mechanism of Action Indications

Succinylcholine ● Direct Acting: Nicotinic ● Depolarizing NMJ Blocker (Anesthesia, Phase

NMJ Receptors 1)
● Causes continuous
stimulation of Nicotinic
NMJ Receptors
● Fasciculation followed
by flaccid paralysis is a
hallmark

Acetylcholinesterase Inhibitors ● Direct Acting: Nicotinic NMJ Receptors

● Causes inhibition of acetylcholinesterase, thereby increasing acetylcholine that
stimulates nicotinic NMJ Receptors

1. Quaternary Ammonium ● Short-acting reversible ● Used as a diagnostic aid myasthenia gravis

Compounds:
➢ Endrophonium

2. Carbamates: ● Moderately reversible ● Used to reverse nondepolarizing NMJ

➢ Neostigmine Blockers
 PHARMACOLOGY
AUTONOMIC PHARMACOLOGY
Dr. Minerva P. Calimag, MD || August 30, 2019

➢ Physostigmine

3. Organophosphates ● Irreversible ● Used as insecticides

● Organophosphate poisoning: Treat with
anticholinergic drugs

CHOLINERGIC ANTAGONISTS (PARASYMPATHOMIMETIC DRUGS)

Muscarinic Sites

Drug Mechanism of Action Indications

I. Tertiary Tertiary compounds are lipid-soluble and can easily penetrate the brain

Naturally-occuring alkaloids

Atropine ● Direct Acting, ● Used as anticholinergic agent to:

Competitive antagonist at ○ Reduce salivation
M Receptors ○ Increases heart rate
○ Decreases gastric motility
○ Cause mild bronchodilatation
● Treatment of organophosphate poisoning

Scopolamine ● Direct Acting, ● Same as Atropine

Competitive antagonist at ● More central effect
M Receptors ● Adverse effect: Mild Sedation

Synthetic Esters

Dicyclomine ● Direct Acting, ● Same as Atropine

Competitive antagonist at
M Receptors

II. Quaternary Quaternary compounds are water-soluble & do not penetrate the CNS well

Ipratropium ● Direct Acting, ● Used as mild bronchodilator in asthma

Competitive antagonist at therapy
M Receptors

Propantheline ● Direct Acting, ● Used as an antispasmodic by decreasing

Competitive antagonist at gastric motility
M Receptors

Glycopyrrolate ● Direct Acting, ● Used as preoperative medication to reduce

Competitive antagonist at salivation & maintain heart rate during
M Receptors surgery
 PHARMACOLOGY
AUTONOMIC PHARMACOLOGY
Dr. Minerva P. Calimag, MD || August 30, 2019

CHOLINERGIC ANTAGONISTS (PARASYMPATHOMIMETIC DRUGS)

NIcotinic Sites

Drug Mechanism of Action Indications

Nonpolarizing NMJ Blockers: ● Competitively inhibits ● Causes nondepolarizing block of NMJ

● Gallamine acetylcholine at nicotinic NMJ ● Block can be reversed by increasing
● Pancuronium receptor sites the amount of acetylcholine at the NMJ
● Atracurium
● Vecuronium
● Rocuronium