AUTONOMIC NERVOUS

SYSTEM
Karl Gabriel A. Bonifacio
 Organization of
Nervous System - Recall

Central Nervous System Peripheral Nervous System

“Brain and spinal cord”

Autonomic Nervous System Somatic Nervous System

Afferent Division Efferent Division

Sympathetic Parasympathetic
“thoracolumbar” “craniosacral”
ORGANIZATION OF THE ANS
ORGANIZATION OF THE ANS
ORGANIZATION OF THE ANS
ANS Receptors

ADRENERGIC RECEPTORS (ADRENORECEPTORS)

a. Alpha1 Receptors
• are located on vascular smooth muscle of the skin and
splanchnic regions, the gastrointestinal (GI) and bladder
sphincters, and the radial muscle of the iris.
• produce excitation (e.g., contraction or constriction)
• are equally sensitive to norepinephrine and epinephrine.
• Mechanism of action: Gq protein, stimulation of
phospholipase C, and increase in inositol 1,4,5-
triphosphate (IP3) and intracellular [Ca2+].
ANS Receptors

b. Alpha2 Receptors
• usually presynaptic (except in the CNS) and function in a
negative feedback loop → inhibition of subsequent
norepinephrine release
• often produce inhibition (e.g., relaxation or dilation).
• Mechanism of action: Gi protein inhibition of adenylate
cyclase and decrease in cyclic adenosine
monophosphate (cAMP).
ANS Receptors

c. Beta1 Receptors
• are located in the sinoatrial (SA) node, atrioventricular
(AV) node, and ventricular muscle of the heart.
• produce excitation (e.g., increased heart rate, increased
conduction velocity, increased contractility).
• are sensitive to both norepinephrine and epinephrine, and
are more sensitive than the α1 receptors.
• Mechanism of action: Gs protein, stimulation of
adenylate cyclase and increase in cAMP.
ANS Receptors

d. Beta2 Receptors
• are located on vascular smooth muscle of skeletal
muscle, bronchial smooth muscle, and in the walls of the
GI tract and bladder.
• produce relaxation (e.g., dilation of vascular smooth
muscle, dilation of bronchioles, relaxation of the bladder
wall).
• are more sensitive to epinephrine than to
norepinephrine
• are more sensitive to epinephrine than the α1 receptors.
• Mechanism of action: same as for β1 receptors.
ANS Receptors

e. Dopamine (D)
• D1 – vasodilation in the kidney, intestine and heart
• D2 – antiemetic
ANS Receptors
CHOLINERGIC RECEPTORS (CHOLINORECEPTORS)

a. Nicotinic receptors
• are located in the autonomic ganglia (NN) of the sympathetic
and parasympathetic
• nervous systems, at the neuromuscular junction (NM), and in
the adrenal medulla (NN).
• The receptors at these locations are similar, but not identical.
• are activated by ACh or nicotine.
• produce excitation.
• are blocked by ganglionic blockers (e.g., hexamethonium) in the autonomic
ganglia, but not at the neuromuscular junction.
• ■ Mechanism of action: ACh binds to α subunits of the
nicotinic ACh receptor. The nicotinic ACh receptors are also ion
channels for Na+ and K+.
ANS Receptors
• b. Muscarinic receptors
• located in the heart (M2), smooth muscle (M3), and glands
(M3).
• inhibitory in the heart (e.g., decreased heart rate, decreased
conduction velocity in AV node) but excitatory in smooth
muscle and glands (e.g., increased GI motility, increased
secretion).
• activated by ACh and muscarine.
• blocked by atropine.
• Mechanism of action:
• (1) Heart SA node: Gi protein, inhibition of adenylate cyclase,
which leads to opening of K+ channels, slowing of the rate of
spontaneous Phase 4 depolarization, and decreased heart
rate.
• (2) Smooth muscle and glands: Gq protein, stimulation of
phospholipase C, and increase in IP3 and intracellular [Ca2+].
Effects on Organ Systems
DRUGS AND THE ANS
CATECHOLAMINES
- compounds with hydroxyl groups on the 3 and
4 positions on the benzene ring of
phenylethylamine

Endogenous:
Epinephrine
Norepinephrine,
Dopamine
Synthetic:
Isoproterenol
Dobutamine
Epinephrine
• Epinephrine is used intravenously in the treatment of
cardiac arrest, circulatory collapse, and anaphylaxis
• Used locally to limit the spread of local anesthetics or to
reduce blood loss.
• Epinephrine activates all adrenergic receptors: α1, α2, β1,
β2.
• Effect is dose related

Epinephrine
β2 1-2 μg/min
(Adrenalin)
β1 +β2 2-10 μg/min
≥10 μg/min
α1 (bolus: 2-10 μg;
0.5-1.0 mg) - arrest
Epinephrine
• Positive inotropy, chronotropy, and enhanced conduction
in the heart (β1)
• Smooth muscle relaxation in the vasculature and
bronchial tree (β2)
• Vasoconstriction (α1), increasing aortic diastolic pressure
and improving coronary flow
• Endocrine and metabolic effects of epinephrine include
increased levels of glucose, lactate, and free fatty acids.
Norepinephrine
• Neurotransmitter liberated by postganglionic SNS nerves
• Stimulates α1 and β1 receptors
• Vasoconstriction, increase in systolic, diastolic, and mean arterial
blood pressure
• Increased afterload produces baroreceptor-mediated
reflex bradycardia
• Cardiac output may be unchanged or decreased with an
increase in coronary blood flow

Norepinephrine
α1, β1, ≫β2 4-12 μg/min
(Levophed)
Norepinephrine
• Norepinephrine differs structurally from epinephrine: lack
of a methyl group.
• Acts at α- and β-receptors, but it is typically used for its
potent α-agonism.
• “Pressor of last resort” in supporting systemic vascular
resistance.
• Short half-life of 2.5 minutes

Norepinephrine
α1, β1, ≫β2 4-12 μg/min
(Levophed)
Dopamine
• Immediate precursor of norepinephrine and
epinephrine
• Low doses (<0.5-2 μg/kg/min IV):
• DA1 receptors are stimulated, and renal and mesenteric
vascular beds dilate, glomerular filtration rate and sodium
excretion increase
High doses
• 2-10 μg/kg/min IV: (+) inotropic effect without marked
changes in heart rate and systemic blood pressure, release
of norepinephrine
• 10->20 μg/kg/min IV : α- and β1-receptors are stimulated,
the α-adrenergic vasoconstrictive effect predominates
NONCATECHOLAMINE
SYMPATHOMIMETIC AMINES
- synthetic drugs obtained by dehydroxylation of hydroxyl group
at position 3 and 4 of the benzene ring
- direct effect at receptor sites
- indirect effect by releasing endogenous norepinephrine
Ephedrine
Phenylephrine
Clonidine
EPHEDRINE
• An indirect acting sympathomimetic with α and β-
adrenergic agonist activity
• increases blood pressure and has a positive
inotropic effect
• Effects:
• As a result of its β1-adrenergic–stimulating effects,
ephedrine is helpful in treating moderate hypotension,
particularly if accompanied by bradycardia.
• Some β2 agonist activity
• Side effects:
• Tachyphylaxis
• Cardiac dysrythmias
PHENYLEPHRINE
• selective α1-agonists; commonly used when peripheral
vasoconstriction is needed and cardiac output is adequate
• e.g. hypotension that may accompany spinal anesthesia,
CAD or aortic stenosis to increase coronary perfusion
pressure without chronotropic side effects
• Also used as mydriatic and nasal decongestant
• Increases venous constrictions more than arterial
constrictions
• rapid onset and relatively short duration of action (5 to 10
minutes)
CLONIDINE
• Primarily sympatholytic
• selective partial agonist for α2-adrenoreceptors, with a
ratio of approximately 200 : 1 (α2 to α1); reducing
peripheral norepinephrine
• reduces activity in peripheral sympathetic neurons without
affecting baroreceptor reflexes
• Withdrawal: Hypertensive crisis (tx: Labetalol)
• Traditionally, used as an antihypertensive, but
applications based on their sedative, anxiolytic, and
analgesic properties are being developed.
Dobutamine
• A synthetic analog of dopamine
• Predominantly β1-adrenergic effect
• At clinical doses it can act at β2- and α1-receptors.
• Particularly useful in CHF and MI complicated by a
low-output state
• In cases of severe hypotension, it may not be
effective because it lacks a significant α1-pressor
effect.
• Adverse effect: tachycardia
• Because dobutamine directly stimulates β1-
receptors, it does not rely on norepinephrine stores
and may still be effective in catecholamine-depleted
states
Isoproterenol
• relatively pure nonselective β-adrenergic stimulation
with no significant effect at α-receptors
• β1-adrenergic stimulation is significantly stronger
than its β2 stimulation, but it still causes more β2-
adrenergic activity than dobutamine does
• Since the development of other inotropes, its
popularity has declined because of its adverse
effects of tachycardia and arrhythmias.
• Currently used as a chronotropic agent in
denervated hearts post-transplantation
Beta 2 selective agonists
• β2-selectivity is only relative, may be lost at higher
doses
• β2-receptors in the sinoatrial node may cause
tachycardia when stimulated
• aerosolized and given by inhaler for rapid onset and
to minimize systemic drug levels and adverse
effects.
• Adverse effect: Susceptibility to arrhythmia by direct
cardiac stimulation or by β2-induced hypokalemia
• Commonly used drugs include metaproterenol
(Alupent, Metaprel), terbutaline (Brethine, Bricanyl),
and albuterol (Proventil, Ventolin).
Beta antagonists
• Current indications for the use of β-blockade include
ischemic heart disease, postinfarction management,
arrhythmias, hypertrophic cardiomyopathy,
hypertension, heart failure, and prophylaxis for
migraine headache.

• Nonselective β-adrenergic blockers act at the β1-

and β2-receptors
• Cardioselective β-blockers have stronger affinity for
β1-adrenergic receptors than for β2-adrenergic
receptors, and the predominant effects are therefore
cardiac.
Beta antagonists
• With β1-selective blockade, AV conduction velocity,
heart rate, and cardiac contractility are decreased,
as is release of renin by the juxtaglomerular
apparatus and lipolysis at adipocytes.

• Some β-antagonists also have vasodilatory effects,

thus making them particularly useful in the treatment
of hypertension and CHF.
Beta antagonists
ANTICHOLINERGIC
- prevent the muscarinic effect of acetylcholine
by competing for the same receptors

Atropine
Scopolamine
Glycopyrrolate
Atropine
• Most efficacious anticholinergic for treating bradycardic
arrythmias
• Has potent effect on the heart and bronchial smooth
muscles
• Associated with mild postoperative memory deficits
• Minimal CNS effects after usual dose
Cholinergic Agonists
• Cholinergic agonists have limited therapeutic use
because of their detrimental effects. As a result of its
diffuse, nonselective actions and rapid hydrolysis by
acetylcholinesterase and butyrylcholinesterase,
acetylcholine has had almost no therapeutic use other
than as an intraocular medication for transient constriction
of the pupil during ophthalmic surgery.
Cholinergic Agonists
• The different systemic effects of the cholinergic agonists
are more quantitative than qualitative, but some limited
organ selectivity is useful therapeutically, as seen with the
synthetic choline esters bethanechol and carbachol.
Methacholine and bethanechol are primarily muscarinic
agonists; carbachol has significant nicotinic and
muscarinic effects.
Cholinergic Agonists
• The different systemic effects of the cholinergic agonists
are more quantitative than qualitative, but some limited
organ selectivity is useful therapeutically, as seen with the
synthetic choline esters bethanechol and carbachol.
Methacholine and bethanechol are primarily muscarinic
agonists; carbachol has significant nicotinic and
muscarinic effects.
Cholinergic Agonists
• The sole current use of methacholine (Provocholine) is as
a provocative agent in diagnosing hyperreactive airways,
thereby making positive use of the deleterious
bronchoconstrictive effect of muscarinic agonists.

• The carbamate derivative of methacholine, bethanecol

(Urecholine), is occasionally used postoperatively to
reinstitute peristaltic activity in the gut or to force the
extrusion of urine from an atonic bladder.

• Carbachol is used topically or intraocularly to constrict the

pupil for the long-term treatment of wide-angle glaucoma.
Synthetic drugs and its Receptor
Receptor Agonist Antagonist
Alpha1 Phenylephrine Prazosin
Phentolamine
Labetalol
Alpha2 Clonidine Yohimbine
Dexmedetomidine Phentolamine
Beta1 Dobutamine Metoprolol
Dopamine Esmolol
Isoproterenol Propanolol
Timolol
Labetalol
Beta2 Albuterol Propanolol
Ritodrine Timolol
Labetalol
Synthetic drugs and its Receptor

Receptor Agonist Antagonist

Dopamine1 Fenoldopam Droperidol
Dopamine2 Dopamine Domperidone
Muscarinic Metacholine Atropine
Carbachol Scopolamine
Glycopyrrolate
Nicotinic Succinylcholine Nondepolarizing
muscle relaxants
THE END