Lecture Outline
• Homeostasis
• Divisions of the ANS
• Cellular Organization of the ANS
• Pathways of the ANS
• Pharmacology of Autonomic Function
• Clinical Correlations
3
Autonomic Nervous System (ANS)
• Involuntary or visceral nervous system
• Regulates the activity of:
– Cardiac Muscle (Heart)
– Smooth Muscle ( In Hollow Organs)
•
•
•
•
Blood Vessels
Digestive System
Bronchioles
Sphincters
– Glands
• Adrenal
• Digestive glands
Negative Feedback Control System
Sensor
Comparator
Set point
+
Effector
-
Controlled variable
Sensory Input
Autonomic Control Centers
Autonomic Outflow-Sympathetic and Parasympathetic
Divisions dual innervation of viscera-
Cellular Organization
• Somatic
efferents
•
ACh
•
•
• Sympathetic efferents
•
ACh
•
nAChR
•
• Parasympathetic efferents
nAChR
NA
Alpha/beta R
ACh
ACh
nAChR
CNS
PNS
mAChR(M1-5)
Cellular Organization
• First Order Neurons
ACh
ACh
ACh
CNS
PNS
• Cell bodies in CNS
• Axons in PNS
• Myelinated
• Cholinergic
Cellular Organization
• Second Order Neurons of ANS Divisions
• Cell bodies in ganglia
• Nicotinic ACh receptors
• Axons in PNS
• Unmyelinated
NA
nAChR
• Sympathetic: adrenergic
• Parasympathetic: cholinergic
ACh
nAChR
CNS
PNS
Cellular Organization
• Target Cells and Receptors
• Somatic efferents: Striated muscle
• Nicotinic ACh receptors
• Autonomic efferents:
• Smooth muscle
• Cardiac muscle
• Glands
• Receptors:
• Sympathetic innervation:
Adrenergic receptors
• Parasympathetic innervation:
Muscarinic ACh receptors
Sympathetic Pathways
Sympathetic Pathways
Paravertebral ganglia
Eye
Salivary glands
Bronchial tree
Heart
Cervical
Liver
Thoracic
Lumbar
GI tract
Sacral
Adrenal medulla
Urinary bladder
Prevertebral
ganglia
Sex organs
Sympathetic Pathways
Paravertebral ganglia
Eye
Salivary glands
Bronchial tree
Heart
Cervical
Liver
Thoracic
Lumbar
GI tract
Sacral
Adrenal medulla
Urinary bladder
Prevertebral
ganglia
Sex organs
Sympathetic Pathways
Paravertebral ganglia
Eye
Salivary glands
Bronchial tree
Heart
Cervical
Liver
Thoracic
Lumbar
GI tract
Sacral
Adrenal medulla
Urinary bladder
Prevertebral
ganglia
Sex organs
Table below gives you an overview of the CNS origin, the paravertebral or
prevertebral ganglia involved, and the targets of sympathetic efferents:
Adrenergic Receptors
Responsiveness-
ISO>A>NA
NA>A>ISO
a1
a2
b1
↑IP3 /DAG
↓ cAMP
↑cAMP
↑Ca2+
↑ I K+
↓ I Ca2+
↑ PKA
↑ PKC
* ISO - isoproterenol
NA>A
b2
↑cAMP
↑ PKA
b3
↑cAMP
↑ PKA
Physiological effects of Adrenergic Receptor activation
RECEPTOR SUBTYPE
TISSUE
EFFECTS
α1
Vascular smooth muscle
Contraction
Genitourinary smooth muscle
Intestinal smooth muscle
Heart
Liver
Contraction
Relaxation
↑ Inotropy and excitability
Glycogenolysis and
gluconeogenesis
α2
Pancreatic β-cells
Platelets
Nerve (pre-synaptic)
Vascular smooth muscle
↓ Insulin secretion
Aggregation
↓ Norepinephrine release
Contraction
β1
Heart
Heart
Renal juxtaglomerular cells
↑ Chronotropy and inotropy
↑ AV-node conduction velocity
↑ Renin secretion
β2
Smooth muscle
Liver
Relaxation
Glycogenolysis and
gluconeogenesis
Glycogenolysis and K+ uptake
Vasculature*
Skeletal muscle
β3
Adipose
Lipolysis
The overall effect of the catecholamines is to increase glucose production
Parasympathetic Pathways
CN III
CN VII
CN IX
CN X
Cervical
Thoracic
Lumbar
Sacral
Eye
Salivary glands
Bronchial tree
Distinct
parasympathetic
ganglia
Terminal parasympathetic
ganglia embedded
in organ walls
Heart
Liver
GI tract
Adrenal medulla
Urinary bladder
Sex organs
Distinct Parasympathetic Ganglia
Pterygopalatine
ganglion
Otic ganglion
Submandibular
ganglion
Picture: copyrighted material, with permission
Ciliary ganglion
Parasympathetic Pathways
CN III
CN VII
CN IX
CN X
Cervical
Thoracic
Lumbar
Sacral
Eye
Salivary glands
Bronchial tree
Distinct
parasympathetic
ganglia
Terminal parasympathetic
ganglia embedded
in organ walls
Heart
Liver
GI tract
Adrenal medulla
Urinary bladder
Sex organs
Parasympathetic Pathways
CN III
CN VII
CN IX
CN X
Cervical
Thoracic
Lumbar
Sacral
Eye
Salivary glands
Bronchial tree
Distinct
parasympathetic
ganglia
Terminal parasympathetic
ganglia embedded
in organ walls
Heart
Liver
GI tract
Adrenal medulla
Urinary bladder
Sex organs
CNS origin, either distinct parasympathetic ganglia or terminal
ganglia, and their target organs are presented in the table below:
The nerve fibers that innervate the adrenal medulla are
best described as
•Adrenergic sympathetic
•Cholinergic sympathetic
•Adrenergic parasympathetic
Cholinergic parasympathetic
Which of the following is caused by activity in th
sympathetic system?
•Decreased heart rate
•Cutaneous vasoconstriction
•Increased gastric secretion
•Constriction of the pupil
•Erection of the penis
Sweat glands are innervated by
•Parasympathetic cholinergic postganglionic fibers
•Sympathetic cholinergic postganglionic fibers
•Sympathetic adrenergic postganglionic fibers
•Parasympathetic cholinergic preganglionic fibers
Sympathetic cholinergic preganglionic fibers
The high ratio of postganglionic to preganglionic fibers in
the sympathetic system has the physiologic result that
•Convergence of stimuli occurs
•Synaptic transmission is slow, leading to a delay in
response
•Stimulation of the sympathetic nervous system leads to
widespread effects
•Stimulation of the sympathetic nervous system leads to
very localized, discrete effects
•Sympathetic effects are very weak
You administer a muscarinic blocker to your patient. This drug is
most effective at blocking
•The somatic neuromuscular junction
•The parasympathetic ganglia
•The sympathetic ganglia
•The parasympathetic neuroeffector junction
The sympathetic neuroeffector junction
Physiological effects of Muscarinic Receptor activation
Muscarinic Receptors
M1
CNS.
Autonomic
Ganglia.
Parietal
Cell
M2
Cardiac;
SA & AV
node.
Autonomic
Ganglia.
M3
Smooth
Muscle contraction.
GI Glands Secrn
Bronchial Secrn
Sweat
Vasodilation*.
M4
CNS.
M5
CNS.
Overview
CNS origin
Preganglionic fiber
Receptor on
postganglionic
Postganglionic fiber
Divergence
Receptor on target
Sympathetic
Parasympathetic





thoraco-lumbar
short
myelinated
cholinergic
nicotinic





cranio-sacral
long
myelinated
cholinergic
nicotinic





long
unmyelinated
noradrenergic (*)
high
adrenergic (*)





short
unmyelinated
cholinergic
low
muscarinic
(*) Sympathetic innervation of sweat glands: cholinergic (!) postganglionic
fibers and muscarinic (!) acetylcholine receptors
Responses of Effector Organs
to Autonomic Nerve Impulses
• Autonomic Control of the Pupil
Adrenergic
Impulses
Effector Organs Rec. Responses
type
Dilator muscle
of pupil
Constrictor muscle
of pupil
α1
M
Cholinergic
Impulses
Responses
Contraction
(mydriasis)
Contraction
(miosis)
Horner’s Syndrome
Unilateral miosis (small pupil), commonly associated with ptosis
(drooping of the upper eyelid) and facial anhydrosis (loss of
sweating).
Horner's syndrome is due to underactivity of the ipsilateral
sympathetic outflow, which can be caused by
(1) central lesions that involve the hypothalamospinal
pathway (transection of the cervical spinal cord),
(2) preganglionic lesions
(compression of the sympathetic chain by a lung tumor), (3)
postganglionic lesions at the level of the internal carotid artery
(tumor in the cavernous sinus).
Responses of Effector Organs
to Autonomic Nerve Impulses
• Autonomic Control of Accommodation
Adrenergic
Impulses
Effector Organs Rec. Responses
type
Ciliary muscle
Cholinergic
Impulses
Responses
Contraction
Relaxation (β2) (near vision)
35
Responses of Effector Organs
to Autonomic Nerve Impulses
• Autonomic Control of Cardiac Function
Adrenergic
Impulses
Effector Organs Rec. Responses
type
Cholinergic
Impulses
Responses
SA Node
β1
β2
Increase
in heart rate
Decrease
in heart rate(M2)
Atria, Ventricles
β1
β2
Increase in
contractility
Decrease in
Contractility(M2)
36
Responses of Effector Organs
to Autonomic Nerve Impulses
• Autonomic Control of the Airways
Adrenergic
Impulses
Effector Organs Rec. Responses
type
Tracheal and
bronchial muscles
β2
Relaxation
Cholinergic
Impulses
Responses
Contraction
37
Responses of Effector Organs
to Autonomic Nerve Impulses
• Autonomic Control of the Urinary Bladder
Adrenergic
Impulses
Effector Organs Rec. Responses
type
Cholinergic
Impulses
Responses
Detrusor muscle
β2
Relaxation
Contraction
Trigone and
sphincter muscle
α1
Contraction
Relaxation
38
Autonomic Control
of Reproductive
Organs
Pharmacological Influence on
Autonomic Function
Drug
Receptor
Function
Medical use
Atenolol
b1 adrenergic Antagonist Hypertension
Salbutamol b2 adrenergic Agonist
Atropine
muscarinic
Asthma
(bronchodilator)
Antagonist Mydriatic;
Reduction of drooling
in Parkinson’s
disease
41
Physiological effects of Muscarinic Receptor activation
Muscarinic Receptors
M1
CNS.
Autonomic
Ganglia.
Parietal
Cell
M2
Cardiac;
SA & AV
node.
Autonomic
Ganglia.
M3
Smooth
Muscle contraction.
GI Glands Secrn
Bronchial Secrn
Sweat
Vasodilation*.
M4
CNS.
M5
CNS.
A middle aged woman was carried to the district hospital in Murewa in a
semiconscious state. Her husband reported that when he returned home from
work he had found his 45 year old wife, Sibongile lying on the bed moaning,
unable to move and barely conscious. On the bed there was vomitus and a wet
patch. He said that when he had left in the morning she had been well but he had
noticed that since the day before she seemed to have been upset about
something and had barely talked to him; but he couldn’t think of a reason why.
Asked if his wife took any medications, he said no. But then his neighbour who had
accompanied him said that he had noticed there was a “Ketokil” tin in the bedroom
and there was an empty cup near it. He explained that Ketokil was the stuff they
used to kill weeds.
On examination, the physician noted that the patient had labored respiration (8
breaths per minute) and that she seemed to be drooling. Her pulse rate was 45
bpm. Auscultation of the thorax revealed rhonchi and auscultation of the abdomen
showed increased abdominal sounds. Meanwhile the hospital pharmacist reported
that the active ingredient of Ketokil was parathion.
1. What symptoms do you expect following intoxication with organophosphates?
2. How do you explain these symptoms from a biochemical-physiological view point?
3. What kind of therapeutic intervention do you suggest? Justify your ideas.
•Parasympathetic Vasodilation:
•Endothelium Derived Relaxing Factor; NO(nitric oxide)
ACh activates Muscarinic (M3) rec. to initiate NO production via eNOS.
NO freely diffusable and produces smooth muscle relaxation / vasodilation.
Muscarinic Receptor Agonists
Which clinical conditions would they benefit?
Muscarinic agonists
Eye:
Contract circular
muscle
Miosis
Benefits glaucoma
GIT
Bladder,
urinary tract
Contract smooth
muscle
Outflow of aqueous
humor
↓ intraocular pressure
↑ Motility
Restore GIT and UT motility after
anesthesia/surgery
Salivary
glands
↑ Salivation
Benefits xerostomia
Muscarinic Receptor Agonists - Parasympathomimetics
Acetylcholine is NOT used clinically – very short t1/2
Methacholine
Carbachol
Bethanechol
Pilocarpine
Methacholine:
Derivatives
of ACh
Differ in pharmacokinetic
properties, resistance to
ChEsterase and their affinity to
both Nm and Muscarinic rec.
used in diagnosis of asthma
Asthmatics are more sensitive to the
bronchial secreting actions of methacholine
Carbachol:
affinity for Nm rec
resistant to ChE
used topically – as a miotic agent to
treat glaucoma
Bethanechol:
Uses:
Selective for Muscarinic receptors
to ↑ GIT and urinary tract motility
Pilocarpine:
Uses
topically as a miotic in glaucoma
as a sialogogue to ↑ saliva secretion
Muscarinic Receptor Antagonists “Parasympatholytics”
Mode of Action
Bind to muscarinic receptors and prevent Ach from
exerting its effects
Competitive antagonists
Prototype:
Actions:
ATROPINE
(Plant alkaloid from Atropa belladonna)
Pupil dilation
Tachycardia
↓ secretions (salivary,
bronchial, GIT)
Clinical Uses of Atropine:
1. To produce mydriasis for ophthalmological
examination (applied topically)
2. To reverse sinus bradycardia caused by excessive
vagal tone
3. To inhibit excessive salivation and mucus secretion
during anesthesia and surgery
4. To counteract the effects of muscarine poisoning
AND poisoning with anticholinesterases
Physiological effects of Adrenergic Receptor activation
RECEPTOR SUBTYPE
TISSUE
EFFECTS
α1
Vascular smooth muscle
Contraction
Genitourinary smooth muscle
Intestinal smooth muscle
Heart
Liver
Contraction
Relaxation
↑ Inotropy and excitability
Glycogenolysis and
gluconeogenesis
α2
Pancreatic β-cells
Platelets
Nerve (pre-synaptic)
Vascular smooth muscle
↓ Insulin secretion
Aggregation
↓ Norepinephrine release
Contraction
β1
Heart
Heart
Renal juxtaglomerular cells
↑ Chronotropy and inotropy
↑ AV-node conduction velocity
↑ Renin secretion
β2
Smooth muscle
Liver
Relaxation
Glycogenolysis and
gluconeogenesis
Glycogenolysis and K+ uptake
Vasculature*
Skeletal muscle
β3
Adipose
Lipolysis
Epinephrine & Norepinephrine
Affinities for a and b adrenoceptors
Epinephrine;higher affinity for b adrenoceptors has a predominant ‘b’ effect.
At higher concentrations it has an effect on a1 adrenoceptors.
At high doses effective at treating anaphylaxis and used for
vasoconstriction in cojunction with local anaesthetic.
Norepinephrine:
Has affinity for a1 and b1 adrenoceptors. Little affinity for b2
adrenoceptors.
a1 Adrenergic receptor agonists & antagonists: Clinical Uses
Major physiological response following a1 receptor activation is increased
peripheral resistance & genitourinary smooth muscle contraction.
a1 Agonists
Methoxamine:
Limited use except for hypotension from circulatory shock.
Side effects: Reflex vagal sinus bradycardia
Phenylephrine:
Used as nasal decongestant. Side efffects: Hypertension
a1 Antagonists
Prazosin: Used for treatment of hypertension and Benign Prostatic Hypertrophy
Side effects: Postural orthostatic/ hypotension related to 1st dose phenomena.
Tamsulosin: Used for Benign Prostatic Hypertension. More selective for
genitourinary smooth muscle receptor subtype (a1A).
Less postural / orthostatic hypotension
a2 Adrenergic receptor agonists & antagonists: Clinical Uses
Major physiological response following a2 rec. activation is reduced NE release
a2 Agonists
Clonidine: Used for treatment of hypertension (decreased peripheral sympathetic
outflow) and opioid withdrawal.
Side Effects: Bradycardia & hypotension.
a2 Antagonists
Yohimbine: Previously used for male impotence.
Side Effects: bradycardia and hypertension
Non Selective b Adrenergic Receptor Agonists: Clinical Uses
Stimulation of β1-adrenergic receptors causes an increase in heart rate and the
force of contraction, resulting in increased cardiac output.
Stimulation of β2-adrenergic receptors causes relaxation of vascular, bronchial,
and gastrointestinal smooth muscle.
Non selective b receptor agonists:
Isoproterenol: Emergency arrhythmias & bronchospasm. More selective
agonists now available.
Side effects: Hypertension, palpitations, tremor
Selective b1 receptor agonists:
Dobutamine: Has prominent inotropic effects resulting in increased contractility
and cardiac output. Short half life due to COMT metabolism. Used in the
ACUTE management of heart failure.
Selective b2 receptor agonists
Used for treatment of Asthma. Pulmonary drug delivery enhances selectivity
of β2-adrenoceptors agonists, avoids cardiac (b1) and skeletal (b2) side
effects.
Albuterol: Used as ‘asthma reliever’. Rapid action (15 min) relative short
duration (4-6 hours).
Salmeterol: Long-acting beta agonists (LABA’s). Have lipophilic side chains
that resist degradation. Enhance duration (12-24-hours), used for
prevention of bronchoconstriction.
β-Adrenergic Antagonists: Clinical Uses
Most significant effect these compounds have to reduce the chronotropic and
inotropic actions of endogenous catecholamines at cardiac β1-receptors,
resulting in decreased heart rate and myocardial contractility. Blockade of b1
receptors in kidney to reduce renin secretion also clinically relevant in
reducing fluid overload and vasomotor tone. Are first line drugs used in
treatment of hypertension. Blockade of b2 receptors is clinically undesirable.
Non-selctive b adrenoceptor antagonists
Propranolol: Clinically used for Hypertension, angina. Side effects include
sedation (central effect) and dyspnoea.
Timolol: As an ocular formulation used in the treatment of glaucoma. MOA
unknown but thought to be through reduced production of aqueous humor.
β1-Selective Adrenergic Antagonists: Clinical Uses
Esmolol Clinically used in emergency b receptor blockade as in a
thyroid storm (Half-life ~ 4 minutes).
Atenolol: Clinically used in treatment of hypertension and angina,
improves life expectancy in patients with HF#.
Side Effects: Similar to Propanolol but much less severe.
# Clinical
benefit in HF through volume reduction (↓afterload) via ↓ renin
production. Contraindicated in severe HF
Partial b1 Agonists: Clinical Uses*
As a partial agonist they are effective at reducing the effect of endogenous NE
at b1 receptors. This leads to smaller decreases in resting heart rate & blood
pressure (compared to b1 receptor antagonists).
Acebutolol Clinically used for treatment of hypertension in patients with
bradycardia or low cardiac reserve.
* Partial agonists are effectively weak ‘antagonists’
Catecholamine Metabolism: MAO & COMT
Mono Amine Oxidase (MAO): Mitochondrial enzyme.
Isoforms; MAO A & MAO B
MAO A: Serotonin > NE > Dopamine & tyramine
MAO B: Dopamine > serotonin>NE
Catechol-O-methyl transferase (COMT):
Cytosolic enzyme expressed primarily in liver
Drugs Affecting Storage Reuptake & Storage
Inhibitors of Re-Uptake:
Cocaine: Inhibits NET.
Tricyclic Antidepressants (TCA’s) inhibit NET.
Imipramine: Used for treating mild depression.
Side effects Postural hypotension & tachycardia
Inhibitors of Storage:
Reserpine blocks VMAT
Tyramine transported via VMAT & displaces vesicular
NE.
Inhibitors of Metabolism:
MAO Inhibitors used for treatment of
mild depression. Phenelzine: Non
selective MAO Inhibitor. Implicated in
elevated tyramine leading to
hypertensive crisis Selegiline:
Selective MAO B Inhibitor. Safer with
respect to dietary restriction also
useful for Parkinson’s
Inhibitors of Re-uptake and Storage
Amphetamines
(i) Displaces endogenous
catecholamines from storage vesicles
(ii) blocks NET
(iii) a weak inhibitor of MAO
Methylphenidate: Used for ADHD
Pseudoephidrine: Used for nasal
decongestion