Sympathetic Nervous System

Dr. Roland van Rensburg

 Autonomic Nervous System
• Conveys all outputs from the CNS to the rest
of the body, except for motor innervation of
skeletal muscles.
• Largely involuntary
 Terminology
• Sympathetic
• Noradrenergic
• Adrenergic

• Catecholamine
Noradrenaline
• Monoamine Adrenaline

• Adrenoceptors
 ANS: Overview

Alpha (α)
Noradrenaline
Sympathetic
(NA)
Beta (β)

ANS

Nicotinic (Nic)
Acetylcholine
Parasympathetic
(Ach)
Muscarinic
(Mus)
 ANS: Functions
1. Contraction & relaxation of vascular and
visceral smooth muscle
2. All exocrine & certain endocrine secretions
3. Heartbeat
4. Energy metabolism, esp. liver & skeletal
muscle
ANS: Receptors - Sympathetic
• Sympathetic system = adrenergic system
= adrenoreceptors
• Main transmitter
– Noradrenaline (NA)
– Norepiniphrine [American]
 Adrenoreceptors

• G protein-coupled receptors
Adrenoceptors • Activate secondary messenger
systems

α β

α1 α2 β1 β2 β3
 α1

• Postsynaptic 1. Constrict/Contract

a. Blood c. GIT f. Seminal g. Iris (radial

b. Bronchi tract
vessels sphincters muscle)
=dilatation
d. Uterus e. Bladder =mydriasis
i. Viscera ii. Skin (pregnant) sphincter
iii. Brain iv. Coronary

v. Erectile tissue
2. Relax 3. Glycogenolysis 4. ↑ 5. Ejaculation 6. Piloerection
secretions

GIT Liver Salivary glands Male Hair (skin)

smooth
muscle
 α2
• Pre- & postsynaptic

Presynaptic Postsynaptic

Inhibits NA & Ach release Blood vessel constriction

GIT relaxation

↓ Insulin secretion

Platelet aggregation
 β1

Heart Kidney Salivary glands

↑ Rate (Chronotropy) Renin secretion Amylase secretion

↑ Contraction (Inotropy)
 β2

Dilate Relax Increase Other

Bronchi (no symp. GIT motility (but ↑ Rate Tremor

innervation – just increases (Chronotropy)
receptors) sphincter tone)
Muscle arterioles Bladder detrusor ↑ Contraction Glycogenolysis
(Inotropy) (liver)
Veins Uterus (non- ↑ Presynaptic NA
pregnant) release
Seminal tract
 β3
• Lipolysis
• Thermogenesis
• Relaxes bladder detrusor
– New avenue
 Metabolism
• Action of NA terminated mainly by reuptake &
intracellular breakdown
• Slow degradation vs. ACh
• Reuptake
– Norepinephrine transporter (NET) – 75%
– Extraneuronal monoamine transporter (EMT) –
25%
• Intracellular breakdown
– Monoamine oxidase (MOA)
• Noradrenergic nerve terminals
• Other tissues
– Catechol-O-methyl transferase (COMT)
• Not in noradrenergic nerve terminals
• Adrenal medulla & other tissues
• Major degradation product (=metabolite) of
MOA & COMT is vanillylmandelic acid (VMA)
– Excreted in urine
– ↑↑ in pheochromocytoma
• Tumour of chromaffin cells of adrenal medulla that
overproduce catecholamines
 Sympathomimetics
• Drugs that stimulate adrenoceptors
– Agonists
– NA & Adrenaline endogenous
 Adrenaline
Endogenous
Noradrenaline

Direct acting
α-agonists

Exogenous
β-agonists
Adrenergic
drugs
Releasers α/β-agonists

Reuptake
Indirect acting
inhibitors

MAO-
inhibitors
 Direct acting - Exogenous
α β α/β
• α1 • β1 • Adrenaline
• Phenylephrine • Dobutamine • Low doses = β agonist
• Nasal decongestant • Cardiogenic shock • Higher doses = α
• HT, reflex • Dysrhythmias agonist as well
bradycardia • β2 • Cardiac arrest,
• Salbutamol anaphylaxis
• α2
• Fenoterol • HT, tachycardia,
• Clonidine dysrhythmias
• Partial agonist • Asthma
• HT, migraine, hot • Tachycardia, tremor
flushes • β3
• Drowsiness, • Mirabegron
hypotension • Overactive bladder
• Tachycardia
 Indirect acting
• Releasers
– Structurally similar to NA
– Transported into nerve terminals by NET  displaces
NA in vesicles  NA releases via NET in exchange for
drug ligand
• Reuptake inhibitors
– Inhibits NET to ↑ NA concentration
– Also inhibits EMT
• MAO-inhibitors
– Inhibits enzyme that degrades NA
 Indirect acting
Releasers Reuptake inhibitors MAO-inhibitors
• Amphetamine • Cocaine • Moclobemide
• Drug of abuse • Drug of abuse/ • Reversible
• HT, tachycardia, • Local anaesthetic/ • Tranylcypromine
insomnia • Vasoconstrictor Irreversible
• Euphoria, HT, • Depression
• Methyphenidate/ tachycardia, septum • Restlessness,
• Atomoxetine erosion anticholinergic effects
• ADHD
• Insomnia, tachycardia • Tricyclic antidepressants
• e.g. Imipramine,
• Ephedrine amytriptyline
• Nasal decongestant • Depression/Eneuresis
• As amphetamine, but • Tachycardia,
less pronounced dysrhythmias,
anticholinergic effects
 Sympatholytics
• Drugs that block adrenoceptors
– Antagonists
– “Blockers”
 α1-blockers
Prazocin/Doxazocin Tamsulosin
Specificity α1-blockers α1A-blockers (more bladder
specific)
Uses HT, Urinary retention in Urinary retention in BPH
BPH
S/E Postural hypotension, Ejaculatory failure
tachycardia
 β-blockers
Non-selective β1-selective α/β non-selective

Examples Propranolol Timolol Atenolol Labetalol Carvedilol

(α non- (α1-
specific) specificity)
Uses Myocardial Open angle As for Hypertensive Heart failure
infarction, glaucoma propranolol emergency
heart failure, (eye drops)
tremor,
thyrotoxicosis
, migraine
prophylaxis
S/E Bronchoconst Irritation, dry As for Postural As for
riction, CCF, eyes, blurry propranolol, hypotension, propranolol
bradycardia, vision but slightly bronchoconst
cold less risk for riction
extremities, bronchoconst
hypoglycaemi riction
a
 β-blocker contraindications
• Asthma or severe obstructive pulmonary
disease (COPD/asbestosis)
• Decompensated heart failure
• 2° or 3 ° heart block
• Sinus bradycardia
• Pregnancy
• Hypoglycaemia
 Basic physiology
• Blood Pressure (BP) = Cardiac output (CO) x Peripheral
Vascular Resistance (PVR)

• CO = Stroke volume x Heart rate

• Stroke volume = Preload + Contractility + Afterload

= End diastolic volume – End systolic
volume

– Preload – Stretching of heart muscles (Starling’s Law)

– Contractility – Extrinsic factors (sympathetic, drugs)
– Afterload – Pressure against which heart must pump
• Supply vs. demand
 Practical application
• Angina pectoris
• Stable angina  demand > supply
• Unstable angina  supply < demand

• β-blockers decrease demand and possible

dysrhythmias
• Same mechanism responsible for its use after
myocardial infarction
• Parkinson’s Disease
– Resting tremor (pill-roll tremor), rigidity, bradykinesia, and postural
instability.
– Dopamine depletion from the basal ganglia

– Drugs used cause ↑ in CNS dopamine

• Dopamine precursors (levodopa)
• Dopamine agonists (pramipexole)
• Antivirals (amantadine)
• MAO-inhibitors (rasagiline)
• COMT-inhibitors (entacapone)

– Levodopa must be combined with peripheral dopa decarboxylase

inhibitor
 Co-transmission
• Most nerve terminals release more than one
neurotransmitter
• NA (intermediate response) is frequently released
together with:
– ATP
• Fast response
• Fast depolarisation/contraction of smooth muscle
– Neuropeptide Y
• Slow response
• Potentiates NA constrictor function in blood vessels