BMED 2801 Lecture 24: Sympathetic Nervous System
Recommended to read textbook chapters  what lectures are based on
Learning objectives:
 Understand the role of the sympathetic nervous system (SNS) in health and disease
 Identify the transmitters and corresponding receptors involved (noradrenaline and adrenaline)
 What adrenoreceptors are involved, where they are found and what responses they mediate within
the body
 How we can modify the functions of the adrenoreceptors and other aspects of the SNS with drugs
The sympathetic nervous system is activated under conditions of stress and during exercise.
Both the PNS and SNS work homeostatically in conjunction all the time – the level of activity in each system
differs with environment and circumstances.
SNS Transmitters
Noradrenaline (NA – norepinephrine) and adrenalin (Adr – epinephrine) act on α- and β- adrenoreceptors
Preganglionic neurons are cholinergic,
releasing aceylcholine (ACh) as the
transmitter. Ganglionic transmission
occurs via nicotinic ACh receptors
The SNS involves autonomic ganglia, which also have nicotinic receptors for ACh (same as parasympathetic).
It is post-synaptically that you see differences:
 In at least 90% of cases, activation by noradrenaline mainly (and some adrenaline) is of
adrenoreceptors on target tissue, not muscarinic receptors as seen in the parasympathetic nervous
system.
 In 5-10% of cases, there is cholinergic receptor activation post-synaptically (in the target tissue of the
SNS, muscarinic receptors are being activated by the release of ACh).
Adrenoreceptors (adrenergic-receptors)
They are all G-protein coupled receptors:
2 types of α-adrenoreceptors – α1 and α2
α1 activate phospholipase C  rise in intracellular IP3 (inositol triphosphate) and DAG (diacylglycerol) 
increased release of calcium from intracellular calcium store
 Constrict smooth muscle of blood vessels and bronchi
o More calcium release, more contractility, vessels constrict
 Relax GI smooth muscle
Expected – exercise activates, don’t want to be digesting food, so slows system down and
reduce contractility
Contract GI and bladder sphincters, smooth muscle of uterus
o Don’t want to be passing food from one part to another as part of digestion when activating
SNS, and don’t want to be having to stop to urinate
Stimulate liver glycogenolysis – breaking down of glycogen, storage form of glucose, for energy 
increases circulating blood glucose levels
o
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α2 inhibits adenylate cyclase  reducing camp (totally different 2nd messenger system)
 Constricts smooth muscle blood vessels
 Relaxes GI smooth muscle (presynaptic effect)
 Decreases release from adrenergic and cholinergic terminals (of noradrenaline and ACh). Can be
pre-synaptic. Prevents release of transmitter from nerve terminal.
 Decreases insulin secretion  higher blood glucose level (decreases amount transported into cell)
 Stimulates platelet aggregation
o If bleeding, aggregation of platelets allows clotting and higher chance of escape
5 types of β-adrenoreceptors:
Main ones are β1, β2 and β3
All β-adrenoreceptors stimulate formation of adenylate cyclase (increase in cAMP).
β1:
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Increases HR, force of contraction and conduction velocity in the muscle and conduction system of
the heart
Increases cardiac output  improves blood delivery to tissue
β2:
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Dilation and relaxation of smooth muscles of blood vessels and bronchi
o Breathe more deeply  increase airway oxygen delivery and more oxygen to exercising
tissue
Relaxation of smooth muscles of uterus, bladder and ciliary (in eye)
Tremor, including muscle mass and speed contraction
Glycogenolysis of skeletal muscle
Glycogenolysis of liver and lypolysis of fat (release fatty acids into blood for sustained energy)
Increased twitch tension and tremor of skeletal muscle
β3:
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Thermogenesis (liberation of heat) of skeletal muscle
o Producing more heat, body temp rises (also associated with metabolic processes)
Lipolysis and thermogenesis of fat and liver
Noradrenaline/Norepinephrine (US)
 Transmitter at postganglionic sympathetic neurons and CNS (in periphery at adrenoreceptors)
 Stimulates α (all kinds) and β1 adrenoreceptors
 Little clinical use except vasoconstriction for surgery (stitching up a wound and don’t want too much
blood)
 Short action – t1/2 approximately 2 minutes
 Side effects:
o Hypertension (HT)  constricting vessels, increases total peripheral resistance, increases
blood pressure
o Vasoconstriction
o Tachycardia (/reflex bradycardia) – if got into systemic circulation, stimulates β1 at heart and
increases HR
 Reflex bradycardia – when BP goes up too much, baroreceptors detect that change
and try and correct that pressure  slowing down of heart the reduce cardiac output
o Ventricular dysrhythmias – abnormal heart rhythm involving increased contractility of the
ventricles
Adrenaline/Epinephrine (US)
 Acts rapidly at α1, α2, β1 and β2 adrenoreceptors
 t1/2 approximately 2 minutes
 All the same actions as noradrenaline, plus the actions at the β2 receptor sites
 Uses:
o Vasoconstrictor with local anaesthetics
o Emergency treatment for asthma or anaphylaxis as bronchodilator (β2 action)
o Decrease swelling
o Increase HR  Increased blood pressure
 Side effects:
o Hypertension
o Cardiac arrhythmias
Example of SNS actions – Running a race
 Release adrenaline from adrenal medulla, which will circulate all over the body
 Direct CNS activation of SNS is going to cause release of noradrenaline at various sites throughout
the body.
 Heart β1: Need to increase rate and force contraction to pump blood to muscles. Better blood delivery
to exercising muscles.
 Blood vessels:
o In skeletal muscle dilate (β2) to improve blood delivery, which will increase oxygenation &
glucose delivery
o Vessels in non-essential areas (GIT) constrict (α) to redirect blood flow to where most needed
 Airways (β2): circulating adrenaline relaxes bronchial smooth muscle, opening up airways to increase
airflow  better oxygen delivery to tissue
 Skeletal muscle (β2): more contractility  increased speed of contraction assists running; glycogen
breakdown releases sugar for energy
 Fat (β3): Fat breakdown releases fatty acids for energy (if long race) once glucose stores are used up
NA Transport
Two mechanisms for recycling:
Uptake 1 –
 In the periphery, responsible for taking NA back up into the synapse so it can be stored in the vesicle
of neuronal cells
 High affinity, low rate of uptake
 More selective for NA than adrenaline (and isoprenaline)
 Accounts for removal of 80% of neuronally released NA
 Tricyclic antidepressants (e.g. imipramine) inhibit Uptake 1
o Increase duration of action of NA but produce unwanted side effects e.g. dry mouth, blurred
vision
o Cocaine – local anaesthetics, CNS stimulant, impedes uptake 1, therefore not only more
noradrenaline but also dopamine
 Unwanted effects – vasoconstriction and tachycardia
Uptake 2 –
 Low affinity, higher rate uptake
 Takes up into non-neuronal cells – heart muscle, endothelium, smooth
 Also accumulate Adr and isoprenaline: affinity - Adr>NA>ISO
Metabolism of NA
Monoamine oxidase (MAO)
 Intracellular
 Two forms: MAO-A and MAO-B
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More important for CNS metabolism of NA (in brain)
Catechol-O-methyl transferase (COMT)
 In neuronal and non-neuronal tissue
 Metabolises circulating catecholamines – NA, Adr and dopamine
Synapse – release of transmitter from vesicle can interact with
either α or β adrenoreceptors; effect will vary if NA or Adr.
If there is enough NA in the synapse, it can feedback inhibit it
own release via pre-synaptic α2 receptors. Main enzymes
responsible for metabolism of catecholamines are MAO and
COMT.
Can recycle NA by Uptake-1 (going into original nerve terminal
and being repackaged for future use) OR can be taken up into
other cells (more via Uptake-2 mediated process)
MAO Inhibitors
MAO drugs:
 Phenelzine, tranylcypromine
 Non-selective – block A- and B Irreversible binding – effect is very long lasting
 Used in depression – where you want drugs to be working for quite a long time
 Note: interactions with drugs and diet (see tyramine and “cheese effect”). Must be very careful of
what other drugs are taken at same time and diet.
o If use other agents that affect uptake mechanisms (amphetamines)  can potentiate
what is going on and can produce way too much NA and can be quite dangerous  really
high BP
o Take these and eat a lot of vegemite/marmite/hard cheese (have tyramine) can interact
as well with uptake system and potentiate amount of NA in the synapse, which can be
dangerous
SNS Transmitter Synthesis
 Start off with tyrosine – from diet
 Enzyme tyrosine hydroxylase adds structure to produce DOPA
 DOPA is decarboxylated by DOPA decarboxylase
 Dopamine is acted on my dopamine β hydroxylase – adds hydroxyl group to side chain
o Have noradrenaline
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Effectively in the periphery only found in the adrenal gland. This is where the adrenal medulla
converts NA into adrenaline – this is why adrenal gland can release both transmitters.
NA and Adr have very similar structures. The only difference is an extra ethyl group on the end of
adrenaline, added in the adrenal medulla.
Drugs affecting NA Synthesis/Release
α-methyl-p-tyrosine
 For phaeochromocytoma
o Tumour of the adrenal gland  excrete huge amounts of catecholamine, pump out lots of Adr and
NA into blood stream – very dangerous
 Prevents synthesis of catecholamine’s including NA, reducing overall amount available
 Can cause hypotension and sedation
Methyldopa
 False transmitter synthesis
 Used for HT in pregnancy
 Pretends to be DOPA, and is then converted in the same way as DOPA into the other catecholamine’s in
that pathway, but is less likely to stimulate adrenoreceptors than NA
α-methyl-p-tyrosin – inteferes with tyrosine
hydroxylase, which is the rate-determining
step in catecholamine synthesis; good for
impairing NA.
Methyldopa – substitues for DOPA, acted
on by same enzymes, methylnoradrenaline
is much less potent at activating
adrenoreceptors than NA, so much less
adrenostimulation
Reserpine
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Inhibits/impairs vesicular
packaging of NA
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Was used for HT, but can induce
depression and parkinsonism (because
also interferes with dopamine)
Guanethidine
 Inhibits/prevents NA release (adrenergic neuron blocker)
 Normal depolarisation occurs but no NA is released
Directly acting sympathomimetics
Drugs that mimic sympathetic activation by interacting directly with the receptors themselves
 All interact directly with adrenoreceptors
 NA, Adr, Isoprenaline (drug, not transmitter)
 Dopamine (DA), dobutamine
 Asthma drugs - Salbutamol, salmeterol, terbutaline
 Phenylephrine – constricts vessels (used on blocked noses, etc.)
Other agonists
Isoprenaline
 Non-selective β-adrenoreceptor agonist
 Short plasma t1/2 – approximately 2 hours
 Used in the past for asthma (has fallen into disuse)
 Cardiac stimulant – tachychardia, including force contraction, and also dysrhythmias
 Decreases BP (activating β2 on skeletal muscle; dilation causes reduction in total peripheral
resistance)
 Relaxes uterus in premature labour
Dopamine
 Precursor of NA and Adr and CNS transmitter
 Stimulates DA receptors and adrenoreceptors in periphery due to structural similarity to other
catelochamines
 Role in control of renal blood flow – dilates blood vessels
 Specialised use as cardiac stimulant – increases force of heart beat
Dobutamine
 Used more in ICU
 Stimulates α and β1 adrenoreceptors (similar to noradrenaline in this sense)
 Greater inotropic (force) effects
 Less chronotropic (rate) effects
 Less arrhythmias
 Used intravenously for acute heart failure – can stimulate heart to pump more forcefully, but don’t
want it to speed up too much because this can increase heart failure (increases oxygen requirements
of heart itself)
 t1/2 approximately 2 minutes
Selective β2- adrenoreceptor Agonists
 Salbutamol (oral/aerosol) – Ventilin (taken as tablets are more long lacting)
 Salmeterol (aerosol, longer acting)
 Terbutaline (aerosol, longer acting)
 Reliever, not a preventative measure
o Asthma-bronchodilators
o Premature uterine contraction (muscle relaxation)
 Side effects – tachycardia, tremor (β2 adrenoreceptors on skeletal muscle), peripheral vasodilation 
associated drop in BP
β2- adrenoreceptor Antagonists (β blockers)
Non-selective
 β1, β2 – Propranolol
 t1/2 approximately 4 hours
 For HT, angina (blocking β1 mediated increase in HR, which will slow the heart down; angina can
promote further angina by depriving the heart of oxygen), tremor
o Taking enough of a non-selective drug, will start to effect β2
 Unwanted effects:
o Bronchoconstriction (blocking β2)
o Heart failure
o Cold extremities
o Fatigue
o
o
Depression
Hypoglycaemia (loss of hypolygcaemic awareness in a diabetic – blocking tremor and
increased heart rate  used to recognise problem)
Selective
 β1 – Atenolol
 Used for HT, heart failure
 Advantage: less bronchoconstriction, decreased risk of cold extremities
α- adrenoreceptor Agonists
 Phenylephrine mainly a directly acting sympathomimetic
 Used in cold and flu preparations
 α1 adrenoreceptor agonist
 Nasal decongestant (oral/intranasal) (vasoconstriction – less leakage of fluid into tissue and less build
up)
 Side effects – HT, reflex bradycardia (slowing of the heart as a compensatory mechanism)
o Can get absorbance into blood vessels and capillaries form nasal spray; worst effects when
taking in high doses or abusing the drug)
α-adrenoreceptor Antagonists
Non-selective
 Phenoxybenzamine
 Works on all α
 Also inhibits Uptake-1 mechanism for NA
 t1/2 is very long - approx 12 hours
 For phaeochromocytoma (tumor of adrenal gland)  blocking α adrenoreceptors, therefore it is
reducing vasconstrction, so more vasodilation can happen, and there is less of a rise in BP. Doses
that would be necessary would create quite a risk
 Unwanted effects: hypotension, tachycardia (reflex increase in HR to lowered BP), flushing (from
increased vasodilation), nasal congestion, impotence
Selective
 Prazosin
 Selective for α1-adrenoreceptors
 t1/2 approximately 4 hours
 Use: HT as a vasodilator (reduction in total periheral resistance, which would thereby lower BP)
Indirectly acting Sympathomimetics
 Drugs that mimic sympathetic activation but not principally through direct interaction with the
receptors themselves
 Related to NA – very similar in structure, and use the Uptake-1 mechanism (this is how they’re
actually working)
 In general, not working directly with adrenoreceptors as their main effect.
 Indirect action by enhancing synaptic NA
 Marked tolerance can develop – if using amphetamine usually need to take higher doses for same
effect
 Main adverse effects: HT (as a result of vasoconstriction), including cardiac rate and force
contraction, palpitations, decreased GI motility
Amphetamine
 Actions: increases NA and DA release
 Inhibits MAO – not breaking NA and DA down as rapidly, helping to boost levels
 Interacting with Uptake-1 – not taking up NA as readily, but rather sitting around for longer stimulating
synapses
 CNS stimulant
 Uses:
o Narcolepsy
o Attention deficit disorder
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Unwanted effects: increase in BP and HR  HT, tachycardia, insomnia, psychosis (may require
hospitalisation), dependency
t1/2 = 12 hours  very long, reason for so many side effect
Tyramine (dietary amine)
 Action is mediated by increasing synaptic NA – not interacting with adrenoreceptors itself, but
affecting Uptake-1 mechanism
 Non-selective MAO inhibiter – normally Mao in the gut will metabolise most the tyramine, but since it
has been inhibted the tyramine can cross into the blood more readily, reach the synapse and intefere
with the Uptake-1 mechanism
 No clinical uses
 Unwated effects: HT, tachycardia
 “Cheese effect” - sources: cheese, red wine, vegemite
 BP can effectively double when consuming tyramine while also on parnate (tranylcyplomine)