Physiology and Pharmacology of the Sympathetic Nervous System Flashcards
Physiology of Sympathetic Nervous System
describe fight and flight response
hr + contractility? why? bp? why? lungs? why? pupils? why? muscle energy? why? sweating? why? gi activity? why?
Sympathetic nervous system prepares the body for
‘’Fear, Fight and Flight’’
Important in exercise, present in anxiety
↑ Heart rate and contractility – ↑ Cardiac output
Diverts blood flow to skeletal muscle – More O2/fuel for movement
↑ Blood pressure – Consequence of diversion of blood
↑ Air into to lungs – ↑ O2 uptake/CO2 removal
Dilation of pupils – more light into eye, better vision
↑ Fuel in muscles – breakdown glycogen/lipids
↑ Sweating – temperature regulation
↓ Non-essential functions (↓ GI tract activity) – limit energy use
To do this sympathetic nervous system acts on:
Heart, blood vessels, kidney, metabolism, lungs, eye, sweat glands, GI tract
General structure of Sympathetic Nervous System
what happens in hypothalamus? send info to where? where next?
what do all pregaglionic fibres do and rlease? exception?
postganglionic fibres relase? effect what?
wheres B2 recep?
where B1 recep?
wheres A1 recep?
‘DANGER’ signal from hypothalamus at rostral ventral lateral medulla (RVLM)
sends excitatory bulbospinal fibres aka the sympathetic drive to the spinal cord at the levels of T1 to L2/L3
all the pre ganglionic fibres will synapse at the ganglia and release ach except the fibre going to the adrenal medulla where adrenaline + Na will affect a1, a2, B1, B2 receptors for heart, blood vessels, liver, skeletal muscle, fat cells + lungs
post-ganglionic fibres release na and go to
B2 receptors - GI, blood vessels
B1 receptors - heart, kidney, GI
a1 recep - blood vessels, eye, sphincters, genitalia, GI
Sympathetic nervous system on heart
what receptor is acted on at the heart?
effect on SAN? what kind of effect?
effect on conduction system? what kind of effect?
effect on muscle cells? what kind of effect?
effect on CO? why?
Noradrenaline and adrenaline act at B1-adrenoceptors
Sino-atrial (SA) node : Increases frequency of pacemaker potentials which produces an increase in heart rate (HR)
Chronotropic effect
Conduction system : Increases rate of impulses through atria to ventricles to maintain balance between heart rate and contractions
Dromotropic effect
Muscle cells : Increases force of contraction of atria and ventricles
Increase stroke volume (SV) -> Inotropic effect
Sympathetic nerve stimulation increases cardiac output (CO)
CO (vol/min) = SV (vol/beat) x HR (beats/min)
Helps CO rise from a resting 5 litres/min to over 20 litres/min during exercise
Sympathetic nervous system on blood vessels
act on which receptors?
effect on radius? why?
effect on veins? why?
what does changing bp do?
affect of adrenaline on B2 adrenorecptors at coronary and skeletal muscle?
Noradrenaline and adrenaline act at a1-adrenoceptors
Constriction of arterioles (vasoconstriction):
Increase in total peripheral resistance - more R for blood flow
Constriction of veins (venoconstriction):
Increases in CO (Starling’s law)
Sympathetic nervous system increases blood pressure to alter blood flow
Blood Pressure (BP) = CO x TPR Blood flow = (Pa-CVP) / TPR
Extra information!
Stimulation of β2-adrenoceptors by adrenaline (released by sympathetic nerve activity on adrenal gland) on coronary arteries and skeletal muscle arteries causes these vessels to dilate – increasing blood flow to heart and skeletal muscle – higher O2/nutrient requirements during ‘’fear, fight, flight’’
Sympathetic nervous system on kidney – Renin secretion
what does renin produce?
what effect does this have on BP and CO?
how is CO increased/ what is released? from where? effect?
what do sympathetic nerves inneravte? what do they release and stimulate what receptors to release renin?
Renin leads to production of Angiotensin II (Ang II)
Ang II causes increased BP and CO:
Vasoconstriction of arterioles (increase TPR)
Release of aldosterone from the adrenal cortex causing
Increasing Na+ and H2O retention leading to increased blood volume (Lower CO)
One of the reasons why B1-blockers (prevent Renin release/Ang II production) are successful at lowering BP
symoathetic nerves innervates at granular cells as they release NA which stimulate the B1 receptor causing the release of renin
Sympathetic nervous system on metabolism
liver + skeletal muscle - stimulate receptors? effect?
pancreas - stimulate receptors? effect? alpha/beta cells?
adipose tissue - stimulate receptors? effect? (2)
Increased fuel (ATP levels) for ‘’Fear-fight-flight’’ in muscles
Liver and skeletal muscle
Stimulation of a/B-adrenoceptors
Breaks down glycogen into glucose (glycogenolysis)
Promotes glucose synthesis (gluconeogensis)
Pancreas
Stimulation of a/β-adrenoceptors
Less Insulin hormone from beta-cells – Less global glucose uptake
Prevents insulin inhibiting glycogenolysis, gluconeogenesis, lipolysis
More glucagon hormone from alpha-cells – More glycogen into glucose
Adipose tissue
Stimulation of B3-adrenoceptors
More lipolysis : triglycerides into free fatty acids + glycerol
Free fatty acids – B-oxidation into acetyl-CoA, enter Krebs cycle
Glycerol – recycled into glycolysis pathway
Both increase ATP yields - energy
Very useful to revisit content for metabolism lectures in Sem 2
Sympathetic NS on GI tract, lungs, eye, sweat glands
Gi tract - receptors stimulated? (2) effect?
lungs - receptors stimulated? effect?
eyes - receptors stimulated? effect?
sweat glands - receptors stimulated? effect?
GI tract
Stimulation of a and B2-adrenoceptors induces inhibition of GI motility
Activation of a1-adrenoceptors evokes contraction of bladder sphincter
B2-adrenoceptors induces relaxation of smooth muscle allowing filling
Bowel / bladder function non-essential during ‘’Fear-fight-flight’’
Lungs
Do not receive sympathetic innervation
Bronchioles contain B2-adrenoceptors which are activated by circulating adrenaline to produce bronchodilation - facilitate breathing
Eye
Stimulation of a1-adrenoceptors on dilator pupillae (radial muscle of iris) cause to dilation of the pupil - More light on the retina – more acute sight
Sweat Glands
Release of Ach acting at Mus receptors (not NA, exception to normal rule) induces sweating – temperature control during ‘’Fear-fight-flight’’
Adrenergic synapse
Na at pre-synaptic terminal?
what breaks down Na?
where does Na negatively feedback?
In the pre synaptic terminal, there is synthesis and storage of NA which will be released to the synaptic cleft where it will bind to a1, B1 and B2 receptors on the post-synaptic membrane e.g. heart, blood vessels leading to a biological repsonse e.g. increase cardiac contraction, vasoconstriction, bronchodilation.
Once this is over, the Na will be uptaken via a transporter where it will either be recycled back into vesicles or it will be broken down by monoamine oxidase (MAO).
NA + circulating adrenaline can negatively feedback on a2 receptors and prevent release of further NA
direct and indirect adrenergic drugs
effect?
Direct – Drugs that act at adrenoceptors
Indirect – Drugs that act at altering release/termination of transmission
Synthesis of Noradrenaline and Adrenaline
where is it mediated? (3)
how is Na made? steps?
how is adrenaline made? steps?
Noradrenaline (NA) and adrenaline mediated at sympathetic post-ganglionic fibres, CNS, adrenal medulla
Tyrosine (via tyrosine hydroxylase - cytoplasm
(rate-limiting step) ) -> Dopa
Dopa ( via DOPA decarboxylase) -> Dopamine
Dopamine ( via dopamine hydroxylase) -> Noradrenaline
Na (via Phenylethanolamine-N-methyl transferase (PNMT) Found in adrenal medulla, which is main site for adrenaline release) -> adrenaline
Adrenergic Transmission - Storage
Drugs
what prevents storage/drug?
effect of this?
why not used?
Reserpine
Prevent storage of NA in vesicles – NA in cytosol broken down by MAO
Reduces NA release
Less sympathetic actions, e.g. Less a1-mediated vasoconstriction
Early treatment for hypertension
Set principle for future treatments – reduce sympathetic nerves decreases BP
BUT this treatment had a lot of side effects as it affected the lungs + heart too as it wasn’t selective and affected NA
Adrenergic Transmission – Facilitation of release
Drugs
what does tyramine do?
what is the cheese effect?
amphetamine effect?
ephedrine effect?
Tyramine Dietary constituent (meats, cheeses, chocolate) Enter terminal, displaces NA into synaptic cleft – Increase sympathetic, Increase BP Normally tyramine broken down by MAO in GI tract – so it has little effect But causes marked hypertension in patients treated with MAO inhibitors for depression – called the ‘cheese effect’ (as tyramine not broken down hence more NA release)
Amphetamine / Ephedrine
Reverses uptake transporters causing release of NA into cleft
Ephedrine (decongestant) – vasoconstriction of nasal blood vessels (as cold dilates them)
Adrenergic Transmission – Inhibition of release
Drugs
Guanethidine effect?
Clonidine effect?
Guanethidine
Compete with NA for inclusion into vesicles, reduces NA release -> more NA breakdown as not in vesicles
Clonidine / a-methyl-DOPA
Stimulate pre-synaptic a2 receptors, reduces NA release -> negative feedback
These drugs maybe used in for hypertensive emergencies (by reducing sympathetic activity) when other mediations are ineffective
Adrenergic Transmission – Termination inhibition
Drugs
what is Na metabolised by and where? (2)
cocaine effect?
moclobemide effect?
NA is terminated by re-uptake unchanged into pre-synaptic terminal
NA is then,
1) recycled back into vesicles
2) Metabolised by monoamine oxidase (MAO) in neurones or catechol-O–methyltransferase (COMT) in non-neuronal sites (e.g. adrenal medulla)
Cocaine / tricyclic anti-depressants (imipramine)
Inhibit Uptake, increase adrenergic transmission -> therefore no recycling + constant stimulation
MAO inhibitor e.g. Moclobemide
Anti-depressant, increase adrenergic transmission in brain -> less breakdown hence more in vesicle therefore more released
Adrenergic receptor pharmacology
Most drugs used to modulate sympathetic nervous system via Activating (agonists) or Blocking (antagonists)
adrenergic receptors
