Physiology + pharmacology Sympathetic Flashcards
- Outline the effects of the fear-fight-flight response on the body - Describe the effect of stimulating the sympathetic nervous system and different adrenoceptors involved in the heart, blood vessels, kidney, metabolism, GI tract, eye, lungs, and sweat glands - Describe adrenergic neurotransmission, and how drugs may alter release and termination of noradrenaline - Outline different adrenoreceptor subtypes and their associated intracellular pathways, and the effects of adrenoreceptor agonists a
Where are the pre-ganglionic sympathetic neurones located?
- Thoracolumbar region
What are the biological effects of the sympathetic nervous system on the body?
Initiates fear-fight-flight response
- Increased heart rate + contractility
- Increased cardiac output
- Increased vasoconstriction
- Increased blood pressure
- Increased air into lungs (bronchodilation)
- Increased oxygen uptake/carbon dioxide removal
- Dilation of pupils, increased light into eyes, better vision
- Increased fuel to muscles: breakdown glycogen/lipids
- Increased sweating: temperature regulation
- Decrease non-essential functions (decreased GI tract activity etc) - limits energy use
What organs does the sympathetic nervous system act on?
- Heart
- Blood vessels (arteries, veins etc)
- Kidney
- Metabolism
- Lungs
- Eye
- Sweat gland
- GI tract
Which receptor does noradrenaline and adrenaline act on in the heart?
Beta 1 adrenoceptors
Which receptor does noradrenaline and adrenaline act on in blood vessels?
Alpha 1 adrenoceptors
What is the effect of stimulation of the sympathetic nervous system on the heart?
- Noradrenaline and adrenaline act at B1 adrenoceptors on heart
- On SAN- increases generation of electrical acuity which increases heart rate- chronotropic effect
- On cardiac muscle cells- increases force of contraction of atria and ventricles, increases stroke volume
Define stroke volume
Volume of O2 blood ejected by heart’s left ventricle through aorta per beat
How do you calculate cardiac output?
Stroke volume X heart rate
What is the effect of stimulation of the sympathetic nervous system on blood vessels?
- Noradrenaline and adrenaline act at alpha 1 -adrenoceptors on blood vessels
- Vasoconstriction (constriction of arterioles) - Increases blood vessel resistance (TPR - total peripheral resistance)
- Venoconstriction - constriction of veins, increases returns of blood to heart, increasing cardiac output
- Overall, all of this combines, then leads to an increase in blood pressure
How do you calculate blood pressure?
CO X TPR
What is the effect of stimulation of the sympathetic nervous system on the kidneys?
- Noradrenaline acts at B1- adrenoceptors (on afferent arterioles) to release renin from prorenin
- Renin causes production of angiotensin II (Ang II) from angiotensinogen
- Ang II increases blood pressure
What is the effect of the sympathetic nervous system on liver and skeletal muscle (metabolism)?
- Stimulation of alpha/beta adrenoceptors
- Breaks down glycogen into glucose (glycogenolysis)
- Promotes glucose synthesis (gluconeogenesis)
What is the effect of the sympathetic nervous system on the pancreas (metabolism)?
- Stimulation of alpha/beta adrenoceptors
- Decreased insulin response, which normally ‘stores glucose’
- Increased glucagon due to increased conversion of glycogen stores into free glucose
What is the effect of the sympathetic nervous system on Adipose tissue (metabolism)?
- Stimulation of Beta 3 adrenoceptors
- Increased lipolysis: triglycerides broken down into free fatty acids + glycerol
- Both increase ATP levels for energy
What is the effect of the sympathetic nervous system on GI tract?
- Stimulation of alpha and B2 adrenoceptors
- Activation of alpha 1 adrenoceptors evokes contraction of bladder sphincter
- B2 adrenoceptors induces relaxation of smooth muscle allowing filling
- Bowel/bladder function non-essential during ‘fear-fight-flight’
What is the effect of the sympathetic nervous system on the lungs?
- Receive sympathetic innervation
- Bronchioles contain Beta 2 adrenoceptors which are activated by circulating adrenaline released from adrenal glands to produce bronchodilation
- Facilitates breathing
What is the effect of the sympathetic nervous system on the eyes?
- Stimulation of alpha1 adrenoceptors on dilator papillae (radial muscle of iris) dilates pupil- increase light on retina- more acute sight
What is the effect of the sympathetic nervous system on the sweat glands?
- Release of ACh and this binds to Mus receptors, induces sweating- temperature control
What is adrenergic transmission?
- Transmission of noradrenaline at a synapse or neuroeffector junction (post ganglionic synaptic terminals and CNS)
What type of receptors are adrenergic receptors?
GPCRs
What are the different types of adrenergic receptors and where are they?
- Alpha 1 - Pupils, GI tract, skin, glands, urinary tract, blood vessels
- Alpha 2 - regulate release of catecholamines (adrenaline, noradrenaline)
- Beta 1 - Heart, urinary tract
- Beta 2 - lungs, skeletal muscle, blood vessels, coronary blood vessels
- Beta 3 - bladder, fat cells
Describe what happens at the adrenergic synapse
- Where drug therapy can be applied
- At pre-synaptic terminal, NA synthesised, packaged into vesicle
- Vesicle moves toward nerve end terminal, fuse with pre-synaptic membrane, release contents via exocytosis into synaptic cleft
- Post- synaptic membrane (heart, blood vessels) acts at different receptors (alpha 1, beta 1, beta 2)
- After NA produced its effects, it can be taken back into the pre-synaptic terminal by an uptake transporter- this is how response is terminated and this is the alpha 2 receptor
- When it has been taken back up, it can be recycled back into the vesicle (by uptake transporters) OR can be broken down by the enzyme monoamine oxidase (MAO)
What is the negative feedback system at the
adrenergic synapse?
- If lots of NA released, they acts at alpha 2 adrenoceptors that are at the presynaptic terminal
- When the alpha 2 adrenoceptors are stimulated, the release of the neurotransmitter at the pre-synaptic terminal is switched off, which will decrease the noradrenaline released, because it inhibits the motility of the vesicle to the pre-synaptic membrane
What happens if the neurotransmitter binds to alpha 1 receptors?
Vasoconstriction increases as alpha 1 receptors are present on blood vessels
What happens if the neurotransmitter binds to Beta 1 receptors ?
Increased cardiac contraction, as Beta 1 receptors are present at the heart
What happens if the neurotransmitter binds to Beta 2 receptors ?
- Increased bronchodilation as Beta 2 receptors line the airways
How are noradrenaline and adrenaline synthesised?
- Tyrosine is converted to DOPA via tyrosine hydroxylase in the cytoplasm
- DOPA is converted to dopamine via DOPA decarboxylase
- Dopamine is converted to noradrenaline via dopamine hydroxylase
- Noradrenaline is converted into adrenaline via phenylethanolamine- N- methyl transferase (PNMT). This enzyme is found in the adrenal medulla
- The adrenal medulla, which is the main site for adrenaline release
What is ephedrine?
- An adrenaline drug
How can drugs facilitate the release of noradrenaline?
- Amphetamine/ ephedrine- Inhibit reuptake transporters, increasing levels of NA (and DA) in synaptic cleft. They can also act as a CNS stimulant
How can drugs inhibit the release of noradrenaline?
- Guanethidine- Competes with NA for inclusion into vesicles/NA release/distribution, reducing NA release
- Clonidine- alpha 2 agonist, specifically stimulates pre-synaptic alpha 2 receptors in brain, reducing NA release by preventing motility of vesicle to fuse with pre-synaptic membrane
These drugs may be used in hypertensive emergencies to reduce sympathetic activity, e.g. reduce peripheral resistance in blood vessels, reduce heart rate, reduce blood pressure
How can drugs terminate the inhibition of noradrenaline?
- Monoamine oxidase (MOA) can break down NT
- Drugs like cocaine inhibit reuptake transporters, stopping reuptake of NA, so NA (and DA- dopamine) in synaptic cleft, increases sympathetic responses
- Cocaine acts like this due to its high affinity for the reuptake transporters on the pre-synaptic membrane, preventing the binding of NT, hence inducing the increase of sympathetic responses
How to most drugs that modulate the sympathetic nervous system work?
- Via activating (agonists) or blocking (antagonists) adrenergic receptors
What type of receptors pathways are involved when drugs modulate the sympathetic nervous system?
All of the G-protein receptor pathways , Gq, Gi, Gs
What type of G protein is the alpha 1 receptor?
- Gq, increases PLC which converts Pip2 into IP3 + DAG.
- This increases release of Ca2+ and increases PKC leading to smooth muscle contraction (blood vessels, bladder, eyes)
What type of G protein is the alpha 2 receptor?
- Gi, decreases AC, leading to a decrease in cAMP
- This decreases PKA leading to inhibition of sympathetic activity and reduced NA release
What type of G protein are the beta 1, 2 and 3 receptors?
- Gs, increases AC, increases cAMP
- Increases PKA, leading to inhibition of smooth muscle contraction.
- Beta 1 = heart/renal actions
- Beta 2 = airways, blood vessels
- Beta 3 = bladder, fat cells
How do adrenergic receptor agonists prolong anaesthetic effect?
- Adrenaline acts at alpha 1, leading to vasoconstriction, preventing loss of local anaesthetic
What adrenergic receptor agonist has anti-obesity effects and what receptor does it act at?
- BRL37344
- Acts at Beta 3 receptor
What adrenergic receptor agonist reduces an overactive bladder and what receptor does it act at?
- Mirabegron drug
- Acts at beta 3 receptor, relaxes detrusor muscle, this will increase the urine being stored in the bladder before it contracts and exits into the urethra
What adrenergic receptor agonist is used in premature labour and what receptor does it act at?
- Salbutamol
- Acts at Beta 2
- Relax myometrium (smooth muscle)
What adrenergic receptor agonist is used for nasal decongestion and what receptor does it act at?
- Phenylepherine
- Acts at alpha 1
- Leads to vasoconstriction of nasal vessels
What adrenergic receptor agonist is used in asthma inhalers and what receptor does it acts act?
- Salbutamol
- Acts at beta 2
- Relaxes airway smooth muscle, leads to bronchodilation
What adrenergic receptor agonists act as a cardiac stimulant and what receptor does it act at?
- Adrenaline/dobutamine
- Acts at beta 1
- Increases heart rate and contractility/stroke volume
What adrenergic receptor agonist can be used in acute anaphylaxis and what receptors does it act at?
-Adrenaline
- Acts at alpha 1, beta 1, beta 2
- Alpha 1 = vasoconstriction
- Beta 1 = Increase heart rate/ contractility
- Beta 3 = bronchodilation
What adrenergic receptor antagonist has an anti-hypertensive effect and what receptor does it act at?
- Prazosin
- Acts at alpha 1, will increase vasodilation, decreasing blood pressure
What adrenergic receptor antagonist can be used for adrenal gland tumours and what receptor does it act at?
- Phenoxybenzamine
- Acts at alpha 1
- Prevent excess vasoconstriction due to high adrenaline levels, decreases BP
What adrenergic receptor antagonist can be used for an underactive bladder and what receptor does it act at?
- Tamsulosin
- Acts at alpha 1
- Relax internal sphincter muscle
What adrenergic receptor antagonist can be used for glaucoma and what receptor does it act at?
- Timolol
- Acts at beta 2
- Reduces secretion
- Reduces intraocular pressure
What adrenergic receptor antagonists can be used for angina, heart failure and arrhythmia and what receptor do they act at?
- Atenlol
- Bisoprolol
- Act at beta 1
- Decrease heart rate, conduction and contractility, reduce oxygen demand
What adrenergic receptor antagonists can be used for hypertension and what receptor do they act at?
- Atenlol
- Bisoprolol
- Act as beta 1
- Reduce renin release
- Decrease RAAS
