SNS Agonists Flashcards
Where do post-gangionic sympathetic neurones originate?
Thoracolumbar spinal cord (T1-L2)
What do most sympathetic post-ganglionic neurones release? State two exceptions to this.
Most sympathetic post-ganglionic neurones release noradrenaline
Exceptions:
- Pre-ganglionic neurone synapses with adrenal medulla (no post-ganglionic neurone)
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Adrenal medulla releases:
- Adrenaline (80%)
- Noradrenaline (20%)
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Adrenal medulla releases:
- Sympathetic post-ganglionic neurone to sweat glands releases acetylcholine
- This ACh acts on muscarinic receptors
Contrast the action of the sympathetic and parasymptathetic nervous system on different parts of the body.
Describe the effects of the SNS on different body parts and state which adrenergic receptor subtypes they are mediated by.
NOTE:
- In the skin you have more beta 2 than alpha 1
- So the sympathetic effects on the skin are vasodilation
- You want to increased cutanoeous blood flow so you get more head being radiated away from your blood
- This is because you want to get rid of all that extra heat being generated due to you being more metabolically active during ‘fight or flight’
- Therefore, a side effect of beta blockers is cold extremities due to cutaneous vasoconstriction
What is a directly acting drug?
A drug which mimics the actions of NA and adrenaline by binding to and stimulating the adrenoceptors (which are G-protein coupled receptors)
- They are principally used for their actions in the:
- CVS
- Eyes
- Lungs
Describe the relative selectivity of adrenaline and noradrenaline to different adrenoreceptor subtypes.
- Noradrenaline is more selective for alpha receptors
- α1 = α2 > β1 = β2
- Adrenaline is more selective for beta receptors
- β1 = β2 > α1 = α2
BUT all adrenoceptors can be activated by both NA and adrenaline
Describe the process of NA metabolism.
- Tyrosine (from diet) → DOPA
- Enzyme: tyrosine hydroxylase - rate limiting enzyme
- DOPA → dopamine → NA
- NA deactivation via :
- Reuptake into the pre-synaptic nerve terminal
- Reuptake into extraneuronal tissue
- Once taken up, NA is then metabolised by enzymes
- NA binds to presynaptic alpha 2 receptors which inhibits further NA release - negative feedback
State five directly acting SNS agonists and their selectvity.
- Adrenaline (non-selective)
- Non-selective in the sense that it can activate all adrenoceptors
- But it is more selective to beta receptors than alpha receptors
- Phenylephrine (α1)
- Clonidine (α2)
- Dobutamine (β1)
- Salbutamol (β2)
What does selectivity depend on?
Selectivity depends on CONCENTRATION
Explanation:
- At low concentrations these drugs will be relatively selective
- But if you increase its concentration, the chance of binding to other receptors increases
- At low concentrations they will most likely bind to the receptors that they have the greatest affinity for
- However, at higher concentrations, once they have bound to their ‘preferential’ receptor, the remaining drug can then bind to other receptors that they have less affinity for
- Therefore no drug is 100% selective to a certain receptor
Describe the development of hypersensitivity following first exposure.
After the first exposure you generate antibodies to the antigen andthese circulate around the body and bind to mast cells
In the subsequent exposure, the mast cells are primed with the antibody on its surface
Cross-linking of these antibodies (IgE) on the surface of mast cells causing degranulation and release of inflammatory mediators (e.g. histamine)
This leads to the symptoms of hypersensitivity.
State some symptoms of hypersensitivity.
- Increase in capillary permeability → increased leakage of fluid out into tissues
- This leads to a fall in circulating fluid volume and hence a fall in blood pressure
- You get ANAPHYLACTIC SHOCK which can lead to unconsciousness
- Shock = a disease state in which tissue perfusion is insufficient to meet metabolic demands
- Anaphylactic = due to a severe allergic reaction
- This can also lead to bronchoconstriction the throat causing respiratory distress.
- It can also lead to GI problems such as vomiting and diarrhoea
- Smooth muscle contraction
- Fluid outflow into gut
Why is adrenaline used in the treatment of anaphylaxis?
Adrenaline is used in this situation as it tackles the key problems first: airways, breathing and circulation
- β2 - bronchodilation
- To open up the airways and allow breathing
- β1 - tachycardia
- To increase BP
- α1 - vasoconstriction
- To increase BP
- β2 - Suppression of mast cell mediator release
State some other clinical uses of adrenaline.
β2 mediated actions:
- Actions:
- Bronchodilation
- Suppression of mediated release
- Uses:
- Treatment of asthma
- Adrenaline administered intramuscularly or subcutaneously
- Treatment of acute bronchospasm associated with chronic bronchitis or emphysema
- Treatment of asthma
β1 mediated actions:
- Actions:
- Positive inotropic effect - increases force of contraction and hence CO
- Uses:
- Treatment of cardiogenic shock
- Cardiogenic shock = the sudden inability of heart to pump sufficient oxygen-rich blood
- Treatment of cardiogenic shock
α1 mediated actions:
- Actions:
- Vasoconstriction
- Uses:
- Administered with spinal anaesthesia
- Vasoconstriction maintains BP - if the spinal block is in the thoracolumbar region which means you are taking away the sympathetic output to the BVs
- Administered with local anaesthesia
- Local vasoconstriction prolongs action - because it prevents the clearance of the anaesthetic from the area
- Administered with spinal anaesthesia
State some unwanted actions of adrenaline.
- Secretions – reduced and thickened mucous
- CNS – minimal
- CVS effects
- Tachycardia, palpitations, arrhythmias
- Cold extremities
- Due to constriction of blood vessels of fingers and toes
- Decrease in peripheral blood flow allows more blood flow to core muscles in arms and legs
- Hypertension
- Overdose leads to: cerebral haemorrahge, pulmonary oedema
- Cerebral haemorrhage due to massively increased blood pressure which can cause an aneurysm/weakening which can then lead onto bursting of BVs in the brain
- Increased systemic resistance due to vasoconstriction by SNS leads to blood backing up → pulmonary congestion → pulmonary oedema
- GIT – minimal
- Skeletal muscle - tremor
- Motor nerve terminals to skeletal muscle have beta 2 adrenergic receptors which facilitates ACh release at the NMJ and skeletal muscle contraction
- So excessive activation of these receptors can lead to involuntary muscle contractions in the form of tremors
Describe the selectivity of phenylephrine.
Alpha 1 >> Alpha 2 >>> Beta 1/Beta 2
Describe the characteristics of phenylephrine.
Phenylephrine is chemically related to adrenaline (i.e. they have a similar structure)
- NOTE: The slight difference in structure impacts adrenoceptor subtype selectivity (in this case, makes it more alpha selective)
It is more resistant to degradation by COMT than adrenaline but not MAO degradation
- COMT - more peripheral enzyme
- MAO - more central enzyme (i.e. CNS)
Therefore, phenyephrine is longer lasting as a peripherally acting agent than adrenaline
What is glaucoma characterised and caused by? What are the consequences if left untreated?
Characterized by:
- Increase in intraocular pressure
Caused by:
- Poor drainage of the aqueous humour
If untreated:
- It permanently damages the optic nerve → blindness.
What is clonidine used to treat?
- Glaucoma
- Stimulates alpha 2 to directly decrease aqueous humour production
- Hypertension
- Migraine
How it helps treat hypertension and migraine:
- Stimulation of alpha 2 receptors (present on presynaptic terminal) inhibits NA release into synapse
- This inhibits vasodilation:
- Hypertension treatment - reduced TPR → reduced BP
- Migraine treatment - link between vasodilation and migraine
- This inhibits vasodilation:
- Central action in brainstem within baroreceptor pathway to reduce sympathetic outflow
-
Presynaptic alpha 2 receptors in vasomotor centre in the brainstem activates which prevents SNS activation (SNS inhibition)
- NOTE: Vasomotor centre regulates BP
- This is particularly useful for hypertension treatement as it could reduce BP via other mechanisms (e.g. reduced RAAS activation, reduced HR)
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Presynaptic alpha 2 receptors in vasomotor centre in the brainstem activates which prevents SNS activation (SNS inhibition)
