8: SNS Agonists Flashcards
Most S post-ganglionic neurones release NA but there are 2 exceptions
- Adrenal medulla: preganglionic S neurone drives the release of Adrenaline (80%) and Noradrenaline (20%)
- Sweat glands: S post-ganglionic neurone that innervates sweat glands releases ACETYLCHOLINE
B3 adrenoceptors are mainly involved in
glycolysis.
Which type of receptor are adrenoreceptors
G-protein coupled
Mechanism of actionof adrenoreceptors
Alpha 2, B1+2 all work through adenylate cyclase to up/downregulate cAMP
- Alpha 2 decreases cAMP
- B1+2 increase cAMP
Alpha 1 works through PLC to make IP3 and DAG
NORADRENALINE is more selective for
ALPHA receptors
ADRENALINE is more selective for
BETA receptors
Noradrenaline Metabolism
- Tyrosine from the diet is converted to DOPA by tyrosine hydroxylase (rate limiting enzyme) in the nerve endings.
- DOPA = dopamine and the dopamine = NA in the vesicles by the action of dopamine = hydroxylase.
- Upon an AP, influx of Ca2+ and the vesicles migrate to the nerve ending, emerge out and release the NT into the synapse.
- Once its been released, it will act on the post-synaptic receptors.
- Deactivation is via reuptake into the nerve terminal itself or into extraneuronal tissue
How do alpha 2 receptors work
They have a negative effect on the synthesis and release of NA. If there is a high [NA] in the synapse, it will stimulate the presynaptic alpha 2 receptors and this will reduce NA synthesis and release
Which receptor does adrenalien stimulate
Non-selective
Example of alpha1 selective drug
phenylephrine
What does clonidine stimulate
alpha 2 receptors
Example of beta 1 selective drug
dobutamine
What does salbutamol stimulate
beta 2 receptors
What happens in allergic reaction
• Blood vessels: increased capillary permeability. Endothelial cells within the membranes of the blood vessels move apart so you get a lot of fluid moving into the tissues. This leads to swelling of tissues (inc tongue) + fall in circulating fluid volume. Histamine is also profound vasodilator, reduced TPR = a fall in BP
o = ANAPHYLACTIC SHOCK and collapse of the circulatory system that leads to unconsciousness.
- Lungs: contraction of bronchial SM and constriction of the muscles around the throat, causing respiratory distress, difficulty breathing + swallowing
- GI tract: constrict SM in the GI tract causing vomiting and diarrhoea, stomach cramps.
Adrenaline’s effects in hypersensitivity reactions
- Heart: β1 effects in heart, increases CO and stimulates tachycardia, support BP. Alsp via α1 receptors cause vasoconstriction.
- Lungs: β2 effects causing bronchodilation and relaxation of throat muscles
- Mast cells: β2 effects suppress histamine release from mast cells
Why adrenaline used for pulmonary obstructive conditions
B2 mediated bronchodilation+ suppresses mediator release. Selective B2 agonists preferable but adrenaline useful in hypotensive crisis
What is cardiogenic shock and what is used to treat it
The sudden inability of the heart to pump sufficient oxygen-rich blood. This can happen when you have a heart attack/MI or cardiac arrest. This action mainly happens via the beta 1 receptor - positive inotropic action - Adrenaline stimulates this to restore CO.
Why adrenaline used for spinal anaethesia
Anaesthetising through the spine, removehe S output to the peripheral resistance vessels = relaxation of peripheral resistance vessels so the patient wont be able to maintain their BP.
Administer a little bit of adrenaline at the same time you can constrict the blood vessels so you can maintain the BP. This is due to alpha-1 mediated vasoconstriction
Why adrenaline used for local anaesthetic
causes constriction of the blood vessels in the local area thus preventing the clearance of the anaesthetic from the area. If the anaesthetic was given without adrenaline, then it will wear off faster. This is due to alpha-1 mediated vasoconstriction
Unwanted Actions of Adrenaline
These are due to adrenaline being non-selective
• Secretions - reduced and thick
• CNS - minimal
• CVS Effects:
o Tachycardia, palpitations, arrhythmias
o Cold extremities, hypertension
o OVERDOSE - cerebral haemorrhage, pulmonary embolism
- GIT - minimal
- Skeletal muscle - tremor
Phenylephrine selectivity and structural properties
Alpha 1 selective
Chemically related to adrenaline. Slight change in structure means that phenylephrine is more resistant to COMT degradation but it is not resistant to MAO degradation – lasts longer in system.
Phenylephrine clinical uses
- Vasoconstriction (people on phenylephrine have a slightly elevated blood pressure)
- Mydriatic: dilates pupils by binding alpha 1 receptors on iris
- Nasal Decongestant- as it vasoconstricts and dries secretions/fluid leakages up. Less fluid flow there also reduces likelihood of gluid leakage
Clonidine selectivity and effects
Alpha 2 selective
• Fall in BP
o Less NA = less vasoconstriction hence a fall in TPR
o Brainstem: has a central effect through the brainstem where it works on the baroreceptors in this pathway and reduces the sympathetic drive coming out of the brain = reduces the TPR and amount of NA released at the nerve terminal = reducing TPR further.
• Kidneys: alpha-2 mediated reduction in NA release = reduced NA binding to beta-1 receptors in kidney = reduced renin secretion and hence reduced Ang2 production (this is a potent vasoconstrictor)
Clinical use of clonidine
hypertension + migraine
What can beused to treat glaucoma
- Phenylephrine: Alpha 1 receptors in the vessels within the ciliary body causing vasoconstriction of these vessels. This means that less blood will be delivered to the ciliary body and the production of aqueous humour is reduced.
- Clonidine: Alpha 2 receptors can also be stimulated, to decrease humour formation
- Beta-blockers would have negative effect in aqueous humour formation by blocking beta-1 receptors
Isoprenanline selectivity and structural properties
Beta selective -both b1 +b2
Chemically similar to adrenaline but less susceptible to uptake 1 and MAO breakdown.
clinical uses of isoprenaline
- Cardiogenic Shock
- Acute Heart Failure
- Myocardial Infarction
Negative effect of isoprenaline
Drives b1 receptors in heart to support heart. Also stimualte b2 receptors VSMC = dilation of vessels = pooling of blood = decreased venous return
Fall in pressure detected by baroreceptors, send message to heart, reflex tachycardia, may give irregular HR and neg impact increased CO
B2 receptor stimualtion not good for pt w heart failure
clinical use of dobutamine
cardiogenic shock.
Lack isoprenaline’s reflex tachycardia bc b1 selective.
Salbutamol selectivity and structural properties
B2 receptor selective.
Synthetic catecholamine derivative with relative resistance to MAO and COMT.
Clinical uses of salbutamol
Asthma: b2 relaxation of bronchial SM. Inhibit release of bronchoconstrictor substances from mast cells.
Threatened premature labour: b2 mediated relaxation of uterine SM. Prevent fetus abortion
Side effects of salbutamol
relflex tachycardia bc some b1 stimulation
tremor
blood sugar dysregulation
