SNS Agonists Flashcards
From which region of the spinal cord do sympathetic fibres originate?
Thoracolumbar
Most sympathetic post-ganglionic neurones release noradrenaline. State two exceptions.
Adrenal medulla – adrenaline (80%) and noradrenaline (20%) Sweat glands – acetylcholine
State the difference between directly and indirectly acting sympathomimetics.
Directly acting – binds to the adrenoceptor and mimic the action of adrenaline and noradrenaline by stimulating the receptors Indirectly acting – inhibits the uptake and breakdown systems leading to the accumulation of neurotransmitter in the synaptic cleft
Describe the mechanism of action of the four different types of adrenoceptor.
ALL adrenoceptors are G-protein coupled
Alpha 1 = PLC -> IP3 + DAG Gq
Alpha 2 = decrease cAMP Gi
Beta 1 + Beta 2 = increase cAMP Gs
State the main actions of beta-1 receptors.
HEART – increase heart rate + increase contractility
KIDNEYS – increase renin release -> increase blood pressure
Lipolysis
State the main actions of beta-2 receptors.
Liver: increases Hepatic glucose output – glycogenolysis + gluconeogenesis
Smooth muscle relaxation in AIRWAYS (bronchodilation), Blood vessels(vasodilation) and Uterus(detrussor relaxation)
State some effects that are mediated by both alpha and beta-receptors.
Exocrine secretions (e.g. salivary gland secretions become thick)
GIT motility – decreased muscle motility and tone + contraction of sphincters to stop food going further down (sympathetic effects to STOP REST AND DIGEST)
Liver- increase Hepatic Glucose output via glycogenolysis and gluconeogenesis mediated by alpha 1 and b2
Lipolysis: a1 and b1
What receptors are responsible for the production of aqueoushumour by the ciliary body?
Beta receptors
State some effects of alpha-1 receptors.
Pupil: Mydriasis (pupil dilation) by acting on a1 receptors on radial muscles
Liver: Increase HGO by glycogenolysis and gluconeogensis
Adipose: lipolysis
Ureters and bladder: constriction of trigone and internal urethral sphincter (sympa stops peeing). Trigone stretching causes the reflex to pee, if you constrict it then you avoid this reflex to pee so less peeing
Blood vessels: vasoconstriction
Skin: piloerection
Where is the principle action of beta-blockers?
KIDNEYS – it inhibits the beta-1 mediated increase in renin secretion It also decreases heart rate and contractility but its main action in reducing blood pressure is through the kidneys
Describe the relative selectivity of adrenaline and noradrenaline.
Noradrenaline is more selective for ALPHA-receptors Adrenaline is more selective for BETA-receptors
Describe the action of pre-synaptic alpha-2 receptors.
Pre-synaptic alpha-2 receptors have a negative influence on noradrenaline synthesis and release
State five directly acting SNS agonists.
Phenylephrine – alpha-1
Clonidine – alpha-2
Dobutamine – beta-1
Salbutamol – beta-2
Isoprenaline – beta 1+ beta 2
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 on the surface of mast cells causes massive release of the stored mediators leading to the symptoms of hypersensitivity.
State some symptoms of hypersensitivity.
CVS: Increase in capillary permeability leads to increased movement of fluid into the tissues, leading to swelling eg in tongue and lips
This depletes the circulating fluid volume leading to adrop in blood pressure -> ANAPHYLACTIC SHOCK (and collapse the circulatory system leading to unconsciousness)
Respiratory: bronchial smooth muscle and constriction of muscles around the throat causing respiratory distress and difficulty in swallowing.
GI tract: It can also constrict GI smooth muscle causing stomach cramps, vomiting and diarrhoea
Why is adrenaline more effective than noradrenaline in dealingwith hypersensitivity?
DR ABC- airway, breathing and circulation
During the hypersensitivity reaction, the most important problem to deal with is to maintain AIRWAY. Adrenaline is more selective for beta receptors than noradrenaline so is better at causing beta-2 mediated bronchodilation, thus opening up the airways.
Adrenaline also stimulates the heart via beta-1 to support blood pressure.
Adrenaline also acts on the alpha-1 receptors to cause vasoconstriction and an increase in TPR and blood pressure.
Adrenaline can also slow down the release of histamine from mast cells via beta-2.
State some other clinical uses of adrenaline other than to deal with hypersensitivity
Asthma (adrenaline helps bronchodilation)
Acute bronchospasm (which narrows bronchi) associated with chronic bronchitis or emphysema
Cardiogenic Shock- sudden inability of heart to pump sufficient oxygen rich blood, can happen in MI which causes heart to lose its ability to work properly
Spinal Anaesthesia- spinal anaesthesia decreases BP because it could interfere with the sympathetic outflow
Local Anaesthesia- Vasoconstriction near point of local anaesthesia – Prolongs action of anaesthesia because you stop blood flow from carrying anaesthesia away
Which receptors are involved in the generation of aqueous humour in the eye?
Alpha-1 involved in vasoconstriction of the vessels in the ciliary body
Alpha 2 decreases humour production
Beta-receptors control the enzyme that makes the aqueous humour and stimulation promotes humour production
Why is adrenaline used as a treatment for glaucoma?
Adrenaline can stimulate the alpha-1 receptors to cause vasoconstriction of the vessels in the ciliary body thus reducing the blood flow within the ciliary body -> reduced production of aqueous humour
State some unwanted actions of adrenaline.
Secretions – reduced and thickened mucous, so dry mouth
The production of saliva is stimulated both by the sympathetic nervous system and the parasympathetic.
The saliva stimulated by sympathetic innervation is thicker, and saliva stimulated parasympathetically is more fluid-like.
CNS – minimal
CVS effects (main side effects)
- tachycardia, palpitations, arrhythmias
- cold extremities, hypertension
- overdose – cerebral haemorrhage, pulmonary oedema
GIT – minimal
Skeletal muscle - tremor caused by adrenergic receptors on the skeletal muscle
Describe the resistance to degradation of phenylephrine.
Phenylephrine is MORE resistant to COMT (uptake 2) degradation than adrenaline but it is NOT resistant to MAO (uptake 1) degradation
Phenylephrine- resistant to COMT
Isoprenaline- resistant to MAO-A
State some clinical uses of phenylephrine.
Mydriatic (pupil dilation)
Nasal decongestant
It causes vasoconstriction
Congestion is caused by inflammation in nasal nose. Inflammation causes fluid leakage from capillaries. Phenylephrine causes vasoconstriction so theres less blood flow and hence less fluid leakage, so less inflammation in the nose
Describe the mechanism of clonidine.
- Clonidine is an a2 agonist and it causes less NA synthesis and release.
- Central action: Central action by binding to a2 receptors in brainstem within the baroreceptor pathway to reduce central sympathetic outflow (baroreceptor reflex uses cranial nerves). This leads to a global antisympathetic effect
It is an antihypertensive that acts by reducing NA binding to B1 receptors in kidneys, hence less A2 formed via the RAAS pathway
State some clinical uses of clonidine.
It is used to treat hypertension and migraine.
Describe the susceptibility to breakdown of isoprenaline compared to adrenaline.
Isoprenaline is resistant to uptake 1/MAO breakdown(MAO is the enzyme in the uptake 1 pathway, COMT is the enzyme in uptake 2)
State three clinical uses of isoprenaline.
Cardiogenic Shock
Myocardial Infarction (can then lead to cardiogenic shock)
Acute Heart Failure (can then lead to cardiogenic shock)
What is a big problem with isoprenaline with regards to its action on beta 2 receptors?
Isoprenaline brings about positive effects via Beta-1 stimulation However, stimulation of Beta-2 leads to vasodilation of blood vessels in the muscles -> pooling of blood within the muscles -> reduced venous return Via the baroreceptors, you get a reflex tachycardia So the beta-1 effects are good for patients with heart failure but the beta-2 effects are not
State a clinical use of dobutamine.
Cardiogenic shock
Why its good:
- Lacks isoprenaline’s reflex tachycardia which is why it is used instead of isoprenaline now
- Plasma half life 2 minutes (rapidly metabolised by COMT), good for emergency and allows control
Describe the relative resistance of salbutamol to degradation.
Relative resistance to MAO and COMT
State and explain two clinical uses of salbutamol.
- Asthma
- b2-relaxation of bronchial smooth muscle
- inhibition of release of brochoconstrictor substances from mast cells (mast cells have B2 receptors too which are inhibitory). - Treatment of threatened premature labour
- b2-relaxation of uterine smooth muscle
State some side effects of salbutamol.
Reflex tachycardia because salbutamol has selectivity of B2 over others
Tremor (beta receptors are on skeletal muscle and so can cause tremor when stimulated),
blood sugar dysregulation (beta receptors on islet cells can affect glucose regulation)
State two indirectly acting SNS agonists.
Cocaine Tyramine
