Lecture 9 - SNS Agonists Flashcards
Which region of the spinal cord do sympathetic nerves originate from?
Thoracolumbar
What is always the neurotransmitter leaving the preganglionic fibre?
Acetylcholine
Most sympathetic post-ganglionic fibres release which neurotransmitter?
Noradrenaline
What are the two other sympathetic neurotransmitters released post-ganglionically?
- Adrenaline (80%) and NA (20%) from adrenal medulla
- Acetylcholine (sweat glands)
What does “directly acting sympathomimetic” mean?
Molecules that mimic the actions of adrenaline and noradrenaline by stimulating (directly acting on) adrenoceptors
Where are directly acting sympathomimetic drugs mainly used?
- Cardiovascular system
- Eyes
- Lungs
ALL adrenoceptors can be activated by NA or Adrenaline, but which molecule is more selective for which receptor type?
Noradrenaline = more selective for alpha receptors
Adrenaline = more selective for beta receptors
What is the process of noradrenaline synthesis in the presynaptic neuron?
- Tyrosine converted to DOPA by tyrosine hydroxylase
- DOPA is then converted to dopamine
- Dopamine is then converted to noradrenaline
How is noradrenaline removed from the synapse?
- Reuptake into the presynaptic terminal
- Uptake into extra neuronal tissue or into blood
What are 5 examples of directly acting SNS agonists and which adrenoceptor types are they selective for?
Adrenaline - non-selective Phenylephrine - alpha 1 Clonidine - alpha 2 Dobutamine - beta 1 Salbutamol - beta 2
What does the selectivity of each directly acting SNS agonist depend on and what does this mean happens?
CONCENTRATION
- At low conc, the drugs are relatively selective
- Increasing the conc increases the chance of binding to other adrenoceptor types
What does “indirectly acting sympathomimetic” mean?
A molecule that mimics the actions of SNS neurotransmitters but does not act at the adrenoceptors
What are the 6 clinical uses of adrenaline?
- Allergic reaction and anaphylactic shock
- COPD, chronic bronchitis, emphysema and asthma (emergencies)
- Cardiogenic shock, acute management of heart block (intravenous)
- Spinal anaesthesia (intravenous)
- To prolong duration of local anaesthetic (local admin)
- Glaucoma treatment (eye drops)
Why is adrenaline clinically useful in cases of allergic reactions and anaphylactic shock?
Reverses severe and potentially life-threatening hypotension and bronchoconstriction
- Administered IV
- Causes vasoconstriction, increase in HR and contractility, bronchodilation, inhibits release of hypotensive and bronchoconstrictor mediators
Why is adrenaline given instead of noradrenaline in cases of allergic reactions and anaphylactic shock?
Adrenaline is more selective to beta adrenoceptors and beta adrenoceptors are more crucial in these cases
- b2 - bronchodilation
- b1 - tachycardia (boosts BP)
- a1 - vasoconstriction
Priority is restoring breathing so selectivity for b2 is prioritised
What does cases of COPD, chronic bronchitis, emphysema and asthma does adrenaline treat and why adrenaline?
- Given intramuscularly or subcutaneously for asthma emergencies
- Acute bronchospasm
Adrenaline has bronchodilator actions (beta2) and suppression of mediator release
- However, b2 selective agonists are preferable (adrenaline non-selective)
What is cardiogenic shock?
Sudden inability of heart to pump sufficient oxygen-rich blood
What does cardiogenic shock lead to?
- Severe heart attack/MI
- Cardiac arrest
How does Adrenaline treat cardiogenic shock and by what route is it given?
Acts on b1 receptors - boosts HR and force of contraction
- Increases peripheral resistance which increases return of blood to the heart
Why is adrenaline administered with spinal anaesthesia and how is it administered?
Maintains blood pressure as epidural anaesthetics affect the sympathetic nerves which usually control BP
- Intravenous administration
How is adrenaline used to prolong duration of local anaesthetics and how is it administered?
Vasoconstrictor properties (a1) reduce blood flow to the region and prolongs duration of action, allows for minimisation of dose of local anaesthetic - Local administration
How does adrenaline treat Glaucoma?
Decreases aqueous humour production
- Stimulates a1 receptors which causes vasoconstriction of blood vessels in the ciliary body, less blood in the vessels reduces the volume of fluid in the aqueous humour thus reducing the intraocular pressure
What are the 5 areas of side effects of adrenaline and what side effects are produced there?
Secretions - reduced and thickened mucus (dry mouth)
CNS - minimal as adrenaline doesn’t cross BBB
CVS - Vasoconstriction (cold extremities), tachycardia, palpitations, arrhythmias, hypertension
- An overdose may cause cerebral haemorrhage, pulmonary oedema/embolism
GI tract - minimal
Skeletal muscle - tremor
What are the 3 administration routes for NA/adrenaline, how well is it absorbed orally, how readily is it metabolised in the gut/liver/other tissues and what is the duration or action?
Intravenous Intramuscular Locally/topically - Poorly absorbed orally - Rapid metabolism in gut, liver and other tissues - Duration of action = minutes
Phenylephrine is very chemically similar to adrenaline but has a difference. What is this difference, what does it mean for the molecule and what is phenylephrine’s selectivity?
- Contains one fewer hydroxyl group
- Makes it more resistant to metabolism by COMT but not by MAO
- Selective for a1 receptors (a1»a2»>b1/b2)
What are the 3 clinical uses of phenylephrine?
- Vasoconstrictor - local anaesthetics and anaphylactic shock
- Mydriatic (eye drops) - a1 constricts radial muscle causing mydriasis, pupil dilation, inspect fungus of the eye
- Nasal decongestant (nose drops/orally) - useful in colds/flu/hayfever, vasoconstricts nasal blood vessels reducing volume of fluid released
What is the unwanted effect produced by phenylephrine?
Hypertension, slight increase in BP
What is clonidine’s selectivity?
A2 receptors
a2»a1»>b1/2
What is clonidine used to treat and how is it administered?
Hypertension and migraine
- decreases sympathetic tone via a2 receptor inhibition of NA release, central action in the brainstem within baroreceptor pathway to decrease sympathetic outflow that would normally increase BP
- administered intravenously or orally
What is isoprenaline’s selectivity, what extra functional groups does it have and what does this mean for the molecule?
Possesses two extra methyl groups than adrenaline
- More resistant to MAO and Uptake 1 protein than A
Non-selective beta agonist (b1=b2»»a1/2)
What are the clinical uses of isoprenaline and what is its plasma half-life?
Treatment for heart block, cardiogenic shock, acute heart failure, MI
- Very potent b1 effects on the heart, increases HR and contractility
Discontinued use in asthma treatment due to unwanted actions
- b2 stimulation in vascular smooth muscle decreased venous BP which triggered reflex tachycardia and dysrhythmias
- 2 hours plasma half-life
What is dobutamine’s selectivity?
B1 agonist
b1»b2»>a1/2
What is the clinical use of dobutamine, why is it preferable to isoprenaline and what is its plasma half-life?
Treats heart block - cardiogenic shock (IV admin)
- Used in hospital settings for emergencies
- Preferable as it lacks isoprenaline’s reflex tachycardia
- Also preferable as only has plasma half-life of 2 minutes
What is Salbutamol a derivative of, what is it resistant to, and what is its selectivity?
Synthetic catecholamine derivative
- Relative resistance to MAO and COMT
- b2 selective (b2»b1»>a1/2)
What is salbutamol used for clinically?
Treatment of asthma
- b2 relaxation of bronchial smooth muscle
- inhibition of release of bronchoconstrictor substances
Treatment of threatened uncomplicated premature labour
- b2 relaxation of uterine smooth muscle
What are the unwanted actions of salbutamol?
Reflex tachycardia
Tremor
Blood sugar dysregulation (b2 mediated in liver)
What is an example of an indirectly acting SNS agonist and how does it do so?
Cocaine!
- Inhibits Uptake 1 (MAO) inhibiting reuptake of dopamine and NA producing euphoria
What is the limited clinical use of cocaine?
Used with local anaesthetic in ophthalmology (rare)
Not co-administered with adrenaline
How well absorbed is cocaine, how readily does it cross BBB, what is its plasma half-life, what enzymes is it metabolised by, and where is it excreted from the body?
- Well absorbed at all sites
- Crosses BBB readily
- 30 mins plasma half-life
- Metabolised by plasma esterases and hepatic enzymes
- Excreted in urine
What are the actions/unwanted actions of cocaine in the CNS and CVS? (also affects somewhere else)
CNS
- Low doses = euphoria, excitement, increased motor activity
- High doses = activation of vomiting centre, respiratory failure, convulsions, death
CVS
- Low doses = tachycardia, vasoconstriction and raised blood pressure
- High doses = ventricular fibrillation and cardiac arrest
Depression of medullary respiratory centre - respiratory failure and death
What is tyramine, where is it found and why is important?
A dietary amino acid (monoamine) found in cheese, red wine and soy sauce
- indirectly acting sympathomimetic
- can cause life-threatening hypertensive crises in patients taking MAO (monoamine oxidase) inhibitors
Why does tyramine cause hypertensive crisis in those taking MAO inhibitors? (which is the key step?)
Normally, tyramine would undergo extensive first-pass metabolism and not enter the CNS.
- However, when it does enter the CNS, it causes its effect in adrenergic neurons
- It has some weak agonistic activity at post-synaptic adrenoceptors
- Competes with catecholamines for Uptake 1 protein and is taken up into presynaptic terminal
- Displaces NA from storage vesicles into cytosol
- (KEY STEP) Competes with NA for sites on MAO, reducing the amount of NA broken down by MAO
- NA now in the cytosol leaks through neuronal membrane into synapse and acts at postsynaptic adrenoceptors along with any NA in vesicles
= results in hypertensive crisis
