Adrenergic Transmission (noradrenaline transmission) Flashcards
Where is the best site for drug intervention in sympathetic transmission and why?
At the neuroeffector junction - allows for specific targeting of function.
If CNS or sympathetic ganglia were targeted, the effects would be non-specific and likely widespread.
How is noradrenaline synthesised?
From tyrosine.
Tyrosine > DOPA > Dopamine > Noradrenaline >Adrenaline
What enzyme converts tyrosine to DOPA?
Tyrosine hydroxylase
How can conversion of tyrosine to DOPA be inhibited?
By α-methyl-tyrosine inhibiting tyrosine hydroxylase (competitive inhibition)
What enzyme converts DOPA to dopamine?
DOPA decarboxylase
What enzyme converts dopamine to noradrenaline?
Dopamine β-hydroxylase
What enzyme converts noradrenaline to adrenaline?
Phenylethanol-amine N-methyl transferase
What is the effect of α-methyl-tyrosine?
Reduced DOPA production > reduced noradrenaline
Less sympathetic effect > decreases blood pressure.
Side effects: sedation, Parkinsonism, Diarrhoea.
How is noradrenaline stored?
In vesicles (transported in via VMAT) If not in vesicles will be broken down by monoamineoxidase (MAO)
What drug inhibits noradrenaline storage? What is the effects of the drug?
Reserpine.
Blocks VMAT - prevents storage in vesicles.
Noradrenaline will be broken down by monoamineoxidase. - Depletes neurons of NA
Used as an antihypertensive.
What drug inhibits noradrenaline release? How does it work?
Clonidine.
Normally α2 receptors have a negative feedback mechanism to reduce NA release once activate.
Clonidine in an V2 agonist - stimulates receptor as NA would - prevents further NA release.
What drugs promote noradrenaline release and how do they work?
Amphetamines.
Enter the pre-ganglionic neuron via uptake-1 channels and displace NA in vesicles.
Amphetamines also inhibits monoamineoxidase hence less NA is broken down so more is free for release across synapse.
What are the 3 types of G-protein and which adrenergic receptors are they associated to?
Gq -α1 receptor
Gi - α2 receptor
Gs - β1,2,3 receptors
What is the signalling pathway of an α1 receptor?
Gq protein coupled.
Activates phospholipase C.
PIP3 > IP3 + DAG
IPs increases Ca2+ concentration from sarcoplasmic reticulum.
DAG activate protein kinase C.
Ultimately leads to smooth muscle contraction.
What is the signalling pathway of an α2 receptor?
Gi coupled. Inhibits adenylylcylase. Decreased cAMP production. Decreased protein kinase A activation Decreased exocytosis - inhibits neurotransmitter release.
What is the function of α-blockers?
Block sympathetic vasoconstriction - decrease blood pressure.
Name two non-selective α-blockers and why they are not in clinical use.
Phenoxybenzamine
Phentolamine
Cause severe reflex tachycardia - shut down negative feedback mechanism.
Name two selective α-blockers.
Doxazosin
Tamsulosin
Safer than non-selective α-blockers.
Outline the β1 and β2 signalling pathways.
Both Gs coupled.
Activate adenylylcyclase.
Increased cAMP production
Activates protein kinase A.
β1 - increased cardiac myocyte contraction
β2 - phosphorylation of myosin light chain kinase - smooth muscle relaxation.
What is salbutamol?
β2 agonist - inhibition causes relaxation of smooth muscle in airways. Bronchodilation.
What is the function of β-blockers?
Block sympathetic nervous input to the heart.
Decrease heart rate and stroke force.
Decrease cardiac output and blood pressure.
What is a non-selective blocker (a1 and β receptors) drug and what does it do?
Labetolol
Reduces arterial blood pressure - fewer side effects than a-blockers.
Used in stable congestive heart failure.
What is a β-selective blocker (β1 and β2) and what is its function?
Propanolol
Treatment in disturbances in cardiac rhythm, myocardial infarction
What is a β1 subtype selective blocker? What is its function?
Atenolol
Treatment in disturbances in cardiac rhythm, myocardial infarction
Give 5 adverse effects of β-blockers.
Fatigue - reduced cardiac output Reduced peripheral blood flow Bronchoconstriction Increased risk of cardiac failure (sympathetic tone effected) Risk of hypoglycaemia
What does monoamineoxidase catalyse?
Noradrenaline > noradrenaline aldehyde > DOMA
Name 3 monoamineoxidase inhibitors?
phenylazine
moclobemide
selegiline
What is the significance of tyramine and the ‘cheese effect’?
Tyramine is found in cheese, yogurt and wine. Tyramine is normally degraded by MAO
In patients taking MAO inhibitors, tyramine is not metabolised and can lead to hypertensive crisis.
What is salbutamol?
β2 agonist - promotes bronchodilation
Treatment of asthma
What is atenolol?
β1 antagonist (beta-blocker)
Treatment of hypertension
What is doxasin?
α1 antagonist
Treatment of hypertension
What is labetolol?
Non-selective blocker (α1 and beta-blocker)
Treatment for hypertension
