Pharmacology Of The Sympathetic NS Flashcards
What receptors are present at ganglions?
Cholinergic nicotinic
What is the main neurotransmitter of the sympathetic NS?
What are the exceptions?
Noradrenaline
Sweat glands - muscarinic (ACh)
Adrenal medulla - nicotinic (ACh)
What are some alpha sympathetic effects?
Mydriasis (a1)
Decreased salivation (a1)
Arteriole constriction (a1)
Gluconeogenesis
Smooth muscle relaxation in GI tract
GI tract and bladder sphincter contraction (a1)
What are some beta sympathetic effects?
Ciliary muscle relaxation
Increased heart rate via SAN (b1)
Increased heart contractile force (b1)
Bronchodilation (b2)
Gluconeogenesis (b2)
Smooth muscle relaxation in GI tract and bladder (b2)
Skeletal muscle relaxation (b2)
Why do we not target the CNS with drugs?
Must pass blood-brain barrier
Likely to have widespread effects
What 5 processes in sympathetic neuroeffector junctions be affected by drugs?
Noradrenaline synthesis
Noradrenaline storage
Noradrenaline release
Post-synaptic adrenergic receptor activation
Termination of signalling
What enzyme metabolises unprotected monoamines?
Monoamine oxidase (MAO)
What are some examples of monoamines?
Noradrenaline
Dopamine
Serotonin
How is noradrenaline taken into vesicles?
Vesicular monoamine transporter (VMAT)
What drug inhibits noradrenaline storage?
Reserpine
How does reserpine work?
Blocks VMAT so noradrenaline isn’t taken up into vesicles
Noradrenaline metabolised by MAO
What reserpine used to treat?
Hypertension
What drug is used to inhibit noradrenaline synthesis?
a-methyl-tyrosine
How does a-methyl-tyrosine work?
Competitive inhibitor against tyrosine
Inhibits tyrosine hydroxylase
Blocks formation of DOPA (from tyrosine)
What is a-methyl-tyrosine used for clinically?
Decrease blood pressure in phaechromocytoma (adrenal gland tumour)
How is noradrenaline transported back into the varicosity after release?
“Uptake 1” channels
How do drugs inhibit noradrenaline storage?
Enter varicosity via “uptake 1” channels
Displace noradrenaline in pre-synaptic vesicles
Noradrenaline metabolised by MAO
What drugs can be used to inhibit noradrenaline release?
Guanethidine
Clonodine
Amphetamine
Tyramine
Ephedrine
How is release of noradrenaline usually regulated?
After release of noradrenaline, noradrenaline binds to a2 adrenoceptor on pre-synaptic membrane
Inhibits further noradrenaline release by a negative feedback system
What is another name for the a2 adrenoceptor?
Autoreceptor
How does clonodine work?
a2 adrenoceptor agonist
Mimics effect of high [NA] in synaptic cleft
How do amphetamine/tyramine/ephedrine affect noradrenaline release?
Enter varicosity via “uptake 1” channels
Compete with noradrenaline to enter vesicles via VMAT
Noradrenaline leaks into cleft
What is the secondary effect of amphetamine?
Inhibits MAO
What type of receptor are adrenoceptors?
7TM GPCR
What G-protein is coupled to a1 adrenoceptors?
Gq
What G-protein is coupled to a2 adrenoceptors?
Gi
What G-protein is coupled to b adrenoceptors?
Gs
Where are a1 adrenoceptors mainly found?
Post-synaptic smooth muscle
What does activation of a1 adrenoceptors cause?
Activation of PLC, IP3, DAG signalling
Constriction and secretion
What does activation of a2 adrenoceptors cause?
Inhibition of adenylyl cyclase
Reduced cAMP so less PKA stimulated
Inhibit neurotransmitter release
What do a-blockers do?
Block sympathetic vasoconstriction tone
To decrease blood pressure
What is the important side effect of non-selective a-blockers?
Severe reflex tachycardia
Why are a2-blockers not used?
Too widespread
What are a1-blockers used as?
Antihypertensive agents (treat hypertension)
Give an example of an a1-blocker
DOXAZOSIN
Tamsulosin
What are some side effects of a1-blockers?
Postural hypotension
Diarrhoea
Nasal congestion
Where are b1 adrenoceptors mainly found?
Cardiac muscle
What does activation of b1 adrenoceptors cause?
Stimulation of adenylyl cyclase
Increase cAMP
Increase force and rate of heart contractions
Where are b2 adrenoceptors mainly found?
Smooth and skeletal muscle
Vasculature and airways
What does activation of b2 adrenoceptors cause?
Stimulate adenylyl cyclase
Increased cAMP
Smooth muscle relaxation (bronchodilation, vasodilation)
(Glycogen mobilisation in liver)
What type of drug is labetolol?
a1 and b blockers
What does labetolol do overall?
Reduce arterial blood pressure
What is an example of a b-selective blocker?
Propanolol
What is propanolol used to treat?
Disturbances in cardiac rhythm
MI
Angina
What are b1-selective blockers often called?
Cardio-selective blockers
What is an example of a b1-blocker?
Atenolol
Why are b1-blockers better than b-blockers?
Fewer side effects
What are some adverse effects of b-blockers?
Fatigue (due to decreased cardiac output)
Reduced peripheral blood flow
BRONCHOCONSTRICTION
Increased risk of cardiac failure
Risk of HYPOGLYCAEMIA (patients on insulin therapy)
What are b2-agonists used for?
Asthma
What is an example of a b2-agonist?
Salbutamol
What does salbutamol do to treat asthma?
Promotes bronchodilation
Also induces premature labour
What are catecholamines metabolised by?
MAO
Catechol-O-methyl transferase (COMT) - in both neuronal and non-neuronal tissue
Where is MAO(A) found? (5)
CNS
Lung endothelium
Liver
GI tract
Placenta
Where is MAO(B) found? (2)
CNS
Blood platelets
What are some examples of MAO inhibitors?
Phenylzine
Moclobemide (A)
Selegiline (B)
What is moclobemide selective for?
MAO(A)
What is selegiline selective for?
MAO(B)
Why is it dangerous to eat cheese/yogurt or drink wine when taking MAO-inhibitors?
Tyramine
Degraded by MAO usually
Tyramine not degraded but converted into noradrenaline
Hypertensive crisis
