From Physiological Systems To Molecular Drug Targets II Flashcards
Name the 3 locations where nicotinic ACh receptors are found
- Muscle (neuromuscular junctions)
- Ganglion
- CNS
What is the function of nicotinic ACh receptors?
Excitation
Name an agonist for nicotinic ACh receptors
Acetyl Choline
How many transmembrane domains does a subunit of a nAChR have?
4
How many subunits does a nicotinic receptor have?
5: alpha, alpha, beta, delta, gamma
What do the nicotinic receptor subunits come together to form?
An ion channel
What is a nicotinic receptor’s ion channel permeable to?
Na+
How do nicotinic receptors cause excitation?
- 2 ACh molecules bind to the nAChR
- Conformational change occurs
- Ion channel opens
- Na+ enters the cell causing an increase in positive charge inside of the cell
- This causes excitation
What acts as the receptor gate in a nicotinic receptor?
- 2 alpha helices, 1 in each alpha subunit
- Conformational change when ACh binds causes them to open the ion channel
What is an issue when synthesising drugs targeted at the ANS ganglia nAChRs?
The drugs do not discriminate between sympathetic and parasympathetic nerves
Where do neuromuscular blocking agents work?
Neuromuscular junction
Name 2 types of neuromuscular blocking agents
- Competitive blockers
- Depolarising blockers
What are competitive blockers?
Competitive antagonists of nAChRs
(Increase concentration of agonist = decrease power of antagonist)
What are depolarising blockers?
Agonists which cause a depolarising block of the muscle fibre endplate
How do depolarising blockers work?
- Switch the receptor on = increase in Na+ entering the cell
- Blocker stops channel from closing so sodium keeps coming into the cell
- Eventually too much sodium enters the cell and prevents further excitation
- Activation of receptor switched off
Give a use of competitive blockers
- Muscle relaxants as an adjunct to anaesthesia
- In particular in obstetrics as they do not cross into the placenta
Name 3 examples of a competitive blocker
- Tubocurarine
- Pancuronium
- Vecuronium
Why are competitive blockers used as muscle relaxants?
They selectively work on the nAChRs at the neuromuscular junction, rather than at the ganglia and the brain/CNS
Why are different competitive blockers used for minor vs major surgeries
Some have shorter half lives than others therefore work for shorter periods of time
Give an example of a use of depolarising blockers
Cause paralysis during anaesthesia
How do depolarising blockers cause paralysis?
- The muscle contracts due to maintained depolarisation
- Muscle cannot repolarise (relax)
- This causes loss of excitability (sodium channels cannot inactivate)
- Therefore the continual stimulation of the NMJ by DB’s causes muscle paralysis
Name an example of a depolarising blocker
Succinylcholine (Suxamethonium)
Works on nAChRs
What is succinylcholine used for?
To cause paralysis during anaesthesia
Minor surgery
Why is suxamethonium so short acting? (10 mins)
Because it is rapidly hydrolysed by cholinesterases
What is the indication for Donepezil?
For the treatment of mild-moderate Alzheimer’s Disease
What is the mechanism of action of Donepezil?
Anticholinesterase = inhibits ACh-esterase
How does botulinum toxin type A work?
It blocks vesicle docking/release and therefore prevents the release of ACh
How can botulinum toxin type A be deadly?
Can cause respiratory paralysis
Why is botulinum toxin type A so toxic?
It has a very low LD50 value
LD50 = 10ng/kg
List 3 therapeutic indications for botulinum toxin
- Excessive muscle spasm - can result from stroke, brain or spinal cord injury, CP
- Migraine/headache treatment - facial muscle contraction stimulates headaches
- Excessive secretion - severe underarm sweating or salivation
What receptors does noradrenaline act on?
α or β-adrenoceptors
What is noradrenaline release regulated by?
Inhibitory presynaptic α2-adrenoceptors
What are β-blockers?
Blockers of the β-adrenoceptors
How is adrenaline released into the bloodstream?
It is secreted from the adrenal gland
What is dopamine?
A precursor for noradrenaline and adrenaline
And a CNS transmitter
Which amino acid are adrenaline, noradrenaline and dopamine generated from?
Tyrosine
Describe the biogenic amine synthesis process
Tyrosine –> DOPA –> Dopamine –> Noradrenaline –> Adrenaline
How can one of the substances in biogenic amine synthesis build up?
If the enzyme which converts the substance into something else becomes inhibited
What acts as negative feedback in biogenic amine synthesis?
- Build up of noradrenaline
- Negative feedback on to tyrosine hydroxylase (converts Tyrosine to DOPA)
How many subtypes of adrenoceptor are there?
5: α1 α2 β1 β2 β3
Where is the β1-adrenoceptor located?
Heart
Where is the β2-adrenoceptor located?
Smooth muscle
Where is the α1-adrenoceptor located?
Smooth muscle
Where is the α2-adrenoceptor located?
Smooth muscle
What type of G protein is the α1-adrenoceptor coupled to?
Gαq
What type of G protein does the α2-adrenoceptor couple to?
Gαi/o
What type of G protein do the β-adrenoceptors couple to?
Gαs
What response does the α1-adrenoceptor cause when its G protein is bound?
Increase in IP3
What response does the α2-adrenoceptor cause when bound to its G protein?
Decrease in cAMP
What response do the β-adrenoceptors cause when their G protein is bound?
Increase in cAMP
Name the enzyme that Gαs (with β1/2/3 adrenoceptors) stimulates
Adenylate cyclase
What process does adenylate cyclase carry out?
Converts ATP –> cAMP
What effect does increased cAMP have?
Increased protein phosphorylation
What would be the agonist of choice to activate the α1-adrenoceptor
Noradrenaline
What would be the agonist of choice to activate the α2-adrenoceptor
Adrenaline
What would be the agonist of choice to activate the β-adrenoceptors
Isoprenaline
What effect does NA cause when bound to an α1 receptor
(α selective)
- Vasoconstriction
- This causes reflex bradycardia due to baroreceptor response
- ACh release = slows vagal nerve
- Overall increase in BP
What effect does isoprenaline have when it binds to β adrenoceptors? (β- selective)
Causes vasodilation (β2) and tachycardia (β1) Overall decrease in BP
What effect does adrenaline have when it binds to a β or α-adenoceptor?
Higher affinity for β receptor but can still bind to α
Slight increase in BP
What are adrenergic synapses also known as?
Varicosities (= swelling)
How do sympathomimetics work?
Mimic CNS
What is the indication for salbutamol?
Asthma treatment
What is the mechanism of action for salbutamol?
Selective β2 adrenoceptor agonist
Causes bronchodilation
What is the indication for atenolol?
Hypertension
What is the mechanism of action of atenolol?
Cardioselective β1 adrenoceptor antagonist
(= β blocker)
What is the indication of pseudoephedrine?
Nasal decongestion
What is the mechanism of action of pseudoephedrine? (Sudafed)
Substrate for biogenic amine uptake system = sympathomimetic
- Mimics NA and gets taken up by uptake system
- Therefore NA displaced from vesicles
- Released NA builds up in synapatic cleft = vasoconstriction of mucosal blood vessels (α1 adrenoceptors)
- This reduces fluid build up in the nose
