1 - mechanism of drug action and drug target Flashcards
G protein coupled receptors
- Neurotransmitter binds
- conformational change in receptor
- activation of G protein
- G protein can bind to to activate or inactivaet ion channels
- Also can result in increase camp - leading to ion conductance of a channel , or trigger kinase cascades that result in phosphorylation or dephosphorylation of target proteins
Kd and affinity
High Kd = low affinity
Kd - conc at which drug is bound to 50% of receptors - could be agonist or antagonist
Potency definition
-how much drug needed if high potency?
How much drug is required in order to produce a particular effect
EC50 - conc of drug producing 50% maximal response
-high potency - small amount of drug required
full agonists, Partial agonists , antagonists reversible and irreversible , inverse agonist , tissue properties
full agonists - affinity and efficacy
partial agonist - Bind with affinity however do not produce maximal response - even when 100% of receptors are bound
antagonist - affinity but no efficacy (no conformational change in receptor) - prevent agonist from binding
irreversible - increase agonist and increase effect
reversible - increase agonist - doesn’t work
Inverse agonist - drug binds and has negative efficacy - decrease receptor activity
agonism - depends on efficacy and also tissue properties
Where do most drugs have their effect
Ion channels, enzymes, carrier proteins, receptors
4 step process of neurotransmission - and how it works?
synthesis, release, binding to receptor, inactivation
Cholien and Na enter cell
Choline and acetyl coa –> Ach (ChAT)
Ach synthesized into vesicles
Action potenial - voltage gated Ca channels open , calcium flows in
ACH will fuse with membrane into synaptic celft
ACH will bind to nicotnic ach receptor on post synaptic cell and also M1 receptor
AChE - will convert Ach to choline and acetate
Choline will go back into cell via choline Na pump
What happens if block synthesis and release
Synthesis - vesicles will be empty, so no neurotransmission
- Choline trasnporter (rate limiting step)
- ChAT enzyme
Release
- calcium channels - voltage dependent can block these - no release of neurotransmitter
- Vesicular Ach transporter - ach packaged into synaptic vesicles (could block this)
- Vesicles held in cytoskeleton by Ca2+ sensitive vesicle membrane proteins
- AP reaches terminal, Ca rushes into cell, triggers vesicular fusion with cell membrane - release of Ach into synapse
Types of receptors
ligand gated ion channels, g protein coupled receptors, tyrosine kinase/ cytokine receptors, nuclear/steroid hormone receptors
How does feedback loop work and what happens if u block it
Presynaptic receptor M2 - can bind ach and this will stop further release of ach by inhibiting voltage gated ca channels
-if you block this receptor then can get increased ach in the synaptic cleft
What happens at low doses of an irreversible antagonist?
can appera to look liek a reversibale antagonist because if u increase hte agonist conc then you can still get emax response - however this shows that you can get emax response even when not all receptors are bound
Inactivation of receptor , what happens if inhibit this
- transport back into the presynaptic synapse
- enzymatic degration (acetyl choline)
- AChE - enzyme breaking down ach
- irreversible ache inhibitors are highly toxic - because they can stop reuptake and keep the ach in cleft causing contraction for ages
- if you inhibit this - sweating, dimmed vision, vomiting ect.
- e.g - DFP
reversible
- work for short amount of time, can help in myasthian gravis (muslce weakness- breakdown of ach receptors) - when here is cholenergic function - once molecuel has tiem to activate more receptors
- also can treat alzihmers disease
Serotonin transporter and inhibitors
synthesis and then packaged back into receptors and moved across membrane
- 5HT -reuptakes serotonin
- Selective serotonin reuptake inhibitors - anti-depressants - can increase serotonin in synaptic cleft to improve mood
