Drug Action Flashcards
Ligand gated ion channels
Fast synaptic transmission -> ms
Acetylcholine-> NAChR-> INa-> depolarisation
Opening a single channel lets thousands of ions through-> amplified
Common characteristic of drug receptors
1) selective binding site for endogenous messengers
2) act as molecular switches
3) signal is amplified -> second messengers, enzyme activity
G protein couple receptors
Most common
Seconds to minuets
800 different types-> three main types-> Gs,GI,Gq
Regulated by guanine binding
All activate heterotrimeric G protiens
-> Ga-> binds guanine nucleotides-> s,i,q isoforms lead to differing responses
-> Gb and Gy-> form a dimer
G protein cycle
Inactive-> Ga binds GDP and forms a complex with Gby
Activated GPCRs catalyse exchange of GDP-> GTP
Ga-GTP and Ga separate
Ga-GTP and Gby activate receptor proteins
GTPase activity of Ga converts GTP to GDP
Ga-GDP re associates with Gby
Cyclic AMP as a second messenger
Synthesised from ATP by adenyl cyclase
Triggers cellular response by binding and activating protein kinase A
PKA -> phosphorylates target protiens
Gs-> stimulate adenyl cyclase -> b2 adrenal receptors
Gi-> inhibit adenyl cyclase-> a2 adrenal receptors
Gq coupled receptors
Activates membrane enzyme-> phospholipase C
- > hydrolyses the plasma membrane lipid phosphatidylinositol 4,5-bis phosphate (PIP2)
- > two intracellular messengers produced
- > inositol 1,4,5 trisphosphate-> diffusable -> Ca release-> DAG-> PKC -> muscle contraction
- > diacylglyceol-> membrane bound
Adrenoceptors
a1 adrenoceptors-> Gq-> increased Ca2+->smooth muscle contraction, increased epithelial cell fluid secretion, increase endocrine hormone secretion
a2-> Gi-> decreased cAMP-> decreased neurotransmitter release! smooth muscle contraction, decreased epithelial cell fluid section and hormone secretion
b1,2,3-> Gs-> increased cAMP-> increased neurotransmitter release! smooth muscle relaxation, increased fluid and hormone secretion
GPCR super family
Senses-> rod and cone opsins, taste receptors, olfactory receptors
Autonomic function-> adrenoreceptors, muscarinic receptors + peptide/nucleotide/lipid
CNS-> all main neurotransmitters
Development-> adhesion GPCRS
Infection-> viral, chemokine
Catalytic receptors
Has enzyme activity activated by hormone binding
Eg tyrosine kinase receptors-> insulin receptor
Tyr binds receptor-> kinase adds phosphate to target protein
Adapter proteins recognise the phosphorylated receptor and produce multiple signals, including gene expression changes
Nuclear receptors
Transcription factors
Eg steroid hormones
Ligands diffuse across membrane to intracellular receptors-> activate receptors-> bind DNA and promote transcription -> amplified-> many mRNA produced per site
Affinity
Ability of drug to bind a receptor
Efficacy
Relationship between receptor occupancy and the ability to initiate a response
Receptor agonist
Binds and activate the target response
Has affinity and efficacy
Reproduces effect of endogenous messenger
Receptor antagonist
Only has affinity
Binds but does not activate target
Blocks messenger responses
Receptor occupancy
Obeys laws of mass action-> equilibrium reached
Receptor occupancy = a
Kd=dissociation constant
a= [D]/[D]+Kd
If conc of D=Kd-> a=1/2
-> Kd can also be defined as conc of drug needed to occupy half of its receptors-> measure of binding affinity
Uses if Kd
Related slightly different drugs to effects on activity
Side effects at lower concs-> greater affinity for those tissue receptors higher selectivity -> higher affinity
Amount of drug molecules in a solution
Use conc=amount of drug in moles/volume in litres
Then Avogadro’s number-> 6x10^23 molecules per mole so x by that
EC50
Concentration response curves-> sigmoid
EC50-> effective concentration of agonist for 50% of its maximal response
A measure of agonist potency -> smaller ec50-> more potent
Rmax-> max response -> lower means lower efficacy
Determined by affinity and efficacy and properties of functional response-> amplification -> so not a direct measure of drug interaction
Competitive agonism
Receptor binding site is shared with agonist drug
Reversible-> agonist binds non covalently and can dissociate from receptor
-> inhibition by agonist is surmountable with increasing agonist conc
-> agonist potency is reduced in the presence of antagonist but not it’s maximal response -> graph shifts right
Non competitive agonism
Agonist binds but at a different (Allosteric site)
- > effects on response are non surmountable
- > decreased max response
