Drug Action

Question 0

Ligand gated ion channels

Answer 0

Fast synaptic transmission -> ms
Acetylcholine-> NAChR-> INa-> depolarisation
Opening a single channel lets thousands of ions through-> amplified

Question 1

Common characteristic of drug receptors

Answer 1

1) selective binding site for endogenous messengers
2) act as molecular switches
3) signal is amplified -> second messengers, enzyme activity

Question 2

G protein couple receptors

Answer 2

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

Question 3

G protein cycle

Answer 3

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

Question 4

Cyclic AMP as a second messenger

Answer 4

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

Question 5

Gq coupled receptors

Answer 5

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

Question 6

Adrenoceptors

Answer 6

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

Question 7

GPCR super family

Answer 7

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

Question 8

Catalytic receptors

Answer 8

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

Question 9

Nuclear receptors

Answer 9

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

Question 10

Affinity

Answer 10

Ability of drug to bind a receptor

Question 11

Efficacy

Answer 11

Relationship between receptor occupancy and the ability to initiate a response

Question 12

Receptor agonist

Answer 12

Binds and activate the target response
Has affinity and efficacy
Reproduces effect of endogenous messenger

Question 13

Receptor antagonist

Answer 13

Only has affinity
Binds but does not activate target
Blocks messenger responses

Question 14

Receptor occupancy

Answer 14

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

Question 15

Uses if Kd

Answer 15

Related slightly different drugs to effects on activity

Side effects at lower concs-> greater affinity for those tissue receptors higher selectivity -> higher affinity

Question 16

Amount of drug molecules in a solution

Answer 16

Use conc=amount of drug in moles/volume in litres

Then Avogadro’s number-> 6x10^23 molecules per mole so x by that

Question 17

EC50

Answer 17

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

Question 18

Competitive agonism

Answer 18

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

Question 19

Non competitive agonism

Answer 19

Agonist binds but at a different (Allosteric site)

• > effects on response are non surmountable
• > decreased max response