Mechanism of Drug Action

Question 1

What are the four primary drug targets?

Answer 1

Ion channels
Enzymes
Carrier molecules
Receptors

Question 2

What is the only other drug target?

Answer 2

DNA

Question 3

What are the four steps of neurotransmission?

Answer 3

Neurotransmitter synthesis
Neurotransmitter release
Action on receptors
Inactivation

Question 4

What are the two sites of action for inhibiting ACh synthesis?

Answer 4

Choline transporter (uptakes choline and is rate limiting step in ACh synthesis)
Choline Acetyl Transferease (synthesis of choline)

Question 5

How is ACh released?

Answer 5

Packed into synaptic vesicles by ACh transporter
Vesicles are held in cytoskeleton by Ca2+ sensitive vesicle membrane proteins
When an action potential reaches the terminal there is vesicular fusion with the membrane and ACh is released

Question 6

What are the four main families of receptor?

Answer 6

Ligand gated ion channels
G-protein coupled receptors
Tyrosine kinase/cytokine receptors
Nuclear/steroid hormone receptor

Question 7

Describe ligand gated ion channels?

Answer 7

Located in the membrane
Select among different ions
Direct coupling
Oligomeric assembly of subunits surrounding the pore

Question 8

What type of receptor is a nicotinic acetylcholinic receptor?

Answer 8

Ligand gated ion channel

Question 9

Describe Nicotinic Acetylcholine Receptors

Answer 9

5 subunits with each subunit having 4 transmembrane domains
ACh binding site is a dimer formed by three or more peptides on a subunit and two peptides on an adjacent subunit
Both ACh binding sites need to be activated for channel opening

Question 10

Describe the receptor pore

Answer 10

Ion conductivity is determined by amino acids
Excitatory neurotransmitters cause an increase in Na+ and K+ permeability
The inside of the cell becomes positive and more likely to have an action potential
For nACh, a mutation causes the ion channel from being cation selective to anion selective

Question 11

What are some ionotropic receptors that are used as drug targets?

Answer 11

GABA
Glutamate
Nicotinic

Question 12

How do G-protein coupled receptors work?

Answer 12

Usually pre synaptic receptors
Leads to inhibition of voltage sensitive Ca2+ channels
Which leads to decreased neurotransmitter release
Drugs which block presynaptic receptors lead to a 10 fold decrease in neurotransmitter release

Question 13

How do tyrosine kinase receptors work and what do they do?

Answer 13

Receptor acts as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins
These receptors mediate the actions of growth factors, cytokines and certain hormones (VEGFR)

Question 14

What are Vascular Endothelial Growth Factor Receptors associated with?

Answer 14

Angiogenesis and pathological conditions (cancer/rheumatoid arthritis)

Question 15

What is the mechanism behind VEGFR2?

Answer 15

Ligand stimulated receptor dimerisation
Autophosphorylation of tyrosine residues in cytoplasmic domain
Causes a number of biological functions

Question 16

Describe the proliferation pathway

Answer 16

Receptor activation activates PLCy
PLCy hydrolyses PIP2 to DAG and IP3
DAG activates PKC
PKC activates ERK via Raf and MEK
ERK leads to increased gene transcription

Question 17

How do drugs bind to receptors?

Answer 17

Van der Waals forces -weak
Hydrogen binding -stronger
Ionic interactions -between atoms with opposite charges, stronger than hydrogen weaker than convalent
Covalent -irreversible

Question 18

What is Kd?

Answer 18

The concentration of a drug which occupies 50% of the receptor population

Question 19

What is affinity?

Answer 19

The higher the affinity of a drug for the receptor, the lower the concentration at which is produces a given level of receptor occupancy

Question 20

Why are concentration-response curves not a good measure of affinity? What is a better measure?

Answer 20

Receptor occupancy and response are not proportional

A better measure is the biological response depending on concentration

Question 21

What is C50?

Answer 21

C50 measures the potency of an agonist
It is the effective concentration of an agonist that produces 50% of the maximal response
The more potent the agonist, the lower the C50

Question 22

What is efficacy?

Answer 22

The ability of a drug to bind to a receptor and cause a change in the receptor’s action-measured by Emax

Question 23

What are the differences between agonists, inverse agonists and antagonists?

Answer 23

Agonists-drug that promotes cellular response (positive efficacy)
Inverse agonists-drug that inhibits basal receptor activity (negative efficacy)
Antagonist-drug that binds but has no effect on activity

Question 24

What is the difference between partial and full agonists?

Answer 24

Full agonists-maximum tissue response

Partial agonists-less than maximum tissue response even at 100% receptor occupancy

Question 25

What is reversible competitive antagonism?

Answer 25

Bind to receptor in a reversible manner to compete directly with agonist binding

Question 26

What is irreversible antagonism?

Answer 26

Drug covalently bonds to receptor which reduces the number of receptors available to the agonist

Question 27

Why is inactivation important and what are its mechanisms?

Answer 27

Once in synapse, the neurotransmitter must be inactivated in order to prevent constant stimulation of the post synaptic cell
Two mechanisms: Transport back into the pre-synaptic synapse
Enzymatic degradation

Question 28

What effect do irreversible inhibitors of acetylcholine esterase have?

Answer 28

Highly toxic loads of side effects

Question 29

What effect do reversible inhibitors of acetylcholine esterase have?

Answer 29

Used to treat myasthenia gravis

Used to treat Alzheimer’s disease

Question 30

What is the serotonin 5HT Transporter?

Answer 30

Involved in sleep, appetite, memory, sexual behaviour
Synthesized from the amino acid precursor tryptophan and released into synapses following an action potential
Reuptake determines the extent and duration of receptor activation

Question 31

Describe how a serotonin transporter works?

Answer 31

Na+ binds to the carrier then to 5HT
Molecules then translocated into the membrane and dissociate
K+ binds and is translocated to the outside of the membrane and dissociates

Question 32

What are SSRIs?

Answer 32

Selective serotonin reuptake inhibitors

Citalopram