Mechanism of Drug Action Flashcards
What are the four primary drug targets?
Ion channels
Enzymes
Carrier molecules
Receptors
What is the only other drug target?
DNA
What are the four steps of neurotransmission?
Neurotransmitter synthesis
Neurotransmitter release
Action on receptors
Inactivation
What are the two sites of action for inhibiting ACh synthesis?
Choline transporter (uptakes choline and is rate limiting step in ACh synthesis) Choline Acetyl Transferease (synthesis of choline)
How is ACh released?
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
What are the four main families of receptor?
Ligand gated ion channels
G-protein coupled receptors
Tyrosine kinase/cytokine receptors
Nuclear/steroid hormone receptor
Describe ligand gated ion channels?
Located in the membrane
Select among different ions
Direct coupling
Oligomeric assembly of subunits surrounding the pore
What type of receptor is a nicotinic acetylcholinic receptor?
Ligand gated ion channel
Describe Nicotinic Acetylcholine Receptors
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
Describe the receptor pore
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
What are some ionotropic receptors that are used as drug targets?
GABA
Glutamate
Nicotinic
How do G-protein coupled receptors work?
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
How do tyrosine kinase receptors work and what do they do?
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)
What are Vascular Endothelial Growth Factor Receptors associated with?
Angiogenesis and pathological conditions (cancer/rheumatoid arthritis)
What is the mechanism behind VEGFR2?
Ligand stimulated receptor dimerisation
Autophosphorylation of tyrosine residues in cytoplasmic domain
Causes a number of biological functions
Describe the proliferation pathway
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
How do drugs bind to receptors?
Van der Waals forces -weak
Hydrogen binding -stronger
Ionic interactions -between atoms with opposite charges, stronger than hydrogen weaker than convalent
Covalent -irreversible
What is Kd?
The concentration of a drug which occupies 50% of the receptor population
What is affinity?
The higher the affinity of a drug for the receptor, the lower the concentration at which is produces a given level of receptor occupancy
Why are concentration-response curves not a good measure of affinity? What is a better measure?
Receptor occupancy and response are not proportional
A better measure is the biological response depending on concentration
What is C50?
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
What is efficacy?
The ability of a drug to bind to a receptor and cause a change in the receptor’s action-measured by Emax
What are the differences between agonists, inverse agonists and antagonists?
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
What is the difference between partial and full agonists?
Full agonists-maximum tissue response
Partial agonists-less than maximum tissue response even at 100% receptor occupancy
What is reversible competitive antagonism?
Bind to receptor in a reversible manner to compete directly with agonist binding
What is irreversible antagonism?
Drug covalently bonds to receptor which reduces the number of receptors available to the agonist
Why is inactivation important and what are its mechanisms?
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
What effect do irreversible inhibitors of acetylcholine esterase have?
Highly toxic loads of side effects
What effect do reversible inhibitors of acetylcholine esterase have?
Used to treat myasthenia gravis
Used to treat Alzheimer’s disease
What is the serotonin 5HT Transporter?
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
Describe how a serotonin transporter works?
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
What are SSRIs?
Selective serotonin reuptake inhibitors
Citalopram
