pharmacology - principles of drug action at receptors

define a receptor

a receptor is a protein macromolecule inserted across the lipid bilayer of cells. their functions are to recognise extracellular molecules and transduction ( change cell activity after detecting presence of an extracellular molecule ). receptors bind with their complimentary ligands as they are highly specific

define the lock and key model of binding

drug molecules bind to receptors complimentarily to produce an effect

what are the two ways that drugs can act when binding to a receptor

they can either mimic or block the effects of endogenous messenger molecules

define what endogenous messenger molecules means

drugs produced in the body to bring about certain biochemical changes

what is the name of the receptor that the neurotransmitter that exogenous nicotine and neurotransmitter ACh bind to

nicotinic acetylcholine receptors

how does the high specificity of drug binding affect side effects of drugs

it means fewer side effects in clinical trials

what graph does the binding of receptor to drug produce and what equation can map this

D on x-axis, percentage on y-axis forming a rectangular hyperbola

D + R ←> DR

plot the proportion of receptors occupied (p) vs log[D]

it produces a log graph showing a symmetrical sygmoid

define the affinity of a drug for its receptor

the affinity of a drug for its receptor is quantified as the molar concentration of drug required to occupy 50% of receptors at equillibrium

• NOTE: drugs with high affinity have low KD

notation of drug concentration

KD

what is KD

the equillibrium dissociation constant a measure of how tighly a receptor holds on to its drug once bound

how does KD affect dissociation rate

drugs with high affinity/low KD have optimal binding to the receptor and stay bound for a long time by having a slow dissociation rate

compare the binding graphs of drugs with high vs low affinity

what is the role of K₊₁ and K_-1 in the equillibrium dissociation constant K_D. include equations

K₊₁ is the rate constant telling us the liklihood of the forward rate occuring while K_-1 tells the liklihood of the backward rate.

rate of forward reaction = K₊₁[D][R]

rate of backward reaction = K_-1[DR]

at equillibrium, backward rate = forward reaction so

K₊₁[D][R] = K_-1[DR]

K_D = K_-1/K₊₁ = [D][R] / [DR]

define an agonist

a chemical substance with affinity to its receptor, binds to activate the receptor and then produces a receptor by having efficacy to the receptor. agonists cause a conformational change of the receptor active site shape leading to a response in the cell or tissue

use an equation to show the pathway of agonists activtating receptors to produce a biological response

A + R < - > AR < - > AR* → response

(the transition from AR < - > AR* represents the efficacy i.e. the ability of a drug to activate its receptor)

define efficacy in a binding reaction

the ability of a drug to activate its receptor and produce a response

differentiate E₅₀ (50% drug response) and K_D (50% occupance of available receptors) in agonists

1. overall response to an agonist is determined by its affinity and efficacy while receptor occupance is determined only by affinity

2. there are many steps between agonist drug binding and the measured response

outline the two broad types of agonists

• all naturally occuring neutrotransmitters and hormones are agonists e.g. adrenaline, ACh, insulin, dopamine

• agonists can be FULL or PARTIAL agonists

• full agonists have high efficacy and so are very effective when activating receptors and producing biological response (often produce maximal response whilst only activating a fraction of available receptors)

• partial agonists have low efficacy and therefore less effective at activating receptors and less able to produce a biological response (often fail to produce a full response despite occupying all available receptors)

draw a log graph depicting the binding response with full versus partial agonists

E_max achieved with full agonists but not in partial

define an antagonist

• drugs than inhibit the effects of ligands like neurotransmitters, hormones and some drugs

• they dont have efficacy but have affinity

• commonly used clinically

• e.g. beta blockers inhibit the beta-1 receptor thus lowering blood pressure

outline and explain 3 forms of antagonism and include examples of each

chemical - use one drug to chemically inactivate another e.g. dimercaprol in arsenic poisoning (no receptors involved)

pharmacokinetic - one drug alters the way the body deals with another e.g. some antacids reduce absorbtion of the antiepileptic drug phenytoin from the gut (no receptors involved)

physiological - two drugs acting to produce opposing effects and cancelling eachother out e.g. noradrenaline increasing HR while acetylcholine decreases it. both drugs are antagonists but working on different receptors

outline the 2 forms of antagonism

1. competitive: compete with the agonist for the same site on the receptor molecule but dont activate it i.e. have affinity but no efficacy . can be reversible or irreversible

2. non-competitive antagonists act on an allosteric site of the receptor or another molecule closely associated with it. they are also reversible or irreversible

examples of reversible competitive antagonists and how they are overcome

pancuronium, cetirizine, propranolol

used to inhibit the effects of a neurotransmitter or hormone

their inhibitory effects can be overcome by increasing the concentration of the agonist i.e. the blockade is surmountable

graph the response of reversible competitive vs non competitive antagonists

graph the response of irreversible competitive vs non competitive antagonists

explain the effects of irreversible competitive antagonist

the graph shift is not parallel when adding the antagonist to the agonist as the inhibition is not surmountable when increasing concentration of the agonist