Year One Pharmacodynamics Gavin Chapman

What is pharmacodynamics? “What a drug does to the body” Drugs act by binding to receptors They then cause either activation or inhibition of a regular body process to give a biological response What do you need to know? A little bit about the different types of receptor Different ways which drugs can affect receptors A little bit about pharmacological terminology

What are receptors? Receptors = Proteins that are situated intracellularly or on cell membrane that ligands bind to Endogenous ligands (e.g. neurotransmitters) and exogenous ligands (i.e. drugs/poisons etc.) Binding of a ligand to a receptor causes the receptor to change shape leading to a functional response Two key points: Binding of a ligand to a receptor is reversible The degree of functional response is proportional to the number of receptors bound i.e. If all receptors are bound by ligand response will be bigger than if only 1 or 2 are bound

Types of Receptor Channel-linked GPCR Ligands bind to receptor which causes channel to open allowing ions to pass in/out of cell e.g. nicotinic acetylcholine receptor GPCR Receptor is linked to family of G proteins which then cause biological response through secondary messenger systems (enzymes, ion channels etc.) Enzymes to be aware of are adenylate cyclase and guanylate cyclase which generate cAMP and cGMP Kinase-linked = receptor is linked to a kinase which leads to series of phosphorylation reactions (e.g. the insulin receptor) DNA-linked = receptor is intracellular and activation/inhibition affects gene transcription so biological response takes longer to occur (hours to days)

Which of these is a GPCR? Insulin receptor Steroid receptor GABAergic receptor Beta-adrenergic receptor Cholinergic receptor

Which of these is a GPCR? Insulin receptor = kinase-linked Steroid receptor = DNA-linked GABAergic receptor = channel-linked Beta-adrenergic receptor Cholinergic receptor = channel-linked

Affinity Ligand (drug) binding to a receptor is a reversible process Constant state of flux where ligand is bound and then not bound to a receptor The rate at which this happens is based on how “attracted” to the receptor the ligand is Affinity = Term used to describe strength of attraction of ligand to receptor High affinity means the drug will be bound for longer

Efficacy and Potency Efficacy = The extent to which a drug can produce a response when it occupies all binding sites on the receptor This is equal to the Emax on a dose-response curve! Therapeutic Efficacy = Comparing drugs which via different pharmacological mechanisms (i.e. receptors) to give the same biological response For examples, loop diuretics and thiazide diuretics and their effect on Na+ excretion at the kidney Potency = The amount of drug required to produce its response The more potent the drug the lower the ED50 Potency is related to affinity – if high affinity then at low dose a drug will still bind and produce its response A more potent drug may not be as efficacious as a less potent drug and vice versa!

Types of drugs Agonist = Binds + initiates a biological response (maximum response!) Partial Agonist = Bind to receptor but is unable to initiate a maximum biological response (even when all receptors are occupied!) Inverse Agonist = Binds to receptor but causes opposite effect of the agonist at the same receptor For a receptor to have an inverse agonist, the receptor itself must have some degree of inherent activity Antagonist = Binds to a receptor and blocks the effect of the agonist at that receptor Competitive = The antagonist competes for the same binding site as the agonist Non-competitive = The antagonist binds elsewhere and in doing so changes the shape of the receptor or in some other way prevents the agonist from binding This will become clearer when we look at dose response curves!

Antagonists and Dose Response Non-competitive antagonists do not compete with the receptor binding site They bind elsewhere Either changes the shape of the agonist binding site or the presence of the antagonist physically blocks access to the site They therefore limit the maximum response that an agonist can have at the receptor, even if you give increasing doses of agonist

The Dose Response Curve This should be really simple to follow… X-axis = Drug dose Y-axis = Biological response Emax = The maximum biological response a drug can produce No matter how much more drug you give you can’t get a bigger response ED50 = The dose of drug which produces half its maximal response (do Emax / 2 and then look on x-axis for drug conc.) Effective Dose Range = Usually between 20-80% Emax

What is each of these drugs? A – most potent D – least potent If B is an agonist then C is a competitive antagonist – it has shifted the dose response curve to the right (but you can still reach maximum response by saturating the receptor with higher concentrations of agonist which will therefore “out-compete” the antagonist for the same binding site)

Selectivity Although we call drugs β1 agonists/antagonists these drugs also most likely have effects on β2 receptors too For an agonist: Selectivity is determined by the ratio of the ED50 at the two different subtypes The ED50 of adrenaline at beta-1 is 10mg and at the beta-2 receptor is 100mg Is adrenaline selective? For which receptor is it selective? Selective for beta-1 receptor by a factor of 10. ED50 lower for beta-1 – this means lower concentration of adrenaline is needed to stimulate beta-1 receptors compared to beta-2 receptors. In practice if you gave adrenaline at 10mg dose you would activate beta-1 receptors but not beta-2 (this needs higher agonist conc!) IMPORTANT: This is an example. The facts (re adrenaline ED50 and selectivity is not true, I have just made up numbers etc to illustrate the point!) For an antagonist: Selectivity is determined by the shift in agonist curve (using a non-selective agonist and again looking at the ED50)

Antagonist Selectivity X-axis is dose of isoprenaline (agonist) and y-axis is response Isoprenaline curve with no antagonist is given by line A Line B and C is the response curve when atenolol is given as well as isoprenaline B is bronchodilatation and is due to isoprenaline’s action on beta-2 receptors C is heart rate and due to isoprenaline’s action on beta-1 receptors Is atenolol selective? For which receptor? How many times? Selective for beta-1 receptors by a factor of 10 (shift in ED50 is 10 times comparing B to C). Beta-1 selective as more agonist is needed to overcome atenolol’s effect on beta-1 compared to beta-2

Important Point Selectivity DOES NOT equal specificity Drugs which are selective can still have effects on other receptors, especially if they are given in high doses NEVER give a person with asthma a beta-blocker!!

Adverse Effects and the Therapeutic Index Receptors are everywhere meaning drugs will have more than one effect Remember they are not specific, only selective! Chemotherapy for cancer often works by stopping cell division Because the drugs work everywhere they stop normal cell division too! Side effects – hair loss etc. Therapeutic Index = Ratio of ED50 for a desirable effect and the ED50 for an adverse effect If TI is less than 10 drugs are tricky to prescribe Main examples are warfarin, digoxin and insulin etc.

Any questions? s1106054@sms.ed.ac.uk