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Drug interactions
| Term | Definition |
|---|---|
| Agonist characteristics | Has affinity and efficacy, can give full or partial response |
| EC50 | Potency of drug at particular [ ] -> [agonist] causing 50% max response |
| What does EC50 not indicate? | Receptor occupation -> # receptors activated not proportional to response size -> amplification |
| Antagonist characteristics | Has affinity but no efficacy -> no response given |
| What is a receptor? | Anything that binds to a drug -> acts as signal transducer |
| What forces bind ligands to receptors | Strongest -> covalent, ionic, H-bond, van der Waals, hydrophobic |
| Nature of covalent bonds | More permanent interaction -> less likely -> phenoxybenzamine to alpha-AR |
| Majority of bonds are which type? | H-bond, vdW, hydrophobic -> many for strength |
| More forces =? | Better binding of ligand w/ receptor -> more specific interaction |
| Where does ACh act? | Sympathetic preganglionic + postganglionic sweat glands/terminating at adrenal medulla, parasympathetic pre/postganglionic, motor nerves for skeletal muscles |
| Where does NA act? | Sympathetic postganglionic |
| Where does 5-HT act? | Luminally/basolaterally from ECF-like cells in GI tract, synthesised in serotonergic CNS neurons |
| Specificity | Ability of drug to produce singular response, low specificity -> receptor may activate multiple effector responses -> side effects |
| Selectivity | Ability of drug to identify receptor of interest, low selectivity -> agonist/antagonist to different receptors in different locations |
| Hyperbolic relationship | [agonist] and response size |
| Sigmoid relationship | log[agonist] and response size |
| Potency | [agonist] causing particular EC50 -> right shift -> higher EC50 -> lower potency -> more drug needed for particular response |
| Competitive antagonist | Shift log[agonist] v response curve right but same max response |
| Formyl/proprionylcholine dose-response curve | Shift curve to right but same max response -> higher EC50 -> less potent at this receptor |
| Butyryl/valerylcholine dose-response curve | Shifts curve to right but lower max response -> partial agonist |
| Drug units | micromolar |
| Receptor units | nanograms |
| DR complex units | nanograms |
| Affinity constant of D | Ka = k+1 / k-1 |
| Affinity constant units | Products/reactants ->1/micromolar -> e6 M-1 -> large Ka values |
| Affinity constant findings | Large Ka -> high affinity of D for R -> more likely DR complex is formed |
| Dissociation constant of D | [D] = 1/Ka when occupancy = 1/2 |
| Dissociation constant units | 1/Ka = M -> e-6 M -> small Kd values |
| Dissociation constant findings | Large Kd -> low affinity of D for R -> less likely DR complex is formed |
| What does dissociation constant not tell us? | Doesn't indicate receptor occupancy |
| Occupancy equation | alpha = [D] Ka / 1 + [D]Ka |
| When is radioligand binding used? | Functional based assays are unsuitable -> many steps to achieve function -> inaccurate experiments |
| What does radioligand binding measure | Binding of drug to receptor -> % receptor occupancy -> doesn't revel absolute receptor # in tissue |
| Radioligand binding experiment | Increase [free drug] -> increase [DR] -> will only detect unbound drug in xcs -> all receptors occupied w/ drug, bound drug has heavier mass -> centrifuge, done under cold temperatures -> prevents [DR] dissociation |
| Total binding =? | Specific binding (D+R) + non-specific binding |
| Total binding curve shape | Parabola |
| Non-specific binding curve shape | Linear |
| Specific binding curve shape | Parabola -> total - non-specific |
| What is B? | Specific binding at radioligand concentration [D] |
| What is Bmax? | Maximal specific binding -> hypothetical as never reaches maximum |
| What plots can we get from radioligand binding? | Double reciprocal plot, Scatchard plot |
| Double reciprocal plot | 1/B v 1/[D], x-intercept = -Ka, y-intercept = 1/Bmax, m = 1/BmaxKa |
| Scatchard plot | B/[D] v B, x-intercept = Bmax, y-intercept = BmaxKa, m = -Ka |
| Assumptions for radioligand binding | Drug in excess to total receptors, reaction is eqbm, reaction is reversible, only one binding site |
| What can Scatchard plot be used for? | Receptors with >1 binding site -> cooperativity |
| Hill plot | log (B / Bmax - B) v log[D], m (nH) = # binding sites |
| Radioligand binding competitive ligand affinity determination | Determine binding affinities of unlabeled drugs bindign to same receptor via competition |
| What types of fixed [radioligand] are used? | Homologous -> competing ligand is same as radioligands, heterologous -> competing ligand is different to radioligand |
| Occupancy for radioligand binding equation | alpha = [U] Ku / 1 + [U]Ku + [L]KL |
| Cheng Prusoff equation | Ku = 1 + [L]KL / IC50 |
| Radioligand binding competitive ligand affinity determination curve | L binding v log[U], -ve sigmoid curve offset from x-axis -> non-specific binding |
| What do spare receptors tell us? | EC50 ≠ Kd -> increasing occupancy by antagonists does not effect max response until all spare receptors are antagonised -> dose-response shifts right before partial agonist curves appear -> increasing EC50 |
| Partial agonist characteristics | Act as competitive antagonists but still have some efficacy -> same EC50 as full agonists = Kd |
| What do partial agonists not have? | No receptor reserve -> no right shift -> all spare receptors occupied -> antagonise full agonist response |
| Fixed [partial agonist] w/ variable [full agonist] | Low [full agonist] -> larger response than full agonist -> partial at receptors generate response, mid [full agonist] -> lower response than full agonist -> competition btwn full/partial, high [full agonist] -> same response as full agonist |
| Dose ratio equation | [D2] / [D1] = 1 + [A]K2 |
| What does dose ratio assume? | 1:1 binding of drug/receptor, antagonist binds reversibly to receptors, spare receptors present |
| What does does ratio not assume? | Any relationships between response and occupancy |
| Schild analysis | % response v log [agonist] -> multiple [antagonist] competing w/ agonist, plot log(dose ratio -1) v log[antagonist] -> x-intercept = -logK2 |
Created by:
vykleung
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