lecture 5 - dose-response curve

agonist & antagonist (post-synaptic)

• drugs can be competitive/orthosteric or non-competitive/allosteric at their “favorite” receptor(s)

• 4 useful things to know about a drug (i.e., its molecules) are:

  1. specificity → how well a drug targets specific NT receptors & their subtypes

  2. affinity → how attracted a drug is to a receptor type, & how strong/long it binds to it; “stickiness” (before dissociation)

  3. potency → dose of drug (usually in mg) needed to produce a given effect (e.g., relive pain or induce sleep)

  4. efficacy → drug’s tendency to activate the receptor once it has bound to it (e.g., drug’s ability to create desired therapeutic effect)

antagonists

• full antagonist → drug is orthosteric w/ endogenous ligand (NT) for receptor site, BUT has no effect on its own; “receptor-blocker”

allosteric modulators

• allosteric modulators → doesn’t directly interfere w/ receptor, BUT messes when also in presence of NT

  • drug is allosteric to NTs binding site, but its presence affects affinity or efficacy of that NT for its receptor

  • positive allosteric modulators (PAM) → increase NT affinity or efficacy

  • negative allosteric modulators (NAM) → decrease NT affinity or efficacy

agonist - full & partial agonist

• full agonist → drug is orthosteric, has nearly identical effect on neural response as the endogenous ligand (NT); an “NT mimic”

• partial agonist → drug is orthosteric, but can’t produce maximum efficacy compared to NT (no matter the dose)

two types of dose response curves

• plotting dose against % of subjects showing a given response at that dose

• plotting dose against intensity of response observed in a single person at a single dose

receptor specificity, affinity, potency & efficacy

• dose-response curves → tells us about a drug’s potency & efficacy

  • potency ex → if 5mg of Drug A relieves pain as effectively as 10mg of Drug B, then A is twice as potent as B

  • efficacy ex → stimulant effects: methamphetamine is slightly more efficacious than d-amphetamine

Measuring Efficacy: Effective Dose (ED)

• ED₅₀ → drug dose producing desired effect in 50% of test subjects (human or non-human animals)

  • effective dose for 50% reduction intensity (e.g., pain threshold)

ED, LD, & Margins of Safety

• drugs have therapeutic effects & side effects (from annoying to lethal)

  • therapeutic effects ↔ side effects ↔ toxicity/lethality'

• Lethal dose (LD₅₀) → dose that is lethal for 50% of experimental animals

  • for animal welfare, being replaced; 3R goals: reduce, refine, replace

• margins of safety → range of which you want to stay in to get desired effects before lethal dose

therapeutic index (T.I.) & toxic dose (T.D.)

• T.I. → ratio of the LD₅₀ to ED₅₀

• ex: T.I. = LD₅₀/ED₅₀

  • used in animal studies during early drug development

  • on human study used to T.I. to compare alcohol to other drugs (using emergency room data, autopsies)

• further refined as data becomes available by replacing LD₅₀ w/ toxic dose (T.D.); ex: T.I. = TD₅₀/ED₅₀

  • “toxic” can mean to a specific body system, organ, etc

  • more refined measure for human safety

• if 2 drugs produce equivalent therapeutic effects, the better drug is the one with the higher T.I.