BIOM 3090 Lecture 4: BIOM 3090 class notes lec 4
9 Jun 2018
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Pharmacodynamics: Dose-Response Relationships
- Drug receptor binding
o The study of pharmacodynamics is based on the concept of drug-
receptor binding
▪ When a sufficient number of receptors are bound in the cell
then a cellular effect can be demonstrated
▪ Cumulative cellular responses produce organ and patient
responses
▪ A drug-receptor binding model predicting cellular effects is
needed
▪ The affinity of a drug is most influences by changes in the off
rate
▪ L+R → Kon/Koff LR
• R = proportion of free (unoccupied or unbound)
receptors
• Kon: forward or association rate of equation
• Koff: reverse or dissociation rate of constant
• Koff/Kon: is the Kd or dissociation rate constant; Kd is the
constant for each drug-receptor combination
• Ka: association rate constant; also equal to 1/Kd
• LR: proportion of ligand (L) bound receptors (R)
o By law of mass action the relationship between free (unoccupied) and
bound receptors can be describe as follows:
▪ [L]•[R]•Kon= [LR]•Koff
▪ Or re-arranged: [L]•[R]/[LR] = Kd
▪ If we let Ro = total # of receptors, then [R0] = [R] + [LR]
▪ Rearranged: [LR]/R0= [L]/ Kd + [L]
• Fraction of total receptors bound by ligand is [LR]/R0
• When [L]= Kd, the [LR]/R0 = 0.5
• Kd corresponds to ligand concentration [L] where 50%
of receptors are bound (occupied) by ligand
• Maximum ligand receptor binding occurs when [LR] =
[R0] or [LR]/[R0] = 1.0
• KdA (Drug A) < KdB (Drug B)
o Lower Kd indicates a tighter ligand receptor
binding or greater affinity
- Dose-response (D-R) relationships
o For many drugs, the response (effect) is proportional to the
concentration of receptors bound by drug
▪ D-R is closely related to drug receptor binding
▪ [DR]/R0 = [D]/Kd + [D] = effect/max. effect
o there are 2 major types of D-R relationships
▪ graded; D-R on an individual
▪ quantal; D-R on a population of individuals
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- Graded D-R relationships
o They are scalar (eg. Heart rate change or % analgesia)
o Efficiency (E-max): maximal response produced by the drug at that
receptor
o Potency (EC50): drug concentration that elicits 50% of the maximal
response (Emax); function of affinity and efficacy
- Quantal D-R relationships
o Quantal D-R plots the % of the population that responds to a given
dose of drug as a function of the drug dose
o Biological variation in individuals sees responses over a range of
doses in differencing individual
▪ Responses define as present or absent (sleep/no sleep, alive or
dead after 12 months)
o Useful for predicting effects of a given drug in a given population
▪ Pop based median effective dose (ED50)
▪ Also determining population based median toxic (TD50) and
lethal doses (LD50)
▪ Therapeutic index (TD50/ED50): gives estimate of relative
safety margin of drug
- Quantifying D-R: agonism
o Agonists are drugs that bind a receptor and stabilize it in a particular
conformation, usually the active conformation
▪ R* (unbound active receptor) and DR (bound inactive
receptor) are unstable forms and assumed to exist only briefly
for most drugs and receptors
o Quantitative description of potency and efficacy
▪ This relationship supports the concepts
• More potent drugs have a greater affinity (lower Kd) for
their receptors
• More efficacious drugs (larger Emax) usually cause a
greater proportion of their receptors to be activated
o Full versus Partial Agonists
▪ Full agonists are capable of eliciting maximal responses at a
given receptor
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
[l] [r] kon= [lr] koff: or re-arranged: [l] [r]/[lr] = kd, rearranged: [lr]/r0= [l]/ [r0] or [lr]/[r0] = 1. 0: kda (drug a) < kdb (drug b, lower kd indicates a tighter ligand receptor binding or greater affinity. Dose-response (d-r) relationships: for many drugs, the response (effect) is proportional to the concentration of receptors bound by drug, d-r is closely related to drug receptor binding. [dr]/r0 = [d]/kd + [d] = effect/max. effect: there are 2 major types of d-r relationships, graded; d-r on an individual, quantal; d-r on a population of individuals. Quantifying d-r: receptor antagonists: a receptor antagonist is a molecule that, usually binds to the active site of the receptor (i. e. agonist binding site, has affinity to the receptor. Inhibits the action of the agonist by preventing its binding to the receptor: has no effect in the absence of the agonist.
