chapter02 (1)

Copyright © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Principles of Pharmacology

The Pathophysiologic Basis of Drug

Therapy

Principles of Pharmacology

The Pathophysiologic Basis of Drug

Therapy


Chapter 2

Pharmacodynamics

Chapter 2

Pharmacodynamics


Ligand–Receptor Binding CurvesLigand–Receptor Binding Curves• Figure 2-1

A. Linear graphs of drug–receptor binding for two drugs with different values of Kd.

B. Semilogarithmic graphs of the same drug–receptor binding. Kd is the equilibrium dissociation constant for a

given drug–receptor interaction—a lower Kd indicates a

tighter drug–receptor interaction (higher affinity). Because of this relationship, Drug A, which has the lower Kd, will bind a higher proportion of total receptors than Drug

B at any given drug concentration.

Notice that Kd corresponds to the ligand concentration [L] at

which 50% of the receptors are bound (occupied) by ligand. [L] is the concentration of free (unbound) ligand (drug), [LR] is the concentration of ligand–receptor complexes, and [Ro]

is the total concentration of occupied and unoccupied receptors.

Thus, [LR]/[Ro] is the fractional occupancy of receptors, or

the fraction of total receptors that are occupied (bound) by ligand.


Graded Dose–Response CurvesGraded Dose–Response Curves

• Figure 2-2

Graded dose–response curves demonstrate the effect of a drug as a function of its concentration.

A. Linear graphs of graded dose–response curves for two drugs.

B. Semilogarithmic graphs of the same dose–response curves.

Note the close resemblance to Figure 2-1: the fraction of occupied receptors [LR]/[Ro] has been replaced by the

fractional effect E/Emax, where E is a quantifiable response to a

drug (for example, an increase in blood pressure). EC50 is the

potency of the drug, or the concentration at which the drug elicits 50% of its maximal effect.

In the figure, Drug A is more potent than Drug B because it elicits a half-maximal effect at a lower concentration than Drug B. Drugs A and B exhibit the same efficacy (the maximal response to the drug). Note that potency and efficacy are not intrinsically related—a drug can be extremely potent but have little efficacy, and vice versa. [L] is drug concentration, E is effect, Emax is efficacy, and EC50 is potency.


Quantal Dose–Response CurvesQuantal Dose–Response Curves

• Figure 2-3

Quantal dose–response curves demonstrate the average effect of a drug, as a function of its concentration, in a population of individuals. Individuals are typically observed for the presence or absence of a response (for example, sleep or no sleep), and this result is then used to plot the percentage of individuals who respond to each dose of drug.Quantal dose–response relationships are useful for predicting the effects of a drug when it is administered to a population of individuals and for determining population-based toxic doses and lethal doses. These doses are called the ED50

(dose at which 50% of subjects exhibit a therapeutic response to a drug), TD50 (dose at

which 50% of subjects experience a toxic response), and LD50 (dose at which 50% of

subjects die). Note that ED50 is the dose at which

50% of subjects respond to a drug, whereas EC50

(as described in the previous figure) is the dose at which a drug elicits a half-maximal effect in an individual subject.


Antagonist ClassificationAntagonist Classification

• Figure 2-4

(Agonist)

(high [agonist] can overcome this antagonist action)

(do not compete, rather change the Kd)

(no competition thus no [agonist] can overcome this antagonist action)


Types of Receptor AntagonistsTypes of Receptor Antagonists

• Figure 2-5

Note the conformational change in the receptor

these agents block agonist binding to the receptor

Note that it binds to a different site than the Agonist


Antagonist Effects on the AgonistAntagonist Effects on the AgonistDose–Response RelationshipDose–Response Relationship

• Figure 2-6

Potency = the concentration of agonist that causes a half-maximal response

Efficacy = the maximal response to an agonist

Competetive AntagonistPotency is reducedEfficacy is unchanged

Noncompetetive AntagonistPotency is unchangedEfficacy is reduced


Full and Partial Agonist Dose–Response Full and Partial Agonist Dose–Response CurvesCurves

• Figure 2-7

Stimulation of muscarinic acetylcholine (Ach) receptors to cause muscle contraction in the gut

Octyl and Heptyl are partial agonists b/c they do not give max effect

Butyl and Hexyl are full agonists (although they have different potencies)

Partial Agonists may be more or less potent than full agonist.

Burprenorphine is more potent than morphine but cannot achieve the same maximum response as morphine


Comparison Between a Drug–Receptor Comparison Between a Drug–Receptor Binding Curve and a Dose–Response Curve Binding Curve and a Dose–Response Curve in the Presence of Spare Receptorsin the Presence of Spare Receptors

• Figure 2-8

In the absence of spare receptors, there often exists a close correlation between a drug–receptor binding curve and a dose–response curve—the binding of additional drug to the receptor causes an incremental increase in response, and EC50 is

approximately equal to Kd.

In situations with spare receptors, however, a half-maximal response is elicited when less than half of all receptors are occupied (the term spare implies that occupation of every receptor with drug is not necessary to elicit a full response).

A. Drug–receptor binding curve.

B. Dose–response curve for the same drug, in the presence of spare receptors. Note that the maximal response occurs at a lower agonist concentration than does maximal binding, and EC50

< Kd. These two relationships confirm the presence of spare

receptors. D is drug, R is receptor, and [DR]/[Ro] is fractional

receptor occupancy. E is response (effect), Emax is maximal

response (efficacy), and E/Emax is fractional response. EC50 is

potency, and Kd is the equilibrium dissociation constant for drug–

receptor binding.


Effect of a Noncompetitive Antagonist on Effect of a Noncompetitive Antagonist on the Agonist Dose–Response Curve in the the Agonist Dose–Response Curve in the Presence of Spare ReceptorsPresence of Spare Receptors

• Figure 2-9In the presence of spare receptors, the potency decreases but the efficacy increases but only if the level of the antagonist is not increased…..if it is it will eventually take over all of the ‘spare’ receptors and switch back …..

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