Principles of Pharmacology & Pharmacodynamics

Graded describes the effect of various doses of a drug on an

*individual* Emax (maximum effective dose)

Quantal shows the effect of various doses of a drug on a

*population* of individuals

Types of receptor antagonists scheme

A schematic illustrating the differences between agonist (active) site and allosteric antagonists. A. The unbound inactive receptor. B. The receptor activated by agonist. Note the conformational change induced in the receptor by agonist binding, for example, the opening of a transmembrane ion channel. C. Agonist site antagonists bind to the receptor's agonist site but do not activate the receptor; these agents block agonist binding to the receptor. D. Allosteric antagonists bind to an allosteric site (different from the agonist site) and thereby prevent receptor activation, even when the agonist is bound to the receptor.

A noncompetitive antagonist reduces the ______ of an agonist

A noncompetitive antagonist reduces the *efficacy* of an agonist (the maximal response to an agonist) The most allosteric noncompetitive antagonists do not affect agonist potency.

Graded Dose-Binding Relationship & Binding Affinity: If the number of binding sites on each receptor molecule is known, it is possible to determine the total number of receptors in the system from the

Bmax

Inverse agonists Vs competitive antagonists: Both types of drug act to _____ the activity of a receptor

Both types of drug act to *reduce* the activity of a receptor

T/F Chemical Antagonists depend on interaction with the agonist's receptor

F. Does not depend on interaction with the agonist's receptor although such interaction may occur

T/F Inverse agonist and antagonist have the same meaning

F. They are not the same. 1. Inverse agonist- effect...active to nonactive 2. Antagonist- no effect, no change Binds to receptor produces effect...Agonist Binds to receptor and NO effect...Antagonist

T/F Quantal Dose-Response Relationships measure the maximal effect of the drug

F. Unlike the graded dose-response determination, no attempt is made to determine the maximal effect (Emax) of the drug

Inverse agonist

Change equilibrium form active to inactive. Lose baseline activity

Therapeutic index Example

For example, on next slide ED50 is approximately 3 mg LD50 is approximately 150 mg Therefore approximately 150/3, or 50 in mice Obviously, a full range of toxic doses cannot be ethically studied in humans Factors such as the varying slopes of dose-response curves make this estimate a poor safety index even in animals

Spare Receptors Scheme

In a system with spare receptors, the EC50 is lower than the Kd, indicating that to achieve 50% of maximal effect, less than 50% of the receptors must be activated. 100 receptors = 100% response, graph should be on itself

In the absence of drug, what determines the degree of constitutive activity

In the absence of drug, the equilibrium between Ri and Ra determines the degree of constitutive activity.

In the presence of a full agonist, both competitive antagonists and inverse agonists act to _______ agonist potency

In the presence of a full agonist, both competitive antagonists and inverse agonists act to *reduce* agonist potency

How does increased affinity relate to dose

Increased affinity = require LOWER dose of that drug

Physiologic Antagonists is different from a Pharmacologic Antagonist. How?

Physiologic Antagonists binds to a *different* receptor molecule Pharmacologic antagonist interacts with the *same* receptor as the drug it inhibits

Competitive and noncompetitive antagonists have different effects on potency and efficacy. What is potency and efficacy

Potency- the concentration of agonist that causes a half-maximal response Efficacy- the maximal response to an agonist

Chemical Antagonists: Pralidoxime

Pralidoxime combines avidly with the phosphorus in organophosphate cholinesterase inhibitors another type of chemical antagonist

Can potency be determined by graded or quantal dose-response curves

Thus, potency can be determined from either graded or quantal dose-response curves (e.g.) but the numbers obtained are not identical

The higher therapeutic index, the

better absorbed

Neutral antagonists

bind the receptor without shifting the Ra versus Ri equilibrium

Affinity: Possible to measure the percentage of receptors bound by a drug

by plotting this percentage against the log of the concentration of the drug, graph similar to the dose-response curve is obtained

Unlike the effects of a competitive antagonist, effects of an irreversible antagonist

cannot be overcome by adding more agonist

If a drug has more affinity to receptor, there is a

quick chemical reaction or binding

Noncompetitive antagonist acts at an allosteric site of the receptor may bind

reversibly or irreversibly

Therapeutic index represents an estimate of the

safety of a drug because a very safe drug might be expected to have a very large toxic dose and a much smaller effective dose

The ______ the Kd, the greater the affinity of the drug for its receptor

smaller

Both the therapeutic index and the therapeutic window depend on the

specific toxic effect used in the determination

Potency is determined mainly by

the affinity of the receptor and number of receptors available

Presence of spare receptors increases sensitivity to the agonist because

the likelihood of a drug-receptor interaction increases in proportion to the number of receptors available

The goal of Quantal is

to generalize a result to a population, rather than to examine the graded effect of different drug doses on a single individual (graded)

Quantal Dose-Response Relationships describe the

concentrations of a drug that produce a given effect in a population

Pharmacokinetics

deals with actions of the biologic system on the drug Movement of the drug (ADME)

Pharmaco*d*ynamics

deals with the effects of *d*rugs on biologic systems Mechanism of the drug

Chemical Antagonists interacts

directly with the drug being antagonized to remove it or to prevent it from binding to its target

The agonist, if given in a high enough concentration, can

displace the antagonist and fully activate the receptors

An Irreversible antagonist causes a

downward shift of the maximum, with no shift of the curve on the dose axis unless spare receptors are present

Pharmacon =

drug

In the presence of a competitive antagonist, the log dose-response curve for an agonist is shifted to

higher doses ie, horizontally to the right on the dose axis ***but the same maximal effect is reached

Physiologic Antagonists Example

Antagonism of the bronchoconstrictor action of histamine (mediated at histamine receptors) by epinephrine's bronchodilator action (mediated at adrenoceptors)

Antagonist classification scheme

Antagonists can be categorized based on whether they bind to a site on the receptor for agonist (receptor antagonists) or interrupt agonist- receptor signaling by other means (nonreceptor antagonists). Receptor antagonists can bind either to the agonist (active) site or to an allosteric site on the receptor; in either case, they do not affect basal receptor activity (i.e., the activity of the receptor in the absence of agonist). Agonist (active) site receptor antagonists prevent the agonist from binding to the receptor. If the antagonist competes with the ligand for agonist site binding, it is termed a competitive antagonist; high concentrations of agonist are able to overcome competitive antagonism. Noncompetitive agonist site antagonists bind covalently or with very high affinity to the agonist site, so that even high concentrations of agonist are unable to activate the receptor. Allosteric receptor antagonists bind to the receptor at a site other than the agonist site. They do not compete directly with agonist for receptor binding, but rather alter the Kd for agonist binding or inhibit the receptor from responding to agonist binding. High concentrations of agonist are generally unable to reverse the effect of an allosteric antagonist. Nonreceptor antagonists fall into two categories. Chemical antagonists sequester agonist and thus prevent the agonist from interacting with the receptor. Physiologic antagonists induce a physiologic response opposite to that of an agonist, but by a molecular mechanism that does not involve the receptor for agonist.

Spare Receptors

If the maximal drug response (Emax) is obtained at less than maximal occupation of the receptors (Bmax)

The receptor is able to assume 2 conformations, What are they

Ri and Ra

Partial agonist

Some receptors present in inactive form, cannot get maximum response to matter if increase dose

T/F Partial agonists have lower maximal efficacy than full agonists

T

T/F Competitive antagonists increase the ED50

T. Irreversible antagonists do not (unless spare receptors are present)

A competitive antagonist reduces the ______ of an agonist, without affecting agonist _______

A competitive antagonist reduces the *potency* of an agonist, without affecting agonist *efficacy* Potency- the concentration of agonist that causes a half-maximal response

Antagonist

A drug that prevents agonist-induced activation of the receptor

Agonist

A drug that, upon binding to its receptor, favors the active receptor conformation

Graded dose-response measurements: effect usually chosen is ___% of the maximal effect. The dose causing this effect is called the ______

50% EC50

Agonists and Antagonists: two conformational states of receptors are

1. *Active state*- can bind to drug AKA affinity-drug bind to receptor 2. *Inactive state* in reversible equilibrium with one another

What is the difference between competitive antagonist and inverse agonist

1. *Competitive antagonist* has no effect in the absence of an agonist 2. *Inverse agonist* deactivates receptors that are constitutively active in the absence of an agonist

Types of Antagonists

1. Competitive and Irreversible Pharmacologic Antagonists 2. Physiologic Antagonists 3. Chemical Antagonists

What are the two dose-response relationships

1. Graded 2. Quantal

Efficacy is determined mainly by

1. the nature of the drug and 2. the receptor and its associated effector system

Spare Receptors might result from 1 of 2 mechanisms

1.Duration of the activation of the effector may be much greater than the duration of the drug-receptor interaction 2. Actual number of receptors may exceed the number of effector molecules available

Scheme

Agonist dose-response curves in the presence of competitive and irreversible antagonists. Note the use of a logarithmic scale for drug concentration. A. A competitive antagonist has an effect illustrated by the shift of the agonist curve to the right. B. An irreversible (or noncompetitive) antagonist shifts the agonist curve downward.

Full agonist

All receptors are present in the active state, maximum response

Potency is

Amount of drug needed to produce a given effect

Antagonist effects on the agonist dose- response relationship Scheme

Competitive and noncompetitive antagonists have different effects on potency (the concentration of agonist that causes a half-maximal response) and efficacy (the maximal response to an agonist). A. A competitive antagonist reduces the potency of an agonist, without affecting agonist efficacy. B. A noncompetitive antagonist reduces the efficacy of an agonist. As shown here, most allosteric noncompetitive antagonists do not affect agonist potency.

Irreversible antagonist has what type of bond

Covalent bond, cannot be displaced

In practice how do you determine is there is spare receptors

Determination is usually made by comparing the concentration for 50% of maximal effect (EC50) with the concentration for 50% of maximal binding (Kd)

Chemical Antagonists: Common example

Dimercaprol, a chelator of lead and some other toxic metals

Effect of drug changes as you change the ______

Dose Increase dose may see therapeutic effect, then toxic effect, then lethal effect

Graded Dose Curve notes

Dose-response curve: Used to see effect of doses increase until flatten out bc of maximum effect Graph of Response vs. Dose Various doses of drug on ONE individual Do not use graded-dose response for testing in humans In population cannot do that because it is not a constant number. Dose is variable and not cause same effect in everybody In animals you can push the doses Graded and Quantal in animals

Difference between Potency & Efficacy graph

Drug A is potent Drug B has higher efficacy

Is EC50 used in graded or quantal dose-response

EC50 is used only for *graded* dose-response curve

Quantal dose-response measurements

ED50, TD 50, and LD50 are also potency variables Median effective, toxic, and lethal doses, respectively, in 50% of the population studied

Physiologic Antagonists: Glucagon

Glucagon acting at glucagon receptors can antagonize the cardiac effects of an overdose of propranolol (acting at receptors)

Affinity Scheme

Graded dose-response and dose-binding graphs. (In isolated tissue preparations, concentration is usually used as the measure of dose.) A. Relation between drug dose or concentration (abscissa) and drug effect (ordinate). When the dose axis is linear, a hyperbolic curve is commonly obtained. B. Same data, logarithmic dose axis. The dose or concentration at which effect is half-maximal is denoted EC50, whereas the maximal effect is Emax. C. If the percentage of receptors that bind drug is plotted against drug concentration, a similar curve is obtained, and the concentration at which 50% of the receptors are bound is denoted Kd, and the maximal number of receptors bound is termed Bmax.

Graded Dose-Response Relationships Graph

Graded dose-response and dose-binding graphs. (In isolated tissue preparations, concentration is usually used as the measure of dose.) A. Relation between drug dose or concentration (abscissa) and drug effect (ordinate). When the dose axis is linear, a hyperbolic curve is commonly obtained. B. Same data, logarithmic dose axis. The dose or concentration at which effect is half-maximal is denoted EC50, whereas the maximal effect is Emax. C. If the percentage of receptors that bind drug is plotted against drug concentration, a similar curve is obtained, and the concentration at which 50% of the receptors are bound is denoted Kd, and the maximal number of receptors bound is termed Bmax.

What is the difference between EC50 in Graded vs. ED50 in Quantal dose-response curves

Graded: *EC50* is the dose at which a drug elicits a half-maximal effect in an individual subject Quantal: *ED50* is the dose at which 50% of subjects respond to a drug

Emax

Greatest effect (Emax) an agonist can produce if the dose is taken to very high levels

Affinity: The concentration of drug required to bind 50% of the receptor sites is denoted as

Kd useful measure of the affinity of a drug molecule for its binding site on the receptor molecule

Effectors

Molecules that *translate* the drug-receptor interaction into a change in cellular activity Example adenylyl cyclase

The responses are defined as either present or not present in graded or quantal

Quantal

Quantal Dose Curve Graph

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) 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. 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 is the dose at which a drug elicits a half-maximal effect in an individual subject.

Endpoints such as "sleep/ no sleep" or "alive at 12 months/ not alive at 12 months" are examples of

Quantal responses

Therapeutic Window is a

Range Min concentration of drug to reach desired effect

Therapeutic index

Ratio of the TD 50 (or LD50) to the ED50 determined from quantal dose-response curves

Response is when

Response is when drug binds to receptor -> activate secondary mechanism -> effect

Binding site

The site on the receptor at which the drug binds

Full and partial agonist dose- response curves Graph

There are many instances in which drugs that all act at the agonist site on the same receptor produce different maximal effects. Various alkyl derivatives of trimethylammonium all stimulate muscarinic acetylcholine (ACh) receptors to cause muscle contraction in the gut, but they produce different maximal responses, even when all receptors are occupied. In this example, the butyl and hexyl trimethylammonium derivatives are full agonists— although they have different potencies, they are both capable of eliciting a maximal response. Agonists that produce only a partial response, such as the heptyl and octyl derivatives, are called partial agonists. Note that the dose- response curves of these partial agonists plateau at values less than those of full agonists. Partial agonists may be more or less potent than full agonists. In this case, buprenorphine (ED50 = 0.3 mg/ kg) is more potent than morphine (ED50 = 1.0 mg/ kg), although it cannot achieve the same maximal response as the full agonist. Buprenorphine is used clinically in the treatment of opioid addiction, where it is desirable to use a partial agonist that is less efficacious than an addicting opioid such as heroin or morphine. Low concentrations of the partial agonist buprenorphine bind tightly to the opioid receptor and competitively inhibit the binding of the more efficacious opioids. Very high doses of buprenorphine show a paradoxically diminished analgesic effect that may be due to lower-affinity interactions of the drug with non- mu-opioid receptors (not shown).

Figure

Upper: One model of drug-receptor interactions. The receptor is able to assume 2 conformations, Ri and Ra. In the Ri state, it is inactive and produces no effect, even when combined with a drug (D) molecule. In the Ra state, it activates its effectors and an effect is recorded, even in the absence of ligand. In the absence of drug, the equilibrium between Ri and Ra determines the degree of constitutive activity. Lower: A full agonist drug (Da) has a much higher affinity for the Ra than for the Ri receptor conformation, and a maximal effect is produced at sufficiently high drug concentration. A partial agonist drug (Dpa) has somewhat greater affinity for the Ra than for the Ri conformation and produces less effect, even at saturating concentrations. A neutral antagonist (Dant) binds with equal affinity to both receptor conformations and prevents binding of agonist. An inverse agonist (Di) binds much more avidly to the Ri receptor conformation, prevents conversion to the Ra state, and reduces constitutive activity. Receptor same, only conformation changed Top Picture: Inactive conformation of receptor

Drug binding to receptor

When drug binds to receptor the conformation goes through a second confirmation for secondary messengers to work. If receptor is active form, then there will be an effect

Physiologic Antagonists binds to

a different receptor molecule producing an effect opposite to that produced by the drug it antagonizes

Efficacy is measured with

a graded dose-response curve but not with a quantal dose-response curve

Inverse Agonist Definition

acts by abrogating intrinsic (constitutive) activity of the free (unoccupied) receptor function by binding to and stabilizing the receptor in the Drug Receptor (inactive) form.

Competitive antagonists

drugs that bind to, or very close to, the agonist receptor site in a reversible way without activating the effector system for that receptor

Therapeutic window Example

if the average minimum therapeutic plasma concentration of theophylline is 8 mg/L and toxic effects are observed at 18 mg/L, the therapeutic window is 8-18 mg/L

Noncompetitive antagonist acts at the receptor site binds

irreversibly

Ra state

it activates its effectors and an effect is recorded, even in the absence of ligand

Ri state

it is inactive and produces no effect, even when combined with a drug (D) molecule

If the EC50 is ____ than the Kd, spare receptors are said to exist

less

Receptors

macromolecules that, upon binding to a drug, *mediate* those biochemical and physiologic changes

Efficacy is often called

maximal efficacy

What symbols will be seen in Quantal

median effective dose (ED50) median toxic dose (TD50) median lethal dose (LD50)

Partial Agonist Definition

molecule that binds to a receptor at its active site but produces only a partial response Even when all of the receptors are occupied (bound) by the agonist

Drugs

molecules that interact with specific molecular components of an organism cause biochemical and physiologic changes

Therapeutic window

more clinically useful index of safety describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose