When a drug binds to a receptor to produce a pharmacologic effect the drug may be called a(n)

PHARMACODYNAMICS

PHA 824

This lecture series is designed to facilitate the learning of key principles and concepts regarding the basic pharmacodynamic principles of drugs, drug receptors and interactions at these receptors.  This knowledge will be critical in the understanding of the various drugs and drug classes to be discussed throughout this course.  More specifically this information will be used to facilitate the understanding of the receptors in the autonomic nervous system and the drugs that interact at these receptors.  The ultimate objective will be the therapeutic uses and toxicities associated with these drugs.

Learning Objectives

The student should be able to explain or describe:

�           the definition of a drug

�           the different types of receptors at which drugs can act

�           the concept of affinity and those factors that cause a drug to bind to a receptor

�           the concept of intrinsic activity

�           the difference between full and partial agonists

�           the definitions of potency and efficacy

�           the definition of ED50

�           the concept of spare receptors

�           the information regarding drugs that can be obtained from the log-dose response curve

�           the properties of a competitive antagonist and how it differs from an irreversible receptor agonist

�           the definition of LD50

�           the concept of a therapeutic index and how it is calculated

BASIC CONCEPTS

Receptor:  Any cellular macromolecule that a neurotransmitter or drug binds to initiate its effects.

The endogenous function of a receptor is to participate in neurotransmission or physiologic regulation.  Humankind has learned that drugs can be given to activate or block these receptors to produce a variety of effects.

Drug:  A chemical substance that interacts with a receptor to produce a physiologic effect.

The ability to bind to a receptor is mediated by the chemical structure of the drug that allows it to interact with complementary surfaces on the receptor.

This is a diagram of a G-protein coupled receptor.  Notice how the amino acids that make up the receptor protein contribute functional groups to allow a neurotransmitter or drug to bind to this receptor.

                                                      

The interaction of drugs with receptors is highly specific.  Examine these drug structures and the receptors at which the drugs act.  Notice how slight structural modifications result in significant differences in receptor interactions.

                 

FACTORS GOVERNING DRUG ACTION

All drugs are chemicals but not all chemicals are drugs.   For a drug to produce a physiologic effect it must first bind to a receptor.  Two factors, related to the chemical nature of a drug, determine the interaction of drugs with receptors and hence the effect a drug will have on physiologic processes.

Affinity is a measure of the tightness with which a drug binds to the receptor.

Intrinsic activity is a measure of the ability of a drug that is bound to the receptor to generate an activating stimulus and produce a change in cellular activity.

Both agonists and antagonists can bind to a receptor. However, only agonist molecules can activate the receptor. 

UNDERSTANDING THE CONCEPT OF AFFINITY�Defining the equilibrium dissociation constant-KD

To bind to a receptor the functional groups on a drug must interact with complementary surfaces on the receptor.  The binding of a drug (illustrated here as D) to the receptor (illustrated as R) can be described by this expression.

This is a reversible reaction and when at equilibrium, the rate of drug-receptor complex formation [DR] is equal to the rate of drug-receptor complex dissociation.  

In other words,

The rate of formation of the drug-receptor complex is described by k1.  In simpler terms k1 describes the association of a drug to its receptor. Similarly, k-1 is a term that describes the ease at which a drug dissociates from its receptor.  KD is defined as follows;

This equation states that the amount of drug bound to the receptor is dependent on the drug concentration and Kd.

AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

To gain an appreciation of the relationship between affinity and receptor occupancy, make the following simple calculations and graphical representations. 

Terazosin is an antagonist at the alpha1-adrenergic receptor.  It is used to treat benign prostatic hyperplasia and is a second line antihypertensive.  Terazosin has an equilibrium dissociation constant of 1.0 nM.  Epinephrine is an agonist at the alpha1-adrenergic receptor and has an equilibrium dissociation constant of 100 nM.  Using the following equation

Epinephrine                 % Receptors                                      

                                    Occupied

50.0 nM

100.0 nM

400.0 nM

1000  nM

solution

Now plot the relationship between concentration and receptor occupancy. 

You should observe a unique relationship between the concentration of a drug and its equilibrium dissociation constant.  Regardless of the drug, when it is given at a concentration equal to its dissociation constant, 50% of the receptors will be occupied. 

UNDERSTANDING THE CONCEPT OF INTRINSIC ACTIVITY

  PROPOSED BINDING OF NE TO THE BETA RECEPTOR

Using the symbol e to represent intrinsic activity the physiologic response of a drug can be described by the equation below:

Full Agonists:  Compounds that elicit a maximal response following receptor occupation and activation.

Partial Agonists:  Compounds that can activate receptors but are unable to elicit the maximal  response of the receptor system.

MAXIMAL DRUG RESPONSES AND SPARE RECEPTORS

As the concentration of a drug in a human organ system increases, the response of that system would be expected to increase until a maximal response is obtained.  The level of response is related to the number of receptors occupied.  However, this relationship is complex.

 In a linear relationship, 50 % of the total receptor population must be occupied to achieve 50 % of the maximal organ system response.  It follows then that a maximal response will occur only when all receptors are occupied.  In most human systems the relationship between receptor occupancy and drug response is hyperbolic.

Because of this hyperbolic relationship between occupancy and response, maximal responses are achieved at less than maximal receptor occupancy. A certain number of receptors are �spare.� Spare receptors are receptors that exist in excess of those required to produce a full effect.

DOSE-RESPONSE CURVES
 

Dose-response relationships are a common way to portray data in both basic and clinical science. 

The dose a which 50% of the maximal effect is observed is referred to as the ED50.  This term is also widely used to describe pharmacologic data. 

Further dose-response relationships can be illustrated with the following examples.

Norepinephrine and phenylephrine are full agonists.

Affinity affects the position of the dose-response curve on the x-axis.

Norepinephrine would be said to have greater potency than phenylephine. 

Drugs with the highest affinity will have dose response curves positioned to the left of curves for drugs with lower affinity.  These dose response curves also demonstrate that after reaching a maximal response, further increases in drug concentration have no additional effect.   

Clonidine and methoxamine are partial agonists. Clonidine has a higher affinity but a lower intrinsic activity than does methoxamine. Efficacy is often used to describe the maximal level of response a drug can produce.  Thus norepinephrine would have a greater efficacy than methoxamine which in turn would have a greater efficacy than clonidine.

ANTAGONISTS

Antagonists are drugs that have the ability to bind to receptors but are unable to bring about receptor activation.   Like agonists, the binding of most antagonists occurs in a reversible manner.  This type of antagonist is referred to as a competitive antagonist.  This can be illustrated with two equilibrium equations:  

In the presence of a competitive antagonist the occupancy of the receptor by an agonist can be expressed by the following equation.   Where [A] is the concentration of antagonist and Ka is the affinity exhibited by the antagonist for the receptor.

Examine the effect of terazosin (Ka= 1.0 nM) on the occupancy of the alpha1-adrenergic receptor by epinephrine.

Epinephrine             % Receptors               %Receptors                 %Receptors
                                  Occupied                     Occupied                    Occupied
                               (Terazosin = 0)           (Terazosin = 1nM)        (Terazosin = 10 nM)

50.0 nM                         33
100.0 nM                       50
400.0 nM                       80
1000.0 nM                     90

Solution

Prazosin is a competitive antagonist of the action of agonist PE

The following dose response curves illustrate the effects of a competitive antagonist on the response of an agonist. 

To summarize, the key features of a competitive antagonist are:

1.         Reversible binding to the receptor.

2.         The blockade can be overcome by increasing the agonist concentration.

3.         The maximal response of the agonist is not decreased.

4.         The agonist dose-response curve in the presence of a competitive antagonist is displaced to the right parallel to   the curve in the absence of agonist.

Irreversible Receptor Antagonists

To summarize, the properties of irreversible receptor blockers are:

1. Chemically reactive compounds

2. The receptor is irreversibly inactivated and the blockade can not be overcome with  increasing agonist concentration.  

APPLICATIONS TO THERAPEUTICS

Most drugs interact with more than one receptor class and thus have the capability to produce distinctly different pharmacologic effects.  Some of these effects could be beneficial, some could be toxic. 

A drug is capable of producing actions at 2 distinct receptors.  At each of these receptors, the ligand has a different affinity as well as pharmacologic effect. To simplify, assume there are no spare receptors in either receptor system.

Receptor System # 1:

KD = 0.40, effect- lowering of systemic arterial blood pressure.

Receptor System # 2:

KD = 40.0, effect- lethal ventricular arrhythmias.

Thus, this drug could either be a highly beneficial therapeutic agent or a lethal poison.  The dose-response curves below reinforce the idea that as the blood concentration increases so does the therapeutic effect.  However, eventually the therapeutic effect reaches a maximum.  No further benefit can be derived by further increasing the drug concentration.  The only result is an increase in the likelihood of drug toxicity. 

The Therapeutic Index

The Therapeutic Index is the ratio of the ED50 of a drug to produce a lethal effect to the ED50 to produce a therapeutic effect.  The dose required to produce death in 50% of a population is referred to as the LD50.  For the drug example above, the ED50 for the beneficial effect of blood pressure lowering is 0.4 nM while the LD50 is 40 nM.  Therefore, the therapeutic index will be:

The Therapeutic Index

ADVANCED CONCEPTS REGARDING PARTIAL AGONISTS

Partial agonists have lower intrinsic activities than full agonists but values greater than competitive antagonists.

What is it called when a drug binds to a receptor?

When a drug binds to a receptor and prevents a response?

What is drug receptor interaction in pharmacology?