Drug Mech: Basic Principles 1

• "Because patient's expect and deserve the best. Don't ever forget that." -Dr. Samir Kouzi
• As a pharmacist, you need to know how drugs cause a therapeutic effect so that you can make an educated difference in the drug therapy of the patient.

• The study of substances/chemicals that interact with living biological systems through chemical processes (particularly by binding to regulatory molecules) and alter (activate or inhibit) biologic function or response.
• These substances may be chemicals (drugs) that are administered to a patient (humans) in order to achieve a beneficial therapeutic effect.
• This is a very broad definition.

A branch of pharmacology; the study of the harmful effects of chemicals on living systems.

• Derived from Greek xenos, meaning “stranger.”
• Any substance/chemical that is foreign to the human body (not synthesized in the body).
• A drug that is not synthesized in the body is called a xenobiotic.

• An ‘inactive’ form of a drug that requires metabolic activation inside the body (bioactivation) in order to release the ‘active’ form of the drug.
• Once released in vivo, the active form of the drug will then exert its pharmacological effect.

• The component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects.
• Most drug receptors are proteins (e.g., regulatory proteins, enzymes, transport proteins, and structural proteins).

Refers to the actions of the drug on the human body (what the drug does to the body).

The pharmacodynamic properties of a drug (e.g., mechanism of drug action, relationship between effect and concentration, …) determine the group or class of drugs in which the drug is classified and play the major role in deciding whether that class of drugs is effective therapy for a particular disease or symptom.

PD is the basis of drug therapeutics.

To plot PD, use concentration vs. response, or in other words, dose vs. effect.

PD can be thought of as the consequences or actions of what happens once a drug binds to a receptor site.

Literally ‘the movement of a drug’, refers to the actions of the human body on the drug (what the body does to the drug).

It is the study of the Absorption, Distribution, and Clearance (Metabolism/Excretion) of a drug (or the ADME properties of the drug) with respect to time, and the establishment of a relationship between drug concentration and time.

To plot PK, use concentration vs. time.

Pharmacokinetic properties of a drug are of great significance in the selection and administration of a particular drug for a particular patient.

The study of the genetic variations among humans that cause differences in pharmacodynamics/pharmacokinetics and lead to individual differences in drug response.

· Most drugs used today can be classified as weak acids or bases. A drug’s acid-base properties can greatly influence its biodistribution and partitioning characteristics, because pH differences in the various compartments (tissues/fluids) of the body may alter the degree of ionization of such drugs.

• · Some drugs are synthesized within the body (e.g.,
• hormones) although the majority are not.
• Drugs may be solid at room temperature, liquid, or gaseous. The physical nature of a drug plays an important role in determining the best route for its administration.

• · Most drugs interact with a specific molecule in the
• biologic system (human body) that is responsible for regulating biologic/physiologic function. This molecule, which is the site of action of the drug, is commonly known as a receptor.

• · To interact chemically with its receptor, a drug
• molecule must have the necessary properties to be transported from its site of administration to its site of action. It must also have the right size, electrical charge, shape, and atomic composition in order to fit into and bind to the active site of its receptor.

• · The ideal drug molecule will show favorable binding characteristics to the receptor, and the equilibrium will lie to the right, where drug-receptor complex is together (and therefore can actually cause a pharmacological response) rather than a separated "drug" and "receptor."
• · Following a pharmacologic response, the
• drug will be expected to dissociate from the receptor and re-enter the systemic circulation to be eliminated from the body.

· A practical drug should be excreted from the body at a reasonable rate so that its actions will be of appropriate duration.

· In other words, the usual use of drugs in therapeutics calls for the drug’s effect to last for a finite period of time. Then, if it is to be repeated, the drug will be administered again. If the patient does not tolerate the drug well, it is even more important that the drug dissociate from the receptor and be excreted from the body.

• This picture is a computer-generated depiction of a drug molecule in a "pocket" of the receptor:
• 

The bonds are weak (non-covalent) in most drug receptor complexes. Therefore, there must be intimacy between the drug and the receptor for the correct conditions to take place. Notice how intimate the drug molecule in each of the pictures.

• This picture is an actual x-ray of a drug-receptor complex:
• 

• This picture shows a drug-molecule that is somewhat unique because covalent bonds are formed. This cephalosporin binds covalently to the beta-lactam of the receptor.
• 

1) The drug molecule must fit into the binding site.

2) The drug molecule must form chemical bonds (or in other words, make the right connections with the amino acid residues) in the binding site.

"Ligand" is used interchangeably when speaking of a drug molecule or for any chemical capable of binding to a receptor in the body. For example, rather than saying a "drug-receptor complex," one might refer to it as a "ligand-receptor complex," which means the same thing.

· Drug Selectivity, also known as Selective Binding of a drug, refers to the number of receptor types or subtypes that the drug binds to in the body.

· Drug selectivity is usually measured by comparing binding affinities of the drug to different receptor types/subtypes.

• · Binding affinity (or affinity) of the drug refers to
• its ability to fit into and bind to the receptor pocket (i.e., the drug’s binding site on the receptor molecule).

· In general, the more selective a drug is, the better. For example, Celebrex is more selective than aspirin.

· Selectivity of a drug is a relative term. For example, say a particular drug may bind to 5 receptors. It would still be considered selective because that's only 5 receptors out of a trillion!

·Drug selectivity is attributed to the following:

1) Drugs bind to one or a few receptor types/subtypes more tightly than to others.

2) Receptors that bind to drugs control discrete cellular processes that result in distinct effects.

· Drug Specificity refers to the number of effects (both beneficial/therapeutic and toxic) that the drug is capable of producing in the body.

· In order to be specific, the drug has to produce a single specific effect in the body. Therefore, NO drug exists that is specific! All drugs produce more than one effect in the body!

• ·No drug causes only a single, specific effect.
• This is attributed to the following:

1) A drug molecule will very likely bind to more than one type of receptor in the body (to help you understand why, think of the number of potential receptors that are present in the body for a particular drug molecule).

• 2) Even if the drug is chemically (ie, structurally) selective in binding to only one type of
• receptor, the biochemical post-receptor processes that are controlled by such binding usually take place in multiple cell types and are coupled to many other biochemical functions. As a result, more than one drug effect will most likely be exerted.

· In summary, drugs are only selective in their actions; they are not specific.

No. First of all, there are different receptors found in different tissues of the body...and the drug molecule could end up binding in several different tissues. Second of all, once binding takes place, there are several post-receptor activities that trigger different signal transduction pathways. All of these different signal transduction pathways can cause different effects.

• · The vast majority of drugs have molecular weights
• between 100 and 1000. In order to achieve selective binding of the drug molecule to only one type of receptor, a drug should, in most cases, have
• a molecular weight of at least 100. Drugs that have a molecular weight greater than 1000 will not diffuse
• readily between compartments of the body; as a result, very large drugs (e.g., proteins) must be administered directly into the body compartment where they will exert their pharmacological effect.

· Drugs interact with receptors by binding to them through chemical bonds.

• There are three major types of drug-receptor bonds:
• 1) Covalent
• 2) Electrostatic
• 3) Hydrophobic

· Covalent bonds are very strong bonds; covalent binding is, in most cases, irreversible. Drugs capable of forming a covalent bond with the receptor are usually ‘highly reactive’ molecules. The drug effect resulting from a covalent drug-receptor binding is reversed only by the synthesis of new receptor molecules, or, in the case of the DNA-alkylating drugs used in cancer chemotherapy, by replacing the cell (ideally with a normal cell).

· Electrostatic binding is much more common than covalent binding in drug-receptor interactions. Electrostatic bonds are weaker than covalent bonds; they (electrostatic bonds) vary from relatively strong ionic bonds between charged ionic molecules, to weaker hydrogen bonds, and very weak induced dipole interactions such as van der Waals forces.

· Hydrophobic bonds are usually very weak. They are important in the interactions of highly lipophilic drugs with the phospholipid bilayers of cell membranes; they are also important in the interaction of drugs with the active site or ‘pocket’ of the receptor.

· Drugs which bind through weak bonds to their receptors are generally more selective in their binding than drugs which bind through very strong bonds. This is attributed to the fact that weak bonds require a very precise fit of the drug into the active pocket of its receptor if an interaction is to occur. Only a very limited number of receptor types are likely to provide such a precise fit for a particular drug structure. Drug molecules that form weak bonds with receptors are likely to be highly selective and short-acting. (highly selective drugs are always the best drugs … Why ?)

· The stereochemistry (3-D structure) of a drug molecule must complement the stereochemistry of its receptor site in the same way that a‘key’ (drug) is complementary to a ‘lock’ (receptor). Although the rigid lock-and-key concept or model is very useful, one must realize that both the drug and the receptor can have considerable flexibility; in fact, molecular graphics and conformational analysis of drug and receptor show that the receptor can undergo an adjustment in 3-D structure when the drug makes contact (ie, when the drug ‘docks’ with the receptor).

According to Wikipedia, "Stereoisomers are isomeric molecules that have the same molecular formula and sequence of bonded atoms (constitution), but which differ only in the three-dimensional orientations of their atoms in space. Structural isomers share the same molecular formula, but the bond connections and/or their order between different atoms/groups differs. In stereoisomers, the order and bond connections of the constituent atoms remains the same, but their orientation in space differ."

· The stereochemistry of a receptor is constant...something that cannot be manipulated. However, the drug can be changed. You can choose which drug, with a specific stereochemistry, to apply to the body.

• · Given the fact that chirality (stereoisomerism) is an
• extremely common phenomenon in nature and in biology, it is not surprising that most drugs are chiral (asymmetric). A number of chiral drugs that are used clinically are available/administered as racemic mixtures, ie, mixtures of ‘optical isomers’ or enantiomers (e.g., S- and R-ibuprofen, S- and R-warfarin, R- and S-verapamil), whereas the
• rest are marketed as a single active enantiomer.

Enantiomers, which are mirror images of each other, contain one or more asymmetric centers and have opposite stereochemistry at all centers.

• 
• · In most cases, one drug enantiomer is much more potent than the other, reflecting a better ‘fit’ to the receptor molecule.

For example, (-) ephedrine shows: 3 times more pressor activity than (+) ephedrine, 5 times more pressor activity than (+) pseudoephedrine, and 36 times more pressor activity than (-) pseudoephedrine.

Another example is (-) epinephrine which exhibits 12 to 15 times more vasoconstrictor activity than (+) epinephrine. Numerous other examples exist in the literature.

(Think of the receptor site as if it is a ‘glove’ into which the drug molecule must fit to bring about its effect !!)



· Another important outcome of drug chirality is that an active or a more active enantiomer/stereoisomer at one type of receptor site may not be active (or more active) at another type of receptor site (e.g., a receptor type that may be responsible for some undesirable side effect), when compared to the other isomer.

• For example, the dextrorotatory isomers
• (the (+) enantiomers) in the morphine series of drugs, such as dextromethorphan, are cough suppressants that possess the anti-tussive
• properties of codeine (which has a levorotatory, (-), stereochemistry), without the analgesic, addictive, central depressant, and constipating features
• exhibited by the (-) form. The (+) form simply does not bind to the receptors involved in analgesic, constipative, addictive, and other actions exerted by the (-) form. As a result, dextromethorphan has largely replaced many older anti-tussives, including codeine, in prescription and nonprescription cough preparations.

• Another example is the local anesthetic levobupivacaine, which is the (S) isomer of bupivacaine. Bupivacaine is available on the market; it is the racemic mixture of the (R)
• and (S) isomers. Both the (R) and (S)
• isomers have good local anesthetic activity, but the (R) isomer causes myocardial depression and ventricular arrhythmias. In contrast, the (S) isomer shows much less cardio-toxicity. Consequently, the
• pure (S) isomer of bupivacaine is now available on the market because of its superior safety profile.

• · A number of drugs are available/marketed as racemic mixtures (a racemic mixture is
• a 50:50 mixture of the (-) and (+) enantiomers).

• In some cases, unfortunately, the patient is receiving drug doses of which 50% is either inactive or toxic. As a result, there is a great deal of interest, at both the FDA and the pharmaceutical industry, in making more chiral drugs available as
• their pure active enantiomers.

• · As dramatic as the above examples of stereoselectivity may be, sometimes it may not be
• cost-effective to resolve the drug into its pure enantiomers. In some cases, it is difficult to conclude that one isomer of a drug is superior to
• the other.

• For example, S-verapamil is a more active calcium channel blocker than R-verapamil, but the former is more rapidly metabolized by the first-pass effect in the liver; this means that R-verapamil has a much
• higher bioavailability than the more active S
• isomer (which of the two isomers is clinically superior ??).

In other cases, it makes little difference whether a racemic mixture or a single pure isomer is administered because of the biotransformation (metabolic) reactions that a drug molecule is subjected to in the body.

• For example, the NSAID ibuprofen is sold as the
• racemic mixture. S-ibuprofen is the active anti-inflammatory isomer (inhibitor of cyclooxygenase). The R isomer, on the other hand, has centrally acting analgesic activity, but it is converted metabolically to the S isomer in vivo.

Binding of the drug to a receptor is essential in order to bring about a pharmacological effect, but it is only the first step in a usually complex sequence of events.

· AGONISTS are drugs that bind to and activate the receptor, which will bring about the pharmacological effect.

Some receptors, once activated, can directly bring about the pharmacological effect, such as the case of enzymes and ion channels.

Other receptors are linked through one or more coupling molecules to a separate Effector molecule; as a result, activating this particular type of receptor will indirectly bring about the pharmacological effect.

An EFFECTOR is a component of a signal transduction pathway that produces the biologic effect after the receptor is activated by an agonist; often an ion channel or enzyme molecule).

• · Some drugs mimic the effect of a receptor
• agonist by inhibiting the molecules responsible for terminating the action of an endogenous agonist (e.g., phosphodiesterase inhibitors, acetylcholinesterase inhibitors).

Although these drugs don’t bind to the receptor, they are able to extend/amplify the pharmacological effect of the receptor agonist.

· FULL AGONISTS are drugs that can activate the receptor-effector system to the maximum extent of which the system is capable when administered at sufficiently high concentrations. As a result, a full agonist produces the maximal pharmacologic effect at its receptor-effector system. Full agonists exhibit high ‘Intrinsic Efficacy’.

• · PARTIAL AGONISTS are drugs that bind and
• activate the receptor; however, the evoked response or effect is not as high as the effect obtained from the binding of a ‘full’ agonist. Consequently, a partial agonist may act as either an ‘agonist’ (in the absence of a full agonist) or as an ‘antagonist’ (in the presence of a full agonist). Partial agonists exhibit low ‘Intrinsic Efficacy’ (Intrinsic efficacy is independent of affinity for the receptor).

· INVERSE AGONISTS are drugs that bind to the receptor and stabilize it in its inactive (nonfunctional) conformation, thus reducing/eliminating any constitutive activity of the receptor and generating effects that are the opposite of the effects produced by conventional agonists at the receptor.

· ALLOSTERIC AGONISTS, also known as Allosteric Activators, are drugs that enhance the efficacy/binding affinity of the receptor agonist by binding to allosteric sites on the receptor molecule (i.e., binding to sites that are different than and away from the binding site of the agonist).

• · PHARMACOLOGIC ANTAGONISTS, also known as ‘Blockers’ or ‘Receptor-Specific
• Antagonists,’ are drugs that bind to
• the same binding site of the agonist on the receptor molecule without activating the receptor, thereby preventing (or blocking)
• the binding of agonist molecules (and preventing activation of the receptor by an agonist).

• Ultimately, they prevent/reduce the effects of the receptor agonist molecules and agonist
• drugs in the body.

• Pharmacologic antagonists can be either ‘Competitive Antagonists’ or ‘Noncompetitive
• Antagonists’.

• A pharmacologic antagonist is Receptor-Specific because it interacts with the same
• receptor as the agonist it antagonizes.

· ALLOSTERIC ANTAGONISTS are also known as Allosteric Inhibitors, Receptor-Specific Allosteric Antagonists or Noncompetitive Allosteric Antagonists.

They are drugs that inhibit/reduce the efficacy/binding affinity of the receptor agonist by binding to allosteric sites on the receptor molecule (i.e., binding to sites that are different than and away from the binding site of the agonist). In other words, they are Noncompetitive Antagonists that bind either reversibly or irreversibly to their allosteric binding sites on the receptor molecule.

An allosteric antagonist is Receptor-Specific because it interacts with the same receptor as the agonist it antagonizes.

Allosteric inhibition/antagonism is not overcome by increasing the concentration/dose of the agonist.

· Modern concepts of drug-receptor interactions consider the receptor to have at least two conformations: Ri (inactive) and Ra (active).

· In the Ri conformation, the receptor is inactive/nonfunctional and produces no effect, even when combined with a drug (D) molecule.

• · In the Ra conformation, the receptor can activate
• its effectors and produce an effect, even in the absence of a ligand/drug.

· The effect produced in the absence of agonist (which is a small observable effect) is referred to as ‘Constitutive Activity’.

· In the absence of ligand, a receptor exists in a state of equilibrium (Ri + Ra) between the two conformations. The equilibrium between the Ri and Ra forms determines the degree of constitutive activity produced by the receptor.

· Other factors involved in determining the degree of constitutive activity include receptor density, the concentration of coupling molecules (if a coupled system), and the number of effector molecules in the system.

· Thermodynamic studies/considerations indicate that, in the absence of any ligand, the Ri form of the receptor is favored (more stable) and that a small percentage of the receptor molecules exist in the Ra form some of the time.

· Receptor systems in humans exhibit a low level of constitutive activity in the absence of agonist, confirming that these receptors exist in a state of equilibrium (Ri + Ra) with most of the receptor molecules are in the Ri form and only a small number of receptor molecules are in the Ra form.

· Full Agonists have a much higher affinity for binding to the Ra conformation and are able to fully stabilize it (i.e., they have high intrinsic efficacy).

• · Binding of full agonists favors the formation of the Ra-D complex with a much larger observed effect.
• As a result, full agonists cause a shift of all of the receptor pool to the Ra-D pool when administered at sufficiently high concentrations, resulting in
• full activation of the effector system and the production of the maximal pharmacologic effect.

· Partial Agonists have an intermediate affinity for binding to both Ri and Ra forms (Ra-D + Ri-D), with somewhat greater affinity for the Ra form.

• · They do not stabilize the Ra form as fully as full agonists, so that a significant fraction of receptor molecules exists in the Ri-D pool (i.e., partial agonists exhibit low intrinsic efficacy). As a
• result, a partial agonist produces less than the full effect at the receptor site, even when it has saturated the receptor molecules.

· In the presence of a full agonist, a partial agonist acts as an antagonist (blocker).

· Pharmacologic Antagonists have equal affinity for binding to both the Ra and Ri forms of the receptor molecule.

· Binding of the antagonist fixes the fractions of Ri-D and Ra-D complexes in the same relative amounts as in the absence of any drug (i.e., binding of the antagonist does not shift the Ra versus Ri equilibrium). As a result, no change in the effect will be observed (i.e., the same level of constitutive activity is maintained).

· However, binding of the antagonist blocks the receptor site and prevents agonists from binding.

· Inverse Agonists have a much higher affinity for binding to the inactive Ri form of the receptor molecule and are able to stabilize it.

· Binding of inverse agonists stabilizes all receptor molecules in the Ri-D pool (and prevents conversion to the Ra state). As a result, inverse agonists reduce/eliminate any constitutive activity and may produce effects that are the opposite of the effects produced by conventional agonists at that receptor.

· Drug action at the receptor level is terminated by one of the following mechanisms:

1) Dissociation of the drug from the receptor. In some cases, dissociation will automatically terminate the pharmacological effect of the drug; in other cases, the effect may persist for a period of time following dissociation (when, for example, a coupling molecule is still present in an activated form).

2) Biosynthesis of new receptor molecules. In the case of drugs that bind covalently to the receptor, the effect may persist until the drug-receptor complex is destroyed and new receptor molecules are biosynthesized.

· The human body is full of endogenous molecules that are capable of binding to drugs. It is important to distinguish, however, between binding of a drug molecule to a ‘Receptor’ and binding of the drug to an ‘Inert Binding Site’.

- A Receptor is usually an endogenous regulatory molecule that must be selective in binding to ligands (drug molecules and other xenobiotics), and must change its function upon activation (binding) in order to alter the biologic function or response.

-Binding of a drug to a nonregulatory, inert molecule in the body (e.g., albumin in plasma) will not alter the biologic function or response; these inert endogenous molecules that can bind to drugs are known as Inert Binding Sites.

Although this type of drug binding does not result in a pharmacological effect, it is of great pharmacokinetic significance because it affects drug distribution in the body and the amount of ‘free’ drug that is available in the general circulation.

A Drug Receptor is the component of a cell or organism that interacts with the drug and initiates the chain of biochemical events leading to the drug’s observed effects.

· Most receptors are proteins. Polypeptide structures provide both the chemical diversity and specificity that are necessary for a receptor-ligand interaction.

Examples of drug receptors include:

1) Regulatory proteins, which mediate the actions of endogenous chemical signals such as neurotransmitters, autacoids, and hormones.

2) Enzymes (e.g., dihydrofolate reductase enzyme is the receptor for the anticancer drug methotrexate).

3) Transport proteins (e.g., Na+/K+ ATPase is the membrane receptor for the cardiotonic digitalis glycosides).

4) Structural proteins (e.g., tubulin is a receptor for colchicine).

• · The ‘receptor’ concept is the central focus of
• investigating drug effects and their mechanisms of action (pharmacodynamics). Today, many
• drug receptors have already been isolated and characterized, which allows for a greater understanding of the molecular basis of drug action.

· Three practical consequences of the ‘receptor’ concept directly influence the therapeutic/clinical use of drugs and the process of drug development:

• 1) Receptors are largely responsible for establishing the quantitative relationships between dose or concentration of the drug and its pharmacologic effects. The receptor’s affinity for binding to
• the drug molecule determines the concentration of the drug required to produce a significant number of drug-receptor complexes, which will influence drug
• effect. In addition, the total number of available receptor molecules may limit the maximal effect that a drug molecule can produce.

• 2) Receptors are responsible for selectivity of drug action. There is a vast array of chemically different receptors (binding sites) available to a drug molecule in a cell or tissue. The chemistry of the drug molecule determines whether the drug is capable of binding to a particular receptor; the chemistry of the drug molecule also determines the drug’s affinity
• for binding to a particular receptor. Consequently, modifications of the chemical structure of a drug can increase or decrease the drug’s affinities for different classes of receptors and alter its therapeutic and toxic effects.

• 3) Receptors mediate the actions of both Agonists and Antagonists. Some drugs and many natural ligands (e.g., neurotransmitters, hormones) interact
• with receptors as agonists; ie, they activate the receptor and produce an effect as a direct result of binding to the receptor. Other drugs interact
• with receptors as antagonists.

‘Pure’ antagonists bind to the receptor without activating it and without producing an effect; as a result, they interfere with (or block) the ability of an agonist to bind to and activate the receptor. Thus, the pharmacological effect of a pure antagonist is based entirely on its ability to prevent the binding of agonist molecules and block their biologic actions.

• · The relationship between the dose of a drug and its
• therapeutic effect in a patient is considerably complex. However, in an in vitro system (e.g., cell culture), the relationship between drug concentration and effect is simple and can be described by a Graded Dose-Response Curve (hyperbolic
• or sigmoid) based on the following equation:

• E = Effect observed at concentration C.
• Emax = Maximal response that can be produced by the drug.
• EC₅₀ = Concentration of the drug that produces
• 50% of the maximal effect.

· During a drug-receptor interaction, drug agonists bind to or occupy receptor molecules with a characteristic affinity for the receptor. The relationship between drug bound to receptor molecules (B) and the concentration of free (unbound) drug (C) can also be described by a Graded Dose-Binding Curve (hyperbolic or sigmoid) based on the following equation:

• B = Drug bound to receptor molecules.
• C = Concentration of free (unbound) drug.
• B_max = Total concentration of receptor sites that are bound to the drug at infinitely high concentrations of free drug.
• K_D = ‘Equilibrium Dissociation Constant’ is
• the concentration of free drug at which 50% of maximal binding is observed.

· E_max characterizes drug efficacy (i.e., pharmacodynamic efficacy) as follows:

• If E_max is low, drug efficacy is low.
• If E_max is high, drug efficacy is high.

EC₅₀ characterizes drug potency as follows:

• If EC₅₀ is low, drug potency is high.
• If EC₅₀ is high, drug potency is low.

*The EC₅₀ and K_D may be identical, but they don’t have to be.

K_D characterizes the drug’s affinity for binding to the receptor as follows:

• If K_D is low, binding affinity is high.
• If K_D is high, binding affinity is low.

*The EC₅₀ and K_D may be identical, but they don’t have to be.

• · Dose-Response (or Dose-Effect) data is usually
• presented as a sigmoid curve of the drug effect (ordinate) as a function of the logarithm of the dose or concentration (abscissa).

The advantage of this type of mathematical presentation is the ability to expand the scale of the drug concentration at the low end where the drug effect is changing rapidly (as compared to a very slow change in the effect at high concentrations).

· Binding of the drug molecule to a receptor leads to a conformational change in the receptor, which is the first of many steps required to produce a pharmacologic response. The transduction process between occupancy of receptor molecules and drug response is known as ‘Coupling’ (or occupancy-response coupling).

· The efficiency of the coupling process is determined by the following factors:

1) Initial Conformational Change in the receptor. As a result, the conformational change (occupancy) that results from binding of a full agonist leads to a much more efficient occupancy-response coupling than the conformational change that results from binding of a partial agonist.

2) Biochemical Events that transduce receptor occupancy into a cellular response and how efficient (or complicated) these events are.

• · High efficiency of a drug-receptor interaction may
• also be attributed to the presence of Spare Receptors.

For a particular pharmacologic response, ‘Spare Receptor Molecules’ are present when the maximal effect or response can be produced by an agonist at a concentration that does not result in occupancy of all of the available receptor molecules.

For example, a maximal ionotropic response of the heart muscle to catecholamines can be elicited even if 90% of the b-adrenoceptors are occupied by an irreversible antagonist. Accordingly, myocardial cells are said to contain a large number of spare b-adrenoceptors.

· Spare receptors are said to exist if the maximal pharmacologic effect (E_max) is obtained at less than maximal occupation of the receptor molecules (B_max).

· The presence of spare receptors is determined by comparing the concentration of 50% of maximal effect (EC₅₀) with the concentration for 50% of maximal binding (K_D). If the EC₅₀ is lower than the K_D, spare receptors are said to exist. This means that to achieve 50% of maximal effect in a system with spare receptors, less than 50% of the receptor molecules must be activated. If EC₅₀ and K_D are equal, spare receptors do not exist.

· The presence of spare receptors may be the result of one of two mechanisms:

1) The duration of the activation of the effector may be much greater than the duration of the drug-receptor interaction.

2) The actual number of receptor molecules may exceed the number of effector molecules available.

· The sensitivity of a cell or tissue to a particular concentration of the agonist depends on both:

• 1) The affinity of the receptor for binding to the agonist (which is characterized by K_D) and
• 2) The degree of spareness of the receptor. The ‘degree of spareness’ is the total number of receptor molecules present compared to the number of receptor molecules that is actually needed to elicit a maximal biologic response (i.e., it is the number of spare receptor molecules that are present).

A high degree of spareness (i.e., a high number of spare receptor molecules) leads to a considerable increase in the sensitivity of a tissue to a particular drug agonist because the likelihood of a drug-receptor interaction increases in proportion to the number of receptor molecules available. Thus, it is possible to change the sensitivity of tissues with spare receptors by changing the receptor concentration.

• · Pharmacologic antagonists bind to the same binding site of the agonist on the receptor molecule without activating the receptor (or without activating the effector system for that receptor). The antagonistic effect of these molecules results from their ability to prevent agonists (drug agonists or
• endogenous agonists) from binding to and activating receptors.

Pharmacologic antagonists are divided into two major classes (Competitive and Noncompetitive Antagonists) based on whether or not they reversibly compete with agonists for binding to receptors.

Competitive antagonists bind to the same binding site of the agonist on the receptor molecule in a reversible way without activating the effector system for that receptor.

• Competitive antagonism is concentration-dependent. Increasing concentrations of a competitive antagonist, in the presence of a fixed concentration of the agonist, will result in a gradual
• decrease or inhibition of the agonist effect; high concentrations of the competitive antagonist will completely abolish the agonist effect.

• High enough concentrations of the agonist will
• displace the antagonist and fully activate the receptor. As a result, the agonist will completely abolish the antagonistic effect of a given concentration of the competitive antagonist. At these high concentrations of the agonist, the agonist E_max remains the same for any fixed concentration of the antagonist.

Because of the competition between the agonist and the antagonist, the concentration of the agonist required to produce a given effect in the presence of a fixed concentration of the competitive antagonist is greater than the concentration of the agonist required to produce the same effect in the absence of the antagonist. Consequently, the agonist concentration-effect (or dose-response) curve will shift to the right (i.e., the curve will shift to higher doses/concentrations), but the same maximal effect (E_max) is reached.



The ‘blocking’ (or inhibitory) effect of a competitive antagonist depends on its concentration. Different patients receiving a fixed dose of a competitive antagonist or ‘blocker’ (e.g., propranolol) exhibit different plasma levels, due to differences in clearance of the antagonist. As a result, the antagonistic effects of a competitive blocker may vary widely among patients, and the dose must be adjusted accordingly.

Clinical response to a competitive antagonist also depends on the concentration of the agonist (e.g., ‘norepinephrine’ in the case of propranolol). An increase in the concentration of the agonist will result in a decrease in the antagonistic effect of the blocker (and a decrease in its therapeutic effect); a considerable increase in the agonist concentration may suffice to abolish the competitive antagonism exhibited by the antagonist.

Noncompetitive pharmacologic antagonists bind to the receptor without activating it (or without activating the effector system for that receptor).

Noncompetitive pharmacologic antagonists bind irreversibly to the same binding site of the agonist on the receptor molecule.

In some cases, irreversible binding is attributed to an extremely high affinity of the antagonist for binding to their receptor sites; as a result, the receptor is practically unavailable for binding to the agonist. In other cases, antagonists bind irreversibly because they form covalent bonds with their receptor sites.

Unlike the effects of a competitive antagonist, the effects of an irreversible antagonist cannot be overcome by increasing the concentration/dose of the agonist.

Once an irreversible antagonist binds to a number of the receptor molecules, the number of unoccupied receptor molecules may not be enough for the agonist to exert its maximal effect. As a result, irreversible antagonists cause a downward shift of the maximum in the agonist dose-response curve (there is no shift of the curve on the dose/concentration axis to higher doses/concentrations unless spare receptors are present).

If Spare Receptors are present, a low dose of the irreversible antagonist will likely leave enough unoccupied receptor molecules for the agonist to exert a maximal effect.



Clinically, there is an advantage in using an irreversible antagonist in therapy (e.g., phenoxybenzamine, an irreversible a-adrenoceptor antagonist). Once it has occupied the receptor, the presence of the unbound form of an irreversible antagonist is not required for inhibition of the agonist responses. As a result, the duration of action of an irreversible antagonist largely depends on the rate of turnover of receptor molecules (not the rate of its own elimination).

Another advantage of using an irreversible antagonist in therapy is its ability to maintain blockade or inhibition of the agonist effect even in the presence of varying and high concentrations of the agonist.

A disadvantage of using an irreversible antagonist as a therapeutic agent is the need to ‘antagonize’ excess effects of the antagonist in case of an overdose.

• · In the absence of spare receptor molecules, the maximal pharmacologic response occurs when an
• agonist binds to all available receptor molecules. Based on that maximal response, agonists can be classified into two major classes: partial agonists and full agonists.

· Partial agonists produce a lower response, at full receptor occupancy, than do full agonists. The inability of a partial agonist to produce a maximal effect at full receptor occupancy is attributed to its mode of interactions with the receptor, i.e., it is attributed to its low intrinsic efficacy at the receptor site and its inability to stabilize the Ra form of the receptor as fully as a full agonist, resulting in a significant fraction of Ri-D complexes (it is not due to decreased affinity for binding to the receptor).

• · Partial agonists competitively inhibit the binding of full agonists at the receptor site (similar to the inhibition produced by a competitive pharmacologic
• antagonist). As a result, partial agonists can be used as competitive antagonists. In fact, many of the drugs that are used clinically as competitive antagonists are partial agonists.

· Many drug antagonists are receptor-specific antagonists (competitive or noncompetitive), but not all of them are receptor-specific. Two other mechanisms of drug antagonism are known; these include Chemical Antagonism and Physiologic Antagonism.

· Chemical Antagonism occurs when one drug (the chemical antagonist) antagonizes the actions of a second drug by binding to and inactivating the second drug. As a result, the chemical antagonist is able to prevent the second drug from binding to its receptor site.

· A chemical antagonist does not depend on interaction with the agonist’s receptor (although such interaction may occur).

• · Examples of chemical antagonists include the
• following:

1) Protamine is a chemical antagonist of the anticoagulant drug heparin. Protamine is used clinically to counteract the effects of heparin.

2) Dimercaprol is a chemical antagonist (or a chelator) of lead and some other toxic metals.

3) Pralidoxime is a chemical antagonist of organophosphate cholinesterase inhibitors.

· Many drug antagonists are receptor-specific antagonists (competitive or noncompetitive), but not all of them are receptor-specific. Two other mechanisms of drug antagonism are known; these include Chemical Antagonism and Physiologic Antagonism.

· Another way to antagonize the effects of a drug or an endogenous substance is to take advantage of the Physiologic Antagonism that already exists between endogenous regulatory pathways in the body.

· Unlike pharmacologic antagonists, a physiologic antagonist binds to a different receptor molecule, producing an effect opposite to that produced by the drug it antagonizes (a pharmacologic antagonist interacts with the same receptor as the drug it antagonizes)

• · When compared to the effects of receptor-specific
• antagonists, the effects of physiologic antagonists are much less specific and more difficult to control.

• · Examples of physiologic antagonists include the
• following:

• 1) Insulin (acting at the insulin receptor) is used to
• antagonize the hyperglycemic effects of glucocorticoids (acting at the glucocorticoid receptor).

• 2) Epinephrine’s bronchodilator action (mediated by the b-adrenoceptors) antagonizes the bronchoconstrictor action of histamine
• (mediated by the histamine receptors).

3) Glucagon (acting at the glucagon receptors) antagonizes the cardiac effects of an overdose of propranolol (acting at the b-adrenoceptors).