I. DRUG RECEPTORS AND PHARMACODYNAMICS

I. DRUG RECEPTORS AND PHARMACODYNAMICS
Therapeutic and/or toxic effects of drugs result from their interactions with molecules in the patient. Most drugs act by associating with specific macromolecules in ways that alter the macromolecules’ biochemical or biophysical activities Drug receptor: 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

I. DRUG RECEPTORS AND PHARMACODYNAMICS
1. Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects. 2. Receptors are responsible for selectivity of drug action size, shape and electrical charge of drug are important 3. Receptors are the sites of binding of pharmacologic agents

II. Macromolecular Nature of Drug Receptors
Until recently, the chemical structures and even the existence of receptors for most drugs could only be inferred from the chemical structures of the drugs themselves. Receptors for many drugs have been biochemically purified and characterized. Most receptors are proteins presumably because the structures of polypeptides provide both the necessary diversity and the necessary specificity of shape and electrical charge.

The best-characterized drug receptors are regulatory proteins mediate the actions of endogenous chemical signals such as neurotransmitters, autacoids and hormones this class of receptors mediates the effects of many of the most useful therapeutic agents enzymes may be inhibited (or, less commonly, activated) by drugs (e.g. dihydrofolate reductase- dhfr- the receptor for the antineoplastic drug methotrexate)

The best-characterized drug receptors are (cont). transport proteins proteins involved in the transport of ions or other biological molecules Na+/K+ ATPase the membrane receptor for cardioactive digitalis glycosides structural proteins proteins involved in maintenance of cellular integrity tubulin the receptor for colchicine, an anti- inflammatory agent

III. Relation Between Drug Concentration and Response
The relationship between dose of a drug and the clinically-observed response may be quite complex. in carefully-controlled in vitro systems, however, the relationship between concentration of a drug and its effect is often simple and can be described with mathematical precision. the idealized relationship underlies the more complex relations between dose and effect that occur when drugs are given to patients.

IIIA. Concentration-Effect Curves and Receptor Binding of Agonists
Even in intact animals or patients, responses to low doses of drug usually increase in direct proportion to dose. as doses increase, the response increment diminishes finally, doses may be reached at which no further increase in response can be achieved.

In idealized or in vitro systems, the relationship between drug concentration (C) and effect (E) is described by a hyperbolic curve according to the equation: E= Emax x C C + EC50

Emax EC50 Emax: the maximal response that can be produced by the drug. EC50: concentration of the drug that produces 50% of maximal effect E: the effect observed at a particular drug concentration C: concentration of drug E= Emax x C C + EC50

In these systems, the relation between drug bound to receptors (B) and the concentration of unbound drug (C) is described by the equation: B = Bmax x C C + Kd In which Bmax is the total concentration of receptor sites sites bound to the drug at infinitely high concentrations of free drug. Kd is the equilibrium dissociation constant represents the concentration of free drug at which half-maximal binding is observed

Bmax Kd is the equilibrium dissociation constant represents the concentration of free drug at which half-maximal binding is observed KD

Kd represents the concentration of free drug at which half-maximal binding is observed. The Kd characterizes the receptor’s affinity for binding the drug in a reciprocal fashion. If Kd is high, binding affinity is low. If Kd is low, binding affinity is high.

Graphic representation of dose-response data is frequently improved by plotting the drug effect against the logarithm of the dose or concentration. the effect of this mathematical maneuver is to transform a hyperbolic curve into a sigmoidal curve with a linear midportion.

IIIB. Receptor-Effector Coupling and Spare Receptors
When a receptor is occupied by an agonist, the resulting conformational change is only the first of many steps usually required to produce a pharmacological effect. The transduction process between occupancy of receptors and drug response is often called coupling.

The relative efficiency of receptor occupancy-response coupling is partially determined by the initial conformational change in the receptor. the effects of full agonists can be considered more efficiently coupled to receptor occupancy than can the effects of partial agonists.

High efficiency of receptor-effector interaction may also be the result of spare receptors. Receptors are said to be spare for a given pharmacologic response when the maximal response can be elicited by an agonist at a concentration that does not result in occupancy of the full complement of available receptors.

spare receptors are not qualitatively different from nonspare receptors. *not hidden or unavailable *when they are occupied, they can be coupled to response. Experimentally, spare receptors may be demonstrated by using irreversible antagonist to prevent binding of agonist to a proportion of available receptors and showing that high concentrations of agonist can still produce an undiminished maximal response.

Thus, a maximal inotropic response of heart muscle to catecholamines can be elicited even under conditions where 90% of the B-adrenoceptors are occupied by a quasi-irreversible antagonist. Myocardium is said to contain a large proportion of spare B-adrenoceptors.

A B C D E Spare Receptors AGONIST EFFECT Max Response
Very High [Antagonist] 0.5 Low [Antagonist] No Antagonist High [Antagonist] E Very Very High [Antagonist] EC50 (D,E) EC50 (A) EC50 (B) EC50 (C) When irreversible antagonist concentration is too high, the “spare receptors” are all occupied and the maximal response is diminished!! (see curves D and E).

KD= the concentration of agonist when half the receptors are bound.
Drug Agonist (purple) binding to receptor (light green) elicits a change in receptor conformation. That enables the receptor to bind to and activate a transducing molecule (yellow). As depicted here, the concentration of agonist is equal to the KD (the concentration of drug at which half of the receptors are occupied). Cell Membrane Here..the transducing molecule does not mediate receptor action b/c no drug has modulated a conformational change in the receptor. In this case, the transducing molecule is not activated by the receptor.

Spare Receptors- More Drug receptors than Receptor-Effector Molecules
As depicted here, the number of receptors has increased and the KD for agonist binding remains unchanged. Here the concentration of agonist is much less than the KD (the concentration of drug at which half of the receptors are occupied). The number of transducing molecules, however, is the same as before… Spare receptors allow a response to be obtained under conditions where the agonist concentration is low. Cell Membrane

The KD of the agonist-receptor interaction determines what fraction (B/Bmax) of total receptors will be occupied at a given free concentration (C) of agonist, regardless of the receptor concentration: B = C Bmax C + Kd

Imagine a responding cell with four receptors and four effectors. Here the number of effectors does not limit the maximal response, and the receptors are NOT spare in number. An agonist present at a concentration equal to the KD will occupy 50% of the receptors, and half of the effectors will be activated, producing a half-maximal response. (ie. Two receptors stimulate two effectors)

Now imagine that the number of receptors increases ten fold and but the total number of effectors remains constant. Most of the receptors are now spare in number.

As a result, a much lower concentration of the agonist is sufficient to bind two of the 40 receptors (5% of the receptors)… and this same low concentration of agonist is able to elicit a half-maximal response. Thus, it is possible to change the sensitivity of tissues with spare receptors by changing the receptor concentration.

IIIC. Competitive and Irreversible Antagonists
Receptor antagonists bind to the receptor but do not activate it. The effects of antagonists, in general, result from preventing agonists (other drugs or endogenous regulatory molecules) from binding to and activating receptors.

Antagonists can be divided into two classes depending on whether or not they reversibly compete with agonists for binding to receptors: reversible antagonists (competitive) irreversible antagonists (noncompetitive) These two classes of antagonists produce quite different concentration-effect and concentration-binding curves.

In the presence of a fixed concentration of agonist, increasing concentrations of a competitive antagonist progressively inhibit the agonist response; high antagonist concentrations prevent response completely. conversely, sufficiently high concentrations of agonist can completely surmount the effect of a given concentration of the antagonist.

Emax Agonist Alone Agonist Effect (E) Agonist + competitive antagonist EC50 EC50 Agonist Concentration In other words: the Emax for the agonist remains the same for any fixed concentration of competitive antagonist. because the antagonism is competitive, the presence of antagonist increases the agonist concentration required for a given degree of response, and the agonist concentration-effect curve shifts to the right.

Emax Agonist Alone Agonist Effect (E) Agonist + competitive antagonist Agonist Concentration C C’ The concentration (C’) of an agonist required to produce a given effect in the presence of a fixed concentration [I] of competitive antagonist is greater than the agonist concentration (C) required to produce the same effect in the absence of antagonist.

Emax Agonist Alone Agonist Effect (E) Agonist + competitive antagonist Agonist Concentration C C’ The ratio of these two agonist concentrations (the “dose ratio”) is related to the dissociation constant (KI) of the antagonist by the SCHILD EQUATION: C’ = 1 + [I]/KI --- C

Emax Agonist Alone Agonist Effect (E) Agonist + competitive antagonist Agonist Concentration C C’ In the presence of a fixed concentration of competitive antagonist, higher concentrations of agonist are required to produce a given effect. Thus, the agonist concentration (C’) required for a given effect in the presence of concentration [I] of antagonist is shifted to the right.

Emax Agonist Alone Agonist Effect (E) Agonist + competitive antagonist Agonist Concentration C C’ High agonist concentrations can overcome inhibition by a competitive antagonist. This is not the case with an irreversible antagonist, which reduces the maximal effect the agonist can achieve

Emax Agonist Alone Agonist Effect (E) Agonist + competitive antagonist Agonist Concentration C C’ C’ = 1 + [I]/KI --- C Pharmacologists often use this relation to determine the KI of a competitive antagonist. Even without knowledge of the relationship between agonist occupancy of the receptor and response, the KI can be determined simply and accurately.

Agonist Alone Emax Agonist Effect (E) Here is a hypothetical example of Schild’s Eqn. (fixed concentration of competitive antagonist): If C’ is twice C, then [I] = KI What if C’ is three times the value of C… what is the KI? 3 = 1 + [I]/KI 2= [I]/KI 2*KI= [I] Agonist + competitive antagonist C C’ Agonist Concentration C’ = 1 + [I]/KI --- C

IIIC. Agonists (% of maximum) EFFECT Agonist Concentration

IIIC. Agonists Under circumstances where there is only agonist (green), only agonist can bind to the receptor. When all the receptors are saturated, we see maximum effect (Emax) (% of maximum) EFFECT Agonist Concentration

IIIC. Agonists (% of maximum) EFFECT (% of maximum) EFFECT Agonist Concentration Agonist Concentration Log-scale The effect of this mathematical maneuver is to transform the hyperbolic curve into a sigmoid curve with a linear midportion.

C’ = 1 + [I]/KI --- C Under circumstances where there is only agonist (green), only agonist can bind to the receptor. When all the receptors are saturated, we see maximum effect (Emax) Emax EFFECT Agonist Concentration

IIIC. Antagonists (% of maximum) EFFECT Agonist Concentration

IIIC. Antagonists As you may have noticed,
Antagonists bind to receptors, but do not ACTIVATE those receptors (% of maximum) EFFECT Agonist Concentration

IIIC. Competitive Antagonists
Under circumstances where there is both agonist (green) and antagonist (red), both can bind to the receptor. Antagonists have the ability to bind the receptor, but they DO NOT ACTIVATE the receptor. So the maximum effect will be diminished, UNLESS more agonist is added. Agonist Alone Agonist + Antagonist Emax EFFECT Agonist Concentration

Fixed concentration of AGONIST alone

Fixed [AGONIST] PLUS A low concentration of REVERSIBLE ANTAGONIST

Fixed [AGONIST] PLUS a higher concentration of REVERSIBLE ANTAGONIST

Fixed [AGONIST] PLUS an even higher concentration of REVERSIBLE ANTAGONIST

Fixed [AGONIST] PLUS even more REVERSIBLE ANTAGONIST! Are you starting to see the trend?

Eventually you may displace all of the agonist with antagonist.

If the antagonist concentration is now held constant, and we INCREASE the concentration of agonist… we can displace the competitive, or reversible, antagonist.

If the antagonist concentration is now held constant, and we INCREASE the concentration of agonist… we can displace the competitive antagonist (also called ‘reversible’).

IIIC. WHAT DO WE MEAN BY ‘Competitive Antagonist?’
ACTIVE Competitive Antagonist NOT ACTIVE ASSUMING that the following conditions apply: *[Agonist] and [Competitive Antagonist] are the same. *Affinity of agonist and competitive antagonist for the receptor are similar

ACTIVE Competitive Antagonist Agonist NOT ACTIVE ASSUMING that the following conditions apply: *[Agonist] and [Competitive Antagonist] are the same. *Affinity of agonist and competitive antagonist for the receptor are similar

NOT ACTIVE NOT ACTIVE

ACTIVE ACTIVE

A competitive antagonist binds reversibly to the same receptor as the agonist. a dose-response curve performed in the presence of a fixed concentration of antagonist will be shifted to the right; with the same maximum response and shape. TRANSLATION: The binding of a reversible or COMPETITIVE antagonist can be overcome with increasing concentrations of agonist– like we just saw. No Antagonist Fixed [antagonist] EFFECT AGONIST CONCENTRATION (Log)

IIIC. WHAT DO WE MEAN BY ‘IRREVERSIBLE Antagonist?’
Some receptor antagonists bind to the receptor in an IRREVERSIBLE or nearly irreversible fashion (i.e. NON-Competitive) The antagonist’s affinity for the receptor may be so high that for practical purposes, the receptor is unavailable for binding of agonist. Other antagonists in this class produce irreversible effects because after binding to the receptor they form covalent bonds with it.

After occupancy of some proportion of receptors by such an antagonist, the number of remaining unoccupied receptors may be too low for the agonist (even at high concentrations) to elicit maximal response. Agonist Alone AGONIST EFFECT Agonist + Irreversible Antagonist NOT LOG SCALE NOTE: EC50 may not change AGONIST CONCENTRATION

If spare receptors are present, however, a lower dose of an irreversible antagonist may leave enough receptors unoccupied to allow achievement of maximum response to agonist. Drug Fixed [Agonist] RESPONSE [Irreversible Antagonist] 0

If spare receptors are present, however, lower dose of an irreversible antagonist (red) may leave enough receptors unoccupied to allow achievement of maximum response to agonist (purple). Fixed [Agonist] RESPONSE [Irreversible Antagonist] LOW

If spare receptors are present, however, lower dose of an irreversible antagonist (red) may leave enough receptors unoccupied to allow achievement of maximum response to agonist (purple). Fixed [Agonist] RESPONSE [Irreversible Antagonist] low med

If spare receptors are present, however, higher doses of an irreversible antagonist (red) may not leave enough receptors to allow achievement of maximum response to agonist (purple). Fixed [Agonist] RESPONSE [Irreversible Antagonist] low med high

Because all of the receptors have been saturated and the binding of the irreversible antagonist is so strong, addition of MORE AGONIST will not re-establish the response. Agonist will not be able to displace the irreversible antagonist. There is no competition for receptor binding, as would be the case with a reversible antagonist. [Agonist] High RESPONSE [Irreversible Antagonist] HIGH As long as the receptors are occupied by irreversible antagonist, addition of MORE AGONIST will not re-establish the response

Therapeutically, irreversible antagonists present distinctive advantages and disadvantages: Once the irreversible antagonist has occupied the receptor, it need not be present in unbound form to inhibit agonist responses. the duration of action, therefore, of such an irreversible antagonist is relatively independent of its own rate of elimination and more dependent upon the rate of turnover of receptor molecules.

Phenoxybenzamine, an irreversible alpha-adrenoceptor antagonist, is used to control the hypertension caused by catecholamines released from pheochromocytoma, a tumor of the adrenal medulla. If administration of phenoxybenzamine lowers blood pressure, blockade will be maintained even when the tumor episodically releases very large amounts of catecholamine. In this case, the ability to prevent responses to varying and high concentrations of agonist is a therapeutic advantage. Overdose, however, can cause major problems. if the alpha-adrenoceptor blockade cannot be overcome, excess effects of the drug must be antagonized ‘physiologically.’ (By using a pressor agent that does not act via alpha receptors)

Alpha-adrenoceptors bind to catecholamines (blue spheres), which act as agonists that stimulate increases in blood pressure BLOOD PRESSURE

BLOOD PRESSURE Secretes catecholamines which can bind to alpha adrenoceptors and result in elevated BP levels Pheochromocytoma (tumor of adrenal medulla)

BLOOD PRESSURE Overdose, however, can cause major problems. if the alpha-adrenoceptor blockade cannot be overcome, excess effects of the drug must be antagonized ‘physiologically.’ (By using a pressor agent that does not act via alpha receptors) Phenoxybenzamine irreversible antagonist that occupies alpha adrenoceptors. WILL NOT be displaced from receptor by the catecholamines

PARTIAL agonists (Yellow) FULL agonists (Purple)
IIID. PARTIAL AGONISTS Agonists can be divided into two classes based on the maximal pharmacologic response that occurs when all receptors are occupied. PARTIAL agonists (Yellow) FULL agonists (Purple) Partial agonists produce a lower response at full receptor occupancy than do FULL agonists. Partial Agonists stimulate a less-than-max response; even when receptors are saturated. Emax RESPONSE Full Receptor Occupancy

IIID. PARTIAL AGONISTS As compared with full agonists, partial agonists produce concentration-effect curves that resemble those with full agonists in the presence of an antagonist that irreversibly blocks receptor sites. FULL AGONIST Emax Drug 1 Drug 2 EFFECT PARTIAL AGONISTS Drug 3 Drug 4 [AGONIST]

TRANSFORMATION OF THE LAST GRAPH TO A LOG-SCALE..
IIID. PARTIAL AGONISTS TRANSFORMATION OF THE LAST GRAPH TO A LOG-SCALE.. FULL AGONIST Emax Drug 1 EFFECT PARTIAL AGONISTS Drug 3 sigmoidal curve with linear midportion Log [AGONIST] A partial agonist, by definition, will never achieve the full effect.

IIID. PARTIAL AGONISTS Radioligand-binding experiments have demonstrated that partial agonists may occupy all receptor sites. Despite the finding that partial agonists can saturate receptor binding sites, the observation remains that they fail to produce a maximal response comparable to that seen with full agonists. Increasing concentrations of partial agonist can displace a fixed concentration of full agonist from the receptor.

IIID. PARTIAL AGONISTS Radioligand-binding experiments have demonstrated that partial agonists may occupy all receptor sites. Increasing concentrations of partial agonist (yellow) can displace a fixed concentration of full agonist (purple) from the receptors. NOTE: this is not an explanation of radioligand-binding experiments; it is simply an illustration of partial agonists competing for receptor binding with full agonists.

IIID. PARTIAL AGONISTS Radioligand-binding experiments have demonstrated that partial agonists may occupy all receptor sites. Increasing concentrations of partial agonist (yellow) can displace a fixed concentration of full agonist (purple) from the receptors.

partial agonists may occupy all receptor sites.
IIID. PARTIAL AGONISTS partial agonists may occupy all receptor sites. The percentage of receptor occupancy resulting from full agonist (present at a single concentration) binding to receptors in the presence of increasing concentrations of a partial agonist. Partial Agonist 100 Percentage of Maximal Binding Full Agonist (fixed concentration) Log [Partial Agonist] Because the full agonist (purple) and partial agonist (yellow) compete to bind the same receptor sites, when occupancy by the partial agonist increases, binding of the full agonist decreases.

IIID. PARTIAL AGONISTS Simultaneous treatment with a single concentration of full agonist and increasing concentrations of the partial agonist. Emax Partial Agonist RESPONSE *Response less than Emax Full Agonist (fixed concentration) Log [Partial Agonist] The response caused by a single concentration of the full agonist (purple) decreases as increasing concentrations of the partial agonist compete to bind the receptor with increasing success. *The response decreases because the partial agonist, now occupying all receptors, is “not as good” at activating the receptor as the full agonist was.

HOW CAN AN AGONIST BE ‘PARTIAL?’
IIID. PARTIAL AGONISTS HOW CAN AN AGONIST BE ‘PARTIAL?’ Envision a receptor as capable of taking on either of two shapes: The receptor oscillates in an equilibrium between the two conformations even in the absence of ligand. (equilibrium favors inactive conformation) INACTIVE ACTIVE NO RESPONSE RESPONSE

IIID. PARTIAL AGONISTS HOW CAN AN AGONIST BE ‘PARTIAL?’ Remember: most receptors will initially be in the inactive conformation Addition of full agonist: Full agonists have negligible affinity for receptors in the inactive conformation. INACTIVE ACTIVE NO RESPONSE RESPONSE

HOW CAN AN AGONIST BE ‘PARTIAL?’ Addition of ligand:
IIID. PARTIAL AGONISTS Full agonist binds to and stabilizes the active conformation and equilibrium drives the inactive receptors to assume active conformations to compensate. HOW CAN AN AGONIST BE ‘PARTIAL?’ Addition of ligand: INACTIVE ACTIVE NO RESPONSE RESPONSE

IIID. PARTIAL AGONISTS HOW CAN AN AGONIST BE ‘PARTIAL?’ Remember: most receptors will initially be in the inactive conformation Addition of partial agonist: Partial agonist can bind to either active or Inactive conformations. INACTIVE ACTIVE NO RESPONSE RESPONSE

IIID. PARTIAL AGONISTS HOW CAN AN AGONIST BE ‘PARTIAL?’ Remember: most receptors will initially be in the inactive conformation Addition of partial agonist: Partial agonist can bind to either active or Inactive conformations. These receptors have already bound the partial agonist and will not assume an active conformation. ACTIVE NO RESPONSE RESPONSE

IIID. PARTIAL AGONISTS HOW CAN AN AGONIST BE ‘PARTIAL?’ Remember: most receptors will initially be in the inactive conformation Addition of partial agonist: Partial agonist can bind to either active or Inactive conformations. ACTIVE These receptors have already bound the partial agonist and will not assume an active conformation. NO RESPONSE RESPONSE

IIID. PARTIAL AGONISTS HOW CAN AN AGONIST BE ‘PARTIAL?’ Compared to full agonists, partial agonists have higher affinity for receptors with inactive conformation. Partial agonists are “ambivalent”… they bind to both inactive and active receptor conformations… in effect, decreasing their maximum effects relative to full agonists. The ability of a partial agonist to stabilize active receptor will depend on its relative affinity for affinities for inactive and active forms. The higher the affinity for inactive receptor conformation, the less efficacious the partial agonist. ANTAGONISTS BIND TO INACTIVE RECEPTOR CONFORMATIONS, explaining their ability to bind without activating a response.

IIIE. Other Mechanisms of Drug Antagonism
Not all of the methods of antagonism involve interactions of drugs or endogenous ligands at a single type of receptor. CHEMICAL antagonists PHYSIOLOGIC antagonists

Chemical Antagonists (red sphere) in this type of antagonism, one drug may antagonize the actions of a second drug by binding to and inactivating the second drug Add chemical antagonist

Chemical Antagonists (red sphere) Foolish agonist, you thought everything was great! I am so happy. Life is GREAT! I am living the dream of every agonist; To activate my receptor. I am a chemical antagonist. I suppose our agonist over there is about to surprised!! HELP! active inactive Add chemical antagonist

Chemical Antagonists (red sphere) One example of chemical antagonism includes: heparin an anticoagulant that is negatively charged protamine a protein that is positively charged at physiologic pH. Protamine can be used clinically to counteract the effects of heparin. One drug antagonizes the effects of the other simply by binding it and making it unavailable for interactions with proteins involved in formation of a blood clot.

Physiologic Antagonists physiologic antagonism takes advantage of endogenous regulatory pathways many physiological functions are controlled by opposing regulatory pathways. For example: INCREASED BLOOD SUGAR Glucocorticoids INSULIN DECREASED BLOOD SUGAR

Physiologic Antagonists INCREASED BLOOD SUGAR Glucocorticoids INSULIN DECREASED BLOOD SUGAR The clinician must sometimes administer insulin to oppose the hyperglycemic effects of glucocorticoid hormone:

Physiologic Antagonists The clinician must sometimes administer insulin to oppose the hyperglycemic effects of glucocorticoid hormone: whether this is elevated by endogenous synthesis (such as by a tumor of the adrenal cortex) or whether this is elevated as a result of glucocorticoid therapy

Physiologic Antagonists (another example) To treat bradycardia (abnormally slow heartbeat) that is caused by increased release of acetylcholine from vagus nerve endings (after an event such as a myocardial infarction) the physician could use isoproterenol a beta-adrenoceptor agonist that increases heart rate by mimicking sympathetic stimulation of the heart. Use of this physiologic antagonist would be less rational than would use of a receptor-specific antagonist such as atropine (atropine is a competitive antagonist at the receptors at which acetylcholine slows heart rate).

I. DRUG RECEPTORS AND PHARMACODYNAMICS

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I. DRUG RECEPTORS AND PHARMACODYNAMICS

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