Drug Mech: Basic Principles 3

Receptors exist in a dynamic equilibrium, being synthesized inside the cell, inserted into the cell membranes, sequestered out of the membranes, and degraded at various rates.

These changes are usually referred to as ‘up-regulation’ or ‘down-regulation’ of the receptor. Receptors may also be reversibly inhibited by biochemical modification.

Receptors are dynamically regulated in number, location, and sensitivity.

Regulatory changes can occur over short times (minutes) and longer periods (days).

Desensitization occurs following frequent or continuous exposure of the receptor to the agonist (i.e., it occurs following continuous activation of the receptor by the agonist) over a short period of time (seconds to minutes).

It is a rapid and reversible process that desensitizes the tissue to further receptor-agonist interaction for only a few minutes. Following desensitization, the original conformational equilibrium of the receptor molecule is restored and the cells recover full responsiveness to the agonist.

The mechanism of desensitization for many receptors is not known. However, a mechanism for the desensitization of the b-adrenoceptor has been proposed (see Figure below).




This particular mechanism of desensitization, which rapidly and reversibly modulates the receptor’s ability to interact with G protein, turns out to be a common mechanism that regulates many G protein-coupled receptors.

Internalization of receptor molecules occurs following frequent or continuous exposure of the receptor to the agonist (i.e., it occurs following continuous activation of the receptor by the agonist) over a relatively short period of time (minutes to hours).

In this particular process, receptor molecules are recycled intact to the plasma membrane via endocytic vesicles. This rapid cycling of receptor molecules facilitates their dephosphorylation and increases the rate of restoring fully functional receptors in the plasma membrane.

Down-Regulation is another important process that regulates receptor-mediated responses. It occurs only after prolonged or repeated exposure of cells to the agonist over a long period of time (hours to days). Down-regulation decreases the number of receptor molecules present in the cell or tissue. It is a much slower process than rapid desensitization and is less readily reversible.

Down-regulation involves degradation of receptor molecules present in the cell (usually by ligand induced endocytosis and delivery to lysosomes), and requires the biosynthesis of new receptor molecules for recovery (unlike the process of rapid desensitization which involves reversible phosphorylation of existing receptors).

Tolerance refers to a decrease in the intensity of the response to a given dose of a drug as a consequence of continued drug administration over an extended period of time.

• Down-regulation may cause relative tolerance to the effects of a drug agonist in some patients (numerous factors are involved; not all patients will experience tolerance as a result of down-regulation).
• Tolerance may also occur as a result of depletion of essential substrates required for downstream effects in the signal transduction pathway following continuous activation of the receptor-effector system.

For example, depletion of thiol cofactors may be responsible for tolerance to nitroglycerin. In some cases, administering the missing substrate can reverse the tolerance.

Up-Regulation of the receptor occurs when receptor activation is blocked for prolonged periods of time (usually several days) by pharmacologic antagonists or by denervation (blocked nerve endings).

In order to select a drug and determine the appropriate dose of the drug for a particular therapeutic effect in a patient, one must know the pharmacologic potency and maximal therapeutic efficacy of the drug in relation to the desired therapeutic effect and be able to distinguish between potency and efficacy.

Efficacy refers to the ability of the drug to accomplish a specified effect.

Potency reflects the amount of drug (i.e., the dose) required to cause an effect.

A drug may have high efficacy but low potency or vice versa.

Potency refers to the concentration (EC₅₀) or dose (ED₅₀) of the drug required to produce 50% of its maximal therapeutic efficacy.

Referring to the graded dose-response curves shown below, Drugs A and B are more potent than drugs C and D. In addition, Drug B (a partial agonist) is more potent than Drug A because the EC₅₀ of A is greater than the EC₅₀ of B (Note that some doses of drug A can produce larger effects than any dose of drug B, despite the fact that B is pharmacologically more potent than A).



Potency of a drug depends on the affinity (K_D) of the drug for binding to the receptor and the efficiency of the occupancy-response coupling process.

Keep in mind that clinical effectiveness of a drug depends on its maximal therapeutic efficacy (E_max) and its ability to reach its site of action (not on its pharmacologic potency).

Reaching the site of action can depend on the route of administration and the pharmacokinetic (ADME) properties of the drug.

In selecting one of two drugs to administer to a patient, one must make that selection based on the relative effectiveness rather than the relative potency of the two drugs.

However, pharmacologic potency is going to largely determine the administered dose of the selected drug.

In therapeutics, potency of a drug is usually stated in dosage units with respect to a particular therapeutic end point.

Maximal efficacy (known simply as efficacy or E_max) is the upper limit of the dose-response relationship on the response axis of the graph shown below. Accordingly, drugs A, C, and D have equal efficacy, while all have greater efficacy than drug B.



Drug efficacy in a patient may be determined by the mode of interactions of the drug with the receptor (as with partial agonists), or by characteristics of the receptor-effector system (e.g., diuretics acting on one portion of the nephron may produce a much greater diuretic effect than the diuretics that act on other parts of the nephron); therapeutic efficacy in a patient also depends on a host of other factors.

The practical clinical efficacy of a drug may in some cases be limited by the drug’s tendency to cause a toxic effect, even if the drug can otherwise exert a greater therapeutic effect.

• A quantal dose-response curve represents the percentage of individuals (or laboratory animals) under study who exhibit a specified drug effect (a
• therapeutic effect, an undesirable drug effect, a lethal effect, or any other drug effect) plotted as a function of log drug dose (the x-axis).

A quantal dose-response curve illustrates the potential variability of responsiveness to the drug among individuals in a given human population.

Median Effective Dose (ED₅₀), is the drug dose at which 50% of individuals exhibit the specified quantal effect.

Median Toxic Dose (TD₅₀), is the drug dose required to produce a particular toxic effect in 50% of individuals or laboratory animals.

If the toxic effect is death of the laboratory animal, a Median Lethal Dose (LD₅₀) can be experimentally defined.

The Therapeutic Index of a drug relates the dose of the drug required to produce a desired effect to the dose of the drug which produces an undesirable effect. It represents an estimate of the safety of a drug. In animal studies, the therapeutic index is defined as the ‘TD₅₀/ED₅₀’ ratio for a particularly relevant therapeutic effect. Keep in mind that the clinically acceptable risk of toxicity from a drug depends on the severity of the disease being treated.

The Therapeutic Window (or Therapeutic Range) of a drug is a more clinically useful index of safety. It describes the dosage range (i.e., the difference) between the minimum effective therapeutic concentration/dose and the minimum toxic concentration/dose of a drug in humans.

Both the Therapeutic Index and the Therapeutic Window depend on the specific toxic effect used in the determination.

• There is a great deal of variability in the
• responsiveness to a drug among individuals; variation in drug responsiveness has also been shown in a single individual at different times during the course of treatment by the same drug.

• Numerous factors affect drug responsiveness
• including age, sex, body size, disease state, genetic factors, and simultaneous administration of other drugs.

Four major mechanisms are known to contribute to variation in drug responsiveness:

1) Alteration in Drug Concentration at the Receptor Site

2) Variation in Concentration of an Endogenous Receptor Ligand

3) Alterations in the number or function of Receptors

4) Changes in Components of Response Distal to the Receptor

1) Alteration in Drug Concentration at the Receptor Site: Due to pharmacokinetic differences (in drug absorption, distribution, metabolism, or excretion) among patients, which leads to variability in the clinical response.

2) Variation in Concentration of an Endogenous Receptor Ligand: This particular mechanism leads to a great deal of variability in responses to drug antagonists and partial agonists.

For example, the levels of endogenous catecholamines affect the clinical response to the b-adrenoceptor antagonist propranolol.

3) Alterations in the Number or Function of Receptors:

An increase or decrease in the number of receptor sites or alterations in the efficiency of the occupancy-response coupling can cause variability in drug responsiveness.

Alteration in the number of receptor sites is sometimes caused by other hormones. For example, thyroid hormones increase both the number of b-adrenoceptors and cardiac sensitivity to catecholamines.

The agonist ligand itself can induce a decrease in the number (e.g., down-regulation) or coupling efficiency (e.g., desensitization) of its receptor sites.

Genetic factors can also contribute to altering the number or function of specific receptors. For example, a combination of a specific a 2C-adrenoceptor genetic variant and a specific b1-adrenoceptor genetic variant confers an increased risk for developing CHF (the risk may be reduced by early intervention using antagonist drugs).

4) Changes in Components of Response Distal to the Receptor:

• Drug response in a patient depends not only on the
• drug’s ability to bind to the receptor, but also on the functional integrity and efficiency of the biochemical processes in the cell (occupancy-response coupling) and the physiologic regulation by interacting organ systems.

Changes in these post-receptor events represent the most important mechanism that causes variation in responsiveness to drug therapy. Factors that influence these events include age and general health of the patient and, most importantly, the severity and pathophysiologic mechanism of the disease that is being treated.

• An unsatisfactory therapeutic response is sometimes
• attributed to the physiologic compensatory mechanisms that respond to and oppose the effects of a drug (e.g., compensatory vasoconstriction and fluid retention by the kidney can cause tolerance to the antihypertensive effects of a vasodilator drug). In such cases, additional drugs may be required to treat the patient.

Clinical selectivity of a drug is determined by separating drug effects into two categories: Beneficial or therapeutic effects versus toxic effects (toxic effects are sometimes called side effects).

Three major mechanisms for mediating the beneficial and toxic effects of drugs are known:

1) Therapeutic and Toxic Effects Mediated by the Same Receptor-Effector Mechanism: Much of the serious drug toxicity encountered clinically is the result of a direct pharmacologic extension of the therapeutic actions of the drug (e.g., bleeding caused by anticoagulant therapy, …etc).

2) Therapeutic and Toxic Effects Mediated by Identical Receptors in Different Tissues (or via different Effector Pathways): Many drugs exert both their therapeutic and toxic effects by acting on a single receptor type in different tissues (e.g., glucocorticoid hormones, digitalis glycosides, methotrexate).

3) Therapeutic and Toxic Effects Mediated by Different Types of Receptors