Pharmacodynamics

PHARMACODYNAMIC CONCEPTS Receptors: Specific molecules in a biologic system with which drugs interact to produce changes in the function of the system. Receptors must be selective in their ligand-binding characteristics. Receptors also must be modified as a result of binding an agonist molecule (so as to bring about the functional change). Many receptors have been identified, purified, chemically characterized, and cloned.

The majority of the receptors characterized to date are proteins; a few are other macromolecules such as DNA.

The receptor site or recognition site for a drug is the specific binding region of the macromolecule and has a high and selective affinity for the drug molecule.

The interaction of a drug with its receptor is the fundamental event that initiates the action of the drug.

Effectors:Effectors are molecules that translate the drug-receptor interaction into a change in cellular activity.

The best examples of effectors are enzymes such as adenylyl cyclase.

Some receptors are also effectors in that a single molecule may incorporate both the drug binding site and the effector mechanism, eg, the tyrosine kinase effector of the insulin receptor, or the sodium-potassium channel of the nicotinic acetylcholine receptor.

Graded Dose-Response Relationships:When the response of a particular receptor-effector system is measured against increasing concentrations of a drug, the graph of the response versus the drug concentration or dose is called a graded dose-response curve.

Plotting the same data on semilogarithmic axes usually results in a sigmoid curve, which simplifies the mathematical manipulation of the dose-response data .

The efficacy (Emax) and potency (ECs0) parameters are derived from these data.

The smaller the EC50, the greater the potency of the drug.

Quantal Dose-Response Relationships:When the minimum dose required to produce a specified response is determined in each member of a population, the quantal dose-response relationship is defined.

When plotted as the fraction of the population that responds at each dose versus the log of the dose administered, a cumulative quantal dose-response curve usually sigmoid in shape, is obtained.

The median effective (ED50), median toxic (TD50), and median lethal doses (LD50) are extracted from experiments carried out in this manner.

Efficacy:Efficacy, often called maximal efficacy, is the maximal effect (Emax) an agonist can produce if the dose is taken to very high levels.

Efficacy is determined mainly by the nature of the receptor and its associated effector system. It can be measured with a graded dose-response curve but not with a quantal dose-response curve.

By definition, partial agonists have lower maximal efficacy than full agonists.

Potency:The amount of a drug needed to produce a given effect. In graded dose-response measurements, the effect usually chosen is 50% of the maximal effect and the dose causing this effect is called the EC50. Potency is determined mainly by the affinity of the receptor for the drug. In quantal dose-response measurements ED50., TD50., and LD50 are typical potency variables (median effective, toxic, and lethal doses, respectively, in 50% of the population studied).

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

Spare Receptors:Spare receptors are said to exist if the maximal drug response is obtained at less than maximal occupation of the receptors.

In practice, the determination is usually made by comparing the concentration for 50% of maximal effect (EC50) with the concentration for 50% of maximal binding (Kd).

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

This might result from one of several mechanisms.

First, the effect of the drug-receptor interaction may persist for a much longer time than the interaction itself.

Second, the actual number of receptors may exceed the number of effector molecules available. The presence of spare receptors increases sensitivity to the agonist because the likelihood of a drug-receptor interaction increases in proportion to the number of receptors available.

Inert Binding Sites:Inert binding sites are components of endogenous molecules that bind a drug without initiating events leading to any of the drug's effects. In some compartments of the body (eg, the plasma), inert binding sites play an important role in buffering the concentration of a drug because bound drug does not contribute directly to the concentration gradient that drives diffusion. The two most important plasma proteins with significant binding capacity are albumin and orosomucoid (a1-acid glycoprotein).

Agonists and Partial Agonists:An agonist is a drug capable of fully activating the effector system when it binds to the receptor.

A partial agonist produces less than the full effect, even when it has saturated the receptors.

In the presence of a full agonist, a partial agonist acts as an inhibitor.

Competitive and Irreversible Pharmacologic Antagonists:Competitive antagonists are drugs that bind to the receptor in a reversible way without activating the effector system for that receptor.

In the presence of a competitive antagonist, the log dose-response curve is shifted to higher doses (ie, horizontally to the right on the dose axis) but the same maximal effect is reached.

In contrast, an irreversible antagonist causes a downward shift of the maximum, with no shift of the curve on the dose axis unless spare receptors are present.

The effects of competitive antagonists can be overcome by adding more agonist.

Irreversible antagonists cannot be overcome by adding more agonist. Competitive antagonists increase the ED50; irreversible antagonists do not (unless spare receptors are present).

ED50

Physiologic Antagonists:A physiologic antagonist is a drug that binds to a different receptor, producing an effect opposite to that produced by the drug it is antagonizing.

Thus it differs from a pharmacologic antagonist, which interacts with the same receptor as the drug it is inhibiting.

A common example is the antagonism of the bronchoconstrictor action of histamine (mediated at histamine receptors) by epinephrine's bronchodilator action (mediated at beta adrenoceptors).

Chemical Antagonists:A chemical antagonist is a drug that interacts directly with the drug being antagonized to remove it or to prevent it from reaching its target.

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

A common example of a chemical antagonist is dimercaprol, a chelator of lead and some other toxic metals.

Pralidoxime, which combines avidly with the phosphorus in organophosphate cholinesterase inhibitors, is another type of chemical antagonist.

Nerve AgentsOrganophosphate insecticidesCholinesterase inhibitorsPralidoximeCholinesterase generatorChemical antagonist

Enzyme active site

Therapeutic Index, Therapeutic Window:The therapeutic index is the ratio of the TD50 (or LD50) to the ED50, determined from quantal dose-response curves. The therapeutic index represents an estimate of the safety of a drug, since a very safe drug might be expected to have a very large toxic dose and a small effective dose.

Unfortunately, factors such as the varying slopes of dose-response curves make this estimate a poor safety index. The therapeutic window, a more clinically relevant index of safety, describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose. For example, if the average minimum therapeutic plasma concentration of theophylline is 8 mg/L and toxic effects are observed at 18 mg/L, the therapeutic window is 8-18 mg/L.

The therapeutic index = TD50 (or LD50) / ED50 = 150/3 = 50

Signaling Mechanisms:Once an agonist drug has bound to its receptor, some effector mechanism is activated.

For most drug-receptor interactions, the drug is present in the extracellular space while the effector mechanism resides inside the cell and modifies some intracellular process.

Thus, signaling across the membrane must occur.

Five major types of transmembrane signaling mechanisms for receptor-effector systems have been defined: Receptors that are intracellular: Some drugs, especially more lipid-soluble or diffusible agents (eg, steroid hormones, nitric oxide) may cross the membrane and combine with an intracellular receptor that affects an intracellular effector molecule. No specialized transmembrane signaling device is required.

2. Receptors located on membrane-spanning enzymes: Drugs that affect membrane-spanning enzymes combine with a receptor on the extracellular portion of enzymes and modify their intracellular activity. For example, insulin acts on a tyrosine kinase that is located in the membrane. The insulin receptor site faces the extracellular environment and the enzyme catalytic site is on the cytoplasmic side. When activated, the receptors dimerize and phosphorylate specific protein substrates.

Receptors located on membrane-spanning molecules that bind separate intracellular tyrosine kinase molecules:

Receptors have extracellular and intracellular domains and form dimers.

After receptor activation by an appropriate drug, the tyrosine kinase molecules (,Janus kinases; JAKs) are activated, resulting in phosphorylation of "STAT" molecules (signal transducers and activators of transcription).

STAT dimers then travel to the nucleus, where they regulate transcription.

Tyrosine-kinase receptorsStructure:Receptors exist as individual polypeptidesEach has an extracellular signal-binding siteAn intracellular tail with a number of tyrosines and a single a helix spanning the membrane

4. Receptors located on membrane ion channels:

Receptors that regulate membrane ion channels may directly cause the opening of an ion channel (eg, acetylcholine at the nicotinic receptor) or modify the ion channel's response to other agents (eg, benzodiazepines at the GABA channel).

The result is a change in transmembrane electrical potential.

Ion channel receptorsStructure:Protein pores in the plasma membrane

5. Receptors linked to effectors via G proteins: A very large number of drugs bind to receptors that are linked by coupling proteins to intracellular or membrane effectors. The best defined examples of this group are the sympathomimetic drugs, which activate or inhibit adenylyl cyclase by a multistep process: activation of the receptor by the drug results in activation of G proteins that either stimulate or inhibit the cyclase.

G protein-linked receptorsStructure:Single polypeptide chain threaded back and forth resulting in 7 transmembrane a helicesTheres a G protein attached to the cytoplasmic side of the membrane (functions as a switch).

More than 20 types of G proteins have been identified; three of the most important are listed in this table.

Signal transduction