Basic Pharmacology - Pharmacodynamics

Pharmacodynamics

Pharmacodynamics deals with the effects of drugs on biological systems, while pharmacokinetics deals with actions of the biological systems on the drug.

Drug receptors

Receptors specific molecules with which drugs interact to produce changes in the system. Following binding of an agonist, the receptor will be modified to produce response.

Most of the receptors are proteins, a few are other macromolecules.
The receptorial site for a drug is the specific region on the macromolecule that has a high & selective affinity for that drug molecule. Without interaction of the two, there will be no action.

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

Graded dose-response curve relationship

It is a curve measuring the response of a particular receptor-effector system against increasing concentrations of the drug. The data on semi-logarithmic axes usually results in a sigmoid curve.

The efficacy (E_max) & potency (EC₅₀) parameters are derived from these data.

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

The slope of the mid-portion of the curve varies from drug to drug. A steep slope indicates that a small in drug dosage produces a large change in response.

Efficacy the maximal response produced by a drug; or the maximal effect produced by an agonist if the dose is taken to very high levels.
Efficacy is determined 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. Partial agonists have lower maximal efficacy than full agonists.

Potency termed also effective dose concentration, is a measure of how much drug is required to elicit a given response/effect. The lower the dose required for a given effect, the more potent the drug. In graded dose-response measurements, the effect usually chosen is 50% of the maximal effect EC₅₀. Potency is determined mainly by the affinity of the receptor to the drug (K_d).

A drug with a low ED₅₀ is more potent than a drug with a larger ED₅₀ (efficacy is more important than potency since it focuses on the effectiveness of the drug).

In quantal dose response measurements ED₅₀, TD₅₀ & LD₅₀ are typical potency variables (median Effective, Toxic & Lethal doses in 50% of the population studied).

Potency can be determined from graded or quantal dose-response curves, but the numbers are not identical.

Graded dose-drug binding relationship & binding affinity

It is possible to measure the fraction of receptors bound by a drug and plotting it against the log of the drug conc. The conc. of drug required to bind 50% of receptor sites is
denoted the K_d and is a useful measure for the affinity of a drug molecule for
this binding site on the receptor molecule. The smaller the K_d, the greater
the affinity of the drug for its receptor. If the # of binding sites on each
receptor molecule is known, it is possible to determine the total number of
receptors in the system from B_max.

Quantal dose-response relationship

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 Vs. the log of the dose administered, a cumulative quantal dose-response curve is obtained, usually sigmoid in shape. The ED₅₀, TD₅₀ & LD₅₀ are extracted from experiments carried out in this manner.

Spare receptors are said to exist if the maximal drug response is obtained at less than maximal occupation of receptors. In practice the determination is made by comparing the conc. for 50% of the maximal effect (EC₅₀) with the conc. for 50% of the maximal binding (K_d).

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

If EC₅₀<K_d system with spare receptors. Meaning: to achieve 50% of max. effect, fewer than 50% of the receptors must be activated. Several mechanisms can explain this:

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

The actual number of receptors may exceed the number of effector molecules available.

Inert binding sites are components of endogenous molecules that bind a drug without initiating events. In plasma e.g. inert binding sites play an important role in buffering the conc. of a drug, since a bound drug doesnt contribute directly to the conc. gradient that drives diffusion.

The two most important plasma proteins with significant binding capacity are albumin & a -acid glycoprotein (orosomucoid, in inflammation).

Agonist an agent that can bind a receptor and elicit a response. The drug effect depends on the conc. at the receptor site, which is determined by the dosage, absorption, distribution & metabolism.

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.

Dose response curves for full agonist & partial agonist:

The partial agonist acts on the same receptor system as the full agonist, but cannot produce such an effect (it has a lower max. efficacy), no matter how much the dose is increased.

Partial agonist may be more, less or equally potent. Potency is an independent factor.

Competitive antagonists drugs that bind 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 for an agonist is shifted to a higher dose (horizontally & to the right on the dose axis), but the same max. effect is reached.
The effects of competitive antagonists can be overcome by adding more agonist.

Irreversible antagonists cause a downward shift of the max. agonist effect, with no shift of the curve on the dose axis unless spare receptors are present. Irreversible antagonists cannot be overcome by adding more agonist.

Physiologic antagonists drugs that bind to a different receptor, producing an effect opposite to that produced by the drug it is antagonizing. The pharmacologic antagonist interacts with the same receptor as the drug it is inhibiting, e.g. antagonism of bronchoconstrictor action of histamine (mediated by H-receptors) by epinephrines bronchodilator action (through b₂-receptors).

Chemical antagonists drugs that interact directly with the drug being antagonized to remove it or to prevent it from reaching its target. A chemical antagonist doesnt depend on interaction with the agonist receptor (e.g. dimercaprol, a chelator of lead).

Therapeutic index the ratio between the toxic dose (TD₅₀ or LD₅₀) to the dose that produces a clinically desired or effective response (ED₅₀).

Therapeutic index = toxic dose / effective dose

The therapeutic index is determined from quantal dose response curves. It 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.

Therapeutic window a more clinically relevant index of safety. It is the dosage range between the minimal effective therapeutic conc. or dose to the minimal toxic conc. or dose.

Signaling mechanisms

Once an agonist drug has bound to its receptor, some effector mechanism is activated. For most useful drug receptor interactions, the drug is present in the extracellular space, while the effector mechanism resides inside the cell & modifies some intracellular process. Thus, signaling across the membrane must occur.

Intracellular receptors drugs which are lipid soluble or diffusible may cross the membrane & combine with an IC receptor that affects an IC effector molecule. No specialized transmembrane signaling is needed. E.g. NO & corticosteroids.

Receptors located on membrane-spanning enzymes drugs that affect membrane-spanning enzymes combine with a receptor on the EC portion of enzymes and modify their IC activity.

Receptors located on membrane-spanning molecules that bind separate IC tyrosine kinase molecules these receptors have EC & IC domains and form dimers. Tyrosine kinase activation results in phosphorylation of STAT molecules. These STAT dimers travel to the nucleus, where they regulate transcription. E.g. insulin, PDGF, EGF & ANF.

Receptor located on membrane ion channels directly cause opening of an ion channel or modify it change in transmembrane electrical potential. E.g. ligand-gated channels, as ACh.

Receptors linked to effectors via G proteins the drug binds a receptor that is linked by coupling proteins to IC or membrane effectors second messengers. E.g. glucagon, 5-HT & histamine.