DOSE–RESPONSE RELATIONSHIPS

Lecture (5) Pharmacology Dr. Dalia A. Muhsin
DOSE–RESPONSE RELATIONSHIPS
Potency: a measure of the amount of drug necessary to produce an effect of a given magnitude. The concentration of drug producing an effect that is 50 percent of the maximum is used to determine potency.
E?cacy: This is the ability of a drug to elicit a response when it interacts with a receptor. Efficacy is dependent on the number of drug–receptor complexes formed and the efficiency of the coupling of receptor activation to cellular responses.
Efficacy , is more important than drug potency. A drug with greater efficacy is more therapeutically beneficial than one that is more potent. Maximal efficacy of a drug assumes that all receptors are occupied by the drug, and no increase in response will be observed if more drugs are added.
Agonist: is defined as an agent that can bind to a receptor and elicit a biologic
response that usually mimics the action of the original endogenous ligand on the receptor , such as norepinephrine on?1 receptors of the heart.
The magnitude of the drug effect depends on the drug concentration at the receptor site, which, in turn, is determined by both the dose of drug administered and by the drug’s pharmacokinetic profile, such as rate of absorption, distribution, metabolism, and elimination.
• Full agonists
If a drug binds to a receptor and produces a maximal biologic response that mimics the response to the endogenous ligand , it is known as a full agonist .
For example, phenylephrine is an agonist at ?1-adrenoceptors, because it produces effects that resemble the action of the endogenous ligand, norepinephrine.
An agonist may have many effects that can be measured, including actions on intracellular molecules, cells, tissues, and intact organisms. All of these actions are attributable to interaction of the drug molecule with the receptor molecule. In general, a full agonist has a strong affinity for its receptor and good efficacy.
• Partial agonists
Partial agonists have efficacies greater than zero but less than that of a full agonist . Even if all the receptors are occupied, partial agonists cannot produce an Emax of as great a magnitude as that of a full agonist. A unique feature of these drugs is that, under appropriate conditions, a partial agonist may act both as an agonist and antagonist .

ANTAGONISTS
Antagonists are drugs that decrease or oppose the actions of another drug or endogenous ligand. Antagonism may occur in several ways:
1. Competitive antagonists
If both the antagonist and the agonist bind to the same site on the receptor, they are said to be “competitive.” The competitive antagonist will prevent an agonist from binding to its receptor and maintain the receptor in its inactive conformational state. For example, the antihypertensive drug terazosin competes
with the endogenous ligand, norepinephrine, at ?1-adrenoceptors, thus decreasing vascular smooth muscle tone and reducing blood pressure.
2. Allosteric antagonist
The second type of antagonist binds to a site ("allosteric site") other than the agonist binding site. This allosteric antagonist prevents the receptor from being activated even when the agonist is attached to the active site.
3. Functional antagonism(physiologic antagonism): An antagonist may act at a completely separate receptor, initiating effects that are functionally opposite those of the agonist. A classic example is the functional antagonism by epinephrine to histamine induced bronchoconstriction.
Histamine binds to H- histamine receptors on bronchial smooth muscle, causing contraction and narrowing of the bronchial tree. Epinephrine is an agonist at ??- adrenoceptors on bronchial smooth muscle, which causes the muscles to actively relax. This functional antagonism is also known as “physiologic antagonism.”
4.Chemical antagonist : drug that prevents the actions of an agonist by modifying or sequestering the agonist so that it is incapable of binding to and activating its receptor. For example, protamine sulfate is a chemical antagonist for heparin . It is a basic (positively charged) protein that binds to the acidic heparin (negatively charged), rapidly preventing its therapeutic as well as toxic effects.
5. Pharmacokinetic antagonism: describes a situation in which antagonism
Effectively reduces the active drug concentration.
This can occur when absorption of the drug is decreased or if the metabolism and renal excretion of the drug are increased.
Other than Drug-receptor binding, drugs also act on processes within or near the cell as :
1. Direct chemical interaction, e.g. antacids.
2. In the case of antimicrobial agents, altering metabolic processes unique to microorganisms, e.g. penicillin interferes with formation of the bacterial cell wall
3. Osmosis, as with diuretics, e.g. mannitol.
Therapeutic index
The therapeutic index (TI) of a drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired or effective response in a population of individuals:
Therapeutic index = TD50/ED50
where TD50= the drug dose that produces a toxic effect in half the population, and ED50 = the drug dose that produces a therapeutic or desired response in half the population. The therapeutic index is a measure of a drug’s safety, because a larger value indicates a wide margin between doses that are effective and doses that are toxic.