Introduction to experimental pharmacology.
It is the science that deals with the study of drugs, which is derived from the Greek word “Pharmacon” which means drugs, and “logos” which means study.
It is that branch of pharmacology that deals with the effect of drugs on the living system. It can be studied under heads:
(a) Preclinical Pharmacology
It deals with the effects of drugs on animals.
(b) Clinical Pharmacology
It deals with the effect of drugs on human living.
Thus, it helps in understudying the nature of drug action and the unalterability of the living systems to attract chemicals that serve as the basis on which:
- (a) New therapeutic agents are developed
- (b) Toxic consequences of chemical exposure may be activated.
Historical Aspects Associated with Experimental Pharmacology
Although drugs have been a subject of interest since ancient times, experimental pharmacology is a relatively new discipline in the life sciences. It is of intellectual interest to the physician to know how drugs are discovered and developed. Often in the past, this was based on folklore or intelligent observation (e.g. digitalis leaf, penicillin). Nowadays, new drugs are mostly developed by the organic chemist working with a pharmacologist, increasingly from basic knowledge about key molecular targets.
Usually, some sort of biological screen is used to select among organic molecules for optimum pharmacological activity.
- 1. Francois Magendie (1783-1855), a French physiologist laid down the dictum “Facts and facts alone are the basis of science.” Experimental procedures with animals are the testing grounds for the determination of drug action.
- 2. Claude Bernard (1813-1878) worked in Magendie’s lab, investigated the plant extract curare, and proposed a site of action for this agent.
- 3. Rudolph Buchheim (1820-1879), 1847 Buchheim established the first laboratory devoted to experimental pharmacology in the basement of his home in Dorpat which is known as the cradle of experimental pharmacology.
- 4. Oswald Schmiedeberg (1838-1921). In 1872 Schmiedeberg set up an institute of pharmacology in Strasbourg, France (Germany at that time) which became a mecca for students who were interested in pharmacological problems.
- 5. J.N. Langley (1852-1925 and Sir Henry Dale (1875-1968) pioneered pharmacology in England, taking a physiological approach.
- 6. John J. Abel (1857-1938) established the first chair of pharmacology in the U.S.A. (U. Michigan, 1891) after training in Germany. Able went to Johns Hopkins in 1893 and trained many U.S. pharmacologists. He is known as “The Father of American Pharmacology”.
- 7. The Second World War was the impetus for accelerated research in pharmacology (the wartime antimalarial program) in the U.S. and introduced strong analytical and synthetic chemical approaches.
Definitions of commonly used pharmacological terms
A drug capable of binding and activating a receptor, leading to a pharmacological response that may mimic that of a naturally occurring substance.
Can be classified as full, partial, or inverse.
(a) Full agonist-
It is capable of eliciting a maximal response as it displays full efficacy at that receptor.
(b) Partial agonist:
It binds to and activates a receptor but is only able to elicit partial efficacy at that receptor. A maximal effect cannot be produced, even when the concentration is increased. When full and partial agonists are present the partial agonist may act as a competitive antagonist.
(c) Inverse agonist
It produces an effect that is pharmacologically opposite to an agonist, yet acts at the same receptor.
The receptor must elicit intrinsic or basal activity in the absence of a ligand and the addition of an inverse agonist will decrease the activity below the basal level. A receptor that possesses basal activity is the receptor; agonists have a sedative effect whilst inverse agonists have an anxiogenic effect.
Does not produce a biological response on binding to a receptor but instead blocks or reduces the effect of an agonist.
It may be competitive or non-competitive.
(A) Competitive antagonism
The drug binds selectively to a receptor without causing activation but in such a way to prevent binding of the agonist The antagonism may be reversible; the effect can be overcome by increasing the concentration of the agonist, which will lead to a shift in the equilibrium.
(B) Non-competitive antagonism
A non-competitive antagonist may affect the reaction by binding to the active site of the receptor or an allosteric site, therefore not competing with the agonist. The magnitude of the maximal response is reduced, regardless of the amount of agonist present.
A drug that binds to a receptor at a site distinct from the active site. A conformational change is induced in the receptor, altering the affinity of the receptor for the endogenous ligand.
Positive allosteric modulators
Increase the affinity of the receptor for the endogenous ligand.
Negative allosteric modulators
Decrease the affinity of the receptor for the endogenous ligand.
The molar concentration of an agonist produces a 50% response of the maximum possible response for that agonist. Figures may also be stated as other percentages of the maximum response EC20 and EC80 representing a 20% and 80% response respectively.
Dose of drug that produces 50% of its maximum response or effect. Can be a term used in-vitro or in-vivo (although it is more common in-vivo).
Used to describe agonist responses to receptor occupation. High efficacy agonists can produce a maximal response whilst occupying a relatively low proportion of receptors. Low efficacy agonists are unable to cause receptor activation to the same degree and a maximal response may not be achieved even at the full occupation of the entire receptor population. Low efficacy agonists are often termed, partial agonists.
Studies are carried out using components of an organism that have been isolated from its usual biological surroundings. The analysis is usually carried out in test tubes or culture dishes.
Experimentation using the whole living organism. Normal physiology will be involved in any response.
Experimentation using tissue in an artificial environment outside the living organism. An example may include a short-term (up to 24 hours) culture of tissue, following its removal from the organism.
An important pharmacokinetic measurement. The metabolic half-life of a drug in-vivo is the time taken for its concentration in plasma to decline to half its original level. Half-life refers to the duration of action of a drug and depends upon how quickly the drug is eliminated from the plasmá.
Clearance and distribution of a drug from the plasma are important parameters for half-life determination.
The molar concentration of an agonist or antagonist causes 50% of the maximum possible inhibition. Figures may also be stated as other percentages of the inhibition.The equilibrium dissociation constant for an agonist; the concentration at which 50% of receptors would be occupied at equilibrium.
The equilibrium dissociation constant for a competitive antagonist; the concentration at which 50% of the receptors would be occupied at equilibrium.
The dissociation is constant. The concentration of a drug at equilibrium occupies 50% of receptors.
The inhibition is constant for a drug where 50% of receptors will be occupied. Provides an absolute value and does not differ between experiments. Calculated from the value using the Cheng-Prusoff equation.
The logarithmic measure of antagonist potency. It is the negative log of the molar concentration of an antagonist that would produce a 2-fold shift in the concentration-response curve for an agonist.
The negative logarithmic measure of the potency of an antagonist.
Measure the effective concentration of a drug. It is a vague term and it is advisable to further categorize the measurement:
The introduction of experimental pharmacology has been studied well.