Pre-clinical Pharmacology and Clinical Pharmacology - An Overview

The aims of experimental pharmacology are discovery and development of the new drugs, study of the mechanism and site of action of different drugs and study the toxicity effect of a drug.  Experimental pharmacology consists of preclinical study and clinical study.

Figure 1: Types of experimental Pharmacology

Preclinical pharmacology

Preclinical studies involve in-vivo and in-vitro experiments using wide range of doses of the sample drug to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug (IND).

In-vivo (animal testing) study is used to measure: how much of a drug is absorbed into the blood, how it is broken down chemically in the body, the toxicity of the drug and its breakdown products or metabolites, and how quickly the drug and its metabolites are excreted from the body. Short-term testing in animals ranges in duration from 2 weeks to 3 months, depending on the proposed use of the substance. Long-term testing in animals ranges in duration from a few weeks to several years. Some animal testing continues after human tests begin to learn whether long-term use of a drug may cause cancer or birth defects.

In-vitro (in the test tube) experiments, cell and tissue cultures can be used instead of using animals to test the product ingredients. The development of in-vitro methods based on biological materials (for example, skin or other human body cells) that will be suitable for reliably verifying the safety and compatibility of product ingredients. Development of High-throughput screening (HTS), Ultra HTS, automation, robotics and miniaturization techniques, made it feasible to screen 50,000 compounds a day with complex work stations. The development of in-silico methods (in the computer) is to determine the compatibility of substances on the basis of their chemical structure. Advantages of in-vitro tests are fast and cheap, human cells and tissues can be used, transgenic cells carrying human genes can be used, reduction of testing in animals, small amount of test material is required, lack of systemic effects, reduction of variability between experiments.

The classical way of pharmacological screening involves sequential testing of new chemical entities or extracts from biological material in isolated organs followed by tests in whole animals, mostly rats and mice but also higher animals if indicated. Most drugs in use nowadays in therapy have been found and evaluated with these methods.

Clinical pharmacology:

It is the scientific study of drugs in human. It includes pharmacokinetic and pharmacodynamic investigation in healthy volunteers and in patients. A clinical trial is a research study that tests a new medical treatment or a new way of using an existing treatment to see if it will be a better way to prevent and screen for diagnose or treatment of a disease. We define a clinical trial as a prospective study comparing the effect and value of intervention(s) against a control in human beings. It is only in the past several decades that the clinical trial has emerged as the preferred method in the evaluation of medical interventions.

Clinical trials for new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate trial. The drug‐development process will normally proceed through all four phases over many years. If the drug successfully passes through Phases I, II and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV are post‐approval (Post marketing surveillance) studies. Now Phase 0 or micro dosing studies are performed to know the action of drug candidate in human being at early.

Table 1: Different phases of drug development.

Preclinical phases	In-vivo and in-vitro studies are carried out for pharmacokinetics, toxicity studies and formulating the drug.
Phase-I of clinical trial	Small scale trials in 20-80 numbers of healthy volunteers. Studied at single center for knowing the safety tolerability, pharmacokinetics and side effects.
Phase-II of clinical trial	Small scale trials in 100-300 numbers of patients as well as healthy   volunteers. Studied at single center to assess the efficacy and dosage. Long term toxicology studies are also carried out.
Phase-III of clinical trial	Large scale controlled trials in 800-3000 numbers of patients. Studied at multi-center for comparing the new drug with the existing drugs.
Phase-IV of clinical trial	Post marketing surveillance in patients for detecting any rare or long term ADRs.

After completion of preclinical studies successfully, the investigators files an ‘Investigational New Drug’ application (IND) to the government bodies [such as Central Drugs Standard Control Organization (CDSCO) in India] for allowance of initial testing in human beings. After the successful clinical trials and laboratory work, the investigators may file a New Drug Application (NDA). Permission to market a drug product will be given by the drug control authority after confirming the drug’s safety and effectiveness.

References:

1.    Ballington, D.A., Laughlin, M.M., 2006. Pharmacology. 3^rd edition, CBS Publishers and Distributers, New Delhi.

2.    Brunton, L., Lazo, J.S., Parker K.L., 2006. Goodman and Gilman’s, The Pharmacological Basis of Therapeutics. 11^th edition, The McGraw-Hill Medical Publishing, New Delhi, India.

3.    Ghosh, M.N., 2011. Fundamentals of Experimental Pharmacology. 3^rd edition, Hliton& Company, Kolkata.

4.    Katzung B.G., Masters S.B., Trevor A.J., 2012. Basic & Clinical Pharmacology. 12th edition, The McGraw-Hill Companies, New Delhi, India.

5.    Medhi, B., Prakash, A., 2010. Practical Manual of Experimental and Clinical Pharmacology. 1^st edition, Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India.

6.    Patil, P.N., Gulati, O.D., Balaraman, R., Goyal, R.K. Topics in the History of Pharmacology. B.S. Shah Prakashan, Ahmedabad.

7.    Rang, H.P., Ritter, J.M., Flower, R.J., Henderson, G., 2016. Rang and Dale’s Pharmacology. 8^th edition, Churchill Livingstone, Philadelphia.

8.    Satoskar, R.S., Bhandarkar, S.D., Rege, N.N., 2009.Pharmacology and Pharmacotherapeutics. Twentieth 1^st edition, Popular Prakashan Pvt. Ltd., Mumbai, India.

9.    Tripathy, K.D., 2013. Essentials of Medical Pharmacology. 7^th edition, Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India.

10. Vogel, H.G., Drug Discovery and Evaluation Pharmacological Assays. 2^nd edition, Springer-Verlag, Berlin, Heidelberg, New York.

Terminology of Pharmacology

Pharmacology: The term pharmacology comes from the two Greek words: pharmacon- a drug or medicine and logos- the truth about or a rational discussion. Pharmacology is a science of drug. It can also be defined as study the effects of drugs on the function of living systems. It deals with interaction of exogenously administered chemical molecules (drugs) with leaving system. Two important and interrelated areas of pharmacology are: pharmacokinetics and pharmacodynamics.

Pharmacokinetics: The term pharmacokinetics comes from a Greek word: kinesis- movement. Pharmacokinetics is what the body dose to the drug. This refers to movement of drug in and alteration of drugs by the body. This includes absorption, distribution, metabolism and excretion (ADME) of the drug. e.g. - Digoxin is 70% absorbed orally, 25% bound to plasma proteins, localized in heart, skeletal muscle, liver and kidney; small fraction is metabolized in liver and excreted in urine.

Pharmacodynamics: The term pharmacodynamics comes from a Greek word: dynamis- Power. Pharmacodynamics is what the drug dose to the body. This includes physiological and biochemical effects of drugs and their mechanisms of action at organ/system/subcellular/ macromolecular levels. e.g. Adrenaline – interact with β₁ adrenoceptors in heart, that is a G-protein coupled receptor, which stimulates adenylyl cyclase and increases intracellular cAMP which leads to cardiac stimulation.

Figure 1: Branches of Pharmacology

Drug: The word drug comes from French: Drogue- a dry herb. Drug is any substances or product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient. Drug is the single active chemical entity present in a medicine that is used for diagnosis, prevention, treatment/cure of a disease.

Essential Drugs: As per the WHO, essential drugs or medicines can be defined as those drugs that satisfy the priority healthcare needs of the population. They are selected with due regard to public health relevance, evidence on efficacy and safety and comparative cost effectiveness. They are intended to be: Available within the context of functioning health systems at all times, available in adequate amounts, in appropriate dosage forms, with assured quality, contains adequate information about efficacy and safety, and at a price the individual and community can afford.

Orphan Drugs: The drugs or biological products developed for diagnosis, treatment or prevention of a rare disease or condition, or a more common endemic disease found in resource poor countries are known as orphan drugs. There is no reasonable expectation that the cost of developing and marketing those drugs will be recovered from the sale of the drug. e.g. sodium nitrite, fomepizole, miltefosine, rifabutin, digoxin immune Fab (digoxin antibody) etc.

Pharmacy: Pharmacy is the art and science of compounding and dispensing drugs or preparing suitable dosage forms for human and veterinary uses. It includes collection, identification, purification, isolation, synthesis, standardization and quality control of medicinal substances.

Pharmacotherapeutics: Application of pharmacological information together with knowledge of the disease for its prevention, mitigation or cure is known as pharmacotherapeutics. It includes selection of the most appropriate drug, dosage and duration of treatment for the specific features of a patient.

Toxicology: It is the study of poisonous effect of drugs and other chemicals with emphasis on detection, prevention and treatment of poisoning. It also includes the study of adverse effects of drugs.

Chemotherapy: It is the treatment of systemic infection or malignancy with specific drugs that have selective toxicity for the infecting organism or malignant cell with no/minimal effects on the host cells.

Preclinical Pharmacology: It is the scientific study which involves laboratory animals using wide‐ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an investigational new drug.

Clinical Pharmacology: It is the scientific study of drugs in human. It includes pharmacokinetic and pharmacodynamic investigation in healthy volunteers and in patients.

Pharmacogenetics: pharmacogenetics is a study of genetic variations that alters drug metabolism and drug response. Originally, pharmacogenetics focused on familial idiosyncratic drug reactions, where affected individuals show an abnormal-usually adverse-response to a class of drug.

Pharmacogenomics: This term overlaps with pharmacogenetics, describing the use of genetic information to guide the choice of drug therapy on an individual basis, i.e. the response to therapeutic drugs between individuals can be predicted from their genetic make-up. Ultimately, linking specific gene variations with variations in therapeutic or unwanted effects of a particular drug should enable the tailoring of therapeutic choices on the basis of an individual's genotype.

Pharmacoepidemiology: This is the study of drug effects at the population level. It is concerned with the variability of drug effects between individuals in a population, and between populations.

Pharmacoeconomics: This branch of health economics aims to quantify in economic terms, the cost and benefit of drugs used therapeutically. It arose from the concern of many governments to provide for healthcare from tax revenues, raising questions of what therapeutic procedures represent the best value for money.

Pharmacovigilance: It is a science and activities related to the detection, assessment, understanding and prevention of adverse effects or any other drug related problem. So this is a science of keeping a watch on adverse reactions. 

References:

Brunton, L., Lazo, J.S., Parker K.L., 2006. Goodman and Gilman’s, The Pharmacological Basis of Therapeutics. 11^th edition, The McGraw-Hill Medical Publishing, New Delhi, India.

Katzung B.G., Masters S.B., Trevor A.J., 2012. Basic & Clinical Pharmacology. 12th edition, The McGraw-Hill Companies, New Delhi, India.

Rang, H.P., Ritter, J.M., Flower, R.J., Henderson, G., 2016. Rang and Dale’s Pharmacology. 8^th edition, Churchill Livingstone, Philadelphia.

Satoskar, R.S., Bhandarkar, S.D., Rege, N.N., 2009.Pharmacology and Pharmacotherapeutics. Twentieth 1^st edition, Popular Prakashan Pvt. Ltd., Mumbai, India.

Tripathy, K.D., 2013. Essentials of Medical Pharmacology. 7^th edition, Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India.

Experimental Pharmacology: Past and Present

Distinctions between the useful actions of drugs and their toxic effects were recognized thousands of years ago. As people tried plant, animal, and mineral materials for possible use as foods, they noted both the toxic and the therapeutic actions of some of these materials. Past civilizations contributed to our present knowledge of drugs and drug preparations. In India Ayurveda, Siddha and Unani systems of medicine provide healthcare for a large part of the population. The word Ayurveda is composed of two parts: Ayu (= life) and Veda (= knowledge). Sage Bhardwaja got this science from Lord Indra and documented as Vedas, hence he is considered as ‘father of Ayurveda’ by many authors. Scholars of Ayurveda had placed the origins of this science of life at sometime around 6000 BC. The principles were recorded in great detail in compendia, which are called Samhitas. Ancient Chinese writings and Egyptian medical papyri represent the earliest compilations of pharmacological knowledge. They included rough classifications of diseases to be treated, and recommended prescriptions for such diseases. While other civilizations made their own discoveries of the medicinal value of some plants. The introduction of many drugs from the new world in the 17^th century stimulated experimentation on crude preparations. These experiments were conducted chiefly to get some ideas about the possible toxic dosage for such drugs as tobacco, nux vomica, ipecac, cinchona bark and coca leaves. By the 18th century, many such descriptive studies were being conducted. 

It was in the German universities during the second half of the 19th century that pharmacology really began to emerge as a well-defined discipline. The bold vision of Rudolf Buchheim, who was appointed to teach material medica at the University of Dorpat in Estonia, created the first pharmacology laboratory at his own house. He established the first institute of pharmacology at the University of Dorpat in 1847.

In 1872, Oswald Schmiedeberg, who received research training in Buchheim’s laboratory, became professor of pharmacology at Strasbourg, regarded as ‘Father of Pharmacology’. Schmiedeberg with his many students from all over the world worked in his pharmacological institute and propounded some of the fundamental concepts in pharmacology. His students later occupied 40 academic chairs in pharmacology departments throughout the world. One of the most eminent of his many distinguished pupils was John Jacob Abel, who brought the new science of experimental pharmacology from Germany to the USA. In the beginning of the 20th century, Paul Ehrlich conceived the idea of specifically seeking special chemical agents with which to treat infections selectively (propounded the “magic bullet” theory), and is thus considered as the ‘Father of Chemotherapy’.

In India, the evolution of pharmacology from material medica is a mirror image of global scenario. Sir Ram Nath Chopra obtained training at Cambridge University in 1908. After arriving to India, he was appointed as the first professor of pharmacology in 1921 and set up experimental pharmacology laboratory at the Tropical School of Medicine in Kolkata. He made the beginning in pharmacological research of traditional drugs; helped the growth of pharmacology in different medical, dental, pharmacy and veterinary colleges. Hence sir Ram Nath Chopra is known as ‘Father of Indian Pharmacology’. M.N. Ghosh, R.B. Arora, U.K. Sheth, P.C. Dandiya, K.P. Bhargava, B. Mukharji are the other pharmacologists who have contributed a lot for the growth of pharmacology discipline in India by their stupendous work.

The progress and contribution of 20th century pharmacology have been immense, with over twenty pharmacologists having received Nobel prizes. Their contributions include discoveries of many important drugs, neurotransmitters and second messengers, as well as an understanding of a number of physiological and biochemical processes. The field of pharmacology in general and the development of highly effective new drugs in particular have increased during the last half of the 20th century. This unprecedented progress has paralleled similar advancement in related disciplines upon which pharmacology builds: molecular biology, biochemistry, physiology, pathology, anatomy and the development of new analytical and experimental techniques and instruments. Within the main subject, fall a number of compartments e.g. neuropharmacology, immunopharmacology, molecular pharmacology, chemotherapy, systems pharmacology, pharmacokinetics, pharmacogenomics, pharmacoepidemiology, pharmacoeconomics etc.

Francois Magendie (1783-1855)	Claude Bernard (1813-1878)	Rudolf Buchheim (1820-1879)
Oswald Schmiedeberg (1838-1921)	Paul Ehrlich (1854-1915)	Sir Ram Nath Chopra (1882-1973)

 Figure 1: Pioneers of Pharmacology

Table 1: Pharmacologists and their outstanding achievements

Name of Scientist	Outstanding achievements
Francois Magendie (1783-1855)	Pioneer of experimental physiology
Claude Bernard (1813-1878)	Father of Physiology
Rudolf Buchheim (1820-1879)	Pioneer of experimental pharmacology
Oswald Schmiedeberg (1838-1921)	Father of Pharmacology
John Jacob Abel (1857-1938)	Father of American pharmacology
Paul Ehrlich (1854-1915)	Father of chemotherapy
Louis Lasagna (1923-2003)	Father of clinical pharmacology
Sir Ram Nath Chopra (1882-1973)	Father of Indian pharmacology

References:

1.    Ballington, D.A., Laughlin, M.M., 2006. Pharmacology. 3^rd edition, CBS Publishers and Distributers, New Delhi.

2.    Brunton, L., Lazo, J.S., Parker K.L., 2006. Goodman and Gilman’s, The Pharmacological Basis of Therapeutics. 11^th edition, The McGraw-Hill Medical Publishing, New Delhi, India.

3.    Ghosh, M.N., 2011. Fundamentals of Experimental Pharmacology. 3^rd edition, Hliton& Company, Kolkata.

4.    Katzung B.G., Masters S.B., Trevor A.J., 2012. Basic & Clinical Pharmacology. 12th edition, The McGraw-Hill Companies, New Delhi, India.

5.    Medhi, B., Prakash, A., 2010. Practical Manual of Experimental and Clinical Pharmacology. 1^st edition, Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India.

6.    Patil, P.N., Gulati, O.D., Balaraman, R., Goyal, R.K. Topics in the History of Pharmacology. B.S. Shah Prakashan, Ahmedabad.

7.    Rang, H.P., Ritter, J.M., Flower, R.J., Henderson, G., 2016. Rang and Dale’s Pharmacology. 8^th edition, Churchill Livingstone, Philadelphia.

8.    Satoskar, R.S., Bhandarkar, S.D., Rege, N.N., 2009.Pharmacology and Pharmacotherapeutics. Twentieth 1^st edition, Popular Prakashan Pvt. Ltd., Mumbai, India.

9.    Tripathy, K.D., 2013. Essentials of Medical Pharmacology. 7^th edition, Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India.

10. Vogel, H.G., Drug Discovery and Evaluation Pharmacological Assays. 2^nd edition, Springer-Verlag, Berlin, Heidelberg, New York.