Historical Landmarks and Scope of Pharmacology
✓ The science of pharmacology has evolved over the period of time. Knowledge about various events during evolution of drugs constitutes historical landmarks of pharmacology.
✓ Along with knowing the history, the scope of pharmacology is also advancing with time. Both the topics are of interest to students of Pharmacology.
1. Historical Landmarks
✓ The knowledge of primitive pharmacology developed from human experiences with use of plants. Some plants were safe while others were toxic. Based on this knowledge, a catalogue of good and bad evolved and was passed down through oral traditions. Over the period of time, the knowledge was transformed to include natural sources which appeared to cure some diseases.
✓ The oldest recorded event cites about events in 16th Century bc when beer, turpentine, myrrh, juniper berries and poppy and other therapies were described to treat disease. Similar historical records exist for most ancient civilizations including the Sumerian, Indian and Chinese. In India, Ayurveda has older traditions even before 16th century BCE. Sumerians around 3400 BCE cultivated the opium poppy in lower Mesopotamia and recorded its action
in clay tablets. It was referred to as the “joy plant” and its reputation lead to its spread across neighbouring civilizations like Egypt. Around 460 BCE Hippocrates, a famous Greek physician and teacher of medicine, described opium as having narcotic properties and described use
of opium in treating internal diseases. In 330 BCE, Alexander the great, introduced opium to Persia and India and by the year 400 it reached China. In the 10th century, the noted Islamic physician Avicenna of Persia described opium as the “most powerful stupefacients”. About the year 1200, the Indian medical treatises The Shodal Gadanigraph and Sharangdhar- Samahita describe the use of opium for diahorrhoea and sexual debility. In the 1300’s opium disappeared from European historical record till 1527; during which Paracelsusprescribed opium as a pain killer.
✓ The modern era began in 1680 when the English apothecary, Thomas Sydenham introduced Sydenham’s Laudanum which mentioned about many opium proprietary brands useful for various ailments. In 1803, the German Friedrich Serturner dissolved opium in acid and then neutralised it with ammonia resulting in formation of morphine which exhibited long-lasting and predictable effects. By 1827, morphine became a commercial product. In 1874, an English researcher, Wright synthesised heroin which went into commercial production in Germany by 1898. The molecular basis of opioid action was revealed by Snyder and Pert who located the molecular site of action for opium in 1972. These opioid receptors were found in neural tissues and mediate the pain reducing effect. Later Hughes and Kosterlitz discovered that humans produce endogenous morphine-like compounds, called as enkephalins, which act on opioid receptors.
✓ Besides opium there are few more milestones in historical development of pharmacology. In early 19th century, physiologists performed many pharmacological studies.
✓ Magendie studied the action of Nux Vomica (a strychnine-containing plant drug) on dogs and showed that the spinal cord was the site of convulsant action. His work was presented to the Parris academy in 1809. Later in 1842, Bernard discovered that the arrow poison curare acts at the neuro-muscular junction to interrupt the stimulation of muscle by nerve impulses. Till 1846, the science of effect of drugs developed under physiology only. It was only in 1847, Buchheim was appointed as professor of pharmacology at University of Dorpat in Estonia (then a part of Russia). Initially there were no funds and professor Buchheim built a laboratory on his own expense in the basement of his home. His studies were mostly descriptive. His student Schmiedeberg (1838-1921) is recognised as founder of modern pharmacology. He obtained his medical doctorate in 1866 with a thesis on the measurement of chloroform in blood. He worked at Dorpat till 1869. In 1872, he became professor of pharmacology at the University of Starssburg, receiving generous Government support for developing an institute of pharmacology. He studied the pharmacology of chloroform and chloral hydrate. In 1869, he showed that muscarine evoked the same effect on heart as electrical stimulation of the vagus nerve. In 1885, he introduced urethane as a hypnotic. He was largely responsible for the pre-eminence of German pharmaceutical industry up to Second World War.
✓ In USA, the first chair in pharmacology was established in the University of Michigan in 1890 under Abel who was trained under Schmiedeberg. In 1893, Abel went to Johns Hopkins University in Baltimore. His contributions include isolation of epinephrine from adrenal gland extracts (1897-98), isolation of histamine from pituitary extract (1919), and preparation of pure crystalline insulin (1926). His student Hunt discovered acetyl choline in adrenal extracts in 1906.
✓ Pharmacology largely depends on experiments conducted in laboratory animals; however there are isolated cases where human beings have been used to study the effect of drugs. Serturner, the German pharmacist who isolated the first alkaloid from opium in 1805, administered a dose of 100 mg to himself and his three friends. All of them experienced the symptoms of severe opium poisoning for several days. Another interesting story where human beings were used for testing drugs occurred in 1940s. Biological assays (bioassays) of digitalis performed in frogs, pigeons and cats were highly unsatisfactory. In 1942, a group of cardiologists published “a method for bioassay of digitalis in humans”. The assay was based on changes in ECG of patients. Of 97 patients in whom ECG was tried, only 18 proved to besatisfactory assay subjects.
✓ Animals are primarily used to detect toxicity of substances,. Most frequently pharmaco- logical studies are conducted in mammals. Mice are preferred because of their small size, ease of breeding and short generation time. Rats, guinea pigs, rabbits and dogs are also used; each has special characteristics that make it optimal for certain type of tests. The efforts of animal activists have restricted use of animals for experimental study on drugs. In India, permission from the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) is necessary for conducting any animal experiments. It is suggested that animals should be used only for research and development and not for education/demonstration. Every pharmacy college is supposed to take permission from CPCSEA, with one of their representative in the committee.
✓ Early in the development of pharmacological techniques, it was found that an isolated organ or tissue remained functional for several hours in a bath containing a physiologic solution of salts through which oxygen was bubbled. Magnus (1802-1870) first applied this method to a strip of small intestine. Later Heymans (1904) worked with mammalian heart and Bernard experimented with isolated nerve-muscle preparation. In 1924, Allen and Doisy used ovarictomized rats to test the action of estrogenic hormone.
✓ With advancement of knowledge of human biochemistry and molecular biology, pharmacological actions are often studied on actions of enzymes and receptors. The drug Captopril was developed by Ondetti and co-workers at Squib in 1970s to inhibit the enzyme – Angiotensin Converting Enzyme (ACE). Subsequently, it was proved that inhibitors of ACE work as anti-hypertensive drugs. Knowledge of cell receptors is yet another milestone. Adrenalin is the neurotransmitter for sympathetic nervous system. Adrenalin acts on α- and β- receptors. Propranolol was the first β-adrenergic receptor blocking agent. From 1964, β-blockers have been used for treating hypertension and cardiac arrhythmia. Synthetic organic chemistry was born in 1828, when Wohler synthesised urea from inorganic substances. Several substances, existing in the body or their derivatives were synthesised in laboratories as an extension of developments in organic chemistry. With the knowledge of receptors, a complimentary substance can be synthesised in laboratories. With the help of Structure – Activity Relationship (SAR) derivatives of main active moiety can be synthesised. In recent years, developments in medicinal chemistry have greatly contributed to development of various synthetic drugs.
2. Scope of Pharmacology
The science of Pharmacology has interfaces with Anatomy and Physiology, Organic and Inorganic Chemistry, Microbiology and Pathophysiology. Pharmacology is related to action and uses of drugs. In development of new drugs, pharmacology has greatest contribution. It has two main components: pharmacodynamics and pharmacokinetics. Pharmacodynamics deals with what drug does to the human/animal body. It involves study of action of drugs on receptors, its mechanism of action, indications for clinical use, contra-indications and adverse reactions caused by drugs. Pharmacokinetics deals with what body does towards drugs. It has four main components: Absorption, Distribution, Metabolism and Excretion (ADME). Out of these four components, absorption, distribution and excretion are dependent on transport through membranes without any chemical. change in the entity. In metabolism, there is chemical change in the moiety because of action of enzymes in the body. Cytochromal enzymes in the liver are the main metabolising enzymes in the liver. A drug may have n number of metabolites. Every metabolite can have different action in the body. Thus, what we observe as action(s) of drugs is the net effect of main drug moiety and its metabolites. Several factors can alter ADME of drugs. It is the main reason why we get different kinds of actions for the same drug in different individuals.
✓ Clinical pharmacology and therapeutics primarily deals with actions of drug in human beings. It incorporates indications, therapeutic uses, contra-indications, posology, bio- availability, prescription writing and drug nomenclature. The science of clinical toxicology is an extension of clinical pharmacology. Forensic toxicology addresses to medico-legal aspects of use of drugs. Pharmacovigilance is gaining vital importance in last few decades. It involves study of adverse reactions of drugs and their safety. Based onobservations on pharmacovigilance, some drugs have been withdrawn from the market due to severe adverse reactions.