GENERAL PHARMACOLOGY Winners of “Nobel” prize for their contribution to pharmacology Year Name Contribution 1923 Frederick Banting Discovery of insulin John McLeod 1939 Gerhard Domagk Discovery of antibacterial effects of prontosil 1945 Sir Alexander Fleming Discovery of penicillin & its purification Ernst Boris Chain Sir Howard Walter Florey 1952 Selman Abraham Waksman Discovery of streptomycin 1982 Sir John R.Vane Discovery of prostaglandins 1999 Alfred G.Gilman Discovery of G proteins & their role in signal transduction in cells Martin Rodbell 1999 Arvid Carlson Discovery that dopamine is neurotransmitter in the brain whose depletion leads to symptoms of Parkinson’s disease Drug nomenclature: i. Chemical name ii. Non-proprietary name iii. Proprietary (Brand) name Source of drugs: Natural – plant /animal derivatives Synthetic/semisynthetic Plant Part Drug obtained Pilocarpus microphyllus Leaflets Pilocarpine Atropa belladonna Atropine Datura stramonium Physostigma venenosum dried, ripe seed Physostigmine Ephedra vulgaris Ephedrine Digitalis lanata Digoxin Strychnos toxifera Curare group of drugs Chondrodendron tomentosum Cannabis indica (Marijuana) Various parts are used ∆9Tetrahydrocannabinol (THC) Bhang - the dried leaves Ganja - the dried female inflorescence Charas- is the dried resinous extract from the flowering tops & leaves Papaver somniferum, P album Poppy seed pod/ Capsule Natural opiates such as morphine, codeine, thebaine Cinchona bark Quinine Vinca rosea periwinkle plant Vinca alkaloids Podophyllum peltatum the mayapple root Etoposide Camptotheca acuminata Topotecan, Irinotecan Expansions need to be known: CPCSEA: Committee for the Purpose of Control and Supervision of Experiments on Animals PETA: People for the ethical treatment of animals CDSCO: Central Drugs Standard Control Organization PSUR: Periodic safety updates report CADD: Computer aided drug design HTS: High throughput screening Terminologies: Pharmacogenetics: The study of interindividual variation in DNA sequences related to pharmacokinetics & pharmacodynamics is known as Pharmacogenetics or it is study of the genetic basis for variation in drug response Pharmacogenomics: It refers to the entire spectrum of genes that interact to determine drug efficacy & safety Pharmacoepidemiology: It is the study of the use and effects of drugs in large number of people Pharmacoeconomics: the science that evaluates the costs & consequences of drug therapy & or other interventions Chronopharmacology: It is the study of how the effects of drugs vary with biological timing & endogenous periodicities Orphan drugsQ: These are drugs or biological products for diagnosis/treatment/intervention of a rare disease or condition or a more common disease (endemic only in resource poor countries) for which there is no reasonable expectation that the cost of developing and marketing willbe recovered from the sales of a drug Examples: Fomepizole, liposomal amphotericin B, somatropin, digoxin immune Fab (digoxin antibody), liothyronine (T3)… Spurious drugs: Also known as counterfeit medicines. They may comprise low quality manufacture of correct ingredients; wrong ingredients; adulteration; insufficient quantity of ingredients; false labeling; or no active ingredient at all. E.g: Glucocorticoids added to herbal medicines, & turmeric dispensed as tetracycline Essential medicines: Essential medicines are those drugs (medications) that satisfy the health care needs of the majority of the population. They should, therefore be available at all times in adequate amounts & in appropriate dosage forms, at a price the individual & the community can afford. Me-too drug: is a term used to describe a pharmaceutical that is usually structurally similar to one or more drugs that already are on the market. E.g: esomeprazole P-drug: These are the drugs you (Physician or personal) have chosen to prescribe regularly, & with which you have become familiar. They are your priority choice for given indications P-treatment: Not every personal treatment includes a P-drug, E.g: Life style modifications in obesity Biopharmaceuticalsis an umbrella term applied to the use of nucleic acids or 'engineered' proteins &antibodies in medicine. Drug discovery & new drug development: Drug discovery sources in context Sources of compounds Therapeutic targets Traditional medical uses of natural Chemical libraries Historical Compound collections products Natural Product libraries Empirical understanding of physiology and combinatorial libraries pathology Rational synthesis Molecular cloning of receptors and signaling molecules Antisense oligonucleotides Genomics Drugs discovery screening assays Lead optimization and candidate selection Drug Development A “Hit” is a molecule with confirmed structure, confirmed activity in primary throughput screening & a good profile in secondary assay. A “lead” is a hit series with proven structure activity relationship both in vitro & in vivo Lead optimization: aim is to increase the potency of the compound on its target and to optimize it with respect to other properties, such as selectivity and metabolic stability The objective of the lead optimization phase is to identify one or more drug candidates suitable for further development. TECHNIQUES OF DISCOVERY Molecular modeling aided by three-dimensional computer graphics (including virtual reality) allows the design of structures based on new and known molecules to enhance their desired and to eliminate their undesired, properties to create highly selective targeted compounds. CADD (Computer aided drug design)Q: CADD is a widely used term that represents computational tools & resources for the storage, management, analysis & modeling of compounds. CADD now plays a critical role in the search for new molecular entities. Current focus includes, i. Improved design & management of data sources ii. Creation of computer programs to generate huge libraries of pharmacologically interesting compounds iii. Development of new algorithms to assess the potency & selectivity of lead candidates iv. Design of predictive tools to identify potential ADME/Tox liabilities Commonly used CADD Technologies include, a) Ligand based drug design ( Pharmacophore based approach) b) Structure based drug design ( Molecular docking based approach) c) Quantitative structure activity relationship (QSAR) d) Quantitative structure property relationship Combinatorial chemistry involves the random mixing and matching of large numbers of chemical building blocks (amino acids, nucleotides, simple chemicals) to produce ‘libraries’ of all possible combinations Genetic medicines: Synthetic oligonucleotides are being developed to target sites on DNA sequences or genes or messenger RNA (the antisense approach), so that the production of disease-related proteins is blocked.E.g: Fomivirsen is an antisense oligonucleotide which has been approved for use in CMV retinitis The stages of development of a 'typical' new drug: Pre-clinical development: The work falls into four main categories i. Pharmacological testing to check that the drug does not produce any obviously hazardous acute effects, such as bronchoconstriction, cardiac dysrhythmias etc. This is termed safety pharmacology ii. Preliminary toxicological testing to eliminate genotoxicity & to determine the maximum non-toxic dose of the drug (usually when given daily for 28 days, & tested in two species) iii. Pharmacokinetic testing, including studies on the absorption, metabolism, distribution & elimination (ADME studies) in laboratory animals iv. Chemical &pharmaceutical development to assess the feasibility of large-scale synthesis &purification, to assess the stability of the compound under various conditions & to develop a formulation suitable for clinical studies. Much of the work of preclinical development, especially that relating to safety issues, is done under a formal operating code, known as Good Laboratory Practice (GLP). Animal toxicity studies: Carried out in rodents such as rat, mice etc. & non-rodents such as dog, monkey. These tests include: a) Systemic toxicity studies: i) with single dose; & ii) with repeated doses b) Local toxicity studies c) Specialized toxicity studies: i) Male Fertility Studies ii) Female Reproduction & Developmental Toxicity Studies iii) Allergenicity/ hypersensitivity tests iv) Genotoxicity tests v) Tests for carcinogenicity Genotoxicity tests: are in vitro & in vivo tests conducted to detect compounds which induce genetic damage directly or indirectly. In-vitro studies should include Ames' Salmonella assay & chromosomal aberrations (CA) in cultured cells. In-vivo studies should include micronucleus assay (MNA) or CA in rodent bone marrow. Ames' Test (Reverse mutation assay in Salmonella)Q: S. typhimurium tester strains such as TA98, TA100 etc or Escherichia coli WP2 uvrAshould be used Carcinogenicity tests: Carcinogenicity studies should be performed for all drugs that are expected to beclinically used for > 6 months. Carcinogenicity studies should be done in a rodent species (preferably rat).At least three dose levels should be used. Observations should include macroscopic changes observed at autopsy &detailedhistopathology of organs & tissues. Additional tests for carcinogenicity: i) Short-term bioassays ii) Neonatal mouse assay iii) Tests employing transgenic animals Clinical development: Clinical development proceeds through four distinct phases, i. Human Pharmacology (Phase I): The objective of studies in this Phase is the estimation of safety &tolerability with the initial