Introduction to Pharmacology

Introduction to Pharmacology CHEM 4000 Chemistry Seminar April 30, 2004 & May 3, 2004 Robin B. Reed Overview of Presentation Definitions  Drug Studies  Drug Manufacture  What is Pharmacology? From the Greek pharmakon (drug), legein (to speak)  Broadly defined as the study of how chemical agents affect living processes.  Hormones  Neurotransmitters factors  local Autocrine factors  Drugs (Pharmaceuticals)  Toxic agents in the environment  Growth  the medicinal/ organic chemist may create the candidate compound (sometimes referred to as a new chemical entity, NCE), it is the pharmacologist who is responsible for testing it for pharmacological activity. ultimately will lead to the discovery of novel drug targets for therapeutic intervention in diseases where distal steps in signal transduction have gone awry     Pharmacology studies the effects of drugs and how they exert their effects. acetylsalicylic acid (ASA) can reduce inflammation, pain and fever inhibit the action of a human cell membrane enzyme known as cyclooxygenase, which is responsible for the synthesis of a number of inflammatory mediators penicillin cures certain bacterial infections disrupt the synthesis of cell walls in susceptible bacterial strains by inhibiting a key enzyme Some Pharmacology Definitions and Areas of Study  Pharmacotherapeutics - use of drugs to treat   disorders; the emphasis is on clinical management Pharmacoepidemiology - study of the effect of drugs on populations; questions dealing with the influence of genetics are particularly important Pharmacoeconomics - study of the costeffectiveness of drug treatments; the cost of medications is of worldwide concern, particularly among certain groups such as the elderly and AIDS patients  Pharmacokinetics  study the fate of drugs once ingested and the variability of drug response in varying patient populations  how the body absorbs, distributes, metabolizes, and excretes drugs  calculation of various rates brings a quantitative component to assessing drug action  Pharmacodynamics  study the mechanisms by which drugs work  also study endogenous agents Basics of Pharmacology  Chemical Shape and Properties of Drug to receptor binding site  Very important in determining if drug will be an agonist or antagonist  Paradigm is requirement of at least three points of contact for specific interaction of drug to receptor  Chiral vs. non-chiral  Flexibility and rotation of internal bonds  Complimentary Model of Drug/Receptor Binding  Binding Studies  Association to receptor  Dissociation from receptor  Forces of binding  Covalent  Electrostatic  Hydrophobic  Clearance  adsorption  t1/2 Types of Pharmaceutical Manufacturers pharmaceutical preparations  finished drugs  biological products, such as serums and vaccines  bulk chemicals and botanicals used in making finished drugs  diagnostic substances such as pregnancy and blood glucose kits  Pharmaceutical Industries Researching Institutes St. Jude GMP Facility     Gene-based molecules Drugs Vaccines Proteins Steps in Manufacture of Drugs  Scientific Research to discover/synthesize new compounds, or improve existing compounds (R & D)   Computer simulation Combinatorial chemistry    Develop safe and effective applications of promising compounds Screen compounds in bacterial cultures or animal subjects Clinical trials on humans  Clinical Trials   Kidneys and liver are two most important organs In Phase I trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. In Phase II trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. In Phase III trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely. In Phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.    Production  Scale-up of Production      chemists chemical engineers packaging engineers production specialists to make production economic, safe, etc. Separation of isomers (Thalidomide) Milling and micronizing machines pulverize substances into extremely fine particles, reduce bulk chemicals to the required size finished chemicals are combined and processed further in mixing machines mixed ingredients are mechanically capsulated, pressed into tablets, or made into solutions  High Degree of Automation     Quality Control/Quality Assurance Alternative Production Methods  Bacteria    Microorganisms to produce simple chemicals for manufacture process Microorganisms to produce full length polypeptides Bacteria produce human insulin Transgenic Sheep carry gene for human Factor IX (Science, vol. 278, 1997) Cows that produce human antibodies  “Pharm Animals”   (http://www.newscientist.com/hottopics/cloning/cl oning.jsp?id=ns99992658)