Introduction and General Principles of Pharmacology.pdf

Introduction and General Principles of Pharmacology  Pharmacology can be defined as the study of substances that interact with living systems through chemical processes.  In other words, Pharmacology is the examination of the interactions between a living organism and chem...

Introduction and General Principles of Pharmacology  Pharmacology can be defined as the study of substances that interact with living systems through chemical processes.  In other words, Pharmacology is the examination of the interactions between a living organism and chemicals that affect normal or abnormal biochemical functions.  It is the study of how a drug affects a biological system and how the body responds to the drug. These effects can either be therapeutic or toxic depending on many factors.  Therapeutics focuses on the effects of drugs and other chemical agents that minimize disease while toxicology is the study of undesirable (adverse or toxic) effects of drugs and other chemical agents.  Introduction and General Principles of Pharmacology (contd.)  Clinical pharmacology encompasses all aspects of the relationship between drugs and humans. The core goal is to improve patient care through the safe and effective use of medicines. This can be achieved by generating data for optimum use of drugs and the practice of 'evidence-based medicine’  It is the scientific discipline that underpins the rational prescribing of medicines to alleviate symptoms, treat illness and prevent future disease  It has a broad scope, from the discovery of new target molecules, to the effects of drug usage in whole populations. Clinical pharmacologists are physicians, pharmacists, and scientists whose focus is developing and understanding new drug therapies.  Historical Concepts  Knowledge of drugs and their uses in diseases are as old as the history of mankind. Ancient civilizations discovered that extracts from plants, animals and minerals had medicinal effects on the body.  Kahun papyrus (2000 BC) is the oldest Egyptian document containing information about veterinary medicines and uterine diseases in women  Ebers papyrus (1550 BC) is also an Egyptian document containing information about a number of diseases and about 829 prescriptions where castor oil and opium like drugs were used.  Hippocrates ( 460-375 BC) was a Greek philosopher considered the “father of Medicine”. He was the first to recognize disease as abnormal reaction of the body.  Paracelsus (1493 – 1541 AD) was a Swiss scholar and alchemist who is often considered the “grandfather of Pharmacology”. He introduced the use of chemicals for treatment of diseases.  History contd: Modern Pharmacology  Conversion of old medicines into the modern pharmacology started taking shape following the introduction of animal experimentation and isolation of active ingredients from plants.  In the late 18th and early 19th centuries, François Magendie (1783-1855) and his student Claude Bernard (1813-1878) began to develop the methods of experimental physiology and pharmacology.  Oswald Schmiedeberg (1838-1921) considered the “founder of Pharmacology” established pharmacology as an independent discipline. A medical doctor, he was a professor of Pharmacology at the University of Strassburg.  In the United States, the first chair in pharmacology was established at the University of Michigan in 1890 under John Jacob Abel (1857-1938), an American who had trained under Schmiedeberg.  Today, there is a pharmacology department in every college of medicine.  Around the 1940s and 1950s, a major expansion of research efforts in all areas of biology began. As new concepts and new techniques were introduced, information accumulated about drug action and the biologic substrate of that action, the drug receptor.  Pharmacology in relation to the Health Professions  Given the central role of drug and medical therapy in modern health care, the need for health care professionals to have a solid foundation in pharmacology is important  A solid knowledge of pharmacology helps health professionals to understand how drugs work in the body, to achieve the therapeutic (intended) effects and to anticipate and recognize the potential side effects or toxicities.  Role of Pharmacology in the Drug Industry  The new drug development process is carried out through a sequence of developmental and evaluative steps  The science of pharmacology provides the backbone for the methodologies developed and implemented across the pharmaceutical industry to improve the odds of success and address the challenges of “getting the dose right.”  In particular, clinical pharmacology integrates basic and clinical biomedical sciences and bring detailed expertise on the mechanism of action of drugs, dose–response relationships, adverse effects, drug metabolism, pharmacokinetics, and pharmacogenetics, coupled with knowledge of clinical trial optimization for drug development and the therapeutic applications of drugs in modern medical practice.  Role of Pharmacology in the Public Health, Social and Preventive Medicine  Many epidemiological studies on drugs and populations are conducted by public health or preventive medicine departments, which provide information on the value of a medicine in the assessment of risk-effectiveness balance  A good foundation in pharmacology, therefore, helps in understanding the relationships between the individual, society and medicinal products viz: efficacy, safety, effectiveness, and related information on drug details, patient compliance, self-medication and user habits; attitudes towards drug products; issues related to rational drug therapy such as the application of evidence-based treatment guidelines; issues related to drug-response variation (polymorphisms, pharmacogenetics); measures to determine drug over- and under-utilization; medication safety as both a clinical function and infrastructure requirement etc.  Sources of Information  One major source of drug information is the Pharmacopeia. It is a book that contains a list of established and officially approved drugs with description of their physical and chemical characteristics and tests for identification, purity, methods of storage etc. Some of the pharmacopeias are; Indian Pharmacopeia (I.P) British Pharmacopeia (B.P.) European Pharmacopeia (E.P.) United States Pharmacopeia (U.S.P.)  Other sources for drug information are:  National formulary (NF), Martindale  Physician Desk Reference (PDR)  Sources of Information contd.  Databases like drug Micromedex, Medline, Cochrane library, etc.  Journals of Pharmacology  Textbooks e.g. Basic and Clinical Pharmacology, Katzung and Trevor; Lippincott Ilustrated Reviews, Pharmacology etc.  The FDA maintains an Internet website that carries news regarding recent drug approvals, withdrawals, warnings, etc. It can be accessed at http://www.fda.gov. The MedWatch drug safety program is a free e-mail notification service that provides news of FDA drug warnings and withdrawals. Subscriptions may be obtained at https://service.govdelivery.com/service/user.html?code=USFDA  For preparation for an examination, a useful text is Pharmacology: Examination and Board Review, by Trevor, Katzung, and Kruidering-Hall. This book provides approximately 1000 questions and explanations in USMLE format. A short study guide is USMLE Road Map: Pharmacology, by Katzung and Trevor. Road Map contains numerous tables, figures, mnemonics, and USMLE-type clinical vignettes. Origin/Sources of Drugs Sources Recombinant DNA Technology Natural Synthetic Semi synthetic (Genetic Engineering) Plants Animals Microorganisms Minerals  Sources of Drugs contd.  Plants represent the oldest source of drugs used empirically. Leaves, seeds, flowers, roots, barks etc. can be used  Various forms of the plant drugs can be used; - extracts, infusions, decoctions, powders, chemicals (alkaloids, oils, resins, glycosides etc.)  Examples of drugs gotten from plant sources are; morphine, digitalis, quinine, atropine, pilocarpine etc.  Problems associated with plant source  Identification of plant  Climatic and social conditions of the area  Season of collection  Condition of storage  Standardization of the active ingredient  Purity of the active ingredient  Maintenance of the supply line  Sources of Drugs contd.  Animal source: Active principles are proteins, oil and fats, enzymes, hormones. Ex. Gonadotropins, heparin (leech), insulin (pork/cow pancreas), thyroid extract, enzymes, anti toxic sera, cod liver oil etc  Microorganisms: Fungi and bacteria are the source of some life saving drugs. Examples; penicillin (Penicillium notatum), chloramphenicol (Streptomyces venezuelace), streptomycin (Streptomyces griseus), griseofulvin (Penicillium grisofullivum) etc.  Mineral sources include metals, metalloids, non-metallic substances and their compounds e.g. magnesium (antacid, laxative), ferrous, aluminium, calcium, sulphur etc.  Humans can also serve as sources of drugs e.g. HMG, hHCG etc.  Assignment; list some drugs gotten from plant sources and their origin  Sources of Drugs contd.  Semi-synthetic: These are mainly obtained by changing the chemical structure of naturally obtained drugs. They are complex molecules, usually expensive and can be used for impure natural compounds. Examples; atropine bromide, semi-synthetic human insulin (pork insulin), hydrocodone, ampicillin from Penicillin-G  Synthetic: Most of the drugs used today are synthetic. Some drugs which were earlier obtained from plants are synthesized in the laboratory today. Examples; paracetamol, anti-histamines, sulphonamides (septrin), etc.  Advantages:  Quality can be controlled  Process is easier and cheaper  More potent  Large scale production  Sources of Drugs contd.  Genetic Engineering: Newer technologies involving the blending of discoveries from molecular biology, rDNA technology, DNA alteration, gene splicing, immunopharmacology. E.g. human insulin of rDNA technology, growth hormone, tissue plasminogen activator, hepatitis-B vaccine  Drug Nomenclature  Naming of Drugs: A drug usually has about three; chemical name, generic name, brand or proprietary name.  The Chemical name is the technical description of the actual molecule  The Generic name (non-proprietary name) is usually derived from the chemical name but shorter. It is usually chosen by official bodies. When a company brings a new drug into the market, a patent is granted that gives the company that developed the drug an exclusive right to sell the drug as long as the patent is in effect under its brand name.  The Brand or proprietary name is usually given by the pharmaceutical manufacturer. It is the name registered by the manufacturer and can only be used by a single manufacturer. Some drugs may have several trade/brand names (depending on the number of manufacturers)  Drug Nomeclature Chemical Name Generic name Proprietary name N-(4-hydroxyphenyl)acetamide Paracetamol or (acetaminophen Panadol, Calpol, Emcap in the USA) Acetylsalicylic acid Aspirin Vasoprin, Disprin Route of Administration of Drugs Routes of Drug Administration Local; Skin Topical Intranasal Systemic Ocular Drops M ucosal – throat, Enteral Parenteral Inhalation  Route of Administration of Drugs  Oral: Can refer to topical application to the mouth or most commonly, swallowing for absorption along the GI tract into systemic circulation. p.o. (from the Latin per os) is the abbreviation used to indicate oral route of medication administration  Advantages:  Convenient: can be self-administered, pain free, easy to take, non-invasive  Cheap compared to most other parenteral routes  No need for sterilization  Disadvantages:  Sometimes inefficient – only part of the drug may be absorbed  First-pass effect – drugs absorbed orally are initially transported to the liver via the portal vein. This may decrease bioavailability  Irritation to the gastric mucosa – nausea and vomiting  Destruction of drugs by gastric acid and digestive juices  Effect too slow for emergencies  Unable to use in unconscious patients  Unpleasant taste of some drugs  Route of Administration of Drugs  Sublingual route: The dosage form is placed under the tongue and absorbed rapidly by sublingual mucosa  Advantages:  Rapid absorption  Avoid first-pass effect  Economical  Disadvantages:  Large quantities not given  Irritation of oral mucosa  Unpleasant taste of some drugs  Few drugs are absorbed via this route  Route of Administration of Drugs  Buccal route: The dosage form is placed between gums and inner lining of the cheek (buccal pouch) under the tongue and absorbed rapidly by sublingual mucosa  Advantages:  Rapid absorption  Avoid first-pass effect  Economical  Disadvantages:  Small dose limit  Advantages lost if drug is mistakenly swallowed  Irritation of oral mucosa  Unpleasant taste of some drugs  Few drugs are absorbed via this route  Route of Administration of Drugs  Rectal route: Can be administered as suppository or enema  Advantages:  Can be used in vomiting or unconscious patients  Can be used in children  Little or no first-pass effect  Higher concentrations rapidly achieved  Disadvantages:  Inconvenient  Absorption is slow and erratic  Irritation or inflammation of rectal mucosa may occur  Route of Administration of Drugs  Parenteral route: Parenteral administration is injection or infusion by means of a needle or catheter inserted into the body. This route bypasses the alimentary canal  Intravascular (intravenous) (IV)- placing a drug directly into the blood stream  Intramuscular (IM) - drug injected into skeletal muscle  Subcutaneous - Absorption of drugs from the subcutaneous tissues. Absorption is slow so action is prolonged and only small volume can be injected  Intra-arterial – rarely used. Can be used for diagnosis of peripheral vascular diseases. Anticancer drugs can also be given via this route for localized effects  Intra-articular - injections of antibiotics and corticosteroids are administered in inflamed joint cavities by experts. E.g hydrocortisone in rheumatoid arthritis.  Intrathecal: can be used to deliver drugs to the CSF  Intradermal: drug is given within skin layers (dermis). It is painful and mainly used for testing sensitivity to drugs  Intravenous route  Advantages:  Bioavailability 100%  Large quantities can be given  Can be used in emergency situations  First-pass effect avoided  Precise and accurate onset of action,  Disadvantages:  High risk of adverse effects e.g. risk of embolism, infection, Irritation and cellulitis  Technical assistance required  Expensive  Can be painful  Danger of infection  Intramuscular route  Advantages:  Absorption reasonably uniform  Rapid onset of action  Gastric factors can be avoided  First-pass effect avoided  Disadvantages:  Only up to 10ml drug given  Risk of nerve damage  Technical assistance required  Expensive  Can be painful  Danger of infection  Topical Dosage forms  Mucosal membranes (nose or lung; sprays and powders)  Eyes or ears solutions, ointments or suspension  Skin  Dermal – ointments, creams, lotions, gels etc (local action)  Transdermal - absorption of drug through skin (systemic action); no first pass metabolism e. g patches   Inhalation route  Inhalation provides the rapid delivery of drug across the large surface area of the mucus membranes of the respiratory tract and pulmonary epithelium, producing an effect almost as rapidly as with an IV injection.  This route of administration is used for drugs that are gases (e.g. some anaesthetics) or those that can be dissolved in an aerosol  This route is particularly effective and convenient for patients with respiratory complaints (such as asthma, COPD) because the drug is delivered directly to the site of action and systemic effects are minimized  Factors governing choice of route of administration  Physical and chemical properties of a drug:  solid/liquid/gas; solubility, stability, pH, irritant quality  Site of desired action  Localized and approachable or generalized and non approachable  Rate and extent of absorption from various routes  Effect of digestive juices & first pass effect  Rapidity of the desired response  Emergency/routine  Accuracy of the dosage  Condition of the patient  Unconscious, vomiting  Biological membranes and transport of drugs  Generally, drugs are administered away from their site of action  To reach their site of action, they permeate from one compartment to another by crossing the different barriers  When a drug is administered by an extravascular route of administration (e.g., oral, topical, intranasal, inhalation, rectal), the drug must first be absorbed into the systemic circulation and then diffuse or be transported to the site of action before eliciting biological and therapeutic activity.  The general principles and kinetics of absorption from these extravascular sites follow the same principles as oral dosing, although the physiology of the site of administration differs.  Many drugs administered by extravascular routes are intended for local effect. Other drugs are designed to be absorbed from the site of administration into the systemic circulation.  For systemic drug absorption, the drug must cross cellular membranes.  Movement of drugs across biological membranes is called drug transport  Biological membranes and transport of drugs  After oral administration, drug molecules must cross the intestinal epithelium by going either through or between the epithelial cells to reach the systemic circulation.  The permeability of a drug at the absorption site into the systemic circulation is intimately related to the molecular structure of the drug and to the physical and biochemical properties of the cell membranes.  Once in the plasma, the drug may have to cross biological membranes to reach the site of action. Therefore, biological membranes potentially pose a significant barrier to drug delivery.  Transcellular absorption is the process of drug movement across a cell.  Some polar molecules may not be able to traverse the cell membrane but, instead, go through gaps or tight junctions between cells, a process known as paracellular drug absorption.  Some drugs are probably absorbed by a mixed mechanism involving one or more processes.  Biological membranes and transport of drugs  Membranes are major structures in cells, surrounding the entire cell (plasma membrane) and acting as a boundary between the cell and the interstitial fluid.  membranes enclose most of the cell organelles (e.g., the mitochondrion membrane).  Functionally, cell membranes are semipermeable partitions that act as selective barriers to the passage of molecules.  Cell membranes are fluid bi-layer of phospholipids. Scattered membrane protein molecules embedded in bi- layer serve as receptors, ion channels, transporters.  Water, some selected small molecules, and lipid-soluble molecules pass through such membranes, whereas highly charged molecules and large molecules, such as proteins and protein-bound drugs, do not.  Mechanisms of drug transport  Passive diffusion  Passive diffusion of non-electrolytes  Passive diffusion of electrolytes  Filtration  Carrier-mediated transport  Active transport  Facilitated diffusion  Endocytosis  Phagocytosis  Pinocytosis  Ion-pair transport  Passive diffusion  Primary means by which drugs cross membranes  It does not need cellular energy or assistance  Fick’s first law of diffusion: the drug molecules diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained. Rate of diffusion is directly proportional to the concentration gradient across the membrane  dQ/Dt = DAK m/w (Cgit-Cp) h  dQ/dt – rate of diffusion (amount per unit time)  D = diffusion coefficient (D, is a constant for each drug and is defined as the amount of a drug that diffuses across a membrane of a given unit area per unit time when the concentration gradient is unity. The dimensions of D are area per unit time—for example, cm2/sec.)  A = surface area  K m/w = Partition coefficient  Cgit-C = concentration gradient (difference between conc. of drugs in the GIT and plasma)  h = thickness of the membrane (The thickness of the hypothetical model membrane, h, is a constant for any particular absorption site)  Low molecular weight drugs that are both water and lipid soluble dissolve in membrane and cross to the other side  Passive diffusion  Only the unionized forms of the drug or the uncharged drug can pass through or across the membranes by passive diffusion.  For weak electrolytes (partially ionized drugs), diffusion would depend on  Degree of ionization  pH of the surrounding environment  Lipid-water partition coefficient of their undissolved form  By controlling the pH of the solution and/or the pKa of the drug, you can control the rate at which the drug is transferred  Weak acids are readily absorbed from the stomach (acidic environment) while weak bases are absorbed readily from alkaline environment – intestine.  Read up Henderson-Hasselbach equation  Filtration  Filtration  In biological systems: Filtration is the transfer of drug across membrane through the pores or through the spaces between cells  Capillary endothelial membranes  Renal glomerulus  The rate of filtration  Driving force: The pressure gradient in both sides.  The size of the compound relative to the size of the pore.  Smaller compound – transfer rapidly  Larger compound – retained  Lipid soluble – passive diffusion  Water soluble – filtration  Carrier mediated transport  Important for drug molecules too large or too insoluble in lipid to diffuse passively through the membrane.  Carriers are trans-membrane proteins. The drug molecules chemically related to naturally occurring peptides, amino acids, or sugars can use these carriers.  Carrier binds one or more of these molecules or ions, changes conformation and releases them on the other side of the membrane  Main sites  Renal tubule  Blood brain barrier  Gastrointestinal tract  Active transport  Against concentration gradient  Energy dependent, obtained from hydrolysis of ATP  Carrier is required  Selective, saturable  Competitive inhibition b another drug binding to same carrier  Examples  Transport of levodopa into the brain  Active absorption of 5-fluorouracil through gut wall  Active proximal renal tubular secretion of penicillin and probenecid  Reverse transporters  These are carriers specialized in expelling foreign molecules as they enter the cells  One large family is ABC (ATP binding cassette) family and this includes;  P-glycoprotein or multidrug resistance type 1 (MDR1) transporter found in the brain, testes and other tissues and in some drug resistant neoplastic. It can be inhibited by grapefruit juice and certain drugs e.g. verapamil  Multidrug resistance-associated protein (MRP) transporters play important role in excretion of drug or its metabolites into urine or bile  Facilitated diffusion  This is a mechanism to enhance diffusion of drugs with low lipid solubility,.  It is along a concentration gradient  Carrier mediated; carrier increases the lipid solubility of the drug increased rate of diffusion  Not energy dependent  Saturable  Competitive inhibition  Endocytosis (phagocytosis and pinocytosis)  Specific receptors for transport proteins must be present for this process to work  Endocytosis: Cellular uptake of exogenous complexes inside membrane derived vesicles. Drugs which have very large molecules can be engulfed by the cell membrane in a vesicle and carried into the cell and released within the cell by pinching off the vesicle and breakdown of its membrane  Example; transport of vitamin B12 with a binding protein (intrinsic factor) across the gut wall, iron is transported into haemoglobin synthesizing RBCs precursors with transferrin  Phagocytosis: Rare process of engulfing larger molecules. E.g. bacteria/foreign bodies by macrophages  Pinocytosis : This is similar to phagocytosis, but substance is liquid or very small particles; fluid uptake – engulfs a fluid/drug in solution. Example; immunoglobulin in neonates gut  Ion pair transport  Strong electrolyte drugs maintain their charge at all physiologic pH values and penetrate membranes poorly. When the ionized drug is linked up with an oppositely charged ion, an ion pair is formed in which the overall charge of the pair is neutral. This neutral drug complex diffuses more easily across the membrane.