MBS-Pharmacology-1.pdf

Introduction to Pharmacology Dr. Kiran C. Patel College of Allopathic Medicine Department of Medical Education Objectives: 1. Describe the difference between an agonist and a pharmacologic antagonist. 2. Describe the basic pharmacodynamic and pharmacokinetic principles that govern...

Introduction to Pharmacology Dr. Kiran C. Patel College of Allopathic Medicine Department of Medical Education Objectives: 1. Describe the difference between an agonist and a pharmacologic antagonist. 2. Describe the basic pharmacodynamic and pharmacokinetic principles that govern drug action in the body including the Henderson– Hasselbalch equation 3. Compare and contrast the common routes of drug administration. 4. Explain the concept of pharmacogenomics using drug examples. 5. Describe the difference between a generic and proprietary drug 6. Outline the different phases of drug development  History Prehistory – benefits vs toxic effects of plant and animal products. Written records list remedies of many types. Most, however, were worthless or actually harmful. British Library, Public domain, via Wikimedia Commons  17th century, concepts based on observation and experimentation began to replace theorizing and speculating in physiology and clinical medicine. Materia medica—the science of drug preparation and the medical uses of drugs—began to develop as the precursor to pharmacology. Advances and development in chemistry and physiology in the 18th, 19th, and early 20th centuries laid the foundation needed for understanding how drugs work at the organ and cellular levels. https://www.baus.org.uk/_userfiles/pages/images/ Museum/Time%20Corridor/Leeches.jpg  During 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 drug receptor. During the last 60 years, many fundamentally new drug groups and new members of old groups have been introduced. Since the 1980’s an even more rapid growth of information and understanding of the molecular basis for drug action has been seen. Terminology Pharmacology is the study of the actions of chemicals on biological systems. Drug- chemical substance that brings about a change in biological function through its chemical actions. Medical pharmacology is the area of pharmacology concerned with the use of chemicals in the prevention, diagnosis, and treatment of disease. Toxicology is the area of pharmacology concerned with the undesirable effects of chemicals on biological systems.  Pharmacokinetics describes the effects of the body on drugs. ADME (absorption, distribution, metabolism and excretion) Pharmacodynamics describes the actions of the drug on the body including their mechanism of action and therapeutic/toxic effects.  Pharmacodynamic Principles Drugs must bind to a receptor to elicit an effect. Agonist drugs bind to the receptor and activate it. Pharmacologic antagonist drugs bind to a receptor, compete with and prevent binding by other molecules (agonists) blocking their actions. Basic Pharmacokinetic Principles A - After administration, a drug must be absorbed , it must then permeate through various barriers to reach its site of action. GI track → blood D - distributed to its site of action M - Drugs may be metabolized to active/inactive products to aid in its elimination from the body. E - The drug must be eliminated from the body after it has brought about its effects. DRUG DOSE ADME ADME Absorption- movement of drug from the site of administration into the bloodstream. Distribution- movement of drug from blood through capillary tubes into extracellular fluid, cells and tissues. Metabolism- movement of drug into hepatic tissues (site of biotransformation) Excretion- movement of drug through kidney for removal from the body.  Drug passage through cell membranes depends on: Molecular size and shape Degree of ionization Relative lipid solubility (of ionized and nonionized forms) Binding to serum and tissue properties Physicochemical Properties of Drugs Polarity (water solubility) of a drug determines its kinetic properties. Described as a partition coefficient- measures the relative affinity of an agent for a polar aqueous medium versus a nonpolar, oil-like medium (water soluble versus lipid soluble). Lipid Solubility- Membranes are lipids and drugs must cross several membrane (lipid) barriers in order to reach their site of action. Determinants of Absorption, Distribution and Elimination Molecular Weight- Large molecules do not readily cross membranes. Ionization- The more charged a drug molecule, the more water soluble and the less lipid soluble it is. Uncharged drugs readily crosses membranes; charged molecules do not. Many drugs are weak acids or weak bases and their charge at any given moment depends on the pH of the medium they are in. Influence of pH on the distribution of a weak acid between plasma and gastric juice separated by a lipid barrier.  Mechanisms of Drug Absorption/permeation Permeation: Movement of drug molecules across biological membranes Absorption Transfer of a drug from its site of administration into the systemic circulation. Rate and efficiency Route of administration. Four Primary mechanisms for the passage of a drug through cell membranes: Aqueous (Passive) diffusion- Driven by concentration gradient Spontaneous and bidirectional. Occurs in large body interstitial space, cytosol, etc. Not saturable and cannot be inhibited. Shows low structural specificity Facilitated Diffusion- Requires specific carrier proteins. Can be saturated. Driven by concentration gradient. Mechanisms of Drug Absorption/permeation Active Transport - Specific carrier proteins involve in absorption. Can be saturated. Energy dependent requiring ATP. Can move drugs against a concentration gradient (i.e. low to high) Endocytosis and exocytosis- Substance is engulfed by the cell membrane and carried into the cell or out of the cell (buds off the cell membrane, and forms a vesicle containing the material, and is released). Energy dependent, saturable process. Carries drugs that are large in size Mechanisms of Drug Absorption Therapeutic Window Routes of Administration of Drugs Drugs enter the body at sites distant from the target tissue or organ Oral, parenteral. rectal In most cases, drugs need to be be transported via blood to their site of action. Drugs must be absorbed from the site of administration unless injected intravenously. Route of administration determines the rate and efficiency of absorption. Selecting the route of administration depends on: desired site of action, drug properties, patient’s condition and clinical state, required rapidity and duration of response, convenience and cost, availability. https://solutionpharmacy.in/wp-content/uploads/2021/08 Parenteral Injection I.V.-Intravenous-rapid onset S.C.-Subcutaneous Useful poorly absorbed drugs. I.M.-Intramuscular patients that are unconscious Rate is limited by: Rapid onset. Vascularity Solubility of the substance in Can better control dosage of interstitial fluid drugs. Molecules size Parenteral Administration- Intravenous Advantages Disadvantages Bioavailability is 100% Most dangerous route Drug levels are more accurately Toxic reactions can be seen controlled immediately Dosing error Extremely rapid Particles Initial absorption step is by-passed Drug must be in aqueous solution Good for irritant drugs Must be performed slowly Suitable for large volumes Once injected the drug cannot be removed Inhalation Rapid onset Volatile drugs - anesthetics Access to systemic circulation is fast thanks to large lung surface area Management of local conditions broncho constriction, emphysema, COPD Solutions can be atomized into fine droplets Aerosols, nebulizer, inhalers Sublingual Rapid onset Sublingual Administration: Absorption from oral mucosa Venous drainage from the mouth is to the superior vena cava. Ex: Nitroglycerin Rectal Rectal absorption is often erratic and incomplete. It depends on location vasculature. Commonly used when oral administration is not possible ~Approximately 50% of the absorbed drug will bypass the liver (less first pass than oral route, PO) Many drugs irritate the rectal mucosa. Useful in pediatrics Route of Administration- Oral Advantages Disadvantages The most convenient route Requires cooperation of patient Administration by patient Absorption may be unpredictable Generally the safest route Gastric irritation- Aspirin Cost Not useful if patient is vomiting No need for sterile equipment Drug may be destroyed by gastric Allows systemic distribution thanks acidity to GI tract blood supply Onset of action  Pharmacogenomics Pharmacogenomics (PG) studies the genetic variations that influence drug metabolism and drug effects. It evaluates how a person’s genes affect their response to medications. PG involves the application of genomic analysis of individual patients to the selection of specific drugs and drug dosage (precision, personalized or tailored medicine) Tailored or personalized medicine is medical treatment that takes into account the genetic factors that contribute to pathology and the pharmacogenomic factors that influence the response to drug treatment. Pharmacogenetics studies the genetic basis for variations in drug response and it implies large effects of a small number of DNA variants vs Pharmacogenomics that studies a larger numbers of variants to explain the genetic component of variable drug responses. Generic and proprietary drug A generic drug Same active ingredient as the brand-name drug Taken the same way Same effect Generic drugs do not need to contain the same inactive ingredients as the name- brand product and they can only be sold after the brand-name drug’s patent expires. Differences between generic and brand-name drugs: Inactive ingredients, such as flavoring or preservatives Cost Drug development Drug development usually begins with the discovery or synthesis of a potential new drug compound or discovering of a new drug target. After a new drug molecule is synthesized or extracted from a natural source, the drug’s interactions with its biologic targets is studied. This leads to the synthesis of related compounds with increased efficacy, potency, and selectivity. In the US, the safety and efficacy of drugs must be established before marketing.  In addition to in vitro studies, relevant biologic effects, drug metabolism, pharmacokinetic profiles, and relative safety of the drug must be characterized in vivo in animals before human drug trials can be started. Upon regulatory approval, human testing may begin before the drug is considered for approval of general public use. A fourth phase of data gathering and safety monitoring is becoming increasingly important and follows after approval for marketing. Once approved, the great majority of drugs become available for use by any appropriately licensed practitioner.