Module 1: Basic Principles of Pharmacology PDF

PHARMACOLOGY 1 1st Tri, A.Y 24-25 TF: 12:30-5:00 PM   Introduction  Principles of Drug action  Pharmacodynamic and Pharmacokinetic Phase  Autacoids  Autonomic Drugs COURSE  Sedative Hypnotics OUTLINE  Anesthetics  Antisei...

PHARMACOLOGY 1 1st Tri, A.Y 24-25 TF: 12:30-5:00 PM   Introduction  Principles of Drug action  Pharmacodynamic and Pharmacokinetic Phase  Autacoids  Autonomic Drugs COURSE  Sedative Hypnotics OUTLINE  Anesthetics  Antiseizure  Drugs for Mood Disorders  Antipsychotic Drugs  Analgesic  NSAIDS Introduction to Pharmacology  Pharmacology  From the Greek pharmakon (drug) + logos (to study) Introduction  It is the study of drugs  It the science of drugs including their origin, composition, pharmacokinetics, therapeutic use, and toxicology  Pharmacology  a medical science that forms a backbone of the medical profession as drugs form the corner stone of therapy in human diseases.  is the science that deals with drugs and their action Introduction on living organisms  the study of interaction of drugs with living organisms. It also includes history, source, physicochemical properties, dosage forms, methods of administration, absorption, distribution mechanism of action, biotransformation, excretion, clinical uses and adverse effects of drugs.  1. Pharmacodynamics – what does the drug do to the body 2. Pharmacokinetics – what does the body do BRANCHES OF to the drug PHARMACOLOGY 3. Pharmaceutics – study of the rational drug use in the management of disease   Clinical Pharmacology: It evaluate the pharmacological action of drug preferred route of administration and safe dosage range in human by clinical trails.  Drugs: Drugs are chemicals that alter functions of living organisms. Drugs are generally given DEFINITIONS for the diagnosis, prevention, control or cure of disease.  Pharmacy: It is the science of identification, selection, preservation, standardization, compounding and dispensing of medical substances.   Toxicology: It’s the science of poisons. Many drugs in larger doses may act as poisons. Poisons are substances that cause harmful, dangerous or fatal symptoms in living substances.  Chemotherapy: It’s the effect of drugs upon microorganisms, parasites and neoplastic cells living and multiplying in living organisms. DEFINITIONS  Pharmacopoeia: An official code containing a selected list of the established drugs and medical preparations with descriptions of their physical properties and tests for their identity, purity and potency e.g. Indian Pharmacopoeia (I.P), British Pharmacopoeia (B.P).   A drug is a chemical substance, typically of known structure, which, when administered to a living organism, produces a biological effect. What is a DRUG?  A pharmaceutical drug, also called a medication or medicine, is a chemical substance used to treat, cure, prevent, or diagnose a disease or to promote well-being.  1. Minerals: Liquid paraffin, magnesium sulfate, magnesium trisilicate, kaolin, etc. 2. Animals: Insulin, thyroid extract, heparin and antitoxin sera, etc. Drugs are 3. Plants: Morphine, digoxin, atropine, castor oil, etc. 4. Synthetic source: Aspirin, sulfonamides, obtained paracetamol, zidovudine, etc. 5. Micro organisms: Penicillin, streptomycin and many from: other antibiotics. 6. Genetic engineering: Human insulin, human growth hormone etc.  Out of all the above sources, majority of the drugs currently used in therapeutics are from synthetic source.   Most drugs have four names:  1. Chemical name, which is used by chemists and researchers—e.g., 1–(2S)-3–mercopto-methyl propionyl L- proline, MW = 217.29— and gives the chemical formula of the drug;  2. Generic or nonproprietary name, e.g., captopril, which gives the biochemistry of the drug. This name is not DRUG NAMES capitalized and is used in formularies;  3. Trade name or proprietary name, e.g., Capoten®, which is created by the manufacturer for commercial and marketing purposes, capitalized with the trademark symbol; and,  4. Official name, which is usually the generic name as listed in the official compendia, the United States Pharmacopoeia (USP) and the National Formulary (NF), e.g., captopril, USP-NF.  Example 1  Chemical name: acetyl salicylic acid  Generic name: aspirin  Brand name: Aspilet®  Official name: Aspilet or baby aspirin DRUG NAMES EXAMPLE Example 2  Chemical name: 1— [(25) —3-mercapto-methyl propionyl]- proline  Generic name: Captopril  Brand name: Capoten®  Official name: Captopril USP-NF  Example 3  Chemical name: 4-thio-1-azabicyclo [3,2,0] heptane- 2-carboxylic acid, 6-Raminophenyacetypamino-3,3- DRUG NAMES dimethyl-7-oxo-, [2 S{2a,-5a,613 (5*)}] EXAMPLE  Generic name: Ampicillin  Brand name: Polycillin®  Official name: Ampicillin®, USP  Drugs may be classified as or according to their:  Therapeutic or clinical indication CLASSIFICATION  Physiological or chemical action OF  Target on the body systems DRUGS  Prototype drugs  Prescription & non-prescription drugs  Health orphan drugs  Illegal or recreational drugs   Therapeutic or clinical indication  Therapeutic Indication  the primary information on the use of a medicine. It should clearly state the CLASSIFICATION disease/condition and population that a medicine is intended to treat. OF DRUGS  Clinical Indication  a combination of three or four words that can be used on a prescription to describe the effect on the patient of a particular drug.   Therapeutic or clinical indication  Examples:  antihypertensives or hypotensive, which tower blood pressure; CLASSIFICATION  antiemetics, which control nausea and vomiting; OF  diuretics, which induce urination; DRUGS  antacids, which are used for hyperacidity; and,  antibiotics, which inhibit growth of microorganisms.   Physiological or chemical action  Physiological Action  Pertaining to the action of a drug when introduced to a healthy person (to contrast from the CLASSIFICATION therapeutic action). OF DRUGS  Chemical Action  Actions of drugs are the biochemical physiological mechanisms by which the chemical produces a response in living organisms.   Physiological or chemical action  Examples: CLASSIFICATION  Beta-adrenergic blockers, OF  Calcium channel blockers, and DRUGS  Anticholinergics  Antiadrenergics   Target on the body system  A drug target is a molecule in the body, usually a protein, that is intrinsically associated with a particular disease process CLASSIFICATION and that could be addressed by a drug to OF produce a desired therapeutic effect. DRUGS  Such as drugs affecting the central nervous system (CNS), cardiovascular system, and the gastrointestinal system.   Prototype drugs  It's the blue print and first form of a drug that is used to make other and alternate forms of the drug. CLASSIFICATION OF  Those whose profile of pharmacologic DRUGS research information is representative of many drugs or is the most commonly used drug in its class in the chemical setting  is the 'lead agent' in a drug class (family).   Prototype drugs  Example: CLASSIFICATION  imipramine, the prototype of tricyclic OF depressants; DRUGS  diazepam, the prototype of benzodiazepines, sedative and hypnotic agents, and anti- anxiety agents.   Prescription drugs  a drug that can be obtained only by means of a physician's prescription. CLASSIFICATION  The most commonly used prescription OF drugs fall into three classes:  Opioids. Examples: oxycodone (OxyContin), DRUGS hydrocodone (Vicodin), and meperidine (Demerol)  Central Nervous System (CNS) Depressants Examples: phenobarbital (Luminal), diazepam (Valium), and alprazolam (Xanax)  Stimulants.   Non-prescription drugs or OTC drugs  defined as drugs that are safe and effective for use by the general public without advice from a health professional. CLASSIFICATION  Most commonly abused over-the-counter drugs OF  Dextromethorphan (DXM) DXM is used for temporary relief of cough caused by the common cold DRUGS  Loperamide  Pseudoephedrine/phenylephrine  Diphenhydramine (DPH)  Acetaminophen  Oxybutynin transdermal system  Antacids  Other regularly abused OTC products   Health orphan drugs  Drugs that are not developed by the pharmaceutical industry for economic reasons but which respond to public health need. CLASSIFICATION OF  Example of which are used to treat rare health conditions like cystic fibrosis, Hansen's disease DRUGS (leprosy), sickle cell anemia, blepharospasm, and infant botulism.   Illegal or recreational drugs  Illegal drugs CLASSIFICATION  drugs which a person is not allowed to own or use. A drug is any chemical that affects the human OF body or mind when taken in any way. DRUGS  a substance that affects the way the body functions. If a drug is classified as 'illegal', this means that it is forbidden by law.   Illegal or recreational drugs  Recreational drugs  a loose term that refers to legal and illegal drugs that are used without medical supervision. CLASSIFICATION  There are four categories of recreational drugs: OF DRUGS  Analgesics - include narcotics like heroin, morphine, fentanyl, and codeine.  Depressants - include alcohol, barbiturates, tranquilizers, and nicotine.  Stimulants - include cocaine, methamphetamine, and ecstasy (MDMA).  Hallucinogens - include LSD (acid), peyote (mescaline), psilocybin (magic mushrooms), marijuana, ketamine, phencyclidine (PCP), and salvia divinorum (diviner's sage).  About 80% of drugs are taken orally and undergo four phases, namely the: GENERAL  1. Pharmaceutic phase or dissolution - which refers to the reduction of drugs in solid form PRINCIPLES (e.g., tablets and capsules) into smaller particles and OF their dissolution into a liquid to facilitate absorption; DRUG ACTION  2. Pharmacokinetic phase - which refers to the process of drug movement—its absorption, distribution, metabolism (or biotransformation), and excretion (or elimination)   3. Pharmacodynamic phase, - or the mechanism of drug action and its effects on the body; GENERAL  4. Pharmacotherapeutic phase PRINCIPLES - includes the different approaches to treating diseases. Most successful treatments require a combination of any OF of the following: DRUG ACTION  Drug therapy, or treatment using drugs;  Diet therapy, or diet restrictions, such as low salt diet for patients with cardiovascular disease and hypertension;  Physiotherapy, which refers to treatment with natural physical forces, such as light, water, and heat; and  Psychological therapy, which identifies stressors and devise to minimize stress and/or the use of illegal drugs.   PHARMACKINETIC PHASE PHARMACOKINETIC  Pharmacokinetics deals with the absorption, distribution, metabolism and excretion drugs in the PHASE body. A. Bio transport of Drug B. Drug Absorption C. Distribution of Drugs D. Metabolism of Drugs E. Excretion of Drugs   It is translocation of a solute from one side of the biological barrier to the other. 1. Structure of biological membrane: The outer surface of the cell covered by a very thin structure known as plasma membrane. It is composed of lipid Bio- and protein molecules. transport of The membrane proteins have many functions like: (a) contributing structure to the membrane drug (b) acting as enzyme (c) acting as carrier for transport of substances (d) acting as receptors.  The plasma membrane is a semipermeable membrane allowing certain chemical substances to pass freely e.g. it allows water, glucose, etc. but it won’t allow sucrose until it is converted into glucose and fructose.  2. Passage of drug across membrane Membrane transport—movement of substances into and out of the cell Bio- Two types of basic mechanisms are involved transport of in the transport of substances across the cell membrane: drug 1. Passive transport mechanism 2. Active transport mechanism  2. Passage of drug across membrane Movements Into and Out of the Cell Bio- Passive (Physical) Transport Require no cellular energy Active (Physiological) Transport Require cellular energy and transport of and include: include: drug Simple diffusion Active transport Facilitated diffusion Endocytosis Osmosis Exocytosis Filtration Transcytosis   PASSIVE TRANSPORT 1. SIMPLE DIFFUSION Movement of substances from regions of higher concentration to regions of lower concentration Solutes are lipid-soluble materials or small enough to pass through membrane pores Transport Oxygen, carbon dioxide and lipid-soluble substances System 2. FACILITATED DIFFUSION  Diffusion across a membrane with the help of a channel or carrier molecule  Transports lipid-insoluble and large subs  Glucose and amino acids   PASSIVE TRANSPORT  3. OSMOSIS Movement of water through a selectively permeable membrane from regions of higher concentration to regions of lower concentration Water moves toward a higher concentration of solutes Transport  4. FILTRATION System Smaller molecules are forced through porous membranes Water and solutes are forced through a membrane by fluid, or hydrostatic pressure A pressure gradient must exist Solute-containing fluid is pushed from a high- pressure area to a lower pressure area Ex. Molecules leaving blood capillaries   ACTIVE TRANSPORT 1. ACTIVE TRANSPORT (SOLUTE PUMPING) Carrier molecules transport substances across a membrane from regions of lower concentration to regions of higher concentration Transport Amino acids, some sugars, and ions are transported by protein carriers called solute pumps System ATP energizes protein carriers In most cases, substances are moved against concentration gradients  EXAMPLE:  Sodium-Potassium Pump - Creates balance by “pumping” three (3) sodium (Na+) OUT and two (2) potassium (K+) INTO the cell   ACTIVE TRANSPORT 2. ENDOCYTOSIS  Cell engulfs a substance by forming a vesicle around the substance  Defined as a transport mechanism by which Transport the macromolecules enter the cell. System  Three types: Pinocytosis –”cell drinking” Phagocytosis –“cell eating” Receptor-mediated endocytosis – requires the substance to bind to a membrane-bound receptor   ACTIVE TRANSPORT 3. EXOCYTOSIS Moves materials out of the cell Material is carried in a membranous vesicle Vesicle migrates to plasma membrane Vesicle combines with plasma membrane Transport System 4. TRANSCYTOSIS  Endocytosis followed by exocytosis  Transports a substance rapidly through a cell  HIV crossing a cell layer Material is emptied to the outside  Absorption is the process by which the drug enters in to the systemic circulation from the site of administration through biological barrier.  In case of intravenous or intra-arterial administration the drug bypasses absorption processes and it enters into the circulation directly. Drug I. ROUTES OF ADMINISTRATION Absorption a) Enteral routes - those in which the drug is absorbed from the gastrointestinal tract i. Oral; e.g. paracetamol tablet, omeprazole capsule ii. Buccal cavity: e.g. fentanyl, naloxone iii. Sublingual; e.g. loratadine, nitroglycerin iv. Stomach: e.g. aspirin, alcohol v. Intestine: e.g. most of non ionized and ionized drugs. vi. Rectum: e.g. rectal suppositories, bisacodyl laxatives.  I. ROUTES OF ADMINISTRATION (cont..) a) Enteral routes Advantages of oral route: This route is safe, convenient and economical. Drug Absorption Disadvantages of oral route: Onset of drug action is slow, irritant drugs cannot be administered and it is not useful in vomiting and severe diarrhea, gastric acid and digestive enzymes may destroy some drugs, and water soluble drugs are absorbed poorly.  I. ROUTES OF ADMINISTRATION (cont..) b) Parenteral routes - the term parenteral is usually used for drugs given by injection or infusion. i. Intradermal: This is given into the layers of the skin Drug e.g. B.C.G. vaccine Absorption ii. Subcutaneous: Non-irritant substances are given into subcutaneous tissue e.g. insulin iii. Intramuscular: Soluble substances, mild irritants, suspensions and colloids can be injected by this route. These injections can be given to deltoid or gluteal muscle. This route is one of the more common routes e.g. multivitamins, streptomycin, etc.  I. ROUTES OF ADMINISTRATION (cont..) b) Parenteral routes iv. Intravenous: Drugs directly given into a vein, produce rapid action, no need of absorption as they enter directly into blood, can be given as bolus e.g. furosemide, morphine, dopamine or as continuous infusion e.g. fluids during shock or dehydration.  Advantages: It can be given in large volumes, production of desired Drug blood concentration can be obtained with a well designed dose.  Disadvantages: Drug effect cannot be halted if once the drug is injected, Absorption expertise is needed to give injection. v. Intrathecal: Injected into subarachnoid space of spinal cord e.g. spinal anesthetics. vi. Intraperitoneal: Injections given into the abdominal cavity e.g. infant saline, glucose. vii. Intra-articular: Injected directly into a joint e.g. hydrocortisone.  I. ROUTES OF ADMINISTRATION (cont..) c) Transcutaneous routes - passing, entering, or made by penetration through the skin transcutaneous infection. i. Iontophoresis: Galvanic current is used for bringing Drug about the penetration of drugs into the deeper tissue e.g. salicylates. Absorption ii. Inunctions: Absorbed when rubbed in to the skin e.g. nitroglycerin ointment in angina pectoris. iii. Jet injection: With help of high velocity jet produced through a micro fine orifice; No need of needle and therefore painless. e.g. mass inoculation programs. iv. Adhesive units: A transdermal therapeutic system produce prolonged systemic effect e.g. scopolamine for motion sickness.  I. ROUTES OF ADMINISTRATION (cont..) d) Topical/Local route - refers to the application of medication to the surface of the skin or mucous membrane of the eye, ear, nose, mouth, vagina, etc. with the intent of containing the Drug pharmacological effect of the drug only to the surface or within the layers of skin or mucous membrane. Absorption - e.g. dusting powder, paste, lotion, drops, ointment, suppository for vagina and rectum.  I. ROUTES OF ADMINISTRATION (cont..) e) Inhalation route - Administration of a substance in the form of a gas, aerosol, or fine powder via the respiratory tract, usually by oral or nasal inhalation, for local or systemic effect. Drug Absorption  e.g. salbutamol spray used in bronchial asthma and volatile general anaesthetics.  II. BIOAVAILABILITY  It is the rate and amount of drug that is absorbed from a given dosage form and reaches the systemic circulation following non-vascular administration. When the drug is given IV, the bioavailability is 100%  it is important to know the manner in which a drug is Drug absorbed. The route of administration largely determines the latent period between administration and onset of action. Absorption  Drugs given by mouth may be inactive for the following reasons: a) Enzymatic degradation of polypeptides within the lumen of the gastrointestinal tract e.g. insulin, ACTH. b) Poor absorption through gastrointestinal tract e.g. aminoglycoside antibiotic. c) Inactivation by liver e.g. testosterone during first passage through the liver before it reaches systemic circulation.  III. FACTORS AFFECTING DRUG ABSORPTION AND BIOAVAILABILITY Seven factors affect absorption and bioavailability, namely:  1. Form and solubility — Drugs given in aqueous solution are more rapidly absorbed than those in oily Drug solutions because they mix more readily with the aqueous phase at the absorptive site. The rate at which the drug Absorption dissolves may be a limiting factor if the drug is solid. Local conditions at the site of absorption, like pH, can alter solubility. This is especially true in the gastrointestinal tract; e.g., aspirin is relatively insoluble in acidic gastric contents.  2. Concentration — More concentrated solutions of a drug are more extensively absorbed.  III. FACTORS AFFECTING DRUG ABSORPTION AND BIOAVAILABILITY (cont..)  3. Route of administration — Parenteral (especially intravenous injections) are more actively absorbed than orally administered drugs. Drug  4. Blood circulation at the site of absorption — Vasoconstrictors decrease blood flow. Shock and some Absorption diseases decrease the rate of absorption while local application of heat and massage increase blood flow and enhance absorption.  5. Surface area available for absorption — Drugs are rapidly absorbed at sites where epithelial membranes have large surface areas; e.g.. drugs are rapidly absorbed in the pulmonary alveolar epithelium, the intestinal mucosa and, in cases of extensive application, the skin. Absorption in the stomach is not as rapid or extensive.  III. FACTORS AFFECTING DRUG ABSORPTION AND BIOAVAILABILITY (cont..)  6. Presence of food and other drugs Drug  7. Changes in liver metabolism caused by dysfunction Absorption and inadequate blood supply.   Definition: Penetration of a drug to the sites of action through the walls of blood vessels from the administered site after absorption is called drug distribution. Drugs distribute through various body fluid compartments such as: (a) Plasma (b) Interstitial fluid compartment Drug (c) Trans-cellular compartment. Distribution  Apparent Volume of distribution (VD): The volume into which the total amount of a drug in the body would have to be uniformly distributed to provide the concentration of the drug actually measured in the plasma. It is an apparent rather than real volume.  Factors Determining the Rate of Distribution Of Drugs: 1. Protein Binding Of Drug:  A Variable And Other Significant Portion Of Absorbed Drug May Become Reversibly Bound To Plasma Proteins. The Active Concentration Of The Drug Is That Part Which Is Not Drug Bound, Because It Is Only This Fraction Which Is Free To Leave The Plasma And Site Of Action. Distribution (A) Free Drug Leave Plasma To Site Of Action (B) Binding Of Drugs To Plasma Proteins Assists Absorption (C) Protein Binding Acts As A Temporary Store Of A Drug And Tends To Prevent Large Fluctuations In Concentration Of Unbound Drug In The Body Fluids (D) Protein Binding Reduces Diffusion Of Drug Into The Cell And There By Delays Its Metabolic Degradation E.G. High Protein Bound Drug Like Phenylbutazone Is Long Acting.  Factors Determining the Rate of Distribution Of Drugs: 2. Plasma Concentration Of Drug (Pc)  It represents the drug that is bound to the plasma proteins (albumins and globulins) and the drug in free form. Drug  It Is The Free Form Of Drug That Is Distributed To The Tissues And Fluids And Takes Part In Producing Distribution Pharmacological Effects.  The Concentration Of Free Drug In Plasma Does Not Always Remain In The Same Level E.G. i. After I.V. Administration Plasma Concentration Falls Sharply ii. After Oral Administration Plasma Concentration Rises And Falls Gradually. iii. After Sublingual Administration Plasma Concentration Rise Sharply And Falls Gradually.  Factors Determining the Rate of Distribution Of Drugs: 5. Affinity Of Drugs To Certain Organs  The concentration of A drug in certain tissues after A single dose may persist even when its plasma concentration is reduced to low. Thus the hepatic concentration of Drug mepacrine is more than 200 times that of plasma level. Distribution  Their concentration may reach a very high level on chronic administration. Iodine is similarly concentrated in the thyroid tissue.  Definition:  Drug metabolism is the process by which the body breaks down and converts medication into active chemical substances.  The process by which the body brings about changes in drug molecule is referred as drug metabolism or biotransformation. Drug Enzymes responsible for metabolism of drugs: Metabolism  a) Microsomal enzymes: Present in the smooth endoplasmic reticulum of the liver, kidney and GIT e.g. glucuronyl transferase, dehydrogenase , hydroxylase and cytochrome P450  b) Non-microsomal enzymes: Present in the cytoplasm, mitochondria of different organs. e.g. esterases, amidase, hydrolase.  Types of biotransformation  The chemical reactions involved in biotransformation are classified as phase-I and phase – II (conjugation) reactions. Drug  In phase-I reaction the drug is converted to more polar metabolite. If this metabolite is sufficiently Metabolism polar, then it will be excreted in urine.  Some metabolites may not be excreted and further metabolized by phase –II reactions.  Phase-I: Oxidation, reduction and hydrolysis.  Phase-II: Glucuronidation, sulfate conjugation, acetylation, glycine conjugation and methylation reactions.   Definition: Excretion of drugs means the transportation of unaltered or altered form of drug out of the body.  The major processes of excretion include renal excretion, hepatobiliary excretion and Drug pulmonary excretion. Excretion  The minor routes of excretion are saliva, sweat, tears, breast milk, vaginal fluid, nails and hair.   The rate of excretion influences the duration of action of drug. The drug that is excreted slowly, the concentration of drug in the body is maintained and the effects of the drug will continue for longer period.  DIFFERENT ROUTES OF DRUG EXCRETION a) Renal excretion: A major part of excretion of chemicals is metabolically unchanged or changed. The excretion of drug by the kidney involves. Drug  i) Glomerular filtration Excretion  ii) Active tubular secretion  iii) Passive tubular reabsorption  DIFFERENT ROUTES OF DRUG EXCRETION The function of glomerular filtration and active tubular secretion is to remove drug out of the body, while tubular reabsorption tends to retain the drug. Drug Excretion i) Glomerular filtration: It is a process, which depends on  (1) the concentration of drug in the plasma  (2) molecular size, shape and charge of drug  (3) glomerular filtration rate. Only the drug which is not bound with the plasma proteins can pass through glomerulus. All the drugs which have low molecular weight can pass through glomerulus e.g. digoxin, ethambutol, etc.  DIFFERENT ROUTES OF DRUG EXCRETION  ii) Active tubular secretion  The cells of the proximal convoluted tubule actively transport drugs from the plasma into the lumen of the tubule e.g. acetazolamide, benzyl penicillin, dopamine, Drug pethidine, thiazides, histamine. Excretion  iii) Tubular reabsorption  The reabsorption of drug from the lumen of the distal convoluted tubules into plasma occurs either by simple diffusion or by active transport. When the urine is acidic, the degree of ionization of basic drug increase and their reabsorption decreases. Conversely, when the urine is more alkaline, the degree of ionization of acidic drug increases and the reabsorption decreases.  DIFFERENT ROUTES OF DRUG EXCRETION  c) Gastrointestinal excretion: When a drug is administered orally, a part of the drug is not absorbed and excreted in the feces. The drugs which do not undergo enterohepatic cycle after excretion into the bile are subsequently passed with stool e.g. aluminum hydroxide Drug changes the stool into white color, ferrous sulfate changes the stool into black and rifampicin into orange red. Excretion  d) Pulmonary excretion: Drugs that are readily vaporized, such as many inhalation anesthetics and alcohols are excreted through lungs. The rate of drug excretion through lung depends on the volume of air exchange, depth of respiration, rate of pulmonary blood flow and the drug concentration gradient.  DIFFERENT ROUTES OF DRUG EXCRETION  e) Sweat: A number of drugs are excreted into the sweat either by simple diffusion or active secretion e.g. rifampicin, metalloids like arsenic and other heavy metals. Drug  f) Mammary excretion: Many drugs mostly weak basic Excretion drugs are accumulated into the milk. Therefore lactating mothers should be cautious about the intake of these drugs because they may enter into baby through breast milk and produce harmful effects in the baby e.g. ampicillin, aspirin, chlordiazepoxide, coffee, diazepam, furosemide, morphine, streptomycin etc.   PHARMACDYNAMIC PHASE PHARMACODYNAMIC  Pharmacodynamics is the study of the biochemical and physiological effects of drugs and their PHASE mechanisms of action. A. Receptor and non-receptor mechanisms B. Site of drug action C. Dose Response relationship D. Structural Activity Relationship   Most of the drugs act by interacting with a cellular component called receptor. Some drugs act through simple physical or chemical reactions without interacting with any receptor. Receptor  Receptors are protein molecules present either on the cell surface or with in the cell e.g. adrenergic receptors, and Non- cholinoceptors, insulin receptors, etc. receptor  The endogenous neurotransmitters, hormones, autacoids Mechanisms and most of the drugs produce their effects by binding with their specific receptors.  Aluminum hydroxide and magnesium trisilicate, which are used in the treatment of peptic ulcer disease act by non- receptor mechanism by neutralizing the gastric acid.   A drug, which is able to fit onto a receptor, is said to have affinity for that receptor. Efficacy is the ability of a drug to produce an effect at a receptor. An agonist has both an affinity and efficacy whereas antagonist has affinity but not efficacy or intrinsic activity. DRUG-  When a drug is able to stimulate a receptor, it is known as an agonist and therefore mimics the endogenous RECEPTOR transmitter.  When the drug blocks a receptor, it is known as INTERACTION antagonist and therefore blocks the action of the endogenous transmitter (i.e. it will prevent the natural chemical from acting on the receptor).  However, as most drug binding is reversible, there will be competition between the drug and the natural stimulus to the receptor.  A drug may act: i. Extracellularly e.g: osmotic diuretics, plasma expanders. Site of Drug Action ii. On the cell surface e.g.: digitalis, penicillin, catecholamines iii. Inside the cell e.g.: anti-cancer drugs, steroid hormones.   The exact relationship between the dose and the response depends on the biological object under observation and the drug employed. Dose  When a logarithm of dose as abscissa and responses as ordinate are constructed graphically, the “S” Response shaped or sigmoid type curve is obtained. Relationship  The lowest concentration of a drug that elicits a response is minimal dose, and the largest concentration after which further increase in concentration will not change the response is the maximal dose.  Dose Response Relationship   1. Graded dose effect: As the dose administered to a single subject or tissue increases, the pharmacological response also increases in graded fashion up to ceiling effect. - It is used for characterization of the action of drugs. The concentration that is required to produce 50 % of the maximum effect is termed as EC50 or ED50.  2. Quantal dose effect: It is all or none response, the sensitive Dose objects give response to small doses of a drug while some will be resistant and need very large doses. The quantal dose- effect curve Response is often characterized by stating the median effective dose and the Relationship median lethal dose.  Median lethal dose or LD50: This is the dose (mg/kg), which would be expected to kill one half of a population of the same species and strain.  Median effective dose or ED50: This is the dose (mg/kg), which produces a desired response in 50 per cent of test population.  Therapeutic index: It is an approximate assessment of the safety of the drug. It is the ratio of the median lethal dose and the median effective dose. Also called as therapeutic window or safety.  The activity of a drug is intimately related to its chemical structure. Knowledge about the chemical structure of a drug is useful for:  (i) Synthesis of new compounds with more specific actions and fewer adverse reactions Structural Activity  (ii) Synthesis of competitive antagonist and Relationship  (iii) Understanding the mechanism of drug action.  Slight modification of structure of the compound can change the effect completely.