Introduction To Pharmacology PDF

INTRODUCTION TO PHARMACOLOGY DEFINITION:  Pharmacology is the science that deals with the study of drugs and their interaction with the living systems.  The word Pharmacology is derived from Greek – Pharmacon means drug and logos means study.  WHAT IS DRUG ? DRUG:  Drug is a s...

INTRODUCTION TO PHARMACOLOGY DEFINITION:  Pharmacology is the science that deals with the study of drugs and their interaction with the living systems.  The word Pharmacology is derived from Greek – Pharmacon means drug and logos means study.  WHAT IS DRUG ? DRUG:  Drug is a substance used in the diagnosis, prevention or treatment of disease.  WHO defines the word drug as a substance or product that is used or intended to be used to modify or explore physiological systems or pathological status for the recipient. SUBDIVISION OF PHARMACOLOGY SOURCES OF DRUGS The sources of drugs could be natural or synthetic NATURAL SOURCES: 1.PLANTS; e.g. Atropine,Morphine,Quinine,digoxine,pilocarpine,physostigmine. 2.ANIMALS e.g. Insulin ,heparin ,gonadotrophins and antitoxic sera. 3.MINERALS; Magnesium sulphate, Aluminium hydroxide ,iron , sulphur and radio active isotopes. 4.MICROORGANISMS ; Antibacterial agents are obtained from some bacteria and fungi. we thus have pencillins, cephalosporins,tetracycline and other antibiotics. 5.HUMAN: some drugs are obtained from man ,e.g Immunoglobulin from blood,growth hormone from anterior pituitary and chorionic gonadotrophins from the urine of pregnant woman. SYNTHETIC :  Most drugs are now synthesized.e.g quinolones,omeprazole,sulfonamides,pancuronium, neostigmine.  Many drugs are obtained from cell culture ,e.g urokinase from cultured kidney cells.  some are now produced by recombinant DNA technology ,e.g human insulin, tissue plasmogen activator and  some drugs by Hybridoma technique, e.g monoclonal antibodies.  PHARMACOKINETICS  Pharmacokinetics is the study of the absorption, distribution , metabolism and excretion of the drugs, i.e. the movement of the drugs into ,within and out of the body.  Once drug is administered it is absorbed, i.e. enters the blood is distributed to different parts of the body, reaches the site of action ,is metabolized and excreted.  All these processes involve passage of the drug molecules across various barriers – like the intestinal epithelium, cell membrane, renal filtering membrane, capillary barrier.  The movement or translocation of drug from one side of biological barrier to other is called Bio-transport and the mechanism underlying the transfer of drug across biological barriers are called the Transport mechanism. The major transport mechanism are : 1. Passive Diffusion 2. Carrier Mediated transport A. Facilitated Diffusion B. Active Transport 3. Pinocytosis or Phagocytosis Passive transport or Passive Diffusion  Passive diffusion is the process by which the drug molecules pass through a biological barrier from a phase of higher concentration to the phase of lower concentration without requiring any expenditure of energy. Carrier-mediated transport  Polar compounds like sugar and amino acids and certain drugs of therapeutic interest cannot penetrate through membrane by passive diffusion but are moved by a carrier system present on the membrane surface  Carrier molecules are usually proteins which combine with a drug substrate and form a complex  After the complex crosses the membrane ; carrier dissociates from the drug and carrier returns to the original side of membrane for reuse. Facilitated diffusion :  Carrier-mediated transport from higher to lower concentration without needing energy and translocates the substrate in the direction of electrochemical gradient. e.g. GLUT 4 enhances the permeation of glucose across a muscle cell membrane Pinocytosis :  Process where a cell drink or engulfs a fluid or a drug in solution. E.g: -Insulin crosses the BBB by this process Phagocytosis:  Process were particulate matter transferred by local invagination of cell membrane Eg: -Poisoning by botulinum toxin ROUTES OF DRUG ADMINISTRATION  Drugs may be administered by various routes.the choice of the route in a given patient depends on the properties of the drug and the patients requirements.  A knowledge of advantage and disadvantage of the routes of drug administration is essential. The route can be broadly divided into:  Enteral  Parenteral  Local ENTERAL ROUTE (ORAL INGESTION )  This is the most common ,oldest and safest routes of drug administration  The large surface area of the GI ,the mixing of its content and the differences in pH at different parts of the gut help effective absorption of the drugs given orally. ADVANTAGES: 1.Safest route 2.Most convenient 3.Most economical 4.Drugs can be self-administered 5.Non-invasive route DISADVANTAGES 1. Onset of action is slower as absorption needs time. 2. Irritant and unpalatable drugs cannot be administered. 3. Irritation to the GIT may lead to vomitting. 4. Some drugs may be destroyed by gastric juices.e.g insulin. 5. Cannot be given to unconscious and uncooperative patients. 6. Some drugs may undergo extensive first pass metabolism in liver. 7. Patients may forget to take the tablet which is the practical problem. PARENTERAL ROUTE  Routes of administration other than the enteral route are known as parenteral routes. Here the drugs are directly delivered into tissue fluids or blood. ADVANTAGES :  Action is more rapid and predictable than oral administration.  These routes can be employed in unconscious or uncooperative patients.  Gastric irritant can be given parenterally and therefore irritation to the GIT can be avoided.  It can be used in patients with vomitting or those unable to swallow.  In emergencies parenteral routes are very useful.  Digestion by the gastric and intestinal juices and the first pass metabolism are avoided. DISADVANTAGES :  Asepsis must be maintained.  Injection may be painful.  More expensive less safe and incovenient.  Injury to nerve and other tissues may occur. Parenteral route include: 1.Injections 2.Inhalation 3.Transdermal route 4.Transmucosal route TOPICAL:  Drugs may be applied on the skin for local action as ointment, cream , gel ,powder, paste etc, drugs may also be applied on the mucous membrane as in the eyes ,ears , and nose as ointment ,drops and sprays.  Drugs may be administered as suppository for rectum, bougie for urethra and pessary (oval shape) and douche for vagina.e.g antifungal pessaries in vaginal candidiasis.  DRUG FORMULATION What is drug formulation?  Pharmaceutical formulation is the process of combining various chemical substances with the active drug to form a final medicinal product, which is called a drug drug formulation. Why is Formulation important?  Formulations are a very important aspect of creating medicines, since they are essential to ensuring that the active part of the drug is delivered to the correct part of the body, in the right concentration, and at the right rate (not too fast and not too slowly).  DIFFERENT FORMS OF DRUG FORMULATION Solid Formulations  Tablets – a tablet is disc-shaped  Enteric Coated Tablets – are coated with a material that does not disintegrate in the acidic medium of the stomach but in the alkaline medium of the intestine.  Sustained release preparations – release a fixed amount of drug over an extended period of time.  Capsules – can be hard or soft. Liquid and Semi-Solid Formulations Oral preparations – Oral preparations are easier to swallow and administer medicines to children and old-age patients.  Topical Preparations – The application of a drug to an area of the body for direct treatment is called topical application. It includes:  Eye drops  Ear drops  Nasal drops  Nebulisers and inhalers  Creams and ointments for skin application  Gels and lotions  Pessaries for vaginal administration of the drug Sublingual and Buccal Administration  Such drugs are administered as tablets under the tongue or between the cheek and the gum and allowed to dissolve. In this manner, the drug directly enters the bloodstream, bypassing the digestive tract and acts faster. Rectal Administration  Suppositories: are used for drugs which are administered through the rectum.  Enemas: are liquid preparations for rectal administration. Parental Drug Administration – is drug administration outside the GI tract of the patient. Drugs can be inserted anywhere with the help of injections.  Intradermal administration:  Subcutaneous injection:  Intramuscular injection:  Intravenous injection: SPECIAL DRUG DELIVERY SYSTEM:  In order to improve drug delivery ,to prolong the duration of action and improve the patient compliance ,special drug delivery system are used.some Ocusert :  Ocusert systems are thin elliptical units that contains the drug reservoir which slowly release the drug by diffusion. e.g Pilocarpine ocusert used in glaucoma is placed under the eye lid can deliver the Pilocarpine for 7 days.  Progestasert is inserted into the uterus where it delivers progesterone constantly for one year. Computerized miniature pumps:  These are Programmed to release drugs at a definite rate and continuously. e.g insulin and anticancer drugs. ABSORPTION  Absorption is defined as the passage of the drug from the site of administration into the circulation for a drug to reach its site of action, it must pass through various membranes depending on the route of administration.  Absorption occurs by one of the processes 1. Passive Diffusion 2. Carrier Mediated transport A. Facilitated Diffusion B. Active Transport 3. Pinocytosis or Phagocytosis Thus except for IV route Factor influence the rate and extent of absorption of a drug they are: 1. Disintegration and dissolution time 2. Formulation 3. Particle size 4. Lipid solubility 5. PH and ionization 6. Area and vascularity of the absorbing surface 7. Gastrointestinal motility 8. Presence of food 9. Metabolism 10. Diseases  FIRST PASS METABOLISM  First pass metabolism is the metabolism of the drug during its passage from the site of absorption to the systemic circulation. it is also called pre- systemic metabolism or first pass effect.  Drugs given orally may be metabolized in the gut wall and in the liver before reaching the systemic circulation. Examples of Drugs with Significant First Pass Effect or Low Bioavailability  Drug: Propranolol- ~26% Bioavailability because 75-85 % is metabolized by the liver before it can reach the circulation when taken orally.  Drug: Morphine-~30% Bioavailability because 70% is metabolized via 1st pass effect if taken orally. Morphine is therefore usually given via s.c. injection to bypass this mechanism.  Drug: Nitroglycerin- is typically taken sublingually (buccal cavity) where it enters the circulation and is rapidly delivered directly to the heart (without having to go through the liver first), thus avoiding the First Pass Effect. Bioavailability is the fraction of the drug that reaches the systemic circulation following administration of any route. Factors Affecting Bioavailability  Absorption.  Food Effect.  Drug metabolism/ biotransformation.  Energy dependent efflux transporters.  Physico-chemical factors.  First pass metabolism.  CYP450 isozymes. Bioeqivalence: it is the study of comparison bioavailability of different formulation of the same drug. Distribution  After a drug reaches the systemic circulation ,it gets distributed to various tissues. it should be cross several barriers before reaching the site of action.  like absorption distribution also involves the same process, i.e filtration, diffusion ,and specialized transport.  Various factors determine the rate and extent of distribution, they are lipid solubility, ionization, blood flow and binding to plasma proteins.  unionized and lipid soluble drugs are widely distributed through out the body. Plasma protein binding  On reaching the circulation, most of the drug bind to plasma protein; acidic drug mainly bind with albumin and basic drugs to acid glycoprotein.  The free or unbound fraction of the drug is the only form available for action, metabolism and excretion Blood brain barrier (BBB):  The endothelial cells of the brain capillaries have tight junctions. moreover glial cells envelope the capillaries and together these form the BBB. Only lipid soluble and unionized drugs can cross BBB. e.g. Penicillin readily penetrates BBB Placental barrier: Lipid soluble ,unionized drugs readily cross the placenta. Metabolism  Metabolism or biotransformation is the process of biochemical alteration of the drug in the body. Body treats most of the drugs as foreign substance and tries to inactivate and eliminate them by various biochemical reactions.  Theses processes convert the drugs into more polar ,water soluble compounds so that they are easily excreted through the kidneys.  Some of the drugs are largely unchanged in urine, e.g frusemide, atenolol. mainly drugs are metabolized in liver some are metabolized kidney, lungs, blood and skin. The chemical reactions of biotrasformation can take place in two phases 1. Phase I (Non-synthetic reactions): Convert the drug to more polar metabolite by oxidation, reduction, or hydrolysis. if the metabolites are not water soluble it undergoes phase II reactions. 2. Phase II (Synthetic reaction): In this reactions water soluble substance present in the body like glucuronic acid, sulfuric acid or an aminoacid combine with the drug to form a highly polar compounds it excreted by the kidneys. large molecules are excreted through the bile. What is Enzyme Induction?  A process in which a molecule (e.g. a drug) induces (i.e. initiates or enhances) the expression of an enzyme.  An enzyme inducer is a type of drug which binds to an enzyme and increases its metabolic activity. Importance of enzyme induction  Essential to understand various reactions that occur inside the body  Important to analyse drug reaction  Study toxicity Enzyme inhibition  An enzyme inhibitor is a molecule that binds to an enzyme and decreases its activity.. How enzyme inhibitors affect enzyme activity?  Enzyme inhibitors are substances which alter the catalytic action of the enzyme and consequently slow down, or in some cases, stop catalysis. Excretion  The major organs of excretion are the kidneys, intestine, biliary system and the lungs. Drugs are small amounts are excreted in saliva, sweat ,and milk.  Kidney is the most important organ of drug excretion. highly lipid soluble drugs are reabsorbed in in the renal tubules ,so their excretion is slow.  Unabsorbed portion of the orally administered drugs are eliminated through the feces. large water soluble conjugates are excreted in the bile.  The lungs are the main route of elimination for gases and liquids, e.g. GA , Alcohol.  Enterohepatic circulation refers to the circulation of biliary acids, bilirubin, drugs or other substances from the liver to the bile, followed by entry into the small intestine, absorption by the enterocyte and transport back to the liver.  Plasma half-life (t1/2) is the time taken for the plasma concentration of a drug to be reduced to half its value.  Plasma clearance (CL) is the volume of biologic fluid (blood, plasma) that is completely freed (cleared) of drug by all routes of elimination. Units for clearance are flow (e.g., milliliters/minute)  Steady-state concentration (Css) is defined as the time during which the concentration remains stable or consistent when the drug is given repeatedly or continuously (IV infusion).  Accumulation represents the relationship between the dosing interval and the rate of elimination for the drug.  Maintenance dose is the maintenance rate [mg/h] of drug administration equal to the rate of elimination at steady state.  Loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose. A loading dose is most useful for drugs that are eliminated from the body relatively slowly, i.e. have a long systemic half-life.  Dosing interval of about a half-life is appropriate for drugs with half-lives of approximately 8-24 hours allowing dosing once, twice or three times daily