General Pharmacology Lecture 1-3 PDF

General Pharmacology Definitions: Drug: A drug can be defined as a chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Medicine: A medicine is a chemical preparation, which usu...

General Pharmacology Definitions: Drug: A drug can be defined as a chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Medicine: A medicine is a chemical preparation, which usually but not necessarily contains one or more drugs, administered with the intention of producing a therapeutic effect. Pharmacology is the study of medicines used for treatment for diseases/disorders of the human body OR Pharmacology can be defined as the study of the effects of drugs on the function of living systems. Pharmacologists work to identify drug targets in order to learn how drugs work. Pharmacologists also study the ways in which drugs are modified within organisms. In most of the pharmacologic specialties, drugs are also used today as tools to gain insight into both normal and abnormal function. The development of pharmacology. Pharmacology today with its various subdivisions  Pharmacokinetics & Pharmacodynamics  The goal of therapeutics is to achieve a desired beneficial effect with minimal adverse effects.  Adverse effects: is an unwanted or harmful events experienced following the administration of a drug.  A rational approach to this objective combines the principles of pharmacokinetics with pharmacodynamics to clarify the dose-effect relationship.  Pharmacokinetics examines the movement of a drug over time through the body.  Pharmacodynamics examines the effect of a drug over time on the body.  Drugs classification Small molecule Biological products 1. Low molecular weight. large molecular weight (e.g. protein). 2. Made by organic and Made from/with live cells. chemical synthesis. 3. Known structure. Structure may not be completely 4. Homogenous. defined. 5. Cheap. Heterogenous. Expensive. Aspirin Interferon-alpha Routes of Drug Administration 1. Enteral: Administration of a drug by mouth, is the simplest and most common means of administering drugs. When the drug is given in the mouth, it may be swallowed, allowing oral delivery, or it may be placed under the tongue, facilitating direct absorption into the bloodstream. Oral: Giving a drug by mouth provides many advantages Drugs are easily self-administered and limit the number of systemic infections that could complicate treatment. toxicities or overdose by the oral route may be overcome with antidotes such as activated charcoal. On the other hand, the drug is exposed to harsh gastrointestinal (GI) environments that may limit its absorption. Some drugs are absorbed from the stomach; however, the duodenum is a major site of entry to the systemic circulation because of its larger absorptive surface. Most drugs absorbed from the GI tract enter the portal circulation and encounter the liver before they are distributed into the general circulation. These drugs undergo first-pass metabolism in the liver, where they may be extensively metabolized before entering the systemic circulation Sublingual: Placement of the drug under the tongue. It allows the drug to diffuse into the capillary network to enter the systemic circulation directly. Merits : No first pass metabolism. Example., Nitroglycerine and Nifedipine Rectal: Administering a drug through anus. Relatively less first pass metabolism, but inconsistent drug absorption Examples., Diazepam, Acetaminophen, Antiemetics. 2. Parenteral Transdermal delivery system Administering a drug through skin patches. Merits : Smooth plasma concentration. Less inter-individual variation. No first pass metabolism. Convenient – better compliance. E.g., Nitroglycerin, Scopolamine, Ortho Evra, Timolol Respiratory Administering a drug by inhalation. Merits : Alveolar epithelium offers good surface area for lipid soluble drugs Rapid action Dose required is less Eg : Volatile anesthetics, Albuterol, Beclomethasone Injections: Intravenous Intramuscular Intradermal Subcutaneous Intraarticular Intrathecal Intravenous Administering a drug directly into the vein Merits : Immediate action Useful in emergencies Avoids gastric juices / liver metabolism Can be used in unconscious patients Irritating drugs can be given Demerits Thrombopheblitis Expertise required Intramuscular Administering a drug in the muscles Merits : Absorption is quick Demerits Volume injected is max.10 ml Irritant drugs cannot be given Intradermal Administering a drug into the layers of the skin. Eg:BCG, allergy testing. Intraarticular Administering a drug between the joints of the bones Eg:Steroids in Rheumatoid arthritis Subcutaneous Administering a drug below the skin Self administration possible - Insulin Pellet implantation – drug released over weeks. Eg : testosterone. Intrathecal / Epidural Administering a drug directly into the cerebrospinal fluid Strict aseptic precautions Eg:Spinal anesthesia ,, amphotericin B,used in treating cryptococcal meningitis Topical Applying drug to the skin or instilling drops in eye for local effects. Pharmacokinetics Pharmacokinetics is the quantitative study of drug movement in, through and out of the body. It includes, Absorption Distribution Metabolism and Excretion. The action of the body on the drug is called as pharmacokinetics OR Pharmacokinetic is what the body does to the drug. Absorption: Absorption is the transfer of a drug from its site of administration to the bloodstream. The rate and efficiency of absorption depend on the route of administration. For IV delivery, absorption is complete; that is, the total dose of drug reaches the systemic circulation. Drug delivery by other routes may result in only partial absorption and, thus, lower bioavailability. For example, the oral route requires that a drug dissolve in the GI fluid and then penetrate the epithelial cells of the intestinal mucosa, yet disease states or the presence of food may affect this process. Factors affecting oral drug Absorption: Gastric emptying time Particle Size pH Surface area Food Effect of pH on absorption of a drug : HA ------ H+ + A- --------- Acid BH+ ------ H+ + B ---------- Base Non-ionized forms like HA and B are lipid soluble and cross the cell membrane. Ionized forms like A- and BH+ are water soluble and do not cross the membrane. Effect of pH on ionization of a drug Weak acids become highly ionized as pH increases, Weak bases become highly ionized as pH decreases. Acidic drugs are best absorbed in Acidic medium Basic drugs are best absorbed in Basic medium Bioavailability : Bioavailability is the fraction of administered drug that reaches the systemic circulation. Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form. For example, if 100 mg of a drug are administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or seventy percent. Factors that influencing bioavailability are First-pass hepatic metabolism: Solubility of the drug Chemical instability Nature of the drug formulation: Amount of drug absorbed or reaching plasma = F x Dose For example the oral bioavailability (F) of digoxin (lanoxin) is 0.7 For digoxin 250 ug given orally, the effective or absorbed dose = 0.7 x 250 ug = 175 ug Morphine has an oral bioavailability of about 0.2, so to achieve similar plasma concentrations as intravenous, oral dose rates need to be 5 times intravenous dose (intravenous dose / 0.2). Bioequivalence: Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations. Cmax: The maximum plasma concentration attained by a drug- administration. Tmax: The time at which maximum concentration is reached. Drug Distribution Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. The delivery of a drug from the plasma to the interstitium primarily depends on Blood flow, Capillary permeability, The degree of binding of the drug to plasma and tissue proteins, The relative hydrophobicity of the drug. Volume of distribution : It is defined as the volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration. The volume of distribution (Vd) of a drug is given by: D D Vd = -------- C0 = -------- C0 Vd D = Total amount of the drug in the body C0 = Drug concentration in plasma at zero time Plasma Protein Binding : Drug molecules may bind to plasma proteins (usually albumin). Bound drugs are pharmacologically inactive; only the free, unbound drug can act on target sites in the tissues, elicit a biologic response, and be available to the processes of elimination. Metabolism It is also called as biotransformation.(chemical alteration of the drug in the body) The process of metabolism transforms lipophilic drugs into more polar readily excretable products. The liver is the major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues, such as the kidney and the intestines. Metabolism (Biotransformation) can be of two types: Phase I reactions – oxidation / reduction reactions. Phase II reactions – conjugation reactions. Biotransformation can lead to ---Inactivation Active metabolite from an inactive drug – Prodrug e.g. Levodopa  dopamine Enalapril  enalaprilat Active metabolite from an active drug e.g. Codeine  morphine Imipramine  desipramine Phase I reactions : Oxidation reactions – carried by liver cytochrome P 450 system. e.g. : barbiturates, acetaminophen, benzodiazepines Reduction reactions – carried by liver cytochrome P 450 system. e.g. : chloramphenicol, methadone Hydrolysis – procaine, oxytocin Phase II reactions : It is the conjugation of a drug to form a polar (ionized) drug which can be easily excreted. Glucuronide conjugation – aspirin, OCP (Oral Contraceptives pills), morphine Acetylation – sulfonamides, INH (Isoniazid) Methylation – adrenaline, histamine Inhibition of drug Metabolism Eg : Ciprofloxacin, Cimetidine, Ketoconazole, Omeprazole, SSRI Grapefruit juice, Acute alcohol Enzyme Induction : Eg : Phenobarbitone, Phenytoin Carbamazepine, Rifampin, Chronic alcohol Drug interactions Drug-drug interaction, drug-food interaction, drug-disease interaction Case of contradiction: warfarin contradicts with Vit K because it decreases the anticoagulant effect of warfarin First pass (Presystemic) Metabolism This refers to metabolism of a drug during passage from the site of absorption into the systemic circulation. All orally administered drugs are exposed to drug metabolizing enzymes in the intestinal wall and liver (where they first reach through the portal vein). Presystemic metabolism of limited magnitude can also occur in the skin (transdermally administered drug) and in lungs (for drug reaching venous blood through any circulation. Excretion Removal of a drug from the body occurs via a number of routes, the most important being through the kidney into the urine. Other routes include the bile, intestine, lung, or milk in nursing mothers. Kidney : excretes all water soluble drugs. Lipid soluble drugs are reabsorbed. Changes in urinary pH affects the excretion of drugs – acidic drugs are excreted in alkaline urine basic drugs are excreted in acidic urine Faeces : purgatives – liquid paraffin Exhaled air : volatile anesthetics, alcohol Saliva and sweat : Rifampin, iodides Milk : Metronidazole, Phenytoin Linear / First Order Kinetics : The rate of elimination of the drugs is proportional to the plasma concentration. Constant fraction of the drug is eliminated in unit time. 80mg 40mg 20mg 10mg 5mg Most of the drugs follow first order kinetics. Saturation / Zero Order Kinetics: The rate of the elimination of drug is constant irrespective of the plasma concentration. Constant amount of drug is eliminated in unit time. Eg : Phenytoin, Alcohol, Theophylline. 80mg 70mg  60mg 50mg 40mg Half Life : Plasma half life: It is the time required for the drug to reduce to half its original plasma value. Half life is a concept which is applied only to drugs following first order kinetics. The half-life of a drug is also called elimination half‑life. The half‑life of a drug is given by: 0.693 t½ = -------------- Ke Ke = Elimination constant Elimination constant is calculated by Ke = CL / Vd The half-life can also be calculated as follows: Vd t½ = 0.693 ---------- CL Pharmacodynamics The study of the action of the drug on the body is called Pharmacodynamics. OR Pharmacodynamics is what the drug does to the body. According to Paul Ehrlich ‘'A drug will not work unless it is bound’ These critical binding sites are often referred to as 'drug targets' Most drug targets are protein molecules. Four main kinds of regulatory protein are commonly involved as primary drug targets, namely:  Receptors  Enzymes (Dihydrofolate reductase inhibitors)  Carrier molecules (transporters) (Diuretics)  Ion channels (Ca2+ Channel inhibitors) Several drugs do not target proteins, but work physically or chemically to produce their actions such as osmotic diuretics and antacid. Receptor A protein macromolecular of the cell to which a drug bind and produce its effect. Functions of the receptors : Propagation of signal Amplification of the signal. Adapt to short and long term changes. Definitions: Affinity: It is the ability of the drug to bind to the receptors. The drug attaches onto binding site of the receptor via different ways: covalent bond, dipole-dipole interaction, hydrogen bond, Van der Waal interaction, hydrophobic interaction Intrinsic activity: It is the ability of a drug to activate the receptor and produce the response. Agonist : A drug which binds to the receptors and activate the receptor. It has both affinity and intrinsic activity. Eg : morphine, epinephrine Antagonist : A drug which binds to the receptor but it will not activate the receptor. It has affinity but no intrinsic activity Eg : atenolol, metoprolol, prazosin Partial Agonist : It activates the receptor and produce sub maximal response. It antagonizes the action of pure agonist. Eg : Pentazocine Partial agonist act as competitive antagonist in presence of an agonist Inverse Agonist : It activates the receptors to produce an effect opposite to that of agonist. Eg : Beta carbolines produce the effects opposite to diazepam Receptor Specialized target macromolecules—present on the cell surface or intracellularly. Receptor Families Channel linked (Ionotropic) G protein linked (Metabotropic) Enzyme linked Intracellular Receptor Channel linked (Ionotropic) : The cell surface has a selective ion channel like Na, K , Ca , or Cl. Onset of action through these types of receptors is fastest – milliseconds. Nicotinic cholinergic receptors, GABA-A and NMDA receptors. G Protein linked (Metabotropic) These are cell membrane receptors which are linked to effector mechanisms through G-proteins. Effector mechanisms includes adenylyl cyclase, phospholipase C, channel regulation Onset of response in seconds. Eg : adrenergic receptors, histamine receptors Enzyme linked: These cell membrane receptors are enzymatic in nature Insulin, atrial natriuretic peptide (ANP) acts through this receptors. Onset of response in minutes. Intracellular receptor :`/Nuclear receptors These includes Steroids, Thyroxine and Vit–D It takes days to produce its actions Graded dose response curve Graded Dose Response Curve (DRC) : Potency: It refers to the amount of drug needed to produce the response. The position of the curve on the dose axis is an index of drug potency. The dose required to produce half the maximum response is an index used to determine the potency. Efficacy : It refers to the maximum response of the drug. The upper limit of the drug response curve is an index of efficacy of the drug. Steepness of the curve indicates the dose range – steep slope indicates that a small increase in the dose markedly increase the response. Slope of the curve is related to the mechanism of action of a drug. Drug X has greater biologic activity per dosing equivalent and is thus more potent than drug Y or Z. Drugs X and Z have equal efficacy, indicated by their maximal attainable response (ceiling effect). Drug Y is more potent than drug Z, but its maximal efficacy is lower. Therapeutic index -Is the ratio of median toxic dose (TD 50) and the median effective dose (ED 50). -TI = TD50/ED50 -It indicates the safety of the drug. Factors affecting drug Action: Age Sex Race/Genetics Psychological/Pathological factors Other drugs Tolerance: It is the requirement of higher dose than usual dose to produce the same effect Tolerance is of two types : a) Natural: Individual is inherently less sensitive to the drug Eg : Certain race are tolerant to mydriatics b) Acquired : repeated use of drug in an individual who was responsive initially results in less response later on. Tachyphylaxis: When a drug is repeated in very quick succession, it results in marked reduction in response. Usually seen with indirectly acting drugs like ephedrine