General Pharmacology PDF

General Pharmacology By; Abebe E. (B.pharm, Msc) 1  BRIEF HISTORY OF PHARMACOLOGY  Medicaments have, since time immemorial, been used for treating diseases in humans and animals.  Belief in the curative powers of plants and certain substances rested excl...

General Pharmacology By; Abebe E. (B.pharm, Msc) 1  BRIEF HISTORY OF PHARMACOLOGY  Medicaments have, since time immemorial, been used for treating diseases in humans and animals.  Belief in the curative powers of plants and certain substances rested exclusively upon traditional knowledge (empirical information not subjected to critical examination)  Claudius Galen (AD 129–200): First attempted to consider the theoretical background of pharmacology. “The empiricists say that all is found by experience. We, however, maintain that it is found in part by experience, in part by theory. Neither experience nor theory alone is apt to discover all.” 2  Theophrastus von Hohenheim (1493–1541), aka Paracelsus: Rejected the irrational concoctions and mixtures of medieval medicine.  Johann Jakob Wepfer (1620–1695): Was the first to verify by animal experimentation assertions about pharmacological or toxicological actions “If you want to explain any poison properly, what then is not a poison? All things are poison, nothing is without poison; the dose alone causes a thing not to be poison.” “I pondered at length. Finally I resolved to clarify the matter by experiments.” 3  Rudolf Buchheim (1820–1879), Estonia: Founded the first institute of pharmacology  T. Frazer (1840–1920), Scotland: Structure–activity relationships  J. Langley (1852–1925), England: Drug receptors  P. Ehrlich (1854–1915), Germany: Selective toxicity  Alexander J. Clarke (1885–1941), England: first formalized receptor theory by applying the Law of Mass Action to drug–receptor interactions. 4  General Pharmacology  Pharmacology came from the Greek words “Pharmacon” meaning drug and “logos” meaning discourse in.  Pharmacology is the science that deals with properties and effects of drugs in relation to their interaction with living systems.  Drugs are chemical substances that interact with human and/or animal body to exert their effects, and intended for prophylactic, diagnostic and treatment purposes. 5  It also includes history,sourse,physicochemical properties,dosage forms,methods of administration, absorbtion, distribution, mechanism of action, biotransformation, excretion,clinical uses and adverse effects of drugs.  Pharmacodynamics: - is the study of the biological and therapeutic effects of drugs.i.e ”what the drug does to the body”. Pharmacokinetics: - is the study of the absorbtion, distribution, metabolism and excretion (ADME) of drugs.i.e “what the body does to the drug”. Pharmacotherapeutics: deals with the proper selection & use of drugs for the prevention and treatment of disease. Toxicology: is a science of poisons. Many drugs in large doses can act as poison. Poisons are substances that cause harmful, dangerous or fatal sympthoms in living organisms. SOURCES OF DRUGS 1. Minerals: Liquid parafine, Magnesium sulphate, Magnesium trisilcate, etc. 2. Animals: Insuline, thyroid extract, heparine, antitoxine sera, etc. 3. Plants: Morphine, digoxine, atropine, castor oil etc. 4. Synthetic sources: Asprine, sulphonamides, paracetamol etc. 5. Micro organisms: Penicilline, streptomycine etc. 6. Genetic engineering: Human insuline, human growth hormone etc. DRUG NOMENCLATURE A drug generally has three categories of names: 1. Chemical name: - describes the substance chemically. E.g. 1-(Isopropyl amino)-3-(1-naphthyloxy) propane-2-ol. This is cumbersome and not suitable for use in prescribing. 2. Non-proprietary (generic) name: - It is the name accepted by a competent scientific body.e.g Mebendazole. 3. Proprietary (Brand) name:-It is the name assigned by the manufacture(s) and its property or trade mark.One drug may have a multiple proprietary names.  Pharmacokinetics  Pharmacokinetics deals with absorption, distribution, metabolism and excretion of drugs.  To produce its characteristic effects, a drug must be present in appropriate concentration at its site of action.  Concentration at the site of action depends on absorption, distribution, binding or localization in tissues, biotransformation, and excretion.  All the pharmacokinetic processes involve passage of drug through membranes. 10 THE MOVEMENT OF DRUG MOLECULES ACROSS CELL BARRIERS Cell membranes: barriers between aqueous compartments in the body Gastrointestinal mucosa or renal tubule: a layer of cells tightly connected to each other  Molecules must traverse at least two cell membranes to pass from one side to the other  Vascular endothelium: more complicated  Gaps between endothelial cells are packed with a loose matrix of proteins that act as filters, retaining large molecules and letting smaller ones through. 11  Contd….  Some organs (e.g. CNS and the placenta), have tight junctions between the cells  Prevent potentially harmful molecules from leaking from the blood into these organs  Have major pharmacokinetic consequences for drug distribution  Other organs (e.g. the liver and spleen) have endothelium which is discontinuous, allowing free passage between cells.  Fenestrated endothelium occurs in endocrine glands, facilitating transfer of hormones or other molecules through pores in the endothelium 12  There are four main ways by which small molecules cross cell membranes:  diffusing directly through the lipid  diffusing through aqueous pores  transmembrane carrier proteins that bind a molecule on one side of the membrane then changes conformation and releases it on the other  by endocytosis 13  Passive diffusion The major mechanism for absorption of drugs. The driving force for this process is the concentration gradient or electrochemical gradient Fick’s first law of diffusion: drug molecules diffuse from a region of higher concentration to one of lower concentration until equilibrium is attained 14 Influence of pH on passive diffusion: The pH partition hypothesis states that the process of absorption is governed by:  The dissociation constant (pKa) of the drug  The lipid solubility of the unionized drug  The pH of the absorption site Most drugs are either weak acids or weak bases that are present, as both nonionized and ionized species. The nonionized molecules are usually more lipid soluble & diffuse more easily than the ionized species The transmembrane distribution of a weak electrolyte usually is determined by its pKa and the pH gradient across the membrane. 15  For weak acids HA H+ + A  ,  For weak bases BH+ H+ + B,  Very weak acids (pKa  8) are essentially unionized at all pH values and therefore their absorption is rapid and independent of GI pH.  Acids in the pKa range 2.5 to 7.5 are better absorbed from acidic conditions of stomach (where pH  pKa) where they largely exist in unionized form.  Stronger acids with pKa  2.5 are ionized in the entire pH range of GIT and remain poorly absorbed. 16  Very weak bases (pKa  5) are essentially unionized at all pH values and therefore have a rapid absorption which is independent of pH.  Bases in the pKa range of 5 to 11 are better absorbed from the relatively alkaline conditions of the intestine where they largely exist in unionized form.  Stronger bases with pKa  11 are ionized in the entire pH range of the GIT and therefore are poorly absorbed. 17 18  Carrier Mediated Transport Involves binding of the drug to specific receptors on the membrane for translocation into the cytoplasm Characteristics of carrier mediated transport  Selectivity  Competitive inhibition by chemical congeners  Requires energy  Saturability  Movement against electrochemical gradient Active transport: when movement is against concentration gradient Facilitated diffusion: movement of drugs is along concentration gradient but in a much faster rate than simple diffusion. 19 Filtration or Pore Transport Is passage through the water filled pores in membranes It is accelerated by the hydrodynamic flow of water occurring under hydrostatic or osmotic pressure gradient Drug should be water soluble and of smaller molecular size than the diameter of the pores. 20 Drug Absorption 21 Drug Absorption: Describes the rate at which a drug leaves its site of administration and the extent to which this occurs. Bioavaillability is a term used to indicate the extent to which a drug reaches its site of action or a biological fluid from which the drug has access to its site of action. Absorption takes place through one or combination of the process described earlier 22 Factors That Modify Absorption Drug solubility at the site of absorption Dosage form Local condition at the site of action Drug concentration at the site of absorption Circulation to the site of absorption Area of the absorbing surface The route of administration 23  The main mechanism of most drug absorption in GI tract is: A. Active transport (carrier-mediated diffusion) B. Filtration (aqueous diffusion) C. Endocytosis and exocytosis D. Passive diffusion (lipid diffusion) What kind of substances can’t permeate membranes by passive diffusion? A. Lipid-soluble B. Non-ionized substances C. Hydrophobic substances D. Hydrophilic substances 24 DRUG DISTRIBUTION 25  Drug distribution is the process by which absorbed drug or drug directly introduced into the circulation is carried to various interstitial and cellular fluids.  Possible Modes of Drug Distribution:  Following its uptake into the body, the drug is distributed in the blood (1)  and through it, the drug may be restricted to the extracellular space (plasma volume plus interstitial space) (2)  or it may also extend into the intracellular space (3).  certain drugs may bind strongly to tissue structures (4). 26  Apparent volume of distribution: The concentration (c) of a solution corresponds to the amount (D) of substance dissolved in a volume (V); thus, c = D/V If the dose of drug (D) and its plasma concentration (c) are known, a volume of distribution (V) can be calculated from However, this represents an apparent (notional) volume of distribution (Vapp), because an even distribution in the body is assumed in its calculation. 27  Homogeneous distribution will not occur if drugs are bound to membranes of cell or intracellular organelles; or are stored within organelles. In these cases, plasma concentration, cp, becomes small and V can exceed the actual size of the available fluid volume Clinical prediction: – If Vd = 2L, you can assume drug is distributed in plasma only – If Vd = 18L, you can assume drug is distributed in plasma and tissues – If Vd > 46L, the drug is likely stored in a depot because the body only contains 40- 46L of fluid 28  Tissue Distribution is determined by the partitioning of drug between blood and the specific tissue, which in turn depends on  Lipid solubility of drugs  pH gradient between plasma and the tissue (ion trapping)  The relative binding of drug to plasma proteins and tissue macromolecules Some tissues act as storage sites by accumulating the drug and releasing it slowly over a period of time 29  WHAT IS THE EFFECT OF ION TRAPPING ON DRUG DISTRIBUTION? Compartment Compartment with Low pH with High pH Unionized Unionized Weak Acid Weak Acid Higher total concentration of weak acid Ionized Ionized Weak Acid Weak Acid 30  Factors Affecting Distribution of Drugs Physico-chemical properties of drugs  Lipid solubility of the drug  pKa of the drug  Degree of plasma protein binding (Albumin-vs- α-1 acid gp) Physiological factors  Rate of blood flow  Tissue uptake Presence of barriers  BBB  Placental barrier  Testicular barrier 31  Redistribution Termination of drug effect usually is by biotransformation and excretion, but it may also result from redistribution of the drug from its site of action into other tissues or sites. E.g. Redistribution of thiopental after an intravenous bolus administration. 32 What do you think is the clinical significance of drug distribution? DRUG BIOTRANSFORMATION (METABOLISM) 34  Drug biotransformation is a process by which drugs are chemically changed in the body to facilitate excretion of drugs by rendering them more polar or by conjugating them with highly polar molecules.  Every tissue has some ability to metabolize drugs (i.e. GI tract, lungs, skin, kidneys); however, the liver is the principal organ for drug metabolism Biotransformation may lead to one of the following:  Inactive or less active metabolite  Metabolite with same activity as the parent drug  More active compounds (prodrugs are employed to improve bioavailability (e.g. enalapril), mask unpleasant odor/taste, alter drug solubility and/or provide site specific delivery)  Toxic compounds (e.g. acetaminophen overdose) 35  Pattern of Biotransformation Biotransformation reactions are classified as phase I and phase II reactions Phase I (functionalization or non-synthetic) reactions  Introduce or expose a functional group on the parent drug.  Generally result in the loss of pharmacological activity, although there are examples of retention, enhancement or alteration of activity.  If not excreted rapidly, the products of phase I biotransformation undergo phase II conjugation reaction.  Prominent reactions in this category include oxidation, reduction and hydrolysis 36 Phase II (conjugation or synthetic) reactions  Lead to the formation of a covalent linkage between a functional group on the parent compound with endogenous substrates (glucuronic acid, sulfate, amino acids, glutathione or acetate).  Form highly polar conjugates which are generally inactive and are rapidly excreted in the urine or feces  Is a saturable process  Higher molecular weight conjugated metabolites are mostly excreted in the bile 37 The two phases of drug metabolism 38 39  Drug Metabolizing Systems Biotransformations are enzymatic in nature The cytochrome P450 enzyme system is the major in terms of catalytic versatility and the number of drugs it metabolizes to inactive or active metabolites. CYP450 is found highly concentrated in liver endoplasmic reticulum (microsomes) 40  Extrahepatic microsomal enzymes (oxidation, conjugation) Hepatic microsomal enzymes (oxidation, conjugation) 41 42 NADP+ Drug CYP Fe+3 CYP e - R-Ase Drug PC DrugOH NADPH CO CYP Fe+3 C CYP-Fe+2 O CYP Fe+2 Drug OH Drug h Drug e- O2 CYP Fe+2 H2O O2 Drug 2H+ Electron flow in microsomal drug oxidizing system 43  Enzyme Induction  Exposure to certain drugs and environmental pollutants is associated with an increased synthesis of CYP450 and hence increased rate of biotransformation.  Induction brings about decreased bioavailability of parent drug and increased concentration of metabolite which depending on the pharmacological activity can result in either decreased activity or toxicity.  Induction of metabolism of ethinylestradiol by rifampicin and phenobarbitone and the associated loss in contraceptive potency of ethinylestradiol. 44 45  Enzyme Inhibition  Competition between two or more drugs for the active site of the same metabolizing enzyme may lead to a decrease in the metabolism of one of these agents, depending on the relative concentration of each substrate and their affinities for the enzyme.  Some drugs bind tightly to the Cytochrome P450 heme iron and reduce the metabolizing activity of the enzymes.  It results in elevated levels of the parent drug and hence prolonged pharmacological effect and an increased incidence of drug-induced toxicity. 46  Factors Affecting Drug Biotransformation  Genetic polymorphism  Disease conditions especially of the major drug metabolizing sites.  Age  Predisposing factors to enzyme induction or inhibition. 47  Clinical Significance: – First-pass (PRESYSTEMIC) metabolism – Altered pharmacological action (Asprin vs salicylic acid) – Toxic metabolites (paracetamol, safe but not too safe when…!) – Use of ethanol in methanol and ethylene glycol Poisoning (the better of two evils!) – Terfenadine vs fexofenadine (offsetting the loss!) – Alcoholism: (Why are Orientals less into it?) – CYP 2D6, beta blockers and…in Ethiopians: (Why we, in Ethiopia, need more clinical pharmacists/clinical researchers!) – CYP 2C19 (Why do Asian physicians prescribe lower doses of Diazepam than those of the West?) – INH toxicity: fast vs slow metabolisers (a double edged sword!) 48 Acetominophen Metabolism ~60% ~35% 49 Drug Excretion 50  Drug excretion is the elimination (passage out) of a systemically absorbed drug from the body in the form of metabolites or unchanged drug.  The kidneys are the main organ of excretion of drugs and their metabolites.  Other routes of drug elimination:  lungs: for volatile substances  Sweat: for volatile oils  Bile and colon (for conjugated large molecular weight drug or metabolite)  Saliva  tears 51  Renal Excretion (water soluble substances)  The amount of drug or its metabolites ultimately present in urine is the cumulative effect of glomerular filtration, tubular reabsorption and tubular secretion.  Glomerular filtration: depends on  Plasma protein binding: for a drug to be filtered through the glomerulas, it should not bind to plasma proteins.  Rate of blood flow  Passive tubular reabsorption  Drugs should be in their non-ionized form to undergo passive reabsorption. Hence, polar drugs are more readily excreted through the kidneys.  Active tubular secretion  An active process which can be inhibited by drugs which use the same transport mechanism. E.g. probenecid prolongs the t½ of penicillins. 52  Biliary Excretion  The liver secretes about 1 L of bile daily  Drugs with mol wt lower than those of most protein reach the hepatic extracellular fluid from where they are transported into hepatocytes by carrier-mediated systems and passive diffusion (more lipophilic drugs).  Drugs Pass into bile through selective systems with only few drugs crossing by diffusion. 53  Most drugs secreted by the liver into the bile are not reabsorbed  Once in the intestine, most are usually passively reabsorbed that the drugs will reenter the blood that perfuse the intestine and again be carried to the liver (enterohepatic recirculation)  Conjugation (esp. glucuronidation) generally enhances biliary excretion since it both  Introduces a strong polar (i.e., anionic) center  Increases its molecular weight 54  Conjugated drugs are hydrolyzed by gut enzymes such as -glucuronidase for reabsorption.  Liver disease or injury usually impairs bile secretion and hepatic drug metabolism  Antibiotics may alter the intestinal flora which diminish the presence of sulfatase and glucuronidase-containing bacteria decreasing enterohepatic recirculation. 55  Pulmonary excretion  Any volatile material, irrespective of its route of administration, has the potential for pulmonary excretion  The rate of loss of gases depends on the rate of respiration and pulmonary blood flow, degree of solubility of the gas in blood 56  Sweat and Saliva  Excretion depends on the diffusion of un-ionized lipid- soluble form across the epithelial cells of the glands.  Quantity excreted is determined by the pKa of the drug and the pH of the secretions formed in the glands  Excretion into sweat may be responsible for the skin reactions caused by some therapeutic agents  Substances excreted into saliva are usually swallowed  Excretion of drugs into saliva accounts for the drug taste of certain compounds given by IV. 57  Excretion in Milk  Concentration of drugs in milk depends on many factors, including  amount of drug in the maternal blood  lipid solubility of the drug  Drug’s degree of ionization  The extent of its active excretion  Milk is more acidic (pH 6.5) than plasma, hence basic drugs are more concentrated in this fluid. 58  What do you think is the clinical significance of drug excretion? Routes of Drug Administration 60  Drugs are administered for either their action in the locality of their administration or for general systemic purpose.  Many factors such as the nature of the target tissue, physico-chemical properties of the drug, the disease state etc.. dictate the route the drug should be administered 61 1. Systemic routes of administration 62  1.1. Oral ingestion  Refers to the administration of drugs though the mouth, mostly, for systemic effect. It is the most common method of drug administration  Advantages  Safe, more convenient and economical  Often painless, need no assistance for administration  Both solid dosage forms and liquid dosage forms can be administered 63  Disadvantages Action slower and thus not suitable for emergencies Unpalatable drugs difficult to administer Not suitable for uncooperative /unconscious/ vomiting patients Certain drugs are not absorbed sufficiently Some drugs are destroyed by digestive juice or liver enzymes (first pass metabolism) 64  1.2. Parenteral route  Par = beyond and enteral = intestine  Drug directly introduced into tissue fluids or blood without having to cross the intestinal mucosa.  Routes include  Intravenous  Intramuscular Major parenteral routes  subcutaneous  Other parenteral routes include  Intraarterial  Intrathecal  Intraarticular 65  Advantages  Action faster (hence valuable in emergencies)  Employed in unconscious/uncooperative/vomiting patients  No interference of food or digestive juice and first pass effect is bypassed to a certain extent.  Disadvantages  Preparation is costlier  Need of assistance by others during administration 66  Intravenous administration  Drug injected as a bolus or infused slowly over hours in one of the superficial veins, the drug directly reaches into the blood stream and effects are produced immediately  Only aqueous solutions can be injected  Dose required is smallest as bioavailability is 100%  Even large volumes can be infused through this route  It is the most risky route 67  Intramuscular administration  Drug is injected in one of the large skeletal muscles: deltoid, triceps, gluteus maximus, rectus femoris etc.  Muscle is less richly supplied with sensory nerves and (mild irritants can be applied) and is more vascular (absorption is faster) 68  Subcutaneous administration  The drug is deposited in the loose subcutaneous tissue  Is richly supplied by nerves (unsuitable for irritant drug administration) but is less vascularized (slow absorption)  Self injection is simple  Oily solution or aqueous suspensions can be injected for prolonged action 69  1.3. Sublingual administration  Tablets are placed under the tongue or crushed in the mouth and spread over the buccal mucosa  Non polar and hence lipid soluble drugs are rapidly absorbed  Drug is protected from first pass metabolism as there is direct drainage into the superior vena cava. 70  1.4. Rectal administration  Certain irritant and unpleasant drugs can be put into the rectum as suppositories or enema for systemic effect.  This is often useful when oral ingestion is precluded by vomiting or when the patient is unconscious.  It is rather inconvenient and embarrassing  Absorption is slower, irregular and often unpredictable 71  1.5. Pulmonary administration  Suitable for gaseous and volatile drugs  Rapid absorption due to large surface area  Solutions can be atomized and the fine droplets in air (aerosol) inhaled  Advantage: Rapid absorption, avoidance of hepatic first pass loss, local application to the pulmonary system.  Disadvantage: Poor ability to regulate the dose and irritation of the pulmonary mucosa 72 73 2. Topical administration 74  Application could be on mucous membranes, skin or the eye.  Mucous membranes  Drugs are applied on the mucous membranes of the conjunctiva, nasopharynx, oropharynx, vagina and colon usually for their local effects.  Absorption through mucous membranes occur readily to cause systemic effects 75  Skin  Absorption is proportional to the surface area and lipid solubility of the drug.  Conditions that increase cutaneous blood flow enhance absorption.  Systemic absorption from skin is sometimes a reason of toxicity.  Eye  Ophthalmic preparations are meant for their local action  Systemic absorption that results from drainage thought the nasolacrimal canal is usually undesirable  Very little is lost through drainage; hence, systemic side effects are minimized. 76 77 Dosage forms of drugs 78  A dosage form of a drug is the form of preparation designed for administration to the body for the purpose of diagnosis, prophylaxis and treatment. After development of a specific chemical entity for its pharmacological effects, it is formulated in a form that is suitable for administration and even efficacy and for the stability of the drug itself. There are different dosage form designs intended for the various routes of administration. 79  Solid dosage forms  Tablets:  tablets are solid dosage forms containing the active ingredient with or without suitable diluents  They may be coated or uncoated.  Coating is intended to mask the contents of the tablet  Enteric coated: intended for intestinal medications without getting disintegrated in the stomach.  Non-enteric coated: intended to mask the unpleasant odour and taste of a drug. 80  Capsules  Are solid dosage forms which the solid or liquid drug is enclosed in a hard or soft soluble gelatin shell to mask its bad taste and odour. They are intended for internal use.  Suppositories  Are solid dosage forms with various sizes and shape for administration into body cavities (rectum, vagina, and urethra)  Rectal suppositories are conical or bullet shaped, vaginal suppositories spherical, and urethral suppositories pencil shaped. 81  Semi-solid dosage forms  Syrups  Syrups are semi-solid, viscous, sticky preparations containing medicinal substance dissolved in a concentrated sugar solution.  Ointments  Are semi-solid preparations containing the medicinal agent intended for use for application on skin or mucous membranes  Creams  Creams are emulsions for external use as protective or emollients to soften and sooth.  Pastes  Are semi-solid dosage forms of heavy consistency. 82  Liquid dosage forms  Solutions  Are liquid preparations prepared by dissolving active medicinal substance in a solvent. It can be for internal or external use.  For internal use solutions  Tinctures: hydroalcoholic or alcoholic solution of vegetable material or chemical substance. They can also be used for external purpose.  Elixirs: hydroalcoholic preparations flavoured and sweetened with or without active substance.  Injectables 83  Injectables are sterile preparations for parenteral route. They may be labeled as  “for injection”: a sterile powder prepacked in a vial which on the addition of a suitable vehicle forms a clear solution.  “injection”: a ready made sterile liquid preparation in an ampoule or vial.  “sterile suspension”: a ready made suspension for parenteral uses, but not for intravenous or intrathecal injection.  “sterile for suspension”: a sterile powder prepacked in a vial which on addition of a sterile vehicle is made into a suspension for parenteral uses, but not for intravenous or intrathecal injection. 84  For external use solutions  Drops: are aqueous preparations intended for topical administration to the nose, throat, eye or ear. Eye drops should be clear and sterile aqueous solutions, adjusted to a suitable pH and osmotic pressure.  Gargles: are aqueous solution used to treat disease of the pharynx or nasopharynx and as deodorant or antiseptic.  Enemas: are aqueous solutions to be placed in the rectum to evacuate the bowel or to bring about local or systemic therapeutic action. 85  Suspensions  Suspensions are preparations containing drugs, uniformly dispersed with the help of a dispersing agent. Every suspension should have a label “shake well before use”  Suspensions include  Emulsions: preparations consisting of two non-miscible liquids, with an emulsifying agent. They may be used for both internal and external use.  Mixtures: preparation of any solid material suspended in a liquid, and intended for internal use.  Lotion: an aqueous suspension to be applied without friction, for soothing, cleansing or antiseptic action on the skin. 86 Dosage regimen 87  Dosage regimen is a systematic way of drug administration. There are two types: constant and variant dosing  Constant dosing is employed only for safe and affordable drugs  Variant dosing includes  A loading dose in one or a series of doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly. It is desirable if the time required to attain steady state by the administration of drug at a constant rate (four elimination half lives) is long relative to the temporal demands of the condition being treated. 88  Use of loading dose has significant disadvantages I. Sensitive individuals may be exposed abruptly to a toxic concentration of a drug. II. If the drug has long half-life. It takes long time for the concentration to fall if the level achieved was excessive III. Loading doses tend to be large, and they are often given parenterally and rapidly; this can be particularly dangerous if toxic effects occur as a result of action of the drug at sites that are in rapid equilibrium with plasma. 89  Maintenace dose: is a dose administered to maintain the target concentratin of a drug. The amount is equivalent to dailly excreted dose. 90 Pharmacodynamics 91  Pharmacodynamics studies the physiological and biochemical effects of drugs and their mechanism of action  Drugs interact with receptors to produce their characteristic effects. Receptors are functional macromolecular components of the organism  Drugs potentially are capable of altering both the extent and rate at which any bodily function proceeds  Drugs do not create effects but instead modulate intrinsic physiological functions. 92  Mechanism of Drug Action  Physical action  Mass of the drug (in bulk laxatives), adsorptive property (activated charcoal), osmotic activity (mannitol)  Chemical action  Antacids, chelating agents (BAL, calcium disodium edetate)  Through protein targets: (Ion channels, carrier molecules, enzymes, receptors)  Through enzymes  Drugs alter rate of enzyme catalyzed reactions  Actions could be  Stimulation: increased substrate affinity to enzyme  Inhibition: is a common mode of drug action and could be  Competitive: drug binds to catalytic site (mostly non-covalently); reversed by increasing concentration of substrate.  Noncompetitive: drug binds to a site adjacent to catalytic site and as a result the catalytic property of the enzyme is lost. 93  Through receptors  Receptors in pharmacology denote to a class of macromolecules that are concerned specifically and directly in chemical signaling between and within cells.  Affinity: ability of a ligand to bind to receptors  Intrinsic activity (efficacy): ability of a ligand to cause change in receptor conformation upon binding.  In view of binding, ligands can be  Agonists: have affinity and intrinsic activity (A=1, IA=1)  Antagonist: have affinity but no intrinsic activity (A=1, IA=0)  Partial agonist/antagonist: have affinity but with submaximal intrinsic activity (A=1, 0