important and most GENERAL PHARMACOLOGY 2024.pptx

purposeful

1. By: Awgichew Shewasinad Assistant Professor of Pharmacology Dep’t of Pharmacy Debre Berhan University GENERAL PRINCIPLES OF PHARMACOLOGY

2. Outline Introduction to General Pharmacology Background Pharmacokinetics Pharmacodynamics Dose response relationships ( quantal & graded dose) Determination of ED50, LD50 & therapeutic index Factors modifying drug effect & dosage

3. Objectives By the end of this lecture, the student should be able to: Understand basic principles of pharmacokinetics and pharmacodynamics Understand Dose response relationships Know the various mechanisms of drug absorption

4. Katzung: Basic & Clinical Pharmacology; 14 th ed. 201 7 G oo d man & G i l ma n ’ s : T h e P h a r ma c o l o g i cal Bas i s o f T h e r a pe u t i cs; 1 3 t h ed. 201 8 Lippincott: Illustrated Reviews; Pharmacology; 6 th ed. 201 5 Ot h e r R e c e n t P h a r ma c ol o g y Boo k s J o u r n a l s , … Recommended reading materials

5. Introduction Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulator These substances may be chemicals administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulatory processes in parasites infecting the patient. Toxicology is the branch of pharmacology that deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystems

6. Drugs Drugs are chemical substances that interact with human and/or animal body to exert their effects, and intended for prophylactic, diagnostic and treatment purposes. Drugs may be synthesized within the body ( eg , hormones ) or may be chemicals not synthesized in the body ( ie , xenobiotics )

7. Drugs…….. Are poisons drugs ??? Poisons are drugs that have almost exclusively harmful effects. However, Paracelsus (1493–1541) famously stated that “the dose makes the poison,” meaning that any substance can be harmful if taken in the wrong dosage. Toxins are usually defined as poisons of biologic origin, ie , synthesized by plants or animals, in contrast to inorganic poisons such as lead and arsenic.

8. Drug Names and Sources of Drugs Any drug can have three types of names: Chemical Name A description of that drug using the nomenclature of chemistry. Generic name Non proprietary name Proposed by the company that first developed the drug and approved by international body. Trade name Name by manufacturer Several name for single drug may occur Expensive

9. Drug names For written and verbal communications about drugs To put labels to identify the medications present in containers Type of drug name Examples Chemical name N-acetyl- para -aminophenol Generic name Paracetamol Trade name Panado , Tylenol, Dapa , Valadol , Valorin , Helenol , etc

10. Sources of Drugs Minerals e.g. Liquid paraffin, magnesium sulfate, magnesium trisilicate , kaolin, etc . Animals e.g. Insulin, thyroid extract, heparin and antitoxin sera, etc. Plants e.g. Morphine. digoxin , atropine, castor oil, etc. Synthetic source e.g. Aspirin, sulphonamides , paracetamol , zidovudine , etc. Microorganisms e.g. Penicillin, streptomycin and many other antibiotics. Genetic engineering e.g. Human insulin, human growth hormone etc.

11. Basic Principles of pharmacology Pharmacokinetics of drugs (ADME) A bsorption D istribution M etabolism E xcretion of drugs

12. Pharmacokinetics Administration Blood Absorption Distribution Metabolism Excretion Different organs & tissues Drug Site of action

13. Sites of Administration Absorption & distribution Elimination

14. Passage across a Cell Membrane

15. Passage of drug Drugs can cross cellular membranes by: (A). Passive transfer (1). Simple passive diffusion (2). Filtration (B). Specialized transport (1). Facilitated diffusion (2). Active transport (3). Endocytosis

16. Absorption

17. Is the passage of drug from its site of administration to the systemic circulation through cell membranes. Drug absorption Sites of Administration Blood Cell membrane

18. Absorption …… The rate determines how soon its effects will begin The amount determines the intensity of a drug effects

19. Factors affecting drug absorption The route of administration Nature of the dosage form Physico -chemical properties of drug Physiological factors Pharmacogenetic factors Disease states

20. Routes of Drug Administration 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

21. 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)

22. Parenteral route 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

23. 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

24. Dosage forms of drugs Particle size: Small particle size is important for drug absorption. Drugs given in a dispersed or emulsified state are absorbed better e.g. vitamin D and vitamin A. Disintegration time and dissolution rate. Disintegration time : The rate of break up of the tablet or capsule into the drug granules. Dissolution rate: The rate at which the drug goes into solution Formulation a faulty formulation can render a useful drug totally useless therapeutically

25. Tablets Hard- gelatin capsule Spansule Soft- gelatin capsule Suspension Emulsion

26. Physico -chemical properties of drug Physical state : Liquids are absorbed better than solids and crystalloids absorbed better than colloids Lipid or water solubility : Drugs in aqueous solution mix more readily than those in oily solution. However at the cell surface, the lipid soluble drugs penetrate into the cell more rapidly than the water soluble drugs

27. iii) Ionization Most of the drugs are organic compounds. Unlike inorganic compounds, the organic drugs are not completely ionized in the fluid. Unionized component is predominantly lipid soluble and is absorbed rapidly and an ionized is often water soluble component which is absorbed poorly. Most of the drugs are weak acids or weak bases. It may be assumed for all practical purposes, that the mucosal lining of the G.I.T is impermeable to the ionized form of a weak organic acid or a weak organic base. These drugs exist in two forms

28. Acidic drugs : rapidly absorbed from the stomach e.g. salicylates and barbiturates. Basic drugs : Not absorbed until they reach to the alkaline environment i.e. small intestine when administered orally e.g. pethidine and ephedrine.

29. Physiological factors Gastrointestinal transit time Rapid absorption occurs when the drug is given on empty stomach. However certain irritant drugs like salicylates and iron preparations are deliberately administred after food to minimize the gastrointestinal irritation. But some times the presence of food in the G.I tract aids the absorption of certain drugs e.g. griseofulvin , propranolol and riboflavin

30. ii) Presence of other agents: Vitamin C enhances the absorption of iron from the G.I.T. Calcium present in milk and in antacids forms insoluble complexes with the tetracycline antibiotics and reduces their absorption iii) Area of the absorbing surface and local circulation: Drugs can be absorbed better from the small intestine than from the stomach because of the larger surface area of the former. Increased vascular supply can increase the absorption

31. iv) Enterohepatic cycling Some drugs move in between intestines and liver before they reach the site of action. v) Metabolism of drug/first pass effect Rapid degradation of a drug by the liver during the first pass (propranolol) or by the gut wall ( isoprenaline ) also affects the bioavailability. Thus a drug though absorbed well when given orally may not be effective because of its extensive first pass metabolism

32. d) Pharmacogenetic factors Individual variations occur due to the genetically mediated reason in drug absorption and response e) Disease states: Absorption and first pass metabolism may be affected in conditions like malabsorption, thyrotoxicosis, achlorhydria and liver cirrhosis

33. BIOAVAILABILITY Is the rate and extent of the drug that reaches the systemic circulation from the site of absorption. For example: if 100mg of a drug is administered orally and 70mg of this drug is reached the systemic circulation, the bioavailability is 70%. Bioavailability of a drug injected in IV is 100%. Bioavailability (F) = AUC after oral dose AUC after IV dose

34. Distribution Drug movement from the blood to the interstitial space of tissues and from there into cells. Distribution controls onset, Duration actions, efficacy and side effect. Distribution of drugs is rarely uniform. Drugs are simultaneously being eliminated and distributed, but distribution is usually faster. Tissue distribution is determined by the partitioning of drug between blood and the particular tissue

35. 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).

36. Factors affecting distribution The distribution of any given drug is determined by: 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

37. Discussion What is the Clinical significance of plasma protein binding ?

38. METABOLISM It is also called as biotransformation. Drug biotransformation is a process by which drugs are chemically changed in the body as a result of their interaction with cells or tissues .

39. Metabolism (Biotransformation) Metabolism of drug occur in all body parts Lung, GIT, kidney, liver, blood…. But mainly take place in liver ; b/c it contain large amount of metabolizing enzyme The primary sites for metabolism is liver!

40. First-Pass Metabolism Following non parenteral administration of a drug, a significant portion of the dose may be metabolically inactivated in either the intestinal endothelium or the liver before it reaches the systemic circulation Limits oral availability of highly metabolized drugs

41. Types of biotransformation Classified as phase-I & phase – II Phase-I: drug is converted to more polar metabolite. Some metabolites may not be excreted and further metabolised by phase –II reactions. Phase-I: Oxidation, reduction ,hydrolysis, de amination Phase-II: Glucuronidation , sulfate conjugation, acetylation , glycine conjugation and methylation reactions.

42. Therapeutic Consequences of Drug Metabolism Promotion of renal excretion, Reduction of therapeutic action, Activation of a prodrug Enhancement of therapeutic action and Alteration of toxicity

43. Factors affecting drug biotransformation Genetic polymorphism Disease conditions especially of the major drug metabolizing sites[liver]. Age Diet :- eg. grape fruit juice ( inhibit cyp3A4) Sex:- eg. Alcohol Co administration of drugs Drug tolerance

44. Induction & inhibition of drug metabolism Enzyme induction ↑ synthesis of microsomal enzyme ↑ metabolism ↑excretion Enzyme inhibition ↓liver enzyme function ↓metabolism ↓excretion-

45. Excretion Drug excretion is the elimination (passage out) of a systemically absorbed drug from the body in the form of metabolites or unchanged drug. It is a process of drug transfer from the internal to the external environment The kidneys are the main organ of excretion of drugs and their metabolites

46. Different routes of drug excretion Renal excretion: A major part of excretion of chemicals is metabolically unchanged or changed. The excretion of drug by the kidney involves. i) Glomerular filtration ii) Active tubular secretion iii) Passive tubular reabsorption. 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

47. Glomerular filtration It is a process, which depends on the concentration of drug in the plasma molecular size, shape and charge of drug 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.

48. Renal excretion Principal organ for most drug removal especially for water soluble (responsible for excreting water soluble substances) and non volatile drug The amount of drug or its metabolites ultimately present in urine is the cumulative effect of: Glomerular filtration Tubular secretion Tubular reabsorption

49. 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, pethidine , thiazides, histamine

50. 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

51. b) Hepatobiliary excretion The conjugated drugs are excreted by hepatocytes in the bile. Molecular weight more than 300 daltons and polar drugs are excreted in the bile. Excretion of drugs through bile provides a back up pathway when renal function is impaired. After excretion of drug through bile into intestine , certain amount of drug is reabsorbed into portal vein leading to an enterohepatic cycling which can prolong the action of drug e.g. chloramphenicol, oral estrogen are secreted into bile and largely reabsorbed and have long duration of action. Tetracylines which are excreted by biliary tract can be used for treatment of biliary tract infection

52. c) Gastrointestinal excretion When a drug is administered orally, a part of the drug is not absorbed and excreted in the faeces . The drugs which do not undergo enterohepatic cycle after excretion into the bile are subsequently passed with stool e.g. aluminium hydroxide changes the stool into white colour , ferrous sulfate changes the stool into black and rifampicin into orange red

53. d) Pulmonary excretion Drugs that are readily vaporized, such as many inhalation anaesthetics 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

54. 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

55. f) Mammary excretion Many drugs mostly weak basic 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.

56. Time Course of Drug Responses

57. Time Course of Drug Responses Plasma Drug Levels there is usually direct correlation between therapeutic and toxic responses and plasma drug levels. Two plasma drug levels A. Minimum effective concentration (MEC) – Is defined as the plasma drug level below which therapeutic effect will not occur. B. Toxic concentration – the plasma drug level At which toxic effects begin is termed as toxic concentration. Drug Half-Life - Time required to reduce the peak plasma concentration by 50 %.

58. Therapeutic Index An estimate of a drugs margin of safety. Mathematically: A more realistic estimate of drug safety would include a comparison of the lowest dose that produces toxicity (LD 1 ) and the highest dose that produces maximal therapeutic response (ED 99 )

59. Therapeutic range Single-Dose Time Course

60. Pharmacodynamics

61. Pharmacodynamics The study of the biochemical & physiological effects of drugs The molecular mechanisms by which these effects are produced. Is the study of what drugs do to the body and how they do it. Most drug produce their effect by binding on receptor

62. 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.

63. Receptors What are receptors ? Receptors are the macromolecular component of the cell to which a drug bind to produce its effect. Are mainly protein molecule whose function is to recognize and respond to endogenous chemicals and xenobiotics Receptor, should have ligand binding and message propagation ( i.e., signaling) Signal transduction: process by which stimulus produced as a result of ligand receptor binding is relayed into the cell.

64. Receptors…… Based on molecular structure and on the linkage between the receptor occupation and the ensuing response, receptors are classified into: Ligand-gated ion channels G-protein-coupled receptors (GPCR) Kinase-linked receptors Nuclear receptors

65. Site of drug action Extracellularly e.g osmotic diuretics On the cell surface e.g digitalis Inside the cell e.g anticancer drugs

66. Drug & Receptor Interaction Affinity : ability of a ligand (the drug) to bind to receptors Intrinsic activity (efficacy): ability of a ligand to activate (cause change in receptor conformation) upon binding and produce the response.

67. In view of binding, ligands can be Agonists: It binds to the receptors and it will activate the receptor. Has both affinity and intrinsic activity (A=1 & IA=1). Antagonist: binds to the receptor but it will not activate the receptor. Has affinity but no intrinsic activity (A=1 & IA=0) Partial agonist/antagonist : It activates the receptor and produce sub maximal response. Has affinity bit with sub maximal intrinsic activity (A=1 & 0<IA<1)

68. Potency & Intrinsic activity Potency It refers to the amount of drug needed to produce the response. Intrinsic activity (IA) (Efficacy) It refers to the maximum response of the drug.

69. Drug-drug interaction Drug-drug interaction – modulation of pharmacological activity one drug by concomitant/prior administration of another drug. Interaction occurs at two stages: At pharmacokinetic level At the level of absorption, distribution, biotransformation or excretion At Pharmacodynamic level At the level of receptors and beyond

70. Pharmacodynamic Interaction i ) Additive effect: - combined effect of the two drugs having the same action is equal to the sum of their individual effects.[AB=A+B] E.g. Ephedrine + Aminophyillin ii) Potentiation: - the effect of one drug is increased by the other which does not have the same action. E.g. Amoxicillin + Clavulenic acid, Caffeine + Ergotamine iii) Supra additive effect (synergism) :- combined effect of two drugs having same action is greater than the sum of their individual effect.[AB>A+B] E.g trimethoprim + sulphemethoxazole

71. At Pharmacodynamic level Types of agonist- antagonist interaction at receptors A. Reversible antagonism Is reversible since week bond b/n receptor & antagonist 1. Competitive antagonism 2. Non-competitive antagonism B. Irreversible antagonism

72. Agonist- antagonist interaction at receptors Competitive antagonist Agonist & antagonist compete for same receptor site Do not produce effect by themselves but ↓ agonist potency ↑ dose of agonist reverse antagonist effect Dose-response curve shift to the right

73. Agonist- antagonist interaction at receptors Non-competitive antagonism Binding site for antagonist is different from agonist Antagonist cannot be overcome by ↑ increasing agonist concentration ↓ maximal response Irreversible antagonist Strong covalent bond Irreversibly activate the receptor Shift the dose response curve to right & ↓ maximal response

74. At Pharmacokinetic level Absorption ca2+ -↓ absorption of tetracycline Caffeine ↑ absorption of ergotamine Distribution Phenyl butazone has high affinty for plasma proteins compared with warfarine Metabolism Enzyme induction ( rifampin - ↑ metabolism of cyclosporine) Enzyme inhibition ( cimetidine - ↓ metabolism of warfarine ) Excretion Probencid - ↓ secretion of penicillin

75. Factors modifying the dosage and action of drugs   1. Drug tolerance: - The phenomenon in which the individual develops resistance to the usual effect of the drug Natural Acquired . 2. Drug intolerance ( hypersusceptibility ) :- is inability of an individual to tolerate a drug. 3. Sex difference: - Special care should be excercised when drugs are administered during menstruation, pregnancy and lactation. 4. Body weight: - The average dose is mentioned either interms of Mg per Kg body weight or as a total single dose for an adult weighing between 50-100

76. Factors modifying the dosage……. For children, the average dose may be calculated by Clark’s formula.   Weight of child in pound Child dose = -------------------------------- × Adult dose 150     OR Body weight (Kg) Individual dose = ------------------------- × average adult dose 70  

77. Factors modifying the dosage……. 5 . Age: - The pharmacokinetics of many drugs change with age. The liver capacity to metabolize drugs is low and liver function is less developed in children. Like children old people, also present problems in dosage adjustment. The metabolism of drugs may diminish in elderly and the renal function declines with age. Age Child dose = ---------------- × Adult dose. (Young’s Rule) Age + 12

78. 6.Genetics: - Genetically mediated variations in drug responces is dealt in pharmacogenetics . Eg . The rate of acetylation of INH, Dapsone , Hydralazine , procainamide and some sulphonamides is controlled by genes and the dosage of these drugs depends upon the acetylator status of the individual. 7. Disease states: - Several diseases can influence drug action. E g. Gastro intestinal diseases, Liver diseases, Kidney diseases, congestive heart failure etc.  

79. Drug adverse effects and drug toxicities These are effects not favorable to the patient Expected adverse effects Side effects : effects observed at therapeutic dose Toxic effects : effects observed at larger concentrations Acute toxicity : acute administration of larger doses. Chronic toxicity : usually with prolonged and repeated use of a drug.

80. Unexpected adverse effects Hypersensitivity reactions : abnormal response due to antigenic nature of some drugs Allergy Anaphylaxis: extreme sensitivity to antigenic substance and subsequent circulatory collapse Idiosyncratic reactions : an abnormal reactivity to a chemical that is peculiar to a given individual.

81. Teratogenic effect Some drugs given in the first three months of pregnancy may cause congenital abnormalities and are said to be teratogenic. The most sensitive period of teratogenesis during pregnancy is 3-10 weeks of pregnancy i.e the time of organogenesis

82. Teratogenic Drug Actions Thalidomide is an example of a drug that may profoundly affect the development of the limbs after only brief exposure. This exposure, however, must be at a critical time in the development of the limbs. The thalidomide phocomelia risk occurs during the 4 th through the 7 th weeks of gestation because it is during this time that the arms and legs develop

83. Teratogenic mechanisms The mechanisms by which different drugs produce teratogenic effects are poorly understood and are probably multifactorial. For example, drugs may have a direct effect on maternal tissues with secondary or indirect effects on fetal tissues. Drugs may interfere with the passage of oxygen or nutrients through the placenta and therefore have effects on the most rapidly metabolizing tissues of the fetus . Finally, drugs may have important direct actions on the processes of differentiation in developing tissues.

84. Teratogen a teratogen— To be considered teratogenic , a candidate substance or process should result in a characteristic set of malformations , indicating selectivity for certain target organs; exert its effects at a particular stage of fetal development , and show a dose-dependent incidence Teratogenic effects are not limited only to major malformations, but also include intrauterine growth restriction ( eg , cigarette smoking), miscarriage ( eg , alcohol), stillbirth ( eg , cigarette smoke), and neurocognitive delay ( eg , alcohol).

85. Teratogen Cont.…. Several vitamin A analogs ( isotretinoin , etretinate ) are powerful teratogens they alter the normal processes of differentiation.

86. Teratogen Cont.…. Deficiency of a critical substance appears to play a role in some types of abnormalities. folic acid supplementation during pregnancy appears to reduce the incidence of neural tube defects ( eg , spina bifida).

87. Teratogen Cont.…. Chronic consumption of high doses of ethanol during pregnancy, particularly during the first and second trimesters may result in the fetal alcohol syndrome In this syndrome, the central nervous system, growth, and facial development may be affected

88. Counselling women about teratogenic risk Clinicians who wish to provide such counsel to pregnant women must ensure that their information is up-to-date and evidence-based and that the woman understands that the baseline teratogenic risk in pregnancy ( ie , the risk of a neonatal abnormality in the absence of any known teratogenic exposure) is about 3%. It is also critical to address the maternal- fetal risks of the untreated condition if a medication is avoided.

89. FDA PREGNANCY CATEGORIES The FDA-assigned pregnancy categories as used in the Drug Formulary are as follows: Category A Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters). Practically there is no safe drug during pregnancy

90. Category B Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women. Category C Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

91. Category D There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Category X Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits

92. Thank You