Chapter 1 general pharmacology

General Pharmacology by Birhanu Geta

1. College of Medicine & Health Sciences Pharmacology for Health Sciences 1 Compiled by: Birhanu G.(B.Pharm) July , 2015 General Pharmacology Compiled by: Birhanu Geta

2. General Pharmacology Birhanu G. ( B.Pharm)

3. Objectives @ the end of this session students will be able to: Define what Pharmacology is? Define what meant by drugs? Identify source of drugs. Differentiate Pharmacokinetics and Pharmacodynamics. Explain principles of Pharmacokinetics and Pharmacodynamics. 3 General Pharmacology Compiled by: Birhanu Geta

4. 4 What Is pharmacology? General Pharmacology Compiled by: Birhanu Geta

5. Derivation Pharmacology => Pharmakon = Active Principle/Active Ingredient or equivalent to drug, medicine or poison & Logia = study. PHARMACOLOGY means: “ THE SCIENCE OF DRUGS ” 5 General Pharmacology Compiled by: Birhanu Geta

6. DEFINITION Pharmacology : Is the study of substances that interact with living systems through chemical process , especially by binding to regulatory molecules & activating or inhibiting normal body process. Includes, history, source, properties, compounding, biochemical and physiological effects, PK and PD, therapeutic and other uses, precautions, adverse effects, interactions and contra-indications of drugs. 6 General Pharmacology Compiled by: Birhanu Geta

7. Drug A French word ‘Drogue’ which means dry herb . Any substance that brings about a change in biologic function through its chemical action. Alters state in the body: =>can’t create new function but alter existing function. Are poisons if they used irrationally. Poisons are drugs that have almost exclusively harmful effects. However, Paracelsus famously stated that "the dose makes the poison," “Poisons in small doses are the best medicines; and useful medicines in too large doses are poisonous. “ Every drug is a medicine but every medicine is not a drug!!!” 7 General Pharmacology Compiled by: Birhanu Geta

8. Receptors Specialized target macromolecules present on the cell surface or intracellularly . The biological molecule plays a regulatory role. Drugs bind with receptors & initiate events leading to alterations in biochemical activity of a cell, and consequently, the function of an organ. Some times, the drug may act through non-specific physicochemical mechanisms . Osmotic properties (bulk laxatives, saline purgatives, mannitol) Adsorbents (kaolin, charcoal) 8 General Pharmacology Compiled by: Birhanu Geta

9. Basic Areas of Pharmacology Pharmacokinetics (Biodisposition of drugs) Pharmacodynamics Pharmacokinetics: deals with absorption, distribution, biotransformation & excretion of drugs. Pharmacodynamics : study of biochemical & physiological effects of drugs & their MOA . Pharmacotherapeutics : use of drugs in prevention & treatment of disease. Chemotherapy : effect of drugs upon microorganisms, parasites and neoplastic cells living & multiplying in living organism. Toxicology: branch of pharmacology which deals with the undesirable effects of chemicals on living systems. Pharmacogenomics: relationship of individual’s genetic makeup to his/her response to specific drugs. 9 General Pharmacology Compiled by: Birhanu Geta

10. History of Pharmacology Prehistoric people recognized beneficial & toxic effects of many plant & animal materials. Preceding the modern era, there were attempts to introduce rational methods into medicine. But none were successful owing to the dominance of systems of thought [without experimentation & observation]. Around end of 17 th century, reliance on observation & experimentation began. About 60yrs ago, controlled clinical trial reintroduced; expansion of research efforts; Drug action & receptor. Now, the molecular mechanism of action of many drugs is known. 10 General Pharmacology Compiled by: Birhanu Geta

11. Application of pharmacology To control speed of onset , intensity of the drug's effect , and duration of action . Hence decide on route of administration, the amount and frequency of each dose, and the dosing intervals. To identify the possible side effect , and withdrawal symptoms of drugs and take measures to manage. To avoid adverse effects from drug interaction and contraindicated drugs . To avoid adverse effects in special populations like geriatrics, paediatrics, pregnant and lactating mothers. To avoid treatment failure due to tolerance & resistance. To control misuse of drugs by the patient & health professionals. 11 General Pharmacology Compiled by: Birhanu Geta

12. Drugs Drugs mostly interact with a specific molecule in a biologic system that plays a regulatory role [receptor]. Clinically, drugs used for: Diagnosis: Barium salts, Prevention: Vaccines, chemoprophylaxis Treatment: ART Cure: Antibiotics Alteration of physiological processes: Hormones & their derivatives (insulin, GH, contraceptives ….) Global effect: General anesthetics 12 General Pharmacology Compiled by: Birhanu Geta

13. To interact chemically with its receptor, a drug molecule must have the appropriate: Size ( MW100 - 1000 Dalton), For specificity of action , the ability to move within the body (e.g., from the site of administration to the site of action). Electrical charge (bonding), exception Xe. Shape ( complementary to that of the receptor site in the same way that a key is complementary to a lock ). Most of drugs are chiral molecules . Atomic composition. 13 General Pharmacology Compiled by: Birhanu Geta

14. A number of useful or dangerous drugs are inorganic elements , e.g. lithium, iron, & heavy metals. Many organic drugs are weak acids or bases . This fact has important implications for the way they are handled by the body, because pH differences in the various compartments of the body may alter the degree of ionization of such drugs. 14 General Pharmacology Compiled by: Birhanu Geta

15. Source of Drugs Drugs are obtained from various sources. Drugs may be synthesized within the body ( hormones ) or not. i.e. xenobiotics (from the Greek x enos , meaning "stranger"). 15 General Pharmacology Compiled by: Birhanu Geta

16. According to sources they are:- Natural drugs A. Plants E.g . . Digoxin from Digitalis purpurea . Atropine from Atropa belladonna . Quinine from Cinchona officinalis B . Animals E.g .. Insulin from pork/beef . Cod liver oil from Cod fish liver. C . Minerals: Iron, Iodine, Potassium salts. D . Micro – organisms: Penicillin from penicillium notatum, Chloramphenicol from Streptomyces venezuelae (Actinomycetes). General Pharmacology Compiled by: Birhanu Geta 16

17. 2. Synthetic drugs: prepared by chemical synthesis in pharmaceutical laboratories. E.g. Sulphonamides, quinolones, barbiturates. 3. Semi-synthetic drugs: prepared by chemical modification of natural drugs. E.g. . Ampicillin from penicillin G. . Dihydroergotamine from ergotamine. 4. Biosynthetic drugs: prepared by cloning of human DNA in to the bacteria like E.coli. E.g.. Human insulin (humulin ), human GH. 17 General Pharmacology Compiled by: Birhanu Geta

18. Drug Nomenclature Existence of many names for each drug causes lamentable & confusing situation. A drug has at least three types of names; Chemical name (IUPAC) or scientific name, Based on molecular structure of the drug Very long, too complex to use in common practice. International Nonproprietary/generic name, - Given by FDA/WHO while approved, the short hand version of chemical name. - Recommended in RX. Proprietary/trademark/Brand name, - Given by the pharmaceutical company. - Costly. 18 General Pharmacology Compiled by: Birhanu Geta

19. Examples : 2-acetoxybenzoic acid Aspirin Jusprin® Ethyl 4-(8-chloro-5,6-dihydro-11 H- benzo [5,6] cyclohepta[1,2-b] pyridin-11-ylidene)-1-piperidine carboxylate. Loratadine Claritin® 19 General Pharmacology Compiled by: Birhanu Geta

20. DOSAGE FORMS (PREPARATIONS) Dosage forms (DFs) are the means by which drug molecules are delivered to sites of action within the body. The need for dosage forms: Accurate dose. Protection e.g. coated tablets, sealed ampules. Protection from gastric juice. Masking taste and odour. Placement of drugs within body tissues. Sustained release medication. Controlled release medication. Optimal drug action. Insertion of drugs into body cavities (rectal, vaginal) Use of desired vehicle for insoluble drugs. 20 General Pharmacology Compiled by: Birhanu Geta

21. Types of Dosage forms According to route of administration: Oral Rectal Vaginal Parenteral Inhaled Topical Ophthalmic Otic 21 General Pharmacology Compiled by: Birhanu Geta

22. Types of Dosage forms … According to physical form of a drug; Solid Tablets – Conventional - Chewable - Sublingual - Extended release Capsules – Hard gelatin & Soft gelatin Powders – Effervesent granules - Insufflations - Dentrifices - Powder for injections d. Suppositories General Pharmacology Compiled by: Birhanu Geta 22

23. Liquid – Solutions, Suspensions, Emulsions Semisolids – Ointments - Creams - Pastes - Jellies - Pessaries 4. Gases (pressurized) - aerosols 23 General Pharmacology Compiled by: Birhanu Geta

24. Orally (swallowed) Through Mucus Membranes Oral Mucosa (e.g. sublingual) Nasal Mucosa (e.g. insufflated) Topical/Transdermal (through skin) Rectally (suppository) According to on set of action Slow Absorption General Pharmacology Compiled by: Birhanu Geta 24

25. Faster Absorption Parenterally (injection) Intravenous (IV) Intramuscular (IM) Subcutaneous (SC) Intradermal(ID)- 15⁰ Intraperitoneal (IP) Inhaled (through lungs) 90⁰ 45⁰ General Pharmacology Compiled by: Birhanu Geta 25

26. Medication Administration Right Medication Right Dosage Right Time Right Route Right Patient Right Documentation 26 General Pharmacology Compiled by: Birhanu Geta

27. Routes of Drug administration Is the path by which a drug , fluid, poison or other substance is brought into contact with the body. 27 General Pharmacology Compiled by: Birhanu Geta

28. Commonly Used Routes of Drug Administration General Pharmacology Compiled by: Birhanu Geta 28 IV = intravenous; IM = intramuscular; SC = subcutaneous.

29. Factors governing choice o f Route General Pharmacology Compiled by: Birhanu Geta 29 Drug characteristics Ease of administration Site of action Onset of action Duration of action Quantity of drug administered Liver and kidney diseases

30. General Pharmacology Compiled by: Birhanu Geta 30 Enteral Routes Enteral - drug placed directly in the GI tract: sublingual - placed under the tongue Oral - swallowing ( p.o. , per os ) Rectal - a bsorption through the rectum

31. Oral Route General Pharmacology Compiled by: Birhanu Geta 31 ADVANTAGES Safe Convenient Economical Usually good absorption Can be self administered DISADVANTAGES Slow absorption slow action Irritable and unpalatable drugs Un co-operative & unconscious pts. Some drugs destroyed First-pass effect

32. Sublingual Route General Pharmacology Compiled by: Birhanu Geta 32 ADVANTAGES Economical Quick termination First-pass avoided Drug absorption is quick Can be self administered DISADVANTAGES Unpalatable & bitter drugs Irritation of oral mucosa Large quantities not given Few drugs are absorbed

33. Rectal Route General Pharmacology Compiled by: Birhanu Geta 33 ADVANTAGES Used in children Little or no first pass effect Used in vomiting/ unconsciuos Higher concentrations rapidly achieved DISADVANTAGES Inconvenient Absorption is slow and erratic Irritation or inflammation of rectal mucosa can occur Vaginal Routes Drug may be administered locally in the vagina in the form of pessaries. E.g. Antifungal vaginal pessaries

34. General Pharmacology Compiled by: Birhanu Geta 34 First-pass Effect The first-pass effect is the term used for the hepatic metabolism of a pharmacological agent when it is absorbed from the gut and delivered to the liver via the portal circulation. The greater the first-pass effect, the less the agent will reach the systemic circulation when the agent is administered orally .

35. General Pharmacology Compiled by: Birhanu Geta 35 First-pass Effect cont’d… Magnitude of first pass hepatic effect: Extraction ratio (ER) ER = CL liver/Q Where, Q is hepatic blood flow (usually about 90 L per hour for 70 kg adult). Systemic drug bioavailability ( F) may be determined from the extent of absorption (f) & the extraction ratio ( ER), F = f x ( 1-ER )

36. First-pass Effect cont’d… General Pharmacology Compiled by: Birhanu Geta 36

37. Systemic Routes General Pharmacology Compiled by: Birhanu Geta 37 Parenteral First-pass metabolism can occur with orally administered drugs.

38. Administration o f d rugs by the Parenteral Route General Pharmacology Compiled by: Birhanu Geta 38 Needle insertion for parenteral drug: Intradermal injection @15⁰. Subcutaneous injection @45 ⁰ . Intramuscular injection @90 ⁰. Intravenous injection

39. Intravascular (IV) General Pharmacology Compiled by: Birhanu Geta 39 Absorption phase is bypassed (100% BA) Precise, accurate and almost immediate onset of action . Large quantities can be given, fairly pain free Greater risk of adverse effects High concentration attained rapidly Risk of embolism and cannot be recalled by strategies such as emesis or by binding to activated charcoal IV is the most common parenteral route for drugs that are not absorbed orally .

40. Intramuscular Route(IM) General Pharmacology Compiled by: Birhanu Geta 40 Advantages Absorption reasonably uniform Rapid onset of action for drugs in aqueous solution. Mild irritants can be given Repository and slow release preparations First pass avoided Gastric factors can be avoided Disadvantages Only up to 10ml drug given Local pain and abscess Expensive Infection Nerve damage

41. General Pharmacology Compiled by: Birhanu Geta 41 Subcutaneous route(SC) Slow and constant absorption Absorption is limited by blood flow, affected if circulatory problems exist Concurrent administration of vasoconstrictor will slow absorption

42. Inhalation Aerosols (gaseous & volatile agents)-lungs Rapid onset of action due to rapid access to circulation Large surface area Thin membranes separates alveoli from circulation High blood flow General Pharmacology Compiled by: Birhanu Geta 42

43. General Pharmacology Compiled by: Birhanu Geta 43 Inhalation cont’d Respiratory system. Except for IN, risk hypoxia. Intranasal (snorting) Snuff, cocaine may be partly oral via post-nasal dripping. Fairly fast to brain, local damage to septum. Some of the volatile gases also appear to cross nasal membranes. Smoke (Solids in air suspension, vapors) absorbed across lung alveoli: Nicotine, opium, THC, freebase and crack cocaine, crystal meth.Particles or vapors dissolve in lung fluids, then diffuse. Longer action than volatile gases. Tissue damage from particles, tars, CO. Volatile gases: Some anaesthetics (nitrous oxide, ether). Lung-based transfer may get drug to brain in as little as five seconds.

44. General Pharmacology Compiled by: Birhanu Geta 44 Topical Mucosal membranes (eye drops , nasal drops, antiseptic, sunscreen, callous removal etc.) Skin Dermal - rubbing in of oil or ointment (local action) Transdermal - absorption of drug through skin (systemic action) i . Stable blood levels ii. No first pass metabolism iii. Drug must be potent or patch becomes to large

45. General Pharmacology Compiled by: Birhanu Geta 45 Routes of administration Time of onset Intravenous 30-60 seconds Intraosseous 30-60 seconds Endotracheal 2-3 minutes Inhalation 2-3 minutes Sublingual 3-5 minutes Intramuscular 10-20 minutes Subcutaneous 15-30 minutes Rectal 5-30 minutes Ingestion 30-90 minutes Transdermal (topical) variable (minutes to hours)

46. General Pharmacology Compiled by: Birhanu Geta 46 Time-release preparations Oral - controlled-release, timed-release, sustained-release D esigned to produce slow, uniform absorption for 8 hours or longer. B etter compliance, maintain effect over night, eliminate extreme peaks and troughs.

47. General Pharmacology Compiled by: Birhanu Geta 47 Time-release preparations Depot or reservoir preparations P arental administration (except IV), may be prolonged by using insoluble salts or suspensions in non-aqueous vehicles . Example: Implantable contraceptives.

48. The ROA is determined by: P hysical characteristics of the drug, Speed which the drug is absorbed and/or released, T he need to bypass hepatic metabolism and achieve high conc. at particular sites Important Info General Pharmacology Compiled by: Birhanu Geta 48

49. No single method of drug administration is ideal for all drugs in all circumstances !!!!!!!!!!!!!!! Very Important Info! General Pharmacology Compiled by: Birhanu Geta 49

50. Pharmacokinetics (The life cycle of a Drug ) Pharmacokinetics: Pharmakon: drug Kinesis: motion Action of body on drug/ how body handles drugs Pharmacokinetics: ADME Four pharmacokinetic properties determine the onset , intensity & duration of drug action . Using knowledge of pharmacokinetic parameters; clinicians can design optimal drug regimens ; including the route of administration , dose , f requency & duration of treatment . 50 General Pharmacology Compiled by: Birhanu Geta

51. Absorption Absorption is the process by which a drug enters the bloodstream without being chemically altered or The movement of a drug from its site of application into the blood or lymphatic system How drugs transfer form site of administration? Filtration [aqueous diffusion]-passage of drugs through aqueous pores. Size should be less than size of pore Has to be water soluble. E.g. Na+, glucose, caffeine. 51 General Pharmacology Compiled by: Birhanu Geta

52. 2. Diffusion: d rugs supposed to pass membrane. Drugs must be lipid soluble. High partition coefficient  high absorption. 3. Carrier mediated absorption a. Facilitated diffusion - Passive but facilitated. E.g. levodopa & amino acid into brain. b. Active transport - Use ATP & carrier proteins. - Against the concentration gradient. E.g. levodopa & methyldopa from the gut . 52 General Pharmacology Compiled by: Birhanu Geta

53. 4. Phagocytosis & pinocytosis Process by which large molecules are engulfed by the cell membrane forming a vesicle & releases them intracellularly. E.g. protein, toxin 53 General Pharmacology Compiled by: Birhanu Geta

54. Summary of transport across a membrane 54 General Pharmacology Compiled by: Birhanu Geta

55. Drug absorption 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. 55 General Pharmacology Compiled by: Birhanu Geta

56. Factors affecting GI absorption PH of media & pKa of the drug Area of absorbing surface Particle size of the drug Formulation Gut motility GIT blood flow Gastric secretion Drug interaction 56 General Pharmacology Compiled by: Birhanu Geta

57. A drug must be in solution to be absorbed, since most drugs are either weak acids or weak bases, pH affects their solubility and hence absorption. Weak bases are absorbed more rapidly from the intestine than stomach. Small intestine is the major absorption site because: It has l arge surface area ( microvilli 200M 2 ) There is good blood supply (1L blood/min compared to 150mL/min stomach) Permeability to drugs is greater 57 General Pharmacology Compiled by: Birhanu Geta

58. Bioavailability (F) Fraction of administered drug that reaches the systemic circulation in a chemically unchanged form. Amount of drug available in the circulation/site of action It is expressed in percentage It is 100% for drugs given IV. For example, if 100 mg of a drug is administered orally and 70 mg of this drug are absorbed unchanged, the bioavailability is 0.7 or 70%. Factors affecting bioavailability Extent of absorption First pass effect 58 General Pharmacology Compiled by: Birhanu Geta

59. 59 Oral Dose Injected Dose Plasma Concentration Time Bioavailability (F) General Pharmacology Compiled by: Birhanu Geta

60. Drug distribution Reversible movement of drug from bloodstream to interstitium (extracellular fluid) and/or cells. Factors affecting drug distribution 1. Plasma protein binding Albumin [acidic & hydrophobic drugs ] -glycoprotein [basic drugs] 2. Tissue uptake of drugs/tissue binding -Adipose tissue [DDT] -Bone [TTC] -Liver [chloroquine] -Thyroid gland [iodine] 60 General Pharmacology Compiled by: Birhanu Geta

61. 3. Barriers –capillary permeability Blood brain barrier (BBB) Placental blood barrier (PBB) Cell membrane 4. Rate of blood flow Brain, Kidney, highly perfused Liver & Lung 5 . Plasma concentration 61 General Pharmacology Compiled by: Birhanu Geta

62. Drug metabolism Enzymatically mediated alteration in drug structure. Transforms lipophilic drugs into more polar readily excretable products. Liver - major site for drug metabolism, but specific drugs may undergo biotransformation in other tissues, such as the kidney and the intestines. Note: Some agents are initially administered as inactive compounds (pro-drugs) and must be metabolized to their active forms. 62 General Pharmacology Compiled by: Birhanu Geta

63. Inducers The cytochrome P450 enzymes are an important target for pharmacokinetic drug interactions. Certain drugs, most notably phenobarbital, rifampin, and carbamazepine, are capable of increasing the synthesis of one or more CYP isozymes. This results in increased biotransformations of drugs. Decreased plasma drug concentrations. Decreased drug activity if metabolite is inactive. Increased drug activity if metabolite is active. Decreased therapeutic drug effect. 63 General Pharmacology Compiled by: Birhanu Geta

64. Inhibitors Inhibition of CYP isozyme activity is also an important source of drug interactions that leads to serious adverse effects. The most common form of inhibition is through competition for the same isozyme . For example, omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism. If the two drugs are taken together, plasma concentrations of warfarin increase, which leads to greater inhibition of coagulation and risk of hemorrhage and other serious bleeding reactions. CYP inhibitors are erythromycin, cimetidine , ketoconazole , and ritonavir , because they each inhibit several CYP isozymes . 64 General Pharmacology Compiled by: Birhanu Geta

65. Inhibition of drug metabolism may lead to; - Increased plasma levels over time with long-term medications. - Prolonged pharmacological drug effect. - Increased drug-induced toxicities. Microsomal enzyme inducers Phenobarbitone Phenytoin Rifampicin Carbamazepine Sulphonamides St. John’s Wort Cigarette smoking Microsomal enzyme inhibitors Isoniazid Disulfiram Cimetidine Allopurinol Chloramphenicol Erythromycin Metronidazole Grape fruit juice 65 General Pharmacology Compiled by: Birhanu Geta

66. First-Pass Effect: significant metabolic inactivation of some drugs by the liver following oral administration. - Drugs absorbed from the GI tract enter the portal circulation and are carried to the liver before entering the systemic circulation. 66 General Pharmacology Compiled by: Birhanu Geta

67. Drug excretion Removal of a drug from the body occurs via a number of routes. The major routes of excretion include renal excretion , hepatobiliary excretion & pulmonary excretion. The minor routes of excretion are saliva, sweat, tears, breast milk, vaginal fluid & hair . The rate of excretion influences the duration of action of drugs. If the drug is excreted slowly, the concentration of drug in the body is maintained and the effects of the drug will continue for longer period. 67 General Pharmacology Compiled by: Birhanu Geta

68. Routes of drug excretion Renal excretion For water soluble and non volatile drugs. The three principal processes that determine the urinary excretion of a drug. Glomerular filtration Active tubular secretion Passive tubular reabsorption The function of glumerular filtration and active tubular secretion is to remove drug out of the body, while tubular reabsorption retain the drug. 68 General Pharmacology Compiled by: Birhanu Geta

69. b. Hepatobiliary Excretion The conjugated drugs are excreted by hepatocytes in the liver. After excretion of drugs through bile to the intestine; certain amount of drug is reabsorbed in to the portal vein leading to an entrohepatic cycling which can prolong the action of drug. E.g. Chloramphenicol, estrogen. 69 General Pharmacology Compiled by: Birhanu Geta

70. c. Gastro intestinal excretion When a drug is administered orally, part of the drug is not absorbed and excreted in the faeces . The drug which do not undergo enterohepatic cycling after excretion in to the bile are subsequently passed with stool. E.g. Aluminum hydroxide changes the stool color in to white, Ferrous sulphate darkens it and Rifampicine gives orange red colour to the stool. 70 General Pharmacology Compiled by: Birhanu Geta

71. d. Pulmonary excretion Many inhalation anesthetics and alcohol are excreted through the lungs. e. Sweat E.g. Rifampcine , metalloids like arsenic are excreted in to the sweat. 71 General Pharmacology Compiled by: Birhanu Geta

72. f. Mammary excretion Many drugs are excreted in to breast milk. Lactating mothers should be cautious about the intake of these drugs because they may enter in to baby through milk and produce harmful effects in the baby. E.g. Ampicillin, Aspirin, Chlorodizepoxide, Streptomycin. 72 General Pharmacology Compiled by: Birhanu Geta

73. Pharmacodynamics Pharmacodynamics include: Mechanism of actions of the drug. How does a drug act in the body? Effects of the drug: both beneficial & harmful effects. What does a drug do in the body 73 General Pharmacology Compiled by: Birhanu Geta

74. Pharmacodynamics… Mechanisms of drug action It is of two types: A. Receptor mediated mechanism Receptors- targets of drug action. May present either on the cell surface or inside the cell. D + R → DR → Biological effect Where; D=Drug, R=Receptor, DR=Drug Receptor Complex B. Non-receptor mechanisms Simple physical or chemical reaction. E.g. Antacids: neutralization reaction. 74 General Pharmacology Compiled by: Birhanu Geta

75. Types of Receptors Regulatory proteins For endogenous regulatory ligands – particularly hormones, growth factors, and neurotransmitters. E.g. Insulin receptors-insulin Enzymes Receptors that are inhibited by binding with a drug. E.g. Cyclooxygenase – Aspirin Transport proteins: Na+/K+ ATPase- Digoxin Structural proteins: Tubulin- colchicine Genetic materials: Rifampcin - RNA polymerase Ion channels: Na, Ca , K, channel blockers . 75 General Pharmacology Compiled by: Birhanu Geta

76. Models of D-R interaction… Lock & key Drug acts as key, receptor as lock, combination yields response. Induced-fit models Dynamic & flexible interaction. 76 General Pharmacology Compiled by: Birhanu Geta

77. Implications of drug-receptor interaction Drugs can potentially alter rate of any function in the body. Drugs cannot impart entirely new functions to cells. Drugs do not create effects, only modify ongoing ones. Drugs can allow for effects outside of normal physiological range. 77 General Pharmacology Compiled by: Birhanu Geta

78. Three aspects of drug receptor function Receptors determine the quantitative relation between drug concentration and response. This is based on receptor’s affinity to bind and it’s abundance in target cells. Receptors (as complex molecules) function as regulatory proteins and components of chemical signaling mechanisms that provide targets for important drugs. Receptors determine the therapeutic and toxic effects of drugs in patients. 78 General Pharmacology Compiled by: Birhanu Geta

79. Dose response relationship Dose: amount of a drug required to produce desired response in an individual. Dosage: the amount, frequency and duration of therapy. Potency: measure of how much a drug is required to elicit a given response. The lower the dose, the more potent is the drug. Efficacy: the intrinsic ability of the drug to produce an effect at the receptor. Maximal efficacy: largest effect that a drug can produce. 79 General Pharmacology Compiled by: Birhanu Geta

80. Dose response relationship... Drug response depends on: Affinity of drug for receptor. Intrinsic activity (degree to which a drug is able to induce intrinsic effects ). 80 General Pharmacology Compiled by: Birhanu Geta

81. Agonism and Antagonism Agonists facilitate receptor response. Antagonists inhibit recepto r response. 81 (Direct Ant/agonists) General Pharmacology Compiled by: Birhanu Geta

82. Types of drug-receptor interactions Agonist drugs : bind to and activate the receptor which directly or indirectly brings about the effect. Some agonists inhibit their binding molecules to terminate the action of endogenous agonists. E.g. slowing the destruction of endogenous acetylcholine by using acetyl cholinesterase inhibitors. Antagonist drugs : bind to a receptor to prevent binding of other molecules, but lack intrinsic activity. E.g. Atropine decrease acetylcholine effects. 82 General Pharmacology Compiled by: Birhanu Geta

83. Types of drug-receptor interactions… Partial agonist drugs : acts as agonist or antagonist depending on the circumstance, have affinity but have lowered maximal efficacy. E.g. Pindolol can act as an antagonist if a “full agonist” like Isoproterenol is present. Inverse agonist: is a ligand which produces an effect opposite to that of the agonist by occupying the same receptor. E.g. metoprolol in some tissues. 83 General Pharmacology Compiled by: Birhanu Geta

84. Full agonist- A drug with high positive efficacy & produce the system maximal response. Partial agonist- maximal response to the ligand is below the system maximal response. Antagonists- no efficacy or such a low level of efficacy with no visible response. Inverse agonist- A ligand with negative efficacy can reduce the basal response. 84 General Pharmacology Compiled by: Birhanu Geta

85. Graded dose–response relations As the concentration of a drug increases, its pharmacologic effect also gradually increases until all the receptors are occupied (the maximum effect). It is used to determine affinity, potency, efficacy and characteristics of antagonists. General Pharmacology Compiled by: Birhanu Geta 85

86. Potency Is relative strength of response for a given dose. Effective concentration (EC 50 ) is the concentration of an agonist needed to elicit half of the maximum biological response of the agonist. The potency of an agonist is inversely related to its EC 50 value. D-R curve shifts left with greater potency. 86 General Pharmacology Compiled by: Birhanu Geta

87. Efficacy Maximum possible effect relative to other agents. Indicated by peak of D-R curve. Full agonist = 100 % Partial agonist = 50 % Antagonist = % Inverse agonist = - 100 % 87 General Pharmacology Compiled by: Birhanu Geta

88. Quantal(cumulative) dose response r/ship: Is between the dose of the drug and the proportion of a population that responds to it. For any individual, the effect either occurs or it does not (‘all’ or ‘none’). Are useful for determining doses to which most of the population responds; ED50 %, TD50 %, LD50 %, TI(r/ship b/n dose & toxicity) & inter subject variability in drug responses. They do not predict idiosyncratic reactions and hypersensitivity. General Pharmacology Compiled by: Birhanu Geta 88

89. Therapeutic index Median Lethal Dose (LD50 ): dose which would be expected to kill one half of a study population. Median Effective Dose (ED50): dose which produces a desired response in 50% of the test population. Therapeutic Index: gives a rough idea about the potential effectiveness and safety of the drug in humans. Therapeutic Index (TI) = LD50/ED50 The smaller the TI, the less safer the drug is. Margin of safety =LD1/ED99 . 89 General Pharmacology Compiled by: Birhanu Geta

90. Therapeutic Index… ED 50 LD 50 90 General Pharmacology Compiled by: Birhanu Geta

91. Factors modifying the dosage & action of drugs Age Sex Body weight Genetics Drug tolerance Drug intolerance Disease states 91 General Pharmacology Compiled by: Birhanu Geta

92. Drug- Drug interactions Consequences of Drug- Drug Interactions Intensification of effects: increased therapeutic or adverse effects. Additive Drug Effects (Summation): 1 + 1 = 2. Most frequently seen when two drugs possess similar intrinsic activity. E.g. sedative-hypnotic type drugs (i.e., barbiturates, alcohol, benzodiazepines (diazepam, etc.) administered in combination will produce additive effects resulting in over-sedation. Synergism - the effect of two drugs in combination is greater than the sum of the drugs administered alone (1 + 1 > 2). E.g. Aminoglycosides with penicillins. Potentiation – one substance alone does not have effect but when added to another chemical, it becomes effective. (1 + 0 > 1). 92 General Pharmacology Compiled by: Birhanu Geta

93. Reduction of effects – inhibit drug effects; Either beneficial or detrimental. Antagonism: it occurs when the effect of one drug is diminished by another drug.( 1+1<1 ). Types of antagonism; Chemical antagonism or inactivation Physiological (functional) antagonism Pharmacologic or Receptor antagonism Pharmacokinetic/Dispositional antagonism 93 General Pharmacology Compiled by: Birhanu Geta

94. Basic mechanisms of Drug- Drug interactions Direct chemical or physical interaction - can occur with drugs mixed together. Pharmacokinetic interaction – can alter all four processes. Absorption – increase or decrease (e.g., PH, laxative, changes in blood flow). Distribution – competition for protein binding or changes in extra cellular PH. Metabolism - induction of drug metabolizing enzymes, inhibition of metabolizing, and competition of metabolism. Excretion - altered renal excretion (e.g. filtration, reabsorption, and secretion). Pharmacodynamic interaction Interactions at same receptor – almost always inhibitory. Interactions resulting from actions at separate sites (if drugs influence same physiologic process). 94 General Pharmacology Compiled by: Birhanu Geta

95. Drug- Food interactions Impact of Food on Drug Absorption Decreasing rate and/or extent of absorption Some foods can increase extent of drug absorption. Impact of Food on Drug metabolism The grapefruit juice effect (can inhibit metabolism of certain drugs  increased drug levels). Impact of Food on Drug Toxicity MAOIs with tyramine Caffeine with theophylline Impact of Food on Drug Action Vitamin K with warfarin. 95 General Pharmacology Compiled by: Birhanu Geta

96. Adverse drug reactions (ADRs) Any undesired response to a drug. Can range in intensity from annoying to life threatening. Types of adverse drug reactions Side Effects: unavoidable secondary drug effect produced at therapeutic drugs doses. E.g. 1. Drowsiness that often accompanies the use of antihistamines 2. Gastric bleeding that can be produced by low therapeutic doses of aspirin. Toxicities: an adverse drug reaction caused by excessive levels of drug. E.g. Coma caused by overdose with morphine. Allergic reactions: Prior sensitization of the immune system. Re- exposure to that drug can bring on an allergic response. E.g. Penicillin allergy 96 General Pharmacology Compiled by: Birhanu Geta

97. ADRs... Idiosyncratic effects: an unusual drug response resulting from a genetic predisposition. Physical dependence: a state in which the body has adapted to prolonged drug exposure in such a way that if drug use is discontinued abstinence syndrome will result. Develop during long-term use of certain drugs (e.g. Opoids , barbiturates etc) Carcinogenic effects: ability of certain mediations /chemicals to cause cancer. Although a number of carcinogenic compounds have been identified, very few of these are employed therapeutically. Teratogenic Effects: drug- induced birth defect. 97 General Pharmacology Compiled by: Birhanu Geta

98. Any??? 10Q!!! 98 General Pharmacology Compiled by: Birhanu Geta