Pharmacology 1 PDF

KOTEBE METROPOLITAN UNIVERSITY MINILK II HEALTH & MEDICAL SCIENCE COLLEGE DEPARTMENT OF PHARMACY COURSE TITLE: Pharmacology I Course Code: Phar 2101 Year II Semester II Course instructor: Tewodros Shegute Department Head: Tewodros Shegute March 2020 ...

KOTEBE METROPOLITAN UNIVERSITY MINILK II HEALTH & MEDICAL SCIENCE COLLEGE DEPARTMENT OF PHARMACY COURSE TITLE: Pharmacology I Course Code: Phar 2101 Year II Semester II Course instructor: Tewodros Shegute Department Head: Tewodros Shegute March 2020 Introduction to pharmacology Tewodros S.  Learning objectives Define pharmacology Describe history Describe branches of Pharmacology Define drugs Describe sources of drugs Describe nomenclature of drugs Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 3  Introduction The word pharmacology is derived from the Greek words pharmakon (drug) & logos (study). Pharmacology may be defined as the study of interactions between chemical agents foreign to the body and living organisms. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 4  Two major aspects of study What the body does to the drug (Pharmacokinetics/PK). It studies the ways in which drugs are modified within an organisms. Absorption, Distribution, Biotransformation and Excretion of drugs. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 5  Cont… What the drug does to the body (Pharmacodynamics/PD). It studies the effects of drugs and how they exert their effects. PK & PD interactions may occur when the chemical substances are intentionally administered (Medical pharmacology) or due to unintended exposure (Toxicology). Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 6  Scope To study changes brought about in living organisms by chemically acting substances. Using drugs as experimental tools i.e. use of drugs to gain insight into both normal and abnormal physiology and biochemistry of a biological system. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 7  History of Pharmacology Early contributors Ancient Chinese - The Pen Tsao - "materia medica" of China written by Sken Ming (2735 BC). – Chinese doctrine of signatures. – Contained classifications of individual medicinal plants and compilations of plant mixtures to be used for medical purposes. – Also contained many vegetable and mineral preparations as well as a few animal products Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 8  Indian Records Ayurveda (2500 BC) contains the earliest Indian records of traditional medicine. – "Dravyaguna" is the first Ayurvedic “materia medica“. Includes sources, descriptions, criteria for identification, properties, and methods of preparation and therapeutic uses of hundreds of medicinal herbs. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 9  Ancient Egyptian Ebers papyrus (1550 B.C.) - contains about 800 prescriptions including; – Active substances as well as vehicles, – Statement on method of preparation, – Means of application & use. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 10  Greek contributors Hippocrates – 5th C BC. ‘Father of medicine’. Theophrastus - 300 BC. ‘Father of Pharmacognosy’ - accurate observations of medicinal plants. Dioscorides – 65 AD. - De Materia Medica - a precursor to all modern pharmacopeias. Galen - 131-201 AD. - introduced the concept of polypharmacy. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 11  Ethiopians Metshafe fews - earliest known text of Ethiopian traditional medicine written around the middle of the 17th C. Metshafe Medhanit - published in the 18th C. – Thousands of prescriptions for a wide range of diseases. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 12  Emergence of Pharmacology Until the end of the 17th century - Materia medica, the science of drug preparation and the medical use of drugs. 19th C. – isolation and synthesis of chemically pure compounds. – Serturner -1806 – isolated Morphine. – Carentou (1795–1877) - isolated Quinine. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 13  – Magendie (1783–1855)– isolated Strychnine. – Wohler (1800–1882) - cocaine by from coca. François Magendie & Claude Bernard - in the late 18th & early 19th C - began to develop the methods of experimental animal physiology. The isolation & use of pure substances allowed the quantitative study of drug action (dose –response relationship). Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 14  Pharmacology originated as a branch of Physiology due to performance of pharmacologic studies by physiologists. Rudolf Bucheim (1820–1879) - first laboratories devoted almost exclusively to drug research Dorpat, Estonia, in the late 1840s. Pharmacology is considered to have emerged as a separate science only established in 1847 at the University of Dorpat in Estonia (then a part of Russia). Rudolf Bucheim was appointed professor of pharmacology. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 15  Oswald Schmiedeberg (1838–1921) "father of modern pharmacology”. – Measurement of chloroform in blood a professor of pharmacology at the University of Strasbourg, where he remained for the next 46 years. John Jacob Abel of USA 1890 isolation of epinephrine from adrenal gland extracts (1897–1898). Reid Hunt discovered acetylcholine in adrenal extracts in 1906. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 16  Rudolf Bucheim, Oswald Schmiedeberg & John Jacob Abel left to right. The three major contributors for Pharmacology Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 17  Branches of Pharmacology Pharmacotherapeutics: the use of drugs in the diagnosis, treatment or prevention of diseases. Toxicology: deals with adverse effects of drugs & poisonous effects of various chemicals. Pharmacogenetics : deals with genetically mediated variations in drug responses. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 18  Pharmacogenomics: deals with the application of genomic technologies to new drug discovery & further characterization of older drugs. Clinical Pharmacology: deals with the pharmacological effects of drugs in man. – It gives information about potency, usefulness, doses & toxicity of new drugs for their safe clinical use. Posology: deals with dosing of medications. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 19  Drugs and source of drugs Drug - from French “drogue” – dried herb. Any chemical substance which, when reacts with biological systems, is able to change them in some way. Any chemical substance that has ability to modify the response of a living cell. Drugs do not give new function to tissues or cells, they can only modify processes. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 20  Sources of Drugs A. Natural Sources Plants:- parts of plants such as leaves, roots, barks, etc. are good sources of pharmacologically active compounds. E.g. Alkaloids - Atropine from Atropa belladonna, Quinine form Cinchona bark, Morphine from Papavarum somniferum etc. Glycosides- digoxin & digitoxin from Digitalis lanata. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 21  Cont… Oils: i) Essential Oils: clove oil, peppermint oil, eucalyptus oil, ginger oil, etc. ii) Fixed oils: castor oil, olive oil etc. Gums: Psyllium as bulk purgative. Resins: Benzoin, Colophony, Podophyllum etc. Tannins: Tannic acid for burns & diarrhoea. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 22  Animal Sources Insulin, extracted from pork and beef pancreas. Hormones used as replacement therapy Vaccines Heparin used as an anticoagulant Cod liver oil, etc. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 23  Microorganisms Antibiotics: – Penicillin from Penicillium notatum, – Chloramphenicol from Streptomyces venezuelae, – Grisofulvin from Penicillium griseofulvum, – Neomycin from Streptomyces fradiae, – Streptomycin from Streptomyces griseous etc. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 24  Mineral Sources Ferrous sulfate - iron deficiency anemia. Magnesium sulfate is employed as purgative. Magnesium trisilicate, aluminum hydroxide & sodium bicarbonate are used as antacids for hyperacidity & peptic ulcer. Radioactive isotopes of iodine, phosphorus, gold are used for the diagnosis/ treatment of cancer conditions. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 25  B. Synthetic sources At present majority of drugs used in clinical practice are synthetic. C. Semi synthetic sources Used when the synthesis of complex molecules is difficult/uneconomical/expensive/ or when the natural sources may yield impure compounds. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 26  D. BIOSYNTHETIC SOURCES (genetically engineered drugs) Use rDNA technology for production of biological product based drugs. – Genetically engineered novel vaccines (Recombinex HB for hepatitis-B vaccine), – Recombinant human insulin (Humulin) for diabetes – Interferon-α-2a and interferon-α-2b for hairy cell leukemia. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 27  Production of recombinant somatostatin Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 28  Drug nomenclature Chemical names: given in accordance to IUPAC or common system of naming. E.g. N-acetylpara amino phenol for paracetamol Non-proprietary /generic name: name proposed by the company that first developed the drug or the investigator and adopted by the United States Adopted Name (USAN) council. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 29  Cont… Used uniformly all over the world by an international agreement through the W.H.O. Usually used for scientific communication e.g. In text books of pharmacology, medical journals etc. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 30  Proprietary /trade/brand name Given by the pharmaceutical company which sells the non- proprietary after registration by the regulatory body. Designate the manufacturer’s ownership of that pharmaceutical product. A single drug may be marketed under many brand names. E.g. Tylenol and Panadol for paracetamol Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 31  Learning objectives Definition, history & branches of Pharmacology. Definition, sources and naming of drugs. Absorption, distribution, biotransformation & excretion of drugs. Basics of Clinical pharmacokinetics. Routes of drug administration. Definition, types and properties of receptors. Drug receptor interaction & theories. Drug targets and modes of drug Saturday, February 9, 2019 action other than receptors. General Pharmacoliogy, Tewodros S. 32  Pharmacokinetics Pharmacokinetics is the study of the time course of drug concentration i.e. what the body does on the drug. It includes absorption, distribution, biotransformation (metabolism) and excretion. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 33  Barriers to Drug Delivery Effect Cellular delivery Target Tissue distribution Liver metabolism Gut metabolism Intestinal absorption Ingestion Systemic Circulation Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 34  Drug absorption The transport of drugs from the site of administration into blood/ lymphatics. Important for all routes of administration except IV & locally acting agents. Involves its passage across cell membranes achieved by one of the following mechanisms. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 35 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 36  Passage through membranes Rate dependent on polarity and size. – Smaller molecules (nm/A0) penetrate more rapidly. Polarity estimated using the partition coefficient. – The greater lipid solubility (↑ o/w partition coefficient) – the faster the rate of diffusion. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 37  Highly permeable to O2, CO2, NO and H2O. Large polar molecules – sugar, amino acids, phosphorylated intermediates – poor permeability. These are essential for cell function – must be actively transported. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 38  MOVEMENT OF SUBSTANCES ACROSS CELL MEMBRANES Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 39  I. Passive diffusion: can be of two types A) Aqueous Diffusion: occurs within The larger aqueous compartments of the body (e.g. interstitial space, etc) and Across epithelial membrane tight junctions and the endothelial lining of blood vessels through aqueous pores. No aqueous pores in the capillaries of the brain, the testes, and some other tissues. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 40  Aqueous diffusion of drug molecules is usually driven by the concentration gradient of the drug. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 41  B) Lipid Diffusion: is the most important limiting factor for drug permeation. The rate of lipid diffusion is determined by the lipid-aqueous (o/w) partition coefficient. A drug will accumulate in the membrane until the ratio of its membrane conc. and its concentration in the extracellular fluid equal its partition coefficient. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 42  A concentration gradient is thereby established between the membrane and the intracellular spaced which acts as a driving force for the passive lipid diffusion. The greater the o/w partition coefficient the higher is the conc. gradient & the faster rate of diffusion. The diffusion of drugs which are weak acidic or weak basic in nature is affected by differences in pH across the membrane. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 43  Characteristics of passive diffusion Down hill transport. Greater the surface area & lesser the thickness of the membrane, faster the diffusion. Equilibrium is attained when the concentration on either side of the membrane become equal. Greater the membrane/ water partition coefficient of drug, faster the absorption. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 44  CARRIER-MEDIATED TRANSPORT A) Facilitated Diffusion: protein carrier mediated transport of drugs across conc. gradient. The driving force for facilitated diffusion is the conc. gradient no energy input is required. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 45  Carrier - mediated Transport Cont… B) Active Transport Is used by drugs which resemble endogenous substances such as sugars, amino acids and nucleic acid precursors. More important process than facilitated diffusion. Transport occurs against the concentration gradient (uphill transport). Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 46  Active transport cont… Since the process is uphill, energy is required in the work done by the barrier. As the process requires expenditure of energy, it can be inhibited by metabolic poisons that interfere with energy production. Saturday, February 9, 2019 47  There are few sites where drugs are transported actively – the renal tubule, biliary tract, blood- brain barrier (BBB) and GIT. An important efflux transporter which plays an important part in the absorption, distribution and elimination of many drugs is P-glycoprotein. Drugs such as levodopa (for Parkinsonism) and α methyldopa (for hypertension) are actively transported. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 48  Ion Pair Transport Is used by some highly ionized compounds since they are not able to cross the membrane. Here the drugs combine reversibly with endogenous compounds to form neutral ion pair complexes which can penetrate the lipid membrane by simple diffusion. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 49  Ion pair transport cont… It is another mechanism is able to explain the absorption of such drugs which ionize at all pH condition. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 50 Bulk Flow – the drug is transported through intercellular pores. The major mechanism of passage of drugs across most capillary endothelial membrane. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 51  ENDOCYTOSIS It involves engulfing extracellular materials within a segment of the cell membrane to form a vesicle (hence also called as vesicular transport) which is then pinched off intracellularlly. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 52  In endocytosis, there are three process: A. Phagocytosis B. Pinocytosis C. Receptor mediated endocytosis This process requires energy in the form of (ATP). Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 53  Phagocytosis Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 54  Receptor Mediated Endocytosis Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 55  ROUTES OF DRUG ADMINSTRATION Route of administration is a path by which a drug is brought into contact with the body. May be classified into 2: ENTRAL & PARENTRAL ENTRAL: means “to do with the GIT” and includes all routes of administration that involve the GI tract; oral, buccal, sublingual & rectal routes of administration. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 56  PARENTRAL: means “not through the GIT” & refers to all routes of administration that do not involve the GI tract. It commonly refers to injections such as IV, IM and SC but also includes other like topical and inhalational routes. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 57  Oral Route of Administration Advantages The safest route, Economical, High patient compliance, No need for sterile equipment. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 58  Disadvantages Absorption may be variable Gastric irritation Onset of action is slow Subjected to first pass effect The oral route have different absorption sites the stomach, small intestine (3 sites), large intestine etc. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 59  First Pass Effect Can be of two types, hepatic or intestinal All drugs that are absorbed from the intestine enter hepatic portal vein and pass through the liver before they are distributed systemically. Some drugs are destroyed /metabolized/ on their first passage through the liver. This has been termed as Hepatic first pass effect. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 60  Some drugs are also destroyed in the GI tract when administered orally by acids of the stomach, digestive enzymes this has been referred to as gastrointestinal first pass effect. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 61  First-Pass Extraction Gut wall Portal Liver vein To site of measurement Metabolism Metabolism To Feces Gut wall and liver are major drug metabolizing organs Saturday, February 9, 2019 Oral Bioavailability General = % absorbed Pharmacoliogy, Tewodros S. - % extracted 62  Advantages of first pass effect Reduces systemic ADRs of accidentally swallowed drugs for local action Examples of drugs with rapid first pass metabolism - Aspirin - Morphine - Salbutamol - Verapamil Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 63  Buccal and Sublingual Routes Buccal route – the drug is held and absorbed in the mouth, between the cheek and the gum. Sub lingual route - the drug is taken under the tongue. – Rapid absorption due to rich blood supply. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 64 Advantages By passes first-pass metabolism. Effective if the drug is nonionic and has very high lipid solubility. E.g. Nitroglycerin Rapid onset of action Disadvantages Limited mucosal surface area. Taste of medicament and discomfort. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 65 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 66  Rectal route The drug is administered via the rectum. Drugs are absorbed via the inferior, middle and superior rectal veins. Advantages: Reduced first pass effect. Useful for unconscious and vomiting patients. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 67 Disadvantages: Small surface area of the rectum and little fluid content for absorption, Absorption may be interrupted by defecation, Many drugs can cause irritation of the rectal mucosa, Erratic absorption i.e. irregular and incomplete. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 68  PARENTRAL ROUTES Intravenous (IV) Route: drug injected via the veins. Advantages Extremely rapid onset of action emergency route Bypass first pass effect Drug levels are more accurately controlled Good for irritant drugs, veins are relatively insensitive to irritant drugs Suitable for large volume. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 69  Disadvantages Most dangerous route - once administered the drug cannot be removed easily. Drug must be aqueous solution Trained personnel are required for administration Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 70  Subcutaneous (SC) Route Injecting under the skin. Advantages Self administration is possible e.g. insulin Absorption is usually complete, sufficiently constant & slow to provide a sustained effect. Bypass first pass effect Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 71  Disadvantages Local tissue damage Small volume accommodated maximum of 2 ml injection Injection can sometimes be painful Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 72  Intramuscular (IM)Route Injecting through the muscles. Advantages Larger volume than SC can be accommodated A depot or sustained release effect is possible No first pass effect Disadvantages Trained personnel required for injections Erratic absorption Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 73 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 74  Inhalational route Suitable for local effect as in the case of bronchodilators or for systemic effect as in the case of general anesthetics. Absorption is very rapid high surface area and rich blood supply of alveoli. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 75  Advantages Rapid onset of action Bypass first pass effect Appropriate for local effect on bronchial smooth muscle. Disadvantage Not appropriate for drugs with large particle size (> 20 μm) & also for very small ones (< 5 μm). Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 76 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 77 Intra-arterial Route: Used for localized effect in a particular tissue or organ. Requires great care and should be reserved for experts. No first-pass effect Intra-thecal Route Drugs injected directly into the spinal subarachnoid space. Bypass the blood-brain barrier and the blood-cerebrospinal fluid (CSF) barrier. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 78 Intra ventricular route Ventricular catheter may be placed for example in the treatment of brain tumor or CNS infections. Intra osseous: into the bone marrow Useful for unconscious patients whom IV route is inaccessible or several attempts at IV access have failed. Other routes such as Intracardiac, Intraspinal, Intraperitonial, etc are also available. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 79  Topical Administration Drugs are applied to the mucous membranes of the conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra, and skin primarily for their local effects. Absorption through mucous membranes occurs readily. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 80  Skin Is commonly used for local effect The main route for the penetration of the drugs is generally through epidermal layer Stratum corneum is the rate limiting barrier in passive percutaneous absorption of drug. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 81 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 82  Transdermal drug delivery Not all drugs readily penetrate the intact skin. The dermis is freely permeable to many solutes; consequently. Systemic absorption of drugs occurs much more readily through abraded, burned, or denuded skin. Absorption can be enhanced by suspending the drug in an oily vehicle & rubbing the resulting preparation into the skin. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 83  Controlled-release topical patches have become increasingly available, including – Nicotine for tobacco-smoking withdrawal – Scopolamine for motion sickness – Nitroglycerin for angina pectoris – Testosterone and estrogen for replacement therapy. – Various estrogens and progestins for birth control. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 84  Iontophoresis Also called electromotive drug administration. – Is a technique using a small electric charge to deliver a medicine or other chemical through the skin. It is basically an injection without the needle. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 85  It is a non-invasive method of propelling high concentrations of a charged substance transdermally by repulsive electromotive force. Done using a small electrical charge applied to an iontophoretic chamber containing a similarly charged active agent and its vehicle. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 86  Unlike transdermal patches, this method relies on active transportation within an electric field. In the presence of an electric field electromigration and electroosmosis are the dominant forces in mass transport. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 87  Iontophoresis cont… Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 88  Ocular Administration Primarily used for local effect. – Eye is the most easily accessible site for topical administration of a medication. Topical application of drug to eyes meant for mydriasis, miosis, anesthesia, treatment of infection, glaucoma etc. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 89  Barrier to intra ocular penetration is cornea. pH of lacrimal fluid is 7.4. Not subjected to first-pass hepatic metabolism Viscosity increases bioavailability e.g. oily solutions, ointment etc. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 90 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 91  Intra-nasal Administration Generally used by drugs for treatment of local condition such as perennial rhinitis, allergic rhinitis, nasal decongestion etc. Presently nasal route is becoming popular for systemic delivery of peptide and proteins because of multiple vasculature nasal mucosa. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 92  Factors Affecting Absorption pH & pKa GIT blood flow Gastric emptying Disease states Physicochemical cxis. Barriers Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 93  1. The influence of PH Weak acidic or basic drug do exist in both unionized /lipid- soluble/ and ionized/water-soluble/ form and the ratio of the two forms varying with pH. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 94  Cont… The ratio of lipid-soluble form to water-soluble form for a weak acid or weak base is expressed by the Henderson- Hasselbalch equation. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 95  The ionized species, BH+ or A-, have very low lipid solubility and unable to permeate membranes except where unless there is specific transport mechanism. The lipid solubility of the uncharged species, B or AH, will depend on the chemical nature of the drug. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 96  For many drugs the uncharged species is sufficiently lipid soluble to permit rapid membrane permeation. For some drugs even the uncharged molecule is insufficiently lipid soluble to cross membranes. E.g. Aminoglycosides Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 97  2. GIT blood flow It plays an important role in drug absorption by continuously maintaining the conc. gradient across the epithelial membrane. Polar molecules that are slowly absorbed show no dependence on blood flow. The absorption of lipid soluble drugs and molecules that are small enough to easily penetrate through aqueous pores is rapid & highly dependent on rate of blood flow. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 98  3. Gastric emptying The process by which food leaves the stomach & enters the duodenum. Rapid Gastric Emptying Advisable when : – Rapid onset of action is desired e.g. Sedatives – Dissolution occurs in the intestine e.g. Enteric coated tablets – Drugs not stable in GIT fluids e.g. penicillin G – Drug is best absorbed from small intestine e.g. Vitamin B12 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 99  Delay in Gastric Emptying recommended when – Food promotes drug dissolution & absorption e.g. Grisofulvin – Disintegration and dissolution is promoted by gastric fluids Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 100  4. Disease states CHF decreases blood flow to the GIT, alters GIT pH, secretions and microbial flora. Cirrhosis influences bioavailability mainly of drugs that undergo considerable 1st pass metabolism e.g. Propranolol GIT infections like cholera and food poisoning also result in malabsorption. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 101  5. Physicochemical factors a. Particle size Smaller particle size – b/c dissolution is thought to take place at the surface area of the solute (Drug). Absorption of drugs with poor water solubility can be increased by Micronization. e.g. Griseofulvin, active IV but not effective when taken orally. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 102 b. Crystal Form Drugs exhibiting polymorphism may vary in their physical properties such as solubility. e.g. Chloramphenicol has a several crystal form c. Adsorption - drug molecules are held on the surface of some inert substances by vanderwall’s forces. Adsorbents reduce the rate and extent of absorption. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 103 d) Complexation Complexation of drug and GI fluids may alter the rate and extent of absorption. e) Drug Stability And Hydrolysis In GIT Wide spectrum of pH & enzymatic activity of GIT. f) Drug Solubility Dissolution, an important step, absorption depends on solubility of drug substance. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 104  6. Barriers P-glycoprotein First Pass Extraction – Gut wall – liver Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 105  P-glycoprotein (P-gp) Found in high levels at the apical surface of cells associated with transport: – Biliary canalicular membrane – Brush border of the renal proximal tubules – Apical surface of the intestinal mucosa cells Can act as a barrier to oral absorption – Endothelial cells of brain and testis Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 106  P-glycoprotein cont…  Encoded by MDR1 gene in humans  170 kd transmembrane protein  2 potential drug binding sites  P-gp uses ATP hydrolysis to pump drugs out of cells. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 107  Location of P-glycoprotein Organ Function Intestine Prevent absorption Liver Excretion into bile Kidney Excretion into urine Brain Prevent entry from blood into brain Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 108  Cont… Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 109 Drug Distribution  Distribution refers to the process of transport of the drug from systemic circulation into tissues. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 111  Steps for drug distribution 1. Dilution in blood The drug has to reach equilibrium with itself in the blood. There is no an area of high & low conc. The concentration needs to be uniform. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 112  2. Movement into extracellular fluid surrounding cells Drugs need to be able to get out of the vascular system, either between endothelial cells or through them. 3. Uptake into cells Drug must be able to cross the cell membrane. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 113  The rate at which a drug penetrates tissues and other body fluids depends on several factors. 1. Ability to cross vascular endothelium Most of the vascular endothelium is permeable to drugs. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 114  2. Plasma Proteins Binding Most drugs in the blood are bound reversibly with one or more of the macromolecules in plasma such as albumin, globulins, transferrin, glycoproteins, and - and -lipoproteins etc. Acidic drugs mainly bind to albumin & basic drugs bind to 1 acid glycoprotein ( 1 AGP). Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 115  Characteristics of plasma protein binding Reversible The unbound (free) drugs occurs in dynamic equilibrium with the bound fraction. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 116  Only the unbound drug can diffuse through the capillary wall, produce its systemic effects, be metabolized, and be excreted. Binding does not prevent the drug from reaching its site of action but only retards the rate at which this occurs. The total amount of a drug that is bound to protein depends on three major factors: – The concentration of drug – Its affinity for the binding sites (proteins) – The concentration of protein. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 117 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 118  Protein Binding: Major Proteins which Drugs Bind Protein Molecular Weight Normal (g/mol) Concentration g/L Albumin 67,000 35-50 Alpha1 acid-glycoprotein 42,000 0.4-1.0 Cortisol binding globulin 53,000 0.03-0.07 Sex-binding globulin 90,000.0036 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 119  Drugs Binding Sites Bilirubin Tetracyclines Acidic Agents Bile acids Probenecid Albumin Fatty Acids Vitamin C Salicylates Sulfonamides Barbiturates Phenylbutazone Adenosine Quinine Basic Agents Streptomycin Chloramphenicol Globulins Ouabain Digitoxin (α1, β1, β2, γ) Coumarin Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 120  Tissue Binding Body fat – accumulates drugs with high lipid –water partition coefficients (lipid soluble drugs). Bone – drugs such as tetracycline’s, Pb & Sr can be absorbed & incorporated into crystal lattice of bones. Eye – some drugs have affinity to the retinal pigment melanin. There are also drugs which accumulate in other organs such as lungs, kidneys etc. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 121  Presence of Barriers Barriers such as blood brain barrier (BBB), (which essentially separate brain endothelial cells from the neurons and prevents entry of molecules), blood – CSF barrier, placental barrier and blood testis/ ovarian barrier affect drug distribution. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 122  Degree of perfusion – refers to the rate of blood flow to the tissue. Tissues can be: - Highly perfused e.g. brain, kidney, heart, liver & lungs, - Intermediate perfusion e.g. skeletal muscles or - Poor perfusion e.g. bone, hair, nails, skin etc. Generally highly perfused organs receive most of the drugs. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 123  Diseases affecting protein binding Hypoalbuminemia results in reduced binding and an increase in the unbound fraction. Cancer, arthritis, myocardial infarction, and Crohn's disease lead to elevated levels of a1-acid glycoprotein and enhanced binding of basic drugs. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 124  Volume of distribution (VD) Pharmacological term used to quantify the distribution of drugs throughout the body. It is defined as: It indicates the extent to which a drug is distributed into extra vascular tissues. Generally drugs with high (VD) are highly concentrated in the extra vascular tissues than the blood vessels and vice versa. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 125  Volumes of distribution (In litres for average 70 Kg adult) Warfarin 7 Small vol. Mainly stays in plasma Gentamicin 16 little in tissues. Theophylline 35 Cimetidine 140 Medium vol. Similar in plasma and tissues Digoxin 510 Mianserin 910 Large vol. Mainly in tissues, little in plasma. Quinacrine 50,000 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 126  Influence of Plasma protein binding on Vd Volume of distribution is directly proportional to unbound fraction. High fu Drugs Medium fu Drugs Low fu Drugs Atenolol Carbamazepoine Naproxen Lithium Quinidine Warfarin Penicillin Verapamil Diazepam Indinavir Furosemide Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 127  Biotransformation (Metabolism) Biotransformation is the process whereby a substance is changed from one chemical to another by a chemical reaction within the body. The major role of biotransformation in drug elimination is to change lipophilic drugs into more polar and hence easily excreteable products. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 128 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 129  Fate of a drug after biotransformation 1. Inactivation of the drug 2. Activation of prodrug e.g. (Carbidopa /levodopa methyldopa) 3. Maintenance of activity 4. Change in pharmacological activity 5. Formation of toxic metabolites Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 130  Biotransformation is broadly classified into Phase I and Phase II reactions. Phase I /Functionalization/ reactions Include oxidation, reduction and hydrolysis. It introduces polar functional groups such as –OH, -SH, -NH2 & – COOH. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 131  Phase II reaction – includes glucuronide conjugation, amino acid conjugation and sulfate conjugation reactions. It is conjugation reaction with highly polar endogenous substance such as amino acids, glucose (carbohydrates) and sulfates. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 132  Biotransformation O O O H R R N lipophilic R S O S N R N R R H H aryl ether thioether alkyl amide sulfonamide amide O Phase I Metabolism Polar groups are exposed on or introduced to a molecule R OH OH SH NH2 NH2 CO2H OH + + + alcohol alcohol thiol alcohol HO2CR HO3SR H2NR hydrophilic A molecule endogenous to the body donates Phase II Metabolism a portion of itself to the foreign molecule Glucuronidation, Sulfation, Methylation, Acetylation, Glutathione conjugation, Amino acid conjugation Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 133  Phase 2 Reactions Glucuronidation Sulfation Methylation Acetylation Aliphatic alcohols Aromatic alcohols Amines Amines (1 & 2) Aromatic alcohols Alcohols Pyridines Alcohols Carboxylic acids Acylamines Thiols Aromatic amines N-hydroxy cmpds Alcohols Free sulfhydryl groups Tertiary amines Acidic carbons Phenylbutazone Glucuronidation UGT UDP-Glucuronic acid N N N N O O O O C C Saturday, February 9, 2019 H C4H9 General Pharmacoliogy, Tewodros S. Gluc C4H9 134  Liver contains high concentration of biotransforming enzymes and is major site of biotransformation. Kidneys and lungs are next with 10-30% of the liver's capacity. Low capacity exists in the skin, intestines, testes, and placenta. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 135  The enzyme cytochrome P 450 (Cyp 450) is the most common enzyme responsible for drug metabolism. About 50% of drugs are metabolized by this enzyme. It has many isoforms namely cyp3A4, cyp2D6 and cyp2C9 are common. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 136  Cytochrome P450 Nomenclature Based on amino acid sequence!! CYP2D6 Cytochrome-P-450 Family (>40% homology) Individual Form Sub-Family (>55% homology) Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 137  The Major P450 Enzymes P450 Expression in Liver CYP1A2 CYP2A6 CYP2B6 CYP2C CYP2D6 CYP2E1 CYP3A OTHER Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 138  Examples of drugs Metabolized by CYP Isoforms CYP 1A2 – Caffeine, theophylline CYP 2C9 – Warfarin, phenytoin CYP 2C19 – Omeprazole, diazepam CYP 2D6 – Antidepressants, quinidine CYP 3A4/5 – Antiretrovirals, calcium channel blockers Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 139  Examples of CYPP450 Reactions Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 140  Factors Affecting Biotransformation Age – generally children & elderly have limited abilities of biotransformation due to deficiency of the metabolizing enzymes. Sex - may cause variations in the level of Cyp 450 enzyme. Genetic factors – affect enzyme level in the body. Drug interactions – enzyme induction or inhibition. Diet - malnutrition causes reduced ability to synthesize Cyp 450. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 141  1. Inhibition of Cytochrome P450 Prevent the metabolism of other drugs and itself which rely on this enzyme. E.g. Cimetidine inhibit Cyp 450, if given with digitoxin Increase level of digitoxin and itself Digitoxin cause severe toxicity (has narrow therapeutic window). Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 142  Inhibition Reactions: some examples by Enzyme 2C9 2D6 – Fluoxetine (Prozac) – Quinidine, paroxetine 3A4/5 2E1 – Ketoconazole – Disulfaram – Itraconazole 1A2 – Ritonavir – Grapefruit juice – Amiodarone Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 143  2. Induction of the production of cytochrome p450 Accelerate the metabolism of drugs which rely on this enzyme. Examples of drugs which induce Cyp p450 Glucocorticoids, macrolide antibiotics, anticonvulsants Ethanol Barbiturates (Phenobarbitone) Rifampin Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 144  Renal Metabolism The kidney is also an organ fully capable of xenobiotic metabolism  Cytochrome P450s  Flavin Monooxygenase  UDP- glucuronosyl transferase  Esterases  Aldehyde Oxidase  Xanthine Oxidase  Monoamine Oxidase  -Glutamyl transferase Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 145  Excretion Is the removal of the drug from the body. The major routes for the excretion of drugs are the kidneys, liver (biliary system), lungs, and intestine. Renal Excretion The kidney is the primary organ of removal for most drugs. The urinary excretion of a drug depends up on three important processes: Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 146 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 147  Glomerular Filtration It is affected by several factors; molecular size, charge, and shape. Tubular secretion The proximal tubules have highly efficient active transport system for charged anionic & cationic drugs which cannot be excreted by filtration. Tubular Reabsorption Occurs mostly by passive back diffusion and few active reabsorption. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 148  Factors that Impact Renal Clearance – Dose – Nutritional Status – Drug pKa – Poly-therapy – Urine pH – Transplantation – Urine flow – Transporter Induction or Inhibition potential – Age – Metabolic Enzyme Induction or – Gender Inhibition Potential – Disease state – Polymorphic Expression – Protein Binding Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 149 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 150  Metabolites are Cleared by the Kidney -lactams/cephalosporins (cefdinir; cefonocid) Aminoglycosides (gent; tobra; netilmicin) Quinolones (levofloxacin) Antineoplastic (ifosfamide; methotrexate) Diuretics (amiloride) Antacids (cimetidine; ranitidine) NSAIDS (ibuprofen; naproxen; salicylate) ACE inhibitors (quinapril) Steroids (prednisolone) Biologic therapeutics (Interlukin-11) Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 151  Biliary Excretion Liver cells transfer various substances, including drugs, from plasma to bile by means of transport systems similar to those of the renal tubule. Liver secretes approx. 1 liter of bile daily. Bile is transported via the common bile duct and stored in the gallbladder, and is later released into the jejunum via the ampulla of vater. Passage of substances into the bile is selective. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 152  Biliary excretion plays a major role in drug removal for some anions, cations and cardiac glycosides which are transported from the liver into bile by three independent carrier mediated transport systems. Once inside the bile/gallbladder, they do not recycle because they are too highly charged to back-diffuse across the intestinal epithelium. E.g. Cardiac glycosides Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 153  Enterohepatic circulation Enterohepatic recycling is the term for the ability of a drug to be secreted into the bile, then passed to the small intestine. In the small intestine, the compound will be reabsorbed into the blood that perfuses the intestine and be carried back to the liver, where it will start the cycle over again. This recycling process will continue until the drug either undergoes metabolic changes in the liver, or is excreted by the kidneys, or both. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 154  This process of enterohepatic recycling allows the conservation of important endogenous substances: – Vitamins D3 and B12 – Folic acid – Estrogens Enterohepatic recycling in many cases increases the half-life of drugs Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 155 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 156  Other routes of Excretion Feces Substances excreted in the feces are mainly unabsorbed orally ingested drugs or metabolites excreted in the bile and not reabsorbed from the intestinal tract. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 157  Breast Milk Excretion Excretion of drugs in breast milk is important, not because of the amounts eliminated, but because the excreted drugs are potential sources of unwanted toxicological effects in the nursing infant. Breast milk is more acidic than plasma, thus basic compounds tend to accumulate – Morphine – Codeine Lipid soluble, nonelectrolytes (i.e. ethanol), antibiotics (tetracycline), all accumulate Saturday, February 9, 2019in milk. General Pharmacoliogy, Tewodros S. 158  Gases and volatile substances are excreted via lungs. Little amount of drugs is also excreted into sweat, saliva and tears. Drug elimination is quantitatively expressed in clearance (Cl) value. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 159  BIOAVALABILITY (F) Defined as the fraction of the administered drug reaching the systemic circulation as intact drug. IV administered drugs have 100% bioavailability. Drugs administered in routes other than IV have bioavailability less than 100% and this is due to incomplete extent of absorption and first pass elimination. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 160  Basics of Clinical Pharmacokinetics Elimination Expressed in Clearance Clearance Clearance: the volume of blood completely cleared of a drug per unit time. Clearance can involve both metabolism of drug (Hepatic clearance) and excretion of drug from the body (e.g. Renal clearance). Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 161  Clearance = Rate of elimination Concentration in plasma  Clearance = Vd X Kel (Vd = C/Cp) When clearance is first-order, it can be estimated by calculating AUC of the time-concentration profile of dose. Systemic clearance Cl systemic = Cl renal + Cl hepatic + Cl others Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 162  Calculations for Renal Clearance A qualitative assessment can be made around secretion or reabsorption using the Excretion Ratio (ER). Excretion Ratio Transport Mechanism Value CL r (mL  min -1 ) ER  Net Reabsorption: f u  GFR (mL  min -1 ) Secretion Filtration Only = Reabsorption or 1 Filtration with Secretion = Reabsorption Net Secretion: >1 Filtration with Secretion or Filtration with Secretion > Reabsorption Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 163  Pharmacokinetic models Single – Compartment Model Highly simplified model of a human being, in which the body considered to behave as a single well mixed container. This model considers drug kinetics after a rapid intravenous injection, an IV bolus injection. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 164 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 165  Assumptions 1. One compartment The drug in the blood is in rapid equilibrium with drug in the extravascular tissues. The drug concentration may not be equal in each tissue or fluid however we will assume that they are proportional to the concentration of drug in the blood at all times. This is not an exact representation however it is useful for a number of drugs to a reasonable approximation. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 166  2. Rapid Mixing The drug is mixed instantaneously in blood or plasma. The actual time taken for mixing is usually very short, within a few of minutes, and in comparison with normal sampling times it is insignificant. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 167  3. Linear Model Drug elimination follows first order kinetics. The rate of change of drug conc. by any process is directly proportional to the drug conc. remaining to undertake that process. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 168  kel = Clearance/ Vd Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 169  Multiple Compartment Model Single compartment model is clearly a physiological over simplification. The characteristics of different parts of the body, such as brain, body fat and muscle, are quite different in terms of their blood supply, partition coefficient for drugs and the permeability of their capillaries to drugs. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 170  These differences, which the single -compartment model ignores, can considerably affect the time course of drug distribution and drug action. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 171  Tissues with high perfusion (e.g. Brain, heart, kidney, liver, lungs) and plasma constitute the central compartment. Other tissues with low perfusion (e.g. adipose tissue, bone, etc.) are lumped together as a peripheral compartment. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 172 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 173  Two Phase in the Cp Vs time plot after IV bolus injection Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 174  The initial fast phase (α-phase) represents the redistribution of the drug & the 2nd slow phase (β-phase) represents elimination of the drug. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 175  Drug concentration–time profiles Single Dose Administration Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 176  Multiple dosing A multiple dose regimen is often required to produce and maintain effective plasma concentration. In the case of multiple dose administration we are expected to give second and subsequent doses before the drug is completely eliminated and thus accumulation of the drug occurs. The required plateau or steady state concentration is achieved with the plasma concentration fluctuating between a minimum and maximum value. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 177  Accumulation Accumulation after Accumulation after repeated IV bolus repeated oral dose Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 178  Loading versus maintenance dose Loading dose An initial larger dose administered to promptly raise the conc. of drug in plasma to the target conc. Maintenance Dose Drugs are administered in such a way as to maintain a steady state of drug in the body i.e. just enough drug is given in each dose to replace the drug eliminated since the preceding dose. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 179 PHARMACODYNAMICS  The study of the biochemical & physiological effects of drugs and their mechanisms of action. Receptors Definition 1: “Any target molecule with which a drug molecule interacts to produce the observed effect”. Most common targets with which the majority of drugs interact include ion channels, enzymes, carrier molecules. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 181  Enzymes as drug targets Drugs may act by inhibiting the activity of enzymes Based on the site of drug binding Allosteric e.g. Nevirapine acting on reverse transcriptase. As false substrates e.g. The anticancer drug fluorouracil. Based on the strength of bond formed Reversibly e.g. Neostigmine, acting on acetyl cholinesterase Irreversibly e.g. Aspirin, acting on cyclooxygenase. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 182  Ion channels as a drug target Some drugs may physically block ion channels. E.g. local anesthetics plug Na+- K+ pump. Some drugs modulate the opening and closure of ion channels. Carrier molecules as drug targets Some drugs targets carrier molecules to block facilitated or active transport system. – Cardiac glycosides inhibit Na+/K+ ATPase. – Omeprazole inhibits proton pump Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 183  The binding of drugs to receptors can involve all known types of interactions ionic, hydrogen bonding, hydrophobic, Van der Waals & covalent bonds. Most interactions between drugs and their receptors involve bonds of multiple types. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 184  If binding is covalent, the duration of drug action is frequently, but not necessarily, prolonged. Non-covalent interactions of high affinity may also be essentially irreversible. Most receptors are proteins and have two functional domains: a ligand-binding domain and an effector domain. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 185  Properties of Receptors Sensitivity - small amount of drug is required to produce response. – There is a signal amplification system. Selectivity – interact only with molecules that are complementary to them. Specificity - the response obtained at a given receptor remains the same in spite of the difference in the type of agonist. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 186  Based on molecular structure and their signal transduction mechanism receptors can be grouped as: – Ligand-gated ion channels – G-protein coupled receptors – Intracellular receptors Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 187  Ligand-gated ion channels Have ligand-binding site in the extracellular domain associated with an ion channel. Binding of a ligand on the extracellular domain modulates the opening/closure or conductance of the ion channel via conformational changes. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 188  Control the fastest synaptic events in the nervous system in which a neurotransmitter acts on the postsynaptic membrane of a nerve or muscle cell and transiently increases its permeability to particular ions initiation of action potential in the post synaptic nerve transition of impulse. E.g. The nicotinic acetylcholine. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 189 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 190  G-protein coupled receptors Coupled to intracellular effector system via G-proteins. – Binding of an extracellular ligand on cell-surface receptor activation of the receptor (Conformational changes in the receptor). – The receptor triggers activation of G protein located on the cytoplasmic face of the plasma membrane. – The activated G protein then changes the activity of an effector element, usually an enzyme or ion channel. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 191  Signal transduction by G proteins involves binding & hydrolysis of GTP. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 192  Effectors controlled by G-proteins Two key pathways are controlled by receptors, via G-proteins. Both can be activated or inhibited by pharmacological ligands, depending on the nature of the receptor and G-protein. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 193  Adenylate cyclase (AC)/c AMP AC catalyzes formation of the intracellular messenger c AMP. c AMP activates various protein kinases, which control cell function in many different ways by causing phosphorylation of various enzymes, carriers and other proteins. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 194  Phospholipase C/inositol triphosphate (IP3)/diacylglycerol (DAG) PLC Catalyzes formation of 2 intracellular messengers, IP3 and DAG, from membrane phospholipid. IP3 acts to increase free cytosolic Ca2+ by releasing Ca2+ from intracellular compartments. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 195  Increased free Ca2+ initiates many events, including contraction, secretion, enzyme activation and membrane hyperpolarization DAG activates protein kinase C, which controls many cellular functions by phosphorylating a variety of proteins. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 196  Kinase-linked and related receptors These receptors comprise an extracellular ligand-binding domain linked to an intracellular domain by a single transmembrane helix. The intracellular domain exhibit catalytic/ enzymatic /activity protein kinase (tyrosine kinase, serine kinase) or guanylate cyclase activity. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 197  Binding of a ligand results in change in receptor conformation. Receptor molecules bind to one another/dimerization/ which brings together the protein kinase domains. Autophosphorylation of tyrosine residues which become enzymatically active. Phosphorylate additional downstream signaling proteins. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 198  Cont… Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 199  Intracellular receptors Receptors for ligands with sufficient lipid solubility to cross the plasma membrane E.g. Thyroid hormone, Steroid hormones, Vitamin D. May be located in the nucleus or cytoplasm. Consist of a conserved DNA-binding domain attached to variable ligand-binding & transcriptional control domains. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 200  Cont… Binding of a steroid molecule via ligand binding domain. The receptor changes its conformation (formation of receptor dimmers). Dimers bind to specific sequences of the nuclear DNA, known as hormone-responsive elements. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 201  Cont… DNA-binding domain recognizes specific base sequences to promote or repress particular genes by transcriptional control domain. Effects are produced as a result of altered protein synthesis. The onset of actions of drugs acting on intracellular receptors is delayed but the duration of action is long. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 202  Theories describing drug receptor interaction Occupation theory - Activation of membrane receptors and target cell responses is proportional to the degree of receptor occupancy. Rate theory - the response of a drug is determined by the rate of association with the receptor. Allosteric Theory - suggests receptors exist in two different conformations which are in equilibrium: active conformation and inactive conformation. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 203  Cont… Agonist binding induces a conformational change in the receptor from the inactive (R) to active (R*) state. Inverse agonist produces the opposite effect. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 204 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 205  Other Modes of Drug Action Not mediated through receptors. Chelation and/ or neutralization reaction Antacids used in gastritis act by neutralizing HCl Osmotic purgatives act without interacting with cellular components. Antimicrobial drugs are meant to attach invading microorganisms without interfering in any cellular process in humans. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 206  Types of Dose - Response Relationship Representation of the relationship between dose administered and response. May be either graded or quantal. Graded dose - response relationship The response continuously increases (up to the maximal responding capacity) as the administered dose continuously increases. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 207  Cont… The response to the drug is directly related to the number of receptors with which the drug effectively interacts. Examples of effects that follow graded response include – vasodilatation, blood pressure change, heart rate change, etc… Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 208  Cont… Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 209  Quantal Dose-Response Relationship Used when is not possible to construct graded dose-response curves. – For drugs with all or none effect e.g. prevention of convulsions, arrhythmia, death, pregnancy, cure, pain relief etc… Also used if we are interested in the relationship between dose and some specified quantum of response among all individuals taking that drug. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 210  Cont… Plots the cumulative frequency distribution of quantum of response versus log dose. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 211  Quantal Dose-Response Curves describe population rather than single individual responses to drugs. The quantal dose effect curve is characterized by; Median effective dose (ED50) - the dose at which 50% of individuals show the specified quantal effect. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 212  Cont… Dose required to produce a particular toxic effect in 50% of animals is called median toxic dose (TD50). If the toxic effect is death of the animal, a median lethal dose (LD50) may be defined. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 213  Cont… Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 214  Receptor-Effector Coupling and Spare Receptors Receptors are considered spare when the maximal response is elicited by an agonist at a conc. that does not produce full occupancy of the available receptors. Pool of available receptors exceeds the no. required for a full response. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 215 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 216  Cont… Spare receptors are not different from “non spare” receptors i.e. they are not hidden. When they are occupied they can be coupled to response. Spare receptors may be demonstrated by using irreversible antagonists to inhibit binding of agonists to a portion of the receptor pool. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 217  Receptor occupancy verses Response With out spare receptors With spare receptors Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 218 - High concentration of agonist may still produce an undiminished maximal response. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 219  Drug Potency & Efficacy Efficacy indicates the maximum effect of a drug. Potency, a comparative measure, refers to the different doses of two drugs needed to produce the same effect. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 220  Cont… Drugs A & B have the same efficacy. Drug A has greater potency than B or C b/c the dose of B or C must be larger to produce the same effect as A. Drug C has lower efficacy than B & more potent than B at lower drug concentrations Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 221  Therapeutic index (TI) Defined as the ratio of the dose required to produce a toxic effect and the dose required to elicit the desired therapeutic response. Drugs with large therapeutic index have wide gap b/n the toxic and effective doses hence less dangerous than drugs with small (narrow) therapeutic index. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 222  Desensitization Effect of an agonist generally diminishes when given continuously or repeatedly a phenomenon called desensitization. Also called adaptation, refractoriness, down-regulation, tachyphylaxis, tolerance. The molecular basis of desensitization is unknown but may involve either a receptor-mediated or non-receptor-mediated mechanisms. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 223  Receptor mediated mechanisms Receptor phosphorylation - activation of arrestins. Receptor internalization - resulting in decrease in receptor number. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 224  Non receptor mediated mechanisms Reduction of receptor-coupled signaling components such as depletion of intracellular secondary messengers. Increase in the rate of metabolism and/or elimination of drug. Reduction of drug effects due to opposing homeostatic response (Physiologic adaptation). Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 225  FACTORS THAT MODIFY DRUG EFFECT & DRUG DOSAGE Drug intolerance – is a quantitative deviation from the anticipated response to a given dose of a drug or inability of the individual to tolerate a drug. Sex differences – there are normal physiological variation b/n males and females. Special care should be exercised when drugs are administered during; Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 226  Cont… Menstruation – drugs producing pelvic congestion should be avoided. Pregnancy – Many Drugs administered to the mother are capable of crossing the placenta and causing fetal malformation (teratogenicity). e.g. thalidomide Breast feeding – most lipid soluble drugs are excreted in milk and harm infant health. Such drugs shouldn’t be used in lactating mothers. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 227  In the 1960’s thalidomide was given to pregnant women to reduce the effects of morning sickness. This led to many disabilities in babies and early deaths in many cases. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 228  Cont… Body weight – the average dose is mentioned as mg/kg body weight or as the total dose for an adult (50-100kg). Age – the pharmacokinetics of many drugs changes with age. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 229  The extent of metabolism, absorption, distribution, and elimination of drugs is reduced in children and elderly hence drug dose should be adjusted in these groups. Children do not have well developed metabolizing and excretory organs and there is a progressive decline in many organs with advancing age. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 230  Race - there is a racial variation in the level & type of different enzymes. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 231  Cont… The Genetic variation – the variation in the number of genes transcribing body enzymes and drug transporter proteins. Liver and kidney disease – kidney failure reduces the level of drug excretion from the body and liver disease affects the extent of metabolism of the drug. In people with these problems, dosage adjustments should be performed. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 232  DRUG INTERACTIONS An interaction is said to occur when the effects of one drug are changed by the presence of another drug, herbal medicine, food, drink or some environmental chemical agent. Interactions can be harmful, reduce the efficacy of drugs or causes drug toxicity or can be beneficial. Drug interactions can occur at pharmacokinetic or pharmacodynamic levels. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 233  Pharmacokinetic drug interactions Drug absorption interactions – the absorption of one drug is affected by the presence of another drug. It can occur by - Changing the gastrointestinal PH and motility, - Chelating and complexation mechanisms, - Induction/inhibition of drug transporters. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 234  Cont… Drug distribution interactions - protein binding interactions Drug metabolism interactions - Changes in hepatic first pass metabolism – induction/ inhibition. - Enzyme induction or inhibition – drugs may alter the activity of Cyp 450. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 235  Drug excretion interactions - Changes in the urinary PH affect reabsorption e.g. urine alkalization increases excretion of weakly acidic drugs. - Changes in the active renal tubular secretion- if two drugs are excreted via the same mechanism, they may compete for it. - Changes in renal blood flow Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 236  Pharmacodynamic drug interactions Summation/Additive interactions (1 + 1= 2) The overall effect observed is the sum of individual effects. Occurs if each drugs act by the same mechanism i. e. on the same receptor. Synergistic interaction ( 1 + 1 > 2 ) The overall effect is more that the sum of individual effects. Occurs if each drug acts by a different mechanism or at different receptors. Potentiation (1 + 0 > 1) e.g. effect of Probencid on Penicillins. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 237  c). Antagonism– Competitive Vs Non Competitive Competitive Antagonism An antagonist competes with the agonist for binding to the receptor site. If binding of the antagonist is reversible Reversible competitive antagonism. If the binding of the antagonist involves an irreversible covalent linkage Irreversible competitive antagonism. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 238  A: - agonist + no antagonist - agonist has maximum potency, maximum efficacy. B: - agonist + competitive antagonist - agonist has reduced potency, but maximum efficacy. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 239 Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 240  Effect of partial agonist Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 241  Non- Competitive Antagonism Some antagonists bind to the receptor at sites unrelated to the agonist binding site. Binding of these antagonists is not reversible or surmountable by increasing agonist. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 242  Cont… Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 243  Other types of antagonism Chemical Antagonism One drug may antagonize the action of a second by binding to and inactivating the second drug. Physiological antagonism/ Functional antagonism Interaction of two drugs with opposing physiological actions. Occurs at the same tissue but at different receptors. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 244  Other interactions 3.) Drug herb interactions – St. John wort is known to interact with many drugs by inducing Cyp 3A4. 4.) Drug food interaction – food can cause changes in drug absorption through effects on GIT motility or drug binding. E.g. Tetracycline antibiotics are not taken with milk, Grape fruit juice inhibits intestinal Cyp 450 whereas cruciferus vegetables such as cabbage are inducers of Cyp 450. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 245 Adverse drug reactions & medication errors  Adverse Drug Events (ADEs) Injuries resulting from medical intervention related to a drug including; – Adverse Drug reactions – Medication errors – Therapeutic failures – Poisoning – Drug abuse Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 247  Adverse Drug Reactions (ADRs) Any noxious /unwanted/ negative consequences with the use of given medication at therapeutic doses. Any response to a drug which is noxious and unintended & which occurs at doses used in man for prophylaxis, diagnosis & therapy (FDA). A reaction which is noxious and unintended which occurs at doses in human for prophylaxis, diagnosis, or therapy (WHO). Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 248  Side effects Vs. toxic effects Side effect - effects of drugs which are trivial for the majority of patients from therapeutic dose (extension of pharmacologic effect). Undesirable in a given therapeutic situation. Might be beneficial effect. E.g. hair growth promotion by Minoxidil. Toxic effects - noxious responses which occur at doses higher than therapeutic dose. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 249  Consequences of ADRs Prolong hospital stay for > 4 days. Responsible for additional cost (> 4000 USD) of hospital admission. About $ 887 million incurred per year to treat preventable ADRs in older patients. 3 $ billion incurred to treat preventable ADRs. One death every 200 hospitalized pts due to ADR. Killer No. 3 in UK. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 250  Classification of ADRs ADRs can be classified in different ways. – Severity – Predictability – Cause – Site of affection Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 251  Based on severity Mild:- no antidote is required. Moderate:- a change in drug therapy is required. Severe:- life threatening and require drug discontinuity and specific therapy. Lethal:- contributing to death. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 252  Types of ADRs Type A ADRs Dose related determined by pharmacological properties of the drug molecule. They are often predictable. Most common at least two-thirds of ADRs. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 253  Type B ADRs These are rare and often unpredictable These are not extension of the pharmacological activity of the drug. Only few ADRs fall to these category ( ̴ 5 %) They are often not related to the dose but may in few instances be dose dependent. Occur in few individuals due to their susceptibility genetic difference. Can be allergic or idiosyncratic types. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 254  Hypersensitivity Reactions Also called “drug allergy”/ “drug hypersensitivity” Defined as an immune-mediated response to a drug agent in a sensitized patient. Classified based on the predominant immune mechanisms that lead to clinical symptoms of drug hypersensitivity. (Gell & Coombs classification system) Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 255  Type I reactions (Ig E -mediated) Drug - Ig E complex binds to mast cells with release of histamine, inflammatory mediators. Occurs minutes to hours after drug exposure. Clinical manifestation ranges from anaphylactic shock to mild effects. Urticaria, angioedema, bronchospasm, pruritus, vomiting, diarrhea. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 256  Type II reactions (cytotoxic) Medicated by cytotoxic antibodies (Ig G, Ig M) Specific Ig G or Ig M antibodies directed at drug - hapten coated cells. Clinical manifestation include hemolytic anemia, neutropenia, thrombocytopenia. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 257  Type III reactions (immune complex) Tissue deposition of drug-antibody complexes with complement activation and inflammation. Clinical manifestation include Serum sickness, fever, rash, arthralgias, lymphadenopathy, urticaria, glomerulonephritis, vasculitis Usually occurs 1 -3 weeks after drug exposure Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 258  Type IV reactions (delayed, cell-mediated) Does not involve antigen - antibody interaction. Mediated by T- cells. Sensitized T- cells interact with the antigen cytokine and inflammatory mediator release tissue damage. E.g. Allergic contact dermatitis Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 259  Idiosyncratic reactions Unexpected & peculiar ADR occurring in small percentage of individuals exposed to the drug. Not related to the drugs known pharmacological properties & are not allergic. E.g. drug induced hemolysis in people with glucose -6- phosphate dehydrogenase (G6PD) deficiency. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 260  Type C ADRs Associated with long-term use of the drug. Often involve dose accumulation. They are well known and can be anticipated E.g. ocular toxicity by antimalarials. Type D ADRs Refer to carcinogenic & teratogenic effects. Are dose independent. These reactions Saturday, February 9, 2019 are delayed inPharmacoliogy, General onset and Tewodros S. are very rare. 261  Mechanisms of ADRs Comorbid disease states – GI damage facilitates absorption – Liver damage affect Distribution through affecting plasma proteins Biotransformation through enzyme inhibition – Renal damage affect excretion of a drug Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 262  Genetic factors Inheriting abnormal alleles of cyp 450 alter drug metabolism. E,g. Inheriting abnormal pseudocholinesterase affect metabolism of drug e.g. Suxamethonium Inheriting abnormal N- acetyltransferase affect the metabolism of drugs like INH. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 263  Drug interactions Kinetic level – Displacement from plasma proteins (for those with PPB of 90% or more), e.g., displacement of warfarin by chloralhydrate. – Inhibiting hepatic enzymes, e.g., inhibition of warfarin metabolism by cimetidine. – Inhibiting drug secretion, e.g., quinidine decreases secretion of digoxin Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 264  Dynamic level Acting on same receptors Additive - furosemide increase digoxin toxicity, amoxicillin increase warfarin toxicity. Antagonistic - inhibition of the response to benzodiazepines by the concurrent use of theophylline. Saturday, February 9, 2019 General Pharmacoliogy, Tewodros S. 265  In the United Kingdom, the ‘yellow card’ has been used for this purpose since 1964. The ‘blue card’ system is used in Australia and Malaysia. In Ethiopia 1. Yellow page, prepaid adverse event reporting form 2. Using a telephone of FMHACA 0115524122 direct 0115524118 3. Website of FMHACA http://www.fmhaca.gov.et Saturday, February 9, 2019