SEMINAR ON DRUG METABOLISM UNDER THE GUIDANCE OF K.SRIKANTH GUPTABY ASST.PROFESSORSAMEERA PRIPM-PHARMACY -1YR(PHARMACEUTICS) UNDER THE CO-GUIDANCE OF11CM1S0313 V.RAMA MOHAN GUPTAPRIP. PRINCIPAL & HOD PRIP
CONTENTSINTRODUCTION TO METABOLISM 1 2 DRUG METABOLISM INTRODUCTION 3 SITES OF DRUG METABOLISM4 METHODS FOR STUDY OF DRUG METABOLISM56
INTRODUCTION TO METABOLISMSum total of all the enzyme –catalyzed reactions that occur in an organism.
IMPORTANCE OF METABOLISM To obtain chemical energy To synthesize complex molecules To convert nutrient molecule into its precursor form for future use
•What is drug metabolism?•Importance of drug metabolism? Why it isnecessary?•How it will takes place?•Where it will takes place?(sites of drug metabolism)•When it will takes place ?
WHY DRUG METABOLISM IMPORTANT? Drugs are mostly lipid soluble, easy to cross membranes, bind to plasma proteins & reabsorb from renal tubules Metabolism changes them to water soluble & easily excretable products; also become inactive or less active
Termination of drug action .Activation of prodrug .Bioactivation and toxication .Carcinogenesis Tetratogenesis
Termination of Drug ActionConversion of drug to active metabolite to active metabolite to inactive metabolite• Parent compound inactive metaboliteAtropine tropic acid & tropinpropranolol hydroxyl propranolol
Inactive active parent compound metaboliteEg: Levodopa dopamine
Some Xenobiotics Are Metabolized to Carcinogenic Agents• 3,4 Benzopyrene• Aflatoxin• N-Acetylaminofluorene Metabolites of these agents interact with DNA
Small Amounts of Acetaminophen is Converted to the Reactive Metabolite N-Acetyl benzo quinone imine bioactivationBioactivation of acetaminophen; under certain conditions, the electrophile N-acetyl benzo quinone imine reacts with tissue macromolecules, causing liver necrosis
Some drugs that produce active or toxic metaboliteInactive drugs Active metabolite:(Pro-drugs)Cyclophophamide Phosphoramide musrardPrednisone prednisoloneActive drug Active metaboliteAmitriptyline NortriptylineDiazepam OxazepamActive drug Toxic metaboliteHalothane Trifluoroacetic acidParacetamol N-acetyl-p-benzo-quinone-imine
Thalidomide is a Teratogen (teratogenesis)THALIDOMIDE: Fetal malformations in humans, monkeys, and rats occur due to metabolism of the parent compound to a teratogen. This occurs very early in gestation
Sites of drug metabolism Liver is the principal organ of drug metabolism Other sites are GI mucosa, lungs, skin and kidneys Every tissue has some ability to metabolize drugs Some drugs, after oral administration (clonazepam & propranolol) are extensively metabolized in GI or liver, before reaching systemic circulation or sit of action, called 1st pass effect, it reduces their bioavailability In the liver cells metabolic enzymes are located in the smooth microsomes of endoplasmic reticulum
CELLULAR SITES OF DRUG METABOLISMCytosol MitochondriaLysosomesSmooth endoplasmic reticulum (microsomes)
Phases of drug metabolism(cont…)Drug metabolism can be categorized to:Phase-I reactions: oxidations, reductions & hydrolysisPhase-II reactions: conjugations Glucuronide conjugation Aspirin Salicylic acid COOH COOH COOH OCOCH3 OH OH O OH HO Phase-I Phase-II O COOH
DRUG METABOLISING ENZYMESMicrosomal enzymesNon microsomal enzymes
METHODS FOR THE STUDY OF DRUG METABOLISM 1. 2.
ENZYME INDUCTION8 ENZYME INDUCTION 8• Enzyme Induction - increased enzyme protein levels in thecell •Phenobarbital type induction by many drugs •Polycyclic hydrocarbon type induction by polycyclic hydrocarbons such as 3,4-benzopyrene and 3- methylcholanthrene
CORRELATION BETWEEN SLEEPING TIME AND PLASMAT1/2 IN CHRONIC PENTOBARBITAL PRETREATED RABBITS
Consequences of InductionIncreased rate of metabolismDecrease in drug plasma concentrationEnhanced oral first pass metabolismReduced bioavailabilityIf metabolite is active or reactive, increased drug effects or toxicity
Therapeutic Implications of InductionMost drugs can exhibit decreased efficacy due to rapid metabolism but drugs with active metabolites can display increased drug effect and/or toxicity due to enzyme induction Dosing rates may need to be increased to maintain effective plasma concentrations
Consequences of InhibitionIncrease in the plasma concentration of parent drugReduction in metabolite concentrationExaggerated and prolonged pharmacological effectsIncreased liklihood of drug-induced toxicity
Therapeutic implications of InhibitionMay occur rapidly with no warningParticularly effects drug prescribing for patients on multidrug regimensKnowledge of the CYP450 metabolic pathway provides basis for predicting and understanding inhibition Esp drug drug interaction
DIETCharcoal broiled foods (contain polycyclic hydrocarbons that increase certain enzyme protein in cells)Grapefruit juice (the active component is the furancoumarin 6,7-dihydroxybergamottin which inhibits a certain a group of microsomal enzymes)
State of health Hepatitis Liver cancer Cardiac insufficiency
CONCLUSION:Final conclusion of this study is enzymes will play a major role In drug metabolism especially cyp 450 .Lack of these enzymes will sometimes makes the drug low efficient
CASE STUDYA37-year-old woman visited her dentist for removal of her wisdom teeth. The teeth were found to be impacted, and removal necessitated extensive surgery. Following completion of the procedure on one side of the mouth, the patient was given a prescription for acetaminophen 300 mg with codeine 30 mg (combination product) for the relief of pain. The patient took the prescription as prescribed for approximately 2 days, but little pain relief was achieved. She called the dentist to get a prescription for another analgesic. What is a possible explanation for this lack of efficacy?
REFERENCES SATYANARAYANA BIOCHEMISTRY J.L.JAIN FUNDAMENTALS OF BIOCHEMISTRY HERPER’S BIOCHEMISTRY MARTIN’S PHYSICAL PHARMACY INTERNET BRAHMANKER-BIOPHARMACEUTICS VENKATESHWARLU-BIOPHARMACEUTICS http://www.hospitalist.net/highligh.htm DR.A.V.S.S.RAMA RAO –A TEXT BOOK OF BIOCHEMISTRY LIPPINCOTT-MODERN PHARMACOLOGY WITH CLINICAL APPLICATIONS GOODMAN GILMAN-PRINCIPLES OF PHARMACOLOGY