TEP Ao ae MUMUN NUE Sib ent lay PART 1 INTRODUCTION TO TalacerelUloid(ela mie) PHARMACOLOGY :MACOLOG o Pharmacology zoom Inotructor Collegeof Pharmacy Ld What is Pharmacology? DIVISIONS of Pharmacology + the science of drugs and their effects on biological systems ” ae : CEE genes ae | (Fe sia we sWhat isa DRUG? ois any substance that brings about a change in biologic function through ifs chemical actions oltis used in: ies Prevention eDiagnosis * Mitigation olreatment/Cure Nature of Drugs 1. Size and Molecular Weight 2. Drug-Receptor Bonds > Sizes from MW 7 (Lithium) to over MW 50,000 (thrombolytic enzymes, other proteins) 2 Majatily of drugs have MW between 100 and 1000. Se S- &3. How are drugs named? p-isobutylphenyl) propionic acid# Chemical nay Ibuprofen Generic name (nonproprietary na INN or USAN fotrin® mp Trade name (proprietary name/brand name) 1. Functional Modifiers valter or modulate the physiologic functions Examples: vAnalgesic drugs vAnti-pyretic drugs “Anfi-inflammatory drugs vAnti-hypertensive drugs Classification of drugs according to use © Functional Modifiers © Replenishers © Diagnostic Agents © Chemotherapeutic Agents Replenishers Supplement endogenous substances that are lacking or deficient in the body Examples: vHormones (Insulin) vIV Fluids/Electrolyte/ORS v MultivitaminsAgents used to determine the presence| or absence of a condition or a disea: Examples Edro Histamine some Radiopharmaceuticals ise and gic Stress Te idamole for 1g” for CAD andl INOTE: Sic st of hear! ied period PART 2.1 els alan lee) eats (ec) ‘Agents used to kill or inhibit growth of cells or nucleic acid considered ign to the body is considered Examples: Anti-infectives Antineoplastics Pharmacokinetics PharmacodynamicsWhat is Pharmacokinetics? oThe study of the fate of drugs in the body : ‘drug disposition= the way in which the body handles drugs LIBERATION The release of active ing its dosage form. 01. Disintegration 02. Dissolution - rate-imiting step in absorption of solid dosage forms and consequently onset, intensity, and duration of action of the drug) =e REVIEW OF PHARMACORINE What is the fate of the drug in vivo? LIBERATION Factors that influence the dissolution rate: Surface area Which one has a larger surface area? Salt forms - dissolve much readily when compared to the drugs ins free form oState of hydration Anhydrous vs. Hydrated formLIBERATION > Factors that influence the dssolution rate: ‘Crystal form or amorphous drug forms © > 6x Choramphenicol palmitate sinactivein ‘crystaline form but when itis administered in ‘amorphous form, absorption in the Giis rapid and, with good therapeutic response. > Ex: Insulin «2. Short-acting> Semilente (100% amorphous) b, Intermediate Lente (30% amorphous and 70%4 ccrystaline) ¢.Long-acting> Ulralente (100% crystalline} FACTORS AFFECTII : 1, Dose size administered - Tdose = Tdrug absorption 2.Degree of perfusion of the absorbing environment Tblood supply = greater extent/ faster absorption ABSORPTION RATE and EXTENT of DRUG entry into the systemic circulation oBioavailability- The proportion of a drug that is delivered to its site of action in the body. FACTORS AFFECTING ABSORPTION 3. Areas of the absorbing surfaceFACTORS AFFECTING ABSORPTION 4. pH of the absorbing environment Environmental pH and lonizatior How will this affect absorption? am HA > HA aspirin Lipid Bilayer um UNDUE UL LlMoral of the story... Acidic drugs are best absorbed from acidic environments. Factors that Increase Gastric Emptying Time: ). Stress Heavy Exercise Gastric Ulcers Hot Food (Protein Rich, Lipid-Rich Foods) Lying on the left side J. Drugs that inhibit gastric motility FACTORS AFFECTING ABSORPTION} 5. Gastric emptying — time it takes for the stomach to empty its contents Factors that Decrease Gastric Emptying Time: |. Mild Exercise Gastrectomy Cold Foods/Drinks Lying on the right side 5. Use of motility enhancing drugs . Diabetes mellitusFACTORS AFFECTING ABSORPTION] 6. Dosage form a FACTORS AFFECTING ABSORPTION 8. First-pass effect- some drugs are partially metabolized in the liver or portal vein before passing into circulatory system. FACTORS AFFECTING ABSORPTION ity- for a drug to be solubility must correspond to the characteristics of the absorption site, 9. Enterohepatic travel intact through the biliary tract after initial absorption and are then reabsorbed into bloodstream through the intestineABSORPTION Factors That Affect Absorption 10. Routes 3A drug's route of administration affects its rate Gnd extent of absorption. Enteral oral, sublingual, buccal, rectal ‘© Parenterak IV (fastes!). IM, SC, ID, others ‘Topica Skin (including transdermal patch), eyes, ‘ea1s, nose, lungs (inhalation). vagina NOTE: hn enteratroute.o uals cbsorbedinto the systemic Steulton rough fis solr pasticmucora. he sal Pa debs Specific Modes ‘ug Transpor (Permeation) | Passive Diffusion 2.Carrier-mediated Transport 3.Convective (Pore) Transport 4Nesicular Transport s5lon-Pair Transport ABSORPTION 11. TRANSPORT MECHANISMS - means of movement of drug molecule across cell membrane Passive transport ‘Active transport Passive diffusion Carrier Mediated Transport© Samples eo oviesup @ _lonsofapposte charge of poretining lenzed utonamices Examples ait glycan starch E vesicutar Wansport LN: ayd Review of alae lee) eats (4 the bloodstre s site of action The extent to wi the drugDISTRIBUTION Parameters = Volume of Distribution + Protein Binding + BBB and Placental Barrier DISTRIBUTION Physiologic Factors Affecting Distribution = Regional Blood —Flow- fraction of cardiac output that is delivered to specific tissues/organs >Aeas of high blood flow: heart, liver, kidneys, brain Areas of low blood flow: DISTRIBUTION Physiologic Factors Affecting Distribution + Cardiac Output Normat=2.2-3.5iters/min/square meter slow CO in the case of CHF low distibution= slower onset of action of drugs “Liver. kidneys, and Brain 25% CO: Lungs 100% CO: ‘Adipose tissues ond Bones <1 %CO High vo \—_tow vo basic drugs acidic drugs -examples: -examples: -atropine, chloroquine -chlorpropamiq -taloxifene tolbutamide =. F 2 Protein pose drugs Lipids or proteins hormones DISTRIBUTION 2. Protein Binding It is the phenomenon that occurs when a Grug combines with plasma {particularly albumin) or tissue protein complex. Cone Pe on SE ‘number of steroidal drug io form a tei pedniine’s (epi) ind to thyroxine ,cynocobalamine ¥-alobulin bind to antigen era Bi-globulin (transferrin ) bind to ferrous ion Vit. ADEK iDISTRIBUTION Factors Affecting Protein Binding The drug itself 2 The protein itself 3 Affinity between the drug & the protein 4.Drug Interactions 5 Physiologic Condition of the patient. DISTRIBUTION Prediction of Extent of Distibution BODY FLUID ET ‘Total Body Fluid 60% ‘liters sntracellular 40% 28L Extracellular 20% ut 2a, Intravascular (High MW 5% al and igh protein bound drugs like Heparin) ‘2b Interstitial (Low MW and 15% ton hydrophilic drugs ike oglycosides DISTRIBUTION 3. Special Barriers: Placental: Most small molecular weight drugs cross the placental barrier, although fetal blood levels are usually lower than maternal aBlood-Brain: It is permeable only to lipid-soluble drugs or those of very low molecular weight. METABOLISM. iotransformation” “Inactivation” “Detoxification”Why is drug biotransformation necessary? Active Drug to Reactive Metabolite Drug Biotransformation Rea Polar Metabolite Inactive Metabolite ACTIVE DRUG Active Metabolite eactive Metabolite| PRODRUG ERE Active Metabolite Where do drug Biot MAJOR SITE:OTHER SITES: What are enzyme inducers and inhibitors? FEvaueeRs: They move bt irst Pass Metabolism the phenomenon whereby drugs may be metabolized following absorption before reaching systemic circulation. aka. “First Pass Effect” Examples: > Morphine Meperidine Pentazocine Catecholamines Propranolol Beta Blockers. re Enzyme Inducers ZA - Bares: “Carbamazepine Phenobarbital ~Phenytoin “Rifampicin Smoking v Chronic Alcoholism + iereaseine metaboxccctvy ‘ofan erayne. ocroase he Phamscologcacton ates: BomnterecarogeEnzyme Inhibitors Examples: “Cimetidine “Ketoconazole “Chloramphenic ~Disutfiram “Grapefruit Juice “Acute Alcoholism < decreas he metabote actly Pharmacologic action of com Sominiteredcuge Te Me gai [war Possible routes for metabolism of drugs wool ~S ase 2 @® uonasoxg Phase 1 Reactions ‘reactions that convert the parent drug to a more polar (water-soluble) or more reactive! product by unmasking or inserting a polar! functional group such as -OH, -SH, or -NH2. oak. “ Functionalization Reactio Oxidation » Reduction c. Hydrolysis2. Oxidation 1. CYP 450 Mediated 2, Non CYP 450 Mediated “YP Substrates Tnducers Inhibitors 226 Artemis, bupropion, Sephora, Phenbarbtal idan, dpitogre ‘ycophesphamide, S-mephentor (K+ cyoohasphamde entation iran, pop, seeing, sertraline 28 To arse ad fang, Tieton battles 29 Caen frien beet, Erbtuats, amin Tee i, ‘bce bata, pheno, toi, sutpteranie trinethadoe, sufphenale, Swati, titer ES CYP Substrates Inducers Inhibitors ‘A eager, apne, calene, Sock are Gzang, une, oniraning heating, trod fonds, foie ‘anata ep, an ers veges, omeprzle 2H6 ouabain, icine (tv Rani, Tenyrening, cane wd yeni) penal — meh, hone i CYP Substrates Inducers Inhibitors 1 Tie Platt 11a, ghia pn Kean tiv nan ral ett fone——— CYP Substrates Tnducers—_nibitors {206 fv bpd chnfraie, Sh ahis wat, uid, partie rape, adene,ebogi, rts Aenean, eae, fai, mene, guaran, pend Iya, 4-etoanpeaig, eto een, cyan, pate, peo, pope, rope, peri, seglie Types of Reaction: > Hydroxylation (Phenytoin) +N-Dealkylation (Morphine) O-Dealkylation (Codeine) -N-Oxidation (Nicotine) 8-Oxidation (Thioridazine) »Deamination (Amphetamine) CYP Substrates Tnducers —_nibitors ee ee tebe rae) toon Mt satan fetal sede, ttn, fam ica, Sly seme ocr ete’ strap, oem, ‘oie dee Samy Guth, Rae et Sycoessunme Soennins, hcl bet, je (ene ‘ten erenen eh ers, pasnere kaa 2. Non CYP 450 Mediated Xanthine Oxidase Flavin Monooxygenase enzyme) ‘Amine Oxidases (Epinephrine) Dehydrogenase(Ethanol) (Ziegler’s4 J. ‘Aye feacrg age! bad Eg Acetohexamide| ° ™ ele So cae Oe RNENR'—FRNH +N; ———_azoreducton 5 “Sutsalazne a0 BF Oye a traduction co — co “Clonazepam Types of Reactions: > Ester Hydrolysis (Cocaine, Aspirin, Enalapril) > Amide Hydrolysis (Lidocaine, Procainamide, Indomethacin) c.Hydrolysis ‘0 is the splitting up of a molecule with water, the -OH group of water becoming part of one molecule and the hydrogen atom becoming part of the other. 0 0 ! rl ACO + HO = R-C—OH + OH Vis Acsgicdé ach CONJUGATION REACTIONS 1. Convert the Phase | metabolites fo more polar and water-soluble products. Attachment of small,polar and ionizable endogenous molecules, such asConjugated products Phase Il reactions relatively water soluble and readily 3.Detoxification excretable in be regarded as detoxifying biologically inactive and nontoxic pathways potas Bhiose res fors SUC The role of GSH is to combine with methylation rd [acetylation | chemically reactive compounds to prevent damage to important do not generally increase water solubility but plomacromolecules such os DNA, RNA mainly 2. serve to terminate or attenuate and proteins pharmacological activity | In neonates and children, glucuronidating processes are often not developed fully. ated Seon of drug ro ‘rug NH.COCH, toxicity Drug:oneonatal hyperbilirubinemia cinability of newboms to conjugal bilirubin with glucuronic acid ogray baby syndrome inability to metabolize chloramphenicol What are the processes involved in the metabolism of Aspirin and Paracetamol? 2, Acetylation Examples: Sulfonamides, Isoniazid, Hydralazine, Procainamide ‘SYSTEMIC Lupus ERYTHEMATOSUS, Acetaminophen oln adults: ‘Major metabolite: O-glucuronide conjugate 00-sulfate conjugate formed in small amounts on infants and young children (ages 3 to years) 00-sulfate conjugate is the main urinar productMeaboksn opi ‘al of paral Factors Affecting Drug Metabolism ‘The mn ei ia gie ue Patol wes ghuion and ‘sition Chemical Structure of Drug Wi ining do gion Wi ines db ts Genetic Differences ee a A i ‘, Diet & Environmental Factors — ein a Physiologic Stress or Disease ‘With ven higher doses the pace 1 this pathway becomes strated a Age “ystems sted ‘epntoiemetbolite ums (oe Gender teingrd rhe) Drug Interactions A reer proportion of te dug gens it tein sige aid Te oft tan enn inary pH Genetic factors Isoniazid metabolism - acetylation plasma etlect hotaite Genetic Polymorphisms in Drug Metabolism ao Se 2, ee vn res Pie rot eeetvoton Ssosetedhepetis (ecetvinyckazineGenetic Polymorphisms in Drug Metabolism ‘Genetic Polymorphisms in Drug Metabolism tae heed py, ee Reem ee edo onan leracis rat nesta nen oy lonaton foros Howry secre (eres) o fcwacis omega erat ied rete icy Diet ‘Charcoal broiled foods Safin (ning) [erg ‘CRUCIFEROUS 7... vegetablesDiet oGrapettuit juice Metabolism of coadministered drug Diseases affecting drug metabolism éer Cigarette smoking Workers exposed to some pesticides EXCRETION = The removal of drugs from the body + A drug or metabolite must be polar or somes; may [PSOE | ee tL —_ ge ‘BRUSEXGRETON wrnss FECESEXCRETION Half-Life othe time it takes for ‘one hail of the original ‘amount of a arug in the body fo be removed. oAmeasure of the rate ayy atwhich drugsare i removed from the body. ernauneareas oo