General Pharmacology Part I PDF

 General pharmacology Part I dr Klaudia Lustyk [email protected] Department of Pharmacodynamics Jagiellonian University Medical College, Kraków, Poland Drug administration  Routes of drug administration...

 General pharmacology Part I dr Klaudia Lustyk [email protected] Department of Pharmacodynamics Jagiellonian University Medical College, Kraków, Poland Drug administration  Routes of drug administration oral inhalation ocular otic nasal parenteral rectal/vaginal topical/transdermal Oral dosage forms tablets capsules solutions syrups suspensions direct absorption disintegration dissolution absorption Advantages & disadvantages of oral route Sublingual application Buccal application  Application by inhalation ~10-20% inhaled Systemic circulation ~80-90% swallowed absorption from GI track systemic side effects inactivation in liver  The size of aerosol particles determines: the speed of their movements in inhaled air depth of penetration into the respiratory tract Nasopharynx Trachea Bronchi Bronchioli Alveoli  Application by inhalation for drugs that are poorly absorbed from the intestine for drugs that are subject of first-pass elimination Nasal application Vasoconstrictors reduce swelling and congestion when applied to mucosa membranes recommended in rhinitis effect begins in 5-10 min after application Ocular application drops gel ointment Otic application drops suspension ointment  Dermatological agents as skin care as drug vehicle & to be absorbed protection into the skin  Rectal application faster onset of action higher bioavailability shorter peak shorter duration than ORAL application Parenteral administration intramuscular subcutaneous intravenous intrathecal Parenteral administration accurate dosage bioavailability ~ 100% drug reaches fastly target tissues when time factor plays important role  Safety & convenience High ORAL > SC > IM > IV Low Bioavailability High&reliable IV> IM = SC > ORAL Low/variable Onset of action Immediate IV> IM > SC > ORAL Delayed  Mode of application and time course of drug concentration Color Atlas of Pharmacology, Thieme 2005 Pharmacokinetics  ADME Absorption Distribution Metabolism Excretion Absorption  Drug absorption enterocytes GUT - intestinal epithelium mucus-producing goblet cells  Membrane permeation Diffusion Fick’s law phospholipid high concentration low concentration  Membrane permeation Passive transport Active transport ATP Facilitated diffusion  Membrane permeation Transcytosis receptor - mediated adsorptive - mediated Y Y Y Factors affecting drug absorption physicochemical properties of the drug form of the drug dosage route of drug administration the size of the absorption surface membrane integrity pH in the absorption area Distribution Compartments of drug distribution intravascular interstitial extracellular intracellular tissue binding  Blood-brain barrier separate circulating blood from the brain and extracellular fluid in the CNS small molecules, fat-soluble molecules, some gases can pass freely into brain tissue  Binding to plasma proteins FREE can have biological effect drug fraction can be metabolized/eliminated bound drug „reservoir”  Binding to plasma proteins instantaneous reversible If affinity for the same site on the albumin is: = drugs can compete for that site Metabolism  Biotransformation of drugs phase I reactions phase II reactions phase I phase II metabolit metabolit oxidation conjugation reduction with hydrolysis glucuronic / sulfuric acid  Cytochrome P-450 catalyze the oxidation and metabolism of xenobiotics and endogenous substances liver & intestinal wall CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 www.wikipedia.org/wiki/CYP2C9  Enzyme inducers many drugs may induce the synthesis of CYP isoenzymes and increase their activity Phenobarbital Rifampicin Carbamazepine  Inducer + Drug metabolized by the same CYP isoform drug is metabolized faster drug is less effective  Enzyme inhibitors many drugs may inhibit the activity of CYP Isoniazid Verapamil Fluoxetine Macrolides  Inhibitor + Drug metabolized by the same CYP isoform increased drug level Overdosing Side effect Color Atlas of Pharmacology, Thieme 2005 Presystemic elimination Color Atlas of Pharmacology, Thieme 2005  First pass effect The > first pass effect is, the < amount of drug will reach systemic circulation  Prodrug biologically inactive substance after administration metabolized into active form design to improve ADME and bioavailability Factors affecting metabolism age disease condition induction / inhibition of drug metabolizing enzymes first-pass effect drug interactions genetics environment Excretion  Drug elimination Renal excretion glomerular filtration active secretion passive reabsorption Color Atlas of Pharmacology, Thieme 2005  P-glycoprotein in intestinal epithelium pump xenobiotics back to intestinal lumen in liver cells pump xenobiotics into bile ducts in cells of proximal tubule of kidney pumps xenobiotics into urinary filtrate in endothelial cells composing blood-brain barrier pumps xenobiotics back into the capillaries Pharmacokinetic parameters  AUC Color Atlas of Pharmacology, Thieme 2005  Bioavailability - fraction of administered dose of the drug that reaches the systemic circulation IV ~ 100% Factors influencing bioavailability ?  Half-life period time required to reduce drug concentration to 50% of its primary value  Volume of distribution apparent volume in which the drug is distributed quantify the distribution of the drug between plasma Excretion and rest of the body high volume of distribution = high tissue distribution  Clearance volume of plasma cleared of a drug over a specified time period Thank You