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Pharmacology An ntegrated oal-directed arrative for the n- raining xam I G N I T E JEFFREY B HORN MD STEPHEN H. SAMS MD FIRST EDITION WHITNEY FALLAHIAN MD JASON HAFER MD An Integrated Goal-directed Narrative for the In-Training Exam Successful and unsuccessful people do not vary greatly in their abilities. They vary in their desires to reach their potential. – John Maxwell IGNITE PHARM(B)-2 [An Integrated Goal-directed Narrative for the In-Training Exam] PHARMACOLOGHY – BASIC EXAM FUNDAMENTALS OF PHARMACOLOGY RELATIONSHIP BETWEEN RELATIONSHIP BETWEEN Drug Dose Drug Dose PHARMACODYNAMICS Tissue Concentration PHARMACOKINETICS Tissue Concentration Elapsed Time Time After Administration “WHAT THE DRUG DOES TO THE BODY” “WHAT THE BODY DOES TO THE DRUG” TAXONOMY ELIMINATION Drug Removal (Biotransformation & Excretion) CLEARANCE Rate of Elimination Site of Administration ABSORPTION BIOTRANSFORMATION Alteration of a Substance by a Metabolic Process ENTERING THE BLOODSTREAM Fraction of UNCHANGED DRUG Reaching MEDIAN LETHAL DOSE BIOAVAILABILITY Dose Leading to DEATH in 50% of the Population Systemic Circulation (LD50) RATIO of: Median Lethal Dose VOLUME OF DISTRIBUTION Theoretical Volume in Which a Drug Is Distributed THERAPEUTIC INDEX (TI) Median Effective Dose MEDIAN EFFECTIVE DOSE (ED50) Dose of Drug Necessary to Generate GIVEN EFFECT IN 50% OF POPULATION Ç Potency of Drug à È ED50 An Integrated Goal-directed Narrative for the In-Training Exam 2. Which of the Following Drugs is Associated with PRO-DRUG PAIN ON INJECTION? A Drug that has Minimal/No Inherent Activity & MUST A. Dexmedetomidine C. Thiopental be METABOLIZED to Exert its Intended Effect B. Fospropofol D. Methohexital DRUG EFFECTIVENESS EFFECT EXAMPLE FULL AGONIST AGONIST Activates Receptor Benzodiazepine Opposes Receptor Response COMPETITIVE ANTAGONIST Neuromuscular Blocker PARTIAL AGONIST (Can OVERCOME with Agonist) Opposes Receptor Response WEAK PARTIAL NON-COMPETITIVE ANTAGONIST Phenoxybenzamine (CANNOT OVERCOME with Agonist) AGONIST PARTIAL AGONIST Partial Receptor Response Buprenorphine NEUTRAL MIXED AGONIST-ANTAGONIST Augments/Opposes Response Nalbuphine IGNITE PHARM(B)-3 [An Integrated Goal-directed Narrative for the In-Training Exam] PHARMACOLOGHY – BASIC EXAM PHARMACOLOGY ELIMINATION HALF-LIFE Time Required for Drug Concentration to È 50% Diazepam TIME TO RECOVERY È Plasma Concentration Necessary for Patient to Awaken Thiopental Time to Achieve È Drug Concentration CONTEXT SENSITIVE HALF-LIFE Midazolam PREDETERMINED PERCENTAGE after STOPPING A CONTINUOUS INFUSION EFFECT SITE EQUILIBRATION Delay Between IV ADMINISTRATION of Drug & ONSET of Clinical Efficacy Propofol Ketamine STEADY STATE Administration = Elimination Etomidate CONTEXT SENSITIVE HALF LIFE DOSE RESPONSE CURVES AFFINITY The Inherent Nature of the Drug to Bind a Receptor POTENCY Measures Activity of a Drug (Amount Required to Produce an Effect of a Given Intensity) EFFICACY Maximum Magnitude of Effect of the Drug SLOPE Depicts the Relationship Between a Drug & Action An Integrated Goal-directed Narrative for the In-Training Exam 2. Which of the Following Drugs is Associated with PRO-DRUG PAIN ON INJECTION? A Drug that has Minimal/No Inherent Activity & MUST A. Dexmedetomidine C. Thiopental be METABOLIZED to Exert its Intended Effect B. Fospropofol D. Methohexital PHARMACOKINETICS ABSORPTION Drug LEAVES ADMINISTRATION SITE & Enters Bloodstream (UNCHARGED Drugs àÇ Absorption) Protein Binding pKa Influences END-ORGAN Accumulation INFLUENCED BY DISTRIBUTION Lipid Solubility Volume of Distribution Alteration of a Substance by a Metabolic Process (LIVERàPrimary Organ Responsible) PHASE 1 REACTION BIOTRANSFORMATION Transformation to Polar Metabolite (OXIDATION, REDUCTION, HYDROLYSIS) PHASE 2 REACTION Couples Drug or Metabolite to Endogenous Substrate (Ç Polarity for Excretion in Urine) IGNITE PHARM(B)-4 [An Integrated Goal-directed Narrative for the In-Training Exam] PHARMACOLOGHY – BASIC EXAM MOLECULE CHARACTERISTICS BIOTRANSFORMATION NON-IONIZED IONIZED LIVER >>> Kidney, Lung GI Tract PHARMACOLOGIC EFFECT ACTIVE NOT ACTIVE DEPENDENT UPON Hepatic Blood Flow SOLUBILITY ACTIVE NOT ACTIVE HEPATIC CLEARANCE Protein Binding CROSSES LIPID BARRIERS YES NO Intrinsic Activity of Enzymes RENAL EXCRETION NO YES EXTRACTION RATIO RATE OF PLASMA DRUG REMOVED BY ORGAN OF ELIMINATION HEPATIC METABOLISM YES NO FORMULA RATE OF PRESENTATION OF THE DRUG An Integrated Goal-directed Narrative for the In-Training Exam DRUG DISTRIBUTION TISSUE GROUP LOCATION BODY MASS PERCENTAGE (%) CARDIAC OUTPUT PERCENTAGE BRAIN HEART KIDNEY VESSEL-RICH 10 LIVER ENDOCRINE GLANDS 75 MUSCLE MUSCLE SKIN 50 20 FAT ADIPOSE 20 4 VESSEL-POOR BONE LIGAMENT CARTILAGE 20 1 3. How many Half-Lives Are Required for Complete Elimination of a Drug? TRANSFER ACROSS A LIPID BILAYER A. Two È Degree of Ionization È Molecular Weight B. Three Ç Lipid Solubility Ç Concentration Gradient C. Four D. Five Hepatic Disease Renal Disease TEMPORARY RESERVOIR OF DRUG Congestive Heart Failure PROTEIN BINDING Protein Bound DrugàUnavailable for End Organ Uptake INFLUENCED BY Cancer (Ç Size & Polarityà Unable to Pass Through Membranes) Myocardial Infarction Pregnancy Nutrition ALBUMIN Binds ACIDIC Drugs ⍺-1-ACID GLYCOPROTEIN Binds BASIC drugs ACUTE INFLAMMATORY STATE Ç ⍺-1-Acid Glycoprotein È Albumin END STAGE LIVER DISEASE & PREGNANCY PHYSIOLOGIC STATES AFFECTING PROTEIN BINDING È ⍺-1-Acid Glycoprotein È Albumin ELDERLY Unchanged ⍺-1-Acid Glycoprotein È Albumin IGNITE PHARM(B)-5 [An Integrated Goal-directed Narrative for the In-Training Exam] PHARMACOLOGHY – BASIC EXAM DRUG ELIMINATION ZERO ORDER KINETICS FIRST ORDER KINETICS Drug Cleared at CONSTANT RATE ZERO-ORDER KINETICS NOT DEPENDENT UPON PLASMA CONCENTRATION ELIMINATION PROPORTIONAL TO CONCENTRATION OF DRUG HALF-LIFE FIRST-ORDER KINETICS Describes Time Required for Concentration to Fall to 50% of Original Value An Integrated Goal-directed Narrative for the In-Training Exam 2-COMPARTMENT MODEL VOLUME OF DISTRIBUTION (VD) VD = Dose of Drug Administered Describes How the Body Theoretically Handles Drugs Administered as IV Bolus FORMULA Plasma Concentration SEQUENCE OF EVENTS A Theoretical Volume into Which Drug has Been Distributed FIRST Instantaneous Rise in Drug Concentration NOT A REAL NUMBER DISTRIBUTION/ ALPHA PHASE Represents Volume of Plasma to Account for Observed Plasma Concentration SECOND Initial Rapid È in Drug Concentration SMALL VD LARGE VD Redistribution of Drug Ç Intravascular Concentration È Intravascular Concentration (CENTRAL COMPARTMENT to PERIPHERAL COMPARTMENT) Hydrophilic Drugs Hydrophobic Drugs ELIMINATION/ BETA PHASE Ç Protein Binding È Protein Binding THIRD È Redistribution Ionized Drugs Non-Ionized Drugs (Elimination from the CENTRAL COMPARTMENT) È Lipid Solubility Ç Lipid Solubility QUESTION ANSWER KEY 1. B 2. D 3. D 4. C 4. Which of the Following is Associated with a LARGE Volume of Distribution (VD)? THERAPEUTIC WINDOW A. Intravascular concentration The Range Between Concentration Associated with Desired Therapeutic B. Ionized Drugs Effect and Concentration Associated with Toxic Drug Response C. Ç Lipid Solubility Narrow Window = Dangerous Medication D. Ç Protein Binding IGNITE PHARM(B)-6 [An Integrated Goal-directed Narrative for the In-Training Exam] PHARMACOLOGHY – BASIC EXAM BASIC EXAM STATISTICS (2015-2018) KEYWORDS YEAR NATIONAL PERCENT (%) CORRECT UNIVERSITY OF UTAH PERCENT (%) CORRECT DRUG METABOLISM: CLEARANCE 2015 74.8 42.9 DRUG ELIMINATION HALF-LIFE 2015 94.5 100 CONTEXT SENSITIVE HALF LIFE 2017 89.9 83.3 CONTEXT SENSITIVE HALF LIFE 2018 76.8 50 PHARMACODYNAMICS: DOSE RESPONSE CURVE 2018 98.7 100 83.4 100 2016 46.3 50 DRUG ELIMINATION KINETICS 2017 43.2 16.7 2018 84.6 80 PHARMACOKINETICS: FIRST ORDER 2015 76.9 83.3 PHARMACOKINETIC PRINCIPLES 2015 97 100 FIRST ORDER PHARMACOKINETICS 2017 68 55.7 PHARMACOKINETICS: FIRST ORDER 2018 78.8 83.3 VOLUME OF DISTRIBUTION: DETERMINANTS 2015 81.8 80 An Integrated Goal-directed Narrative for the In-Training Exam IGNITE PHARM(B)-7 .
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