O'Donnell's Drug Injury

PART I: THE PHARMACEUTICAL PROCESS Chapters 1 – 9 Chapter 1: FDA and Drug Approval Process Megan Walter, Pharm.D. and CDR Lindsay Wagner, Pharm.D., BCPS 1.1 Introduction 1.2 The New Drug Development Process A. Discovery and Preclinical Research B. Clinical Research C. Investigational New Drug Application D. Phases of Clinical Studies E. Expanded Access Programs F. Right to Try 1.3 New Drug and Therapeutic Biologic Application Process A. New Drug Applications and Biologic License Applications B. Fundamentals of NDA and BLA Submissions C. NDA Classifications 1.4 FDA Review A. Expedited Development and Review Programs 1. Accelerated Approval 2. Priority Review 3. Fast Track 4. Breakthrough Therapy B. Labeling Review 1. Physician Labeling Rule (PLR) 2. Pregnancy and Lactation Labeling Rule (PLLR) 3. Additional FDA-Approved Patient Labeling C. Risk Evaluation and Mitigation Strategies D. Advisory Committee Meetings 1.5 The Generic Drug Approval Process A. Abbreviated New Drug Applications B. ANDA Approval C. Generic Drug User Fee Amendments 1.6 Biosimilar Pathway 1.7 Over-the-Counter Drug Products 1.8 Postmarketing Surveillance A. Adverse Event Reporting B. FDA Adverse Event Reporting System C. Post Marketing Requirements and Commitments D. Sentinel Network E. Drug Safety Oversight Board 1.9 Applicable Statutes and Implementing Regulations A. Food and Drug Acts – 1906 B. Food, Drug and Cosmetic Act – 1938 C. Durham-Humphrey Amendment – 1951 D. Kefauver-Harris Amendment – 1962 E. Orphan Drug Act – 1983 F. Drug Price and Competition and Patent Term Restoration Act – 1984 1. Revision of New Drug Application Regulations - 1985 2. Revision of Investigational New Drug Application Regulations - 1987 3. Treatment Use of Investigational New Drugs - 1987 G. Prescription Drug User Fee Act (PDUFA) – 1992 H. FDA Modernization Act (FDAMA) – 1997 I. FDA Amendments Act (FDAAA) – 2007 J. Food and Drug Administration Safety and Innovation Act (FDASIA) – 2012 K. The Drug Quality and Security Act (DQSA) – 2013 L. 21st Century Cures Act – 2016 M. Food and Drug Administration Reauthorization Act (FDARA) – 2017 N. Coronavirus Aid, Relief, and Economic Security Act (CARES Act) – 2020 1.10 Conclusion 1.11 Glossary of Terms References Chapter 2: The Front Lines of Clinical Research: The Industry and Ethical Considerations Jonathan Young, Ph.D. 2.1 Introduction 2.2 Clinical Trial Service Providers A. Food and Drug Administration B. Clinical Trial Sponsor C. Contract Research Organizations D. Study Monitors 2.3 Clinical Trial Site A. Site Management Organizations B. Institutional Review Boards 2.4 The Evolution of Ethical Principles in Clinical Research A. Respect for Persons B. Beneficence C. Justice D. How the Investigator Applies Ethical Principles 2.5 Regulations Governing Institutional Review Boards A. What Institutional Review Board Members Should Know about Clinical Research B. What Institutional Review Board Members Should Know about Their Responsibilities 2.6 What the Site Should Know about Institutional Review Boards A. What Research Requires Institutional Review Board Approval and Oversight B. Requirements of an Investigator for Institutional Review Board Research Approval 2.7 Risks-vs.-Benefits Analysis: The Human Advocate A. Identifying and Assessing the Risks B. Minimal Risk vs. Greater-than-Minimal Risk C. Vulnerable Populations and Minimal Risk D. Determining Whether Risks Are Minimized E. Assessing Anticipated Benefits F. Determining Whether Risks Are Reasonable G. Continuing Review and Monitoring of Data 2.8 Informed Consent: Not Just a Document A. Elements of an Informed Consent B. Additional Required Elements 2.9 Research Participants 2.10 Industry Trade Organizations and Support Services 2.11 Summary: Ethical Dilemmas in Clinical Research References Chapter 3: Search and Analysis of the Food and Drug Administration’s FDA Adverse Event Reporting System (FAERS) Paul N. Danese, Ph.D. 3.1 Introduction 3.2 Background A. Small Clinical Trial Populations B. Narrow Patient Demographics C. Restricted Co-Administration of Medications 3.3 History of the FDA’s Drug Safety Surveillance Systems 3.4 Submission of Adverse Event Reports to the FDA A. Mandatory Reports B. Voluntary Reports 3.5 Adverse Drug Reaction Information Captured by FAERS 3.6 Searching FAERS Data to Identify Possible Safety Problems A. Statistical Methods to Identify Drug Safety Signals B. Dechallenge and Rechallenge Data and Causality C. Identifying Drug-Drug Interactions D. Timelines and Deadlines of Adverse Event Reporting 3.7 The Food and Drug Administration’s Use of FAERS in Regulatory Decisions A. Boxed Warnings B. Other Changes to a Medication’s Prescribing Information C. Determinations that No Action is needed and Continuing Investigations 3.8 Limitations of FAERS A. Lack of Demonstration of Causality for Individual Reports B. Extensive Under-reporting C. Reporting Biases D. Lack of Comparator Populations (Lack of a Denominator) 3.9 Search and Retrieval of Adverse Event Reports from the FDA’s FAERS A. Raw Data Files B. FDA Public Dashboard C. FOIA Requests D. Commercial Vendors 3.10 Other FDA Adverse Event Reporting Systems A. VAERS B. MAUDE C. Sentinel Initiative 3.11 Summary and Conclusions References Chapter 4: The Safety of Medicines: PharmacoVigilance, PharmacoSurveillance, PharmacoEmpowerment? David Healy, M.D. 4.1 RxISK.org 4.2 Antidepressants: Data Based or Evidence Based? 4.3 Access to Adverse Event Data 4.4 RCTs and Adverse Events // Ghost Writers 4.5 RCTs & Primary Endpoints 4.6 Post 1962: Confounding & Causality 4.7 Pharmacovigilance 4.8 RxISK.org and Pharmacovigilance 1.0 4.9 Pharmacosurveillance 4.10 TaperMD and Pharmacovigilance 2.0 4.11 Summary and Conclusions References Chapter 5: Important Code of Federal Regulations Applicable to Drug Product Liability Suits S. Albert Edwards, Pharm.D., RAC, FRAPS Chapter 6: The Regulation of Drug Product Information to Consumers Frank J. Ascione, Pharm.D., MPH, PhD 6.1 The Historical Development of Food and Drug Administration (FDA)’s Regulatory Role A. Early phase (prior to 1906): No significant government intervention B. Early Regulatory Phase (1906-1938): Minimal Government Control C. Greater Government Control (1938-1961) D. Debating Increased Consumer Access to Drug Product Information (1962-1983) E. Expanding Information Available to Consumers (1983-present) 6.2 Current State of Prescription Drug Product-Related Information Provided to Consumers 6.3 Evolution of Drug Advertising to US Consumers (DTCA) A. Emergence of DTCA (1981-1982) B. Voluntary Moratorium Period of DTCA (1983-1985) C. Establishment of DTCA Regulations (1985–1999) 6.4 Current State of Direct-to-Consumer Advertising A. Advantages and Disadvantages of DTCA 6.4 Summary and Conclusions References Chapter 7: The Role of Investigative Journalism in Improving Drug Safety Martha Rosenberg 7.1 Introduction 7.2 Direct-To-Consumer Advertising Increased with Covid A. Unbranded DTC Advertising B. Industry Funded Disease Awareness Groups C. Encouraging Victim Politics 7.3 The Opioid Epidemic A. Growing an Untapped Market B. Aggressive Opioid Marketing C. Fostering Opioid Addiction D. Pill Mills and Addiction Medicine E. Opioid Lawsuits Surface F. Lack of Opioid Efficacy and Serious Side Effects G. Paying for the Opioid Epidemic 7.4 Effective Hepatitis C Drugs Debut A. Lawmakers Investigate Hep C Prices B. Aggressive Hep C Marketing C. Screening as a Hep C Sales Tool D. Hepatitis C Safety Signals Emerge 7.5 Asthma Drug Safety Signals A. Xolair Leaves a Trail of Questions B. More Improper Xolair Marketing C. Safety Signals Surface with Xolair and a Lawsuit is Dismissed 7.6 Long-Acting Beta Agonists A. Glaxosmithkline Settlement included a Laba 7.7 Safety Questions About Leukotriene Receptor Antagonists A. Parents Report LTRA Side Effects B. LTRA Safety Signals Emerged Early C. Patients and Parents Fight Back D. Black Box Added to Singulair 7.8 Baldness Treatments Become Popular and Controversial A. Finasteride Side Effects Create Concern B. Medical Literature Confirms Finasteride Side Effects C. FDA Adds Warnings to Finasteride D. Finasteride User Speaks Out E. No Satisfying End for Finasteride Users 7.9 Biologic Drugs A. Tumor Necrosis Factor (Tnf) Blockers B. Tnf Blocker Risks 7.10 Other Popular Medications Come Under New Scrutiny A. N-Nitrosodimethylamine (NDMA ) Found in Medicines 1. Zantac Taken Off Shelves 2. NDMA Also Found in Metformin 7.11 Popular Stimulant Drugs Reveal Risks A. Risks Seen with Modafinil B. Fetal Risks Seen with Modafinil and Armodafinil C. European Union Sues Provigil Makers 7.12 Fetal Risk Seen with NSAIDs 7.13 Bisphosphonates Continue to Present Risks 7.14 SSRI Antidepressants Linked to New Risks A. SSRI Bone Thinning B. SSRI Addictive Potential 7.15 Belviq, A Diet Drug Withdrawn from Market 7.16 Sleeping Pills Given Boxed Warnings A. Public Figures on Sleeping Pills Make the News B. Other Sleeping Pill Risks 7.17 Risks Associated with Fluoroquinolone Antibiotics A. Fluoroquinolones Warnings Continue B. Hormone Therapy Still Linked to Risks C. Beware of Testosterone Marketing D. New PPI Questions References Chapter 8: Evaluation of Causation in Drug Injury Cases Donald H. Marks, M.D., Ph.D. and James T. O'Donnell, Pharm.D., M.S., FCP 8.1 What is Causation? 8.2 Importance of Establishing Causation 8.3 Definitions 8.4 Degree of Adverse Effects Relate to Intervention 8.5 Methodology to Investigate Causation 8.6 Structured Algorithms for Determination of Causation A. Hill Criteria—Expanded Discussion 1. Strength of Association 2. Consistency of Results 3. Specificity 4. Temporal Relationship 5. Dose Response 6. Biological Plausibility 7. Biological Coherence 8. Experimentation 9. Analogy 8.7 Comments on the Individual Riddell Criteria for Causation, 8.8 Daubert and the Evolution of Causation, 8.9 Does Causation Need to be Established Before a Warning is Given? 8.10 What are the Qualifications needed to Give Expert Causation Opinions? 8.11 Case Reports Demonstrating Applications of Causation Principles A. Case Report: Acyclovir Overdose – Pharmacist Recommended Overdose B. Case Report: Challenging Cause of Death in a Malpractice Matter C. Case Report: Determination of the Effects of Morphine in a Will Contest D. Case Report: Proof of Drug-Induced Mental Changes in Complainant in Sexual Abuse Case 8.12 Summary and Conclusions References Chapter 9: General Principles of Pharmacology James J. O'Donnell III, M.S., Ph.D., James T. O'Donnell, Pharm.D., M.S., FCP, and Vanessa Juettner, Ph.D. 9.1 Introduction 9.2 Basic Principles A. Absorption B. Lipid Diffusion C. Determinants of Absorption 1. Lipid/aqueous partition coefficient and pH 2. Bioavailability 3. First pass effect 9.3 Routes of Administration 9.4 Extravascular Administration A. Oral Administration B. Rectal Administration C. Other Routes of Administration 9.5 Intravascular Administration 9.6 Distribution A. Diffusion B. Volume of Distribution C. Binding to Plasma Proteins and Cellular Constituents D. Re-Distribution E. Blood-Brain Barrier (BBB) F. Placental Barrier G. Therapeutic Range H. Bioequivalence vs. Bioinequivalence 10.7 Drug Metabolism (Biotransformation) A. Phase I Reactions 1. The families of human P450s 2. Induction of P450 enzymes 3. P450 Inhibition B. Phase II Reactions 1. Metabolism of drugs to toxic products 9.8 Factors Affecting Drug Metabolism A. Disease B. Age C. Gender D. Genetic Factors 9.9 Drug Excretion A. Urinary Excretion 1. Glomerular filtration 2. Tubular secretion (active secretion) 3. Tubular reabsorption 4. Effects of pH on urinary excretion of ionizable drugs 9.10 Pharmacokinetics A. Introduction B. Therapeutic Window and Therapeutic Index C. Blood Levels for Narrow Therapeutic Index (NDI) Drugs D. Kinetic Modeling E. Drug Absorption and Elimination 1. Absorption rate 2. Elimination rate 3. Clearance (CL) 4. Area Under the Curve (AUC) 5. Elimination (k) 6. Elimination half-life 7. Steady state F. Dosing 1. Loading dose 2. Maintenance doses (MD) 3. Example—dosage adjustment in renal impairment G. Therapeutic Drug Monitoring (TDM) H. Pharmacokinetics Summary 9.11 Drug Receptor and Pharmacodynamics A. Agonists and Antagonists B. Drug-Receptor Interactions 9.12 Dose Responses A. Potency B. Agonism and Antagonism 1. Partial agonists 9.13 Competitive Antagonism 9.14 Non-Competitive Antagonism 9.15 Summary and Conclusions PART II: HIGH RISK DRUG THERAPIES RESULTING IN INJURY AND LITIGATION Chapters 10 - 25 Chapter 10: Adverse Drug Reactions: Allergic Focus James T. O'Donnell Pharm.D., M.S., FCP and James J. O'Donnell III, M.S., Ph.D. 10.1 Adverse Drug Reactions: How Large is the Problem? What Drugs are Involved? What are the Injuries? A. Historical Perspective B. Incidence of Adverse Drug Reactions C. Food and Drug Administration Reporting Requirements D. The “Seven Deadly Sins”: Why Doctors Fail to Report Adverse Drug Reactions E. Attitudes Toward Adverse Drug Reactions F. Investigator Fraud 10.2 Classification of Adverse Drug Reactions A. Categories of Adverse Drug Reactions 1. Type A reactions: Augmentation of the Pharmacological Response 2. Type B reactions: Bizarre (idiosyncratic) 10.3 Types of Drug Allergy and Hypersensitivity A. The Nature of Drug Allergy B. Dangerous Drug-Allergy Reactions C. Drug Sensitivities Mimic Allergy Symptoms D. Definitions of Allergic/Hypersensitivity Reactions E. Idiosyncratic Reactions F. Intolerance G. Toxicity H. Hypersensitivity Vasculitis I. Predominantly Organ-Specific Reactions J. Urticaria K. Fixed Drug Eruptions L. Photosensitivity Reactions M. Generalized Exfoliative Dermatitis N. Thrombocytopenia O. Hemolytic Anemia P. Agranulocytosis Q. Treatment: Withdrawal of the Suspected Drug R. Symptomatic Treatment S. Prevention of Allergic Drug Reactions T. Pseudoallergy U. Angioedema V. Hypersensitivity Reactions 10.4 Risk Factors, Drugs and Patients A. Hypersensitivity Risk Factors B. Identification of a Drug Allergy C. Allergy to Antibiotics D. Case Report: Cross-Allergenicity 10.5 Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis A. Fixed Drug Eruptions B. Erythema Multiforme-Like Eruptions Case Report: Lamictal Induced Stevens Johnson Syndrome C. Fluoroquinolones E. NSAIDs Cross Reactivity Case Report F. Radiographic Contrast Media G. Local Anesthetics H. Anticonvulsants (AED) 10.6 Summary and Conclusions References Chapter 11: Drug Induced Falls James T. O'Donnell Pharm.D., M.S., FCP and James J. O'Donnell III, M.S., Ph.D. 11.1 Introduction 11.2 The Definition of Fall 11.3 Epidemiology 11.4 Causes and Risk Factors A. Physiological Risk Factors for Falls in the Elderly B. Psychological Risk Factors C. Medical Conditions 11.5 Medication-related Falls 11.6 Types of Medications that Increase the Risk of Fall A. Centrally Active Medications B. Benzodiazepines C. Antipsychotics D. Antihypertensives 1. Orthostatic Hypertension and Risk of Fall E. Opioids 11.7 Marijuana 11.8 Alcohol 11.9 Hip Fractures 11.10 Polypharmacy 11.11 Fall Risk Assessment 11.12 Types of Assessments 11.13 Strategies for Fall Prevention in Institutionalized Settings A. Screening B. Addressing Risk Factors 1. Monitoring Patients 2. Environmental Interventions 3. Educational Programs 4. Reducing Fall Injury C. Discharge Planning D. Disseminating Evidence: Awareness and Intervention Work! 11.14 Summary and Conclusions References Chapter 12: Drug Induced Movement Disorders Jadwiga Najib, B.S. Pharm.D., BCPS, and Meagan Bailey, M.D. 12.1 Introduction 12.2 Presentation 12.3 Agents Associated with Drug-Induced Movement Disorders 12.4 Risk Factors 12.5 Sequelae of Drug-Induced Movement Disorders 12.6 Theories of Causation 12.7 Drug-Induced Movement Disorders in Children and Adolescents 12.8 Drug-Induced Movement Disorders in the Elderly 12.9 Acute/Intermediate Drug-Induced Movement Disorders A. Dystonia 1. Presentation 2. Implicated agents 3. Risks 4. Management B. Ataxia C. Bruxism D. Neuroleptic Malignant Syndrome E. Serotonin Syndrome 12.10 Chronic Drug-Induced Movement Disorders A. Akathisia 1. Presentation 2. Case study: Trazodone-induced akathisia 3. Implicated agents 4. Other drugs 5. Risks 6. Management B. Parkinsonism 1. Presentation 2. Case Study: Neuroleptic-Induced Parkinsonism 3. Implicated agents 4. Other drugs 5. Risks 6. Management C. Myoclonus, Tremor, Tics, Asterixis 12.11 Persistent/Tardive Drug-Induced Movement Disorders A. Tardive Dyskinesia 1. Presentation 2. Case Study: Neuroleptic induced oral buccal dyskinesia and akathisia 3. Implicated agents 4. Case Study: Metoclopramide induced oral buccal lingual dyskinesia 5. Risks 6. Management B. Tardive Akathisia C. Tardive Dystonia 1. Case Report: Neuroleptic induced cervical dystonia D. Other Tardive Variants 12.12 Drugs Used for Movement Disorders 12.13 Monitoring 12.14 Clinical and Legal Issues in Psychiatry 12.15 Summary and Conclusions References Chapter 13: Acute Adverse Drug Events in Critical Care Emergency Department and Intensive Care Units Gourang P. Patel, Pharm.D., M.Sc., BCPS, BCCCP, FCCM 13.1 Background A. Epidemiology B. Environment 13.2 High-Risk Medication-Related Events A. Hypersensitivity Reactions B. Cardiovascular Reactions 1. Blood pressure (BP) 2. Heart rate (HR) 3. Arrhythmias C. Nephrotoxicity 1. Aminoglycosides 2. Amphotericin B 3. Intravenous contrast D. Hypoglycemic Events E. Infusion-Related Reactions 1. Extravasations 2. Propofol-related infusion syndrome (PRIS) 3. Intravenous N-acetylcysteine (NAC) F. Reversal Agents 1. Protamine 2. Vitamin K 3. Naloxone 4. Flumazenil 13.3 Summary and Conclusions References Chapter 14: Nephrotoxic Drugs Jason M. Kidd MD, Domenic A. Sica, M.D. and Todd W. B. Gehr, M.D. 14.1 Introduction 14.2 Framework of the problem 14.3 Basis for the kidney being susceptible to damage 14.4 Patient groups most susceptible to nephrotoxicity 14.5 Demographics of chronic kidney disease 14.6 Methods to assess renal function and/or damage 14.7 Level of renal function at which drug accumulation occurs 14.8 Nephrotoxic drugs A. What constitutes prompt clinical action in the face of nephrotoxicity? 14.9 Nephrotoxicity scenarios A. Lithium toxicity B. Gentamicin toxicity C. Dialysis-related issues D. Drug Clearance in Relationship to Renal Failure 1. Case 1 2. Case 2 E. Angioedema with an ACE inhibitor F. Fatal hyperkalemia with medications G. Statin therapy and the development of myopathy H. Nephrotoxicity related to checkpoint inhibitor use 14.10 Summary and Conclusions References Chapter 15: Drug Induced Liver Disease James T. O’Donnell, Pharm.D., M.S., FCP, James J. O’Donnell III, M.S., Ph.D., Donald H. Marks, M.D., Ph.D., Paul Danese, Ph.D. 15.1 Introduction: The Problem of Drug-Induced Liver Disease 15.2 History of Adverse Drug Reactions 15.3 Overview of DILD, Epidemiology Risk Factors, Histopathology, and Diagnoses A. Epidemiology of Drug Hepatotoxicity B. Risk Factors C. Histopathology D. Diagnosis 15.4 Hepatic Drug Metabolism 15.5 FDA and DILD 15.6 Types of Liver Injury A. Hepatitis B. Massive Hepatic Necrosis (Fulminant Hepatitis) C. Drug-induced Vanishing Bile Duct Syndrome 15.7 Specific DILD Product Areas and Case Discussions A. Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Use and Hepatoxicity B. Isoniazid-Induced Hepatotoxicity C. Acetaminophen 1. Acetaminophen Toxicity Assessment Nomograms 2. FDA Report - Acetaminophen Induced Liver Disease D. Macrolide Hepatotoxicity E. Methotrexate (MTX) Hepatotoxicity F. Estrogens and Oral Contraceptive Steroids G. Statins H. Ticlopidine I. ACE Inhibitors and AT II Receptor Antagonists J. Fluoroquinolones K. Terbinafine L. Ketoconazole M. Selective Serotonin Reuptake Inhibitors – Serzone Liver Toxicity N. Herbal and Other Dietary Supplements and Hepatotoxicity 15.8 Summary and Conclusions References Chapter 16: Antineoplastic Therapy Kathryn Schultz, Pharm.D. and Eris Tollkuci, Pharm.D. 16.1 Background 16.2 Chemotherapy - Antimetabolites 16.3 Chemotherapy - Antimicrotubules 16.4 Chemotherapy - Alkylators 16.5 Chemotherapy - Topoisomerase I Inhibitors 16.6 Chemotherapy - Topoisomerase II Inhibitors 16.7 Chemotherapy - Antitumor Antibiotics 16.8 Chemotherapy - Miscellaneous 16.9 Targeted Therapy A. Infusion-related reactions (IRRs) B. Immunotherapy (Immune Checkpoint Inhibitors) 1. Infusion-related reactions 2. Immune-Related Adverse Events (irAEs) 16.10 Tumor Lysis Syndrome 16.11 Hepatotoxicity 16.12 Summary and Conclusions References Chapter 17: Dangers of Opioids Jennifer Splawski, M.S., Pharm.D., BCPS, James T. O’Donnell, M.S., Pharm.D., James J. O’Donnell III, M.S., Ph.D. 17.1 Introduction A. Definitions B. History 17.2 Pharmacology of Opioids A. Effects B. Opioid Neural Receptors 1. Central Nervous System (CNS) Receptors 2. Peripheral Nervous System (PNS) Receptors C. Routes of Administration 1. Oral 2. Intramuscular 3. Subcutaneous 4. Intravenous 5. Transdermal 6. Sublingual and Buccal 7. Neuraxial D. Metabolism E. Excretion 17.3 Toxicity of Opioids A. Respiratory Depression B. Symptoms of Overdose 17.4 Epidemiology of Opioid Abuse A. Opioid Abuse in Adolescents and Young Adults B. Opioids in Pregnancy 17.5 Contributions to the Opioid Epidemic A. Opiates Handed Out Like Candy to ‘Doped-up’ Veterans B. United States Reaches $22 Million Settlement Agreement with CVS For Unlawful Distribution of Controlled Substances C. Former Walmart Pharmacists Say Company Ignored Red Flags as Opioid Sales Boomed D. Federal Judge Approves Landmark $8.3 Billion Purdue Pharma Opioid Settlement 17.6 Combatting the Opioid Epidemic A. Prescription Monitoring Programs (PDMP) B. Naloxone Dispensing C. Medication for Opioid Use Disorder (MOUD) 1. Buprenorphine A. Pharmacokinetics B. Adverse Effects C. Place in therapy 1. Methadone A. Pharmacokinetics B. Equianalgesic Dosing C. Drug Interactions D. Cardiovascular Effects E. Consequences of Ignorance of Proper Dosing of Methadone F. Methadone Legal Case Examples Involving Patient Demise G. Applying Lessons Learned and Action for Institutional Committees 17.7 Case Reports: Opioid Toxicity Causing Respiratory Arrest, Brain Damage, and Death A. Case Report: Respiratory Arrest and Brain Damage Following Morphine Overdose B. Case Report: Fentanyl Epidural Respiratory Arrest C. Case Report: Fentanyl (Duragesic®) Death in Discharged Patient D. Case Report: High Dose Fentanyl Patch Prescribed in Opiate-Naïve Patient—Death E. Case Report: Heroin and Other Opioids F. Case Report: Hydromorphone (Dilaudid®) Respiratory Arrest 17.8 Investigation and Prosecution of Pain Clinics by the Department of Justice (DOJ) 17.9 Summary and Conclusions References Chapter 18: Adverse Effects of Diabetic Drugs: Focus on Hypoglycemia Gourang P. Patel, BS Chem, PharmD, MSc, BCPS and James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN 18.1 Diabetes Demographics and Epidemiology 18.2 Insulin 18.3 Insulin Preparations 18.4 Clinical Use of Insulin A. Dosing 18.5 Hypoglycemia (Low Blood Sugar) A. Etiologies of hypoglycemia B. Insulin-induced hypoglycemia C. Deaths by Hypoglycemia 18.6 Pathophysiology and Clinical Symptoms of Hypoglycemia 18.7 Incidence 18.8 Pathophysiology and Biochemistry of Hypoglycemia 18.9 Adverse Reactions Involving Hypoglycemia A. Insulin damages baby’s brain; pharmacist error suggested 18.10 End Product Testing Recommended 18.11 Insulin Murders 18.12 Hypoglycemia from the Sulfonylurea Derivatives 18.13 Adverse Effects of the Sulfonylureas 18.14 Drug Interactions with Sulfonylureas 18.15 The Gliptin Class New drugs for Diabetes Treatment Type 2 Diabetes 18.16 Thiazolidinediones A. Hepatic Failure B. Bladder Cancer 18.18 Summary and Conclusions References Chapter 19: Parenteral Nutrition Related Errors and Complications Erica M. Fernandez, Pharm.D., BCCCP, BCPS 19.1 Introduction 19.2. Basic principles of PN 19.3 PN Provision Categories A. Prescribing B. Transcribing and Verification C. Compounding D. Administration 19.4. Monitoring and Complications A. Glycemic Control B. Refeeding Syndrome C. Hepatobiliary Complications D. Complications involving micronutrients 19.5 PN Component Shortages and Adverse Events 19.6 Summary and Conclusion References Chapter 20: Antidepressants: Clinical Use and Litigation Henry Cohen, Pharm.D., M.Sc., FCCM, BCPP, BCGP and Michael Liu, Pharm.D., MBA, BCCCP, BCNSP, BCPS 20.1 Major Depressive Disorders 20.2 Antidepressant Pharmacology 20.3 Antidepressant Overdose A. Trazodone and Permanent Neurologic Sequelae 20.4 Antidepressants and the Patient with Suicidal Ideation A. Prozac and Suicidal Ideation 1. Woulfe v. Eli Lilly & Co. 2. Espinoza v. Eli Lilly & Co. 3. Cassidy v. Eli Lilly & Co B. Paxil and Suicidal Ideation 1. Dolin v. GlaxoSmithKline C. Antidepressant and Increased Suicidality in Pediatrics 1. Schilf v. Eli Lilly & Co. 20.5 Broken Heart Syndrome: Tako Tsubo Cardiomyopathy Associated with Use of Antidepressants 20.6 The Adverse Effects of Antidepressants and the Duty to Warn A. Docken v. Ciba-Geigy B. Stebbins v. Concord Wrigley Drugs, Inc. et al. C. Morgan et al. v. Wal-Mart Stores, Inc. D. Kampmann v. Mason E. Cottam v. CVS 20.7 Antidepressants and Alcohol A. Kirk v. Michael Reese Hospital B. Hand v. Krakowski 20.8 Selective Serotonin Reuptake Inhibitors and the Serotonin Syndrome 20.9 Hepatic Cytochrome P450 Drug Interactions and Cyclic Antidepressants 20.10 Antidepressants and Herbal Agents Drug Interactions 20.11 Serzone and Liver Disease 20.12 High Blood Pressure Associated with Venlafaxine Use 20.13 SSRI use and Birth Defects 20.14 Bupropion XL and Seizures 20.15 The Pharmacist’s Role 20.16 The Omnibus Budget Reconciliation Act 20.17 How Safe is it to Buy Prescription Medications Over the Internet? 20.18 In a Perfect World 20.19 Summary and Conclusions References Chapter 21: Contrast Media Neurotoxicity Following Myelography Stephanie E. Tedford, Ph.D., and James T. O’Donnell, Pharm.D., M.S., FCP 21.1 Introduction 21.2 Case Reports A. Case I Intrathecal Iopamidol B. Case II Intrathecal Iothalamate 21.3 Discussion A. Mechanisms for cerebral (neurotoxic) injury B. Contrast-induced neurological and cognitive deficits C. Contrast-induced visual and auditory impairment: Further evidence for cerebral insult to cortical brain structures 21.4 Summary and Conclusions References Chapter 22: Fetal Drug Exposure Damani Parran, Ph.D., MBA, DABT, James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, James J. O’Donnell III, M.S., Ph.D. 22.1 Introduction 22.2 Critical Periods of Human Development and Susceptibility 22.3 Special Considerations of Drug Exposure during Pregnancy 22.4 Historical Human Developmental Toxicants A. Thalidomide B. Ethanol C. Diethylstilbestrol D. Retinoids E. Cocaine 22.5 Developmental Toxicity of Prescription Drugs A. Valproic Acid B. Phenytoin C. Warfarin D. Benzodiazepines 22.6 Additional Prenatal Environmental Influences A. Malnutrition B. Poverty C. Emotional State D. Mother’s Age E. Infections and Diseases 22.7 FDA Pregnancy Categories for Prescription Drug Labeling; Final Rule 22.8 Analyses of Litigated Cases Alleging Fetal Drug Injury A. Effects of Methadone and Smoking on the Fetus B. Effects of Lisinopril on Fetus – Defense of Causation 22.9 Summary and Conclusions References Chapter 23: Geriatric Medication Misadventures Rodney G. Richmond, M.S., Pharm.D., BCGP, FASCP and James C. Norris, Ph.D., DABT, ERT 23.1 Introduction A. Outpatient Medication Use B. Hospital Medication Use C. Long-Term Care Medication Use 23.2 Altered Clinical Response to Drugs A. Pharmacokinetics B. Pharmacodynamics 23.3 Preventable Drug-Related Problems A. Polypharmacy B. Transitions of Care C. Inadequate Monitoring D. Potentially Inappropriate Medication Use 23.4 Legal Cases Application 23.5 Summary and Conclusions References Chapter 24: Medication Errors James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, R.Ph. and James J. O’Donnell III, M.S., Ph.D. 24.1 History and Overview 24.2 Medication Errors in Epidemic Proportions 24.3 Types of Medication Errors A. Enhancing Healthcare Team Outcomes B. Improving Reporting of Medication Errors 24.4 Medication Use Process 24.5 System Errors 24.6 Which Drugs are Most Often Involved in Medication Errors? 24.7 Prevalence of Medication Errors 24.8 Vaccine Errors 24.9 How has Modern Research Improved Therapeutics and Reduced Drug-Related Morbidity? Pharmacogenomics 24.10 Systems for Medical Error Prevention A. Electronic Prescribing (E-prescribing) B. When Electronic Prescribing is Unavailable C. Effective Drug Monitoring Systems D. The Importance of Continuing Education E. Reporting All Adverse Drug Events 24.11 Summary and Conclusions References Chapter 25: Anticoagulants: Therapeutics, Risks, And Toxicities James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, James J. O’Donnell III, M.S., Ph.D., Stephanie E. Tedford, Ph.D. 25.1 Introduction 25.2 Summary of Anticoagulant Therapy A. Definition B. Use 1. Treatment of coronary heart disease 2. Warfarin and dabigatran 3. Treatment of thrombogenesis 25.3 Limitations of Current Therapy A. Heparin B. Low Molecular Weight Heparin (LMWH) C. Heparin-Induced Thrombocytopenia (HIT) 1. Pathogenesis of the autoimmune response 2. Pathogenesis of the prothrombotic state 3. Clinical presentation of HIT 4. Diagnosis a. Dismissing HIT b. Diagnosing HIT 2. Two Approaches: class and titer 5. Treatment of HIT a. Fondaparinux b. Re-exposure to heparin 6. Conclusion HIT and HITT D. Warfarin 25.4 Monitoring Warfarin Oral Anticoagulation 25.5 Alternatives to Warfarin - DOACs A. Pradaxa (Dabigatran) vs. Warfarin B. Direct Oral Anticoagulation (DOAC) Therapies C. DOAC reversal agents D. Antiplatelet Therapy 25.6 Summary and Conclusions References Part III: PHARMACISTS, PHARMACY AND PHARMACY PRACTICE Chapters 26 - 33 Chapter 26: Pharmacy Practice, Managed Care, And Manufacturers F. Randy Vogenberg R.Ph., Ph.D. and Rita Marcoux R.Ph., MBA 26.1 Introduction to Pharmacy and the Related Managed Health Care Environment 26.2 Pharmacists as Health Care Professionals: Training, Support Staff, and Life-long Learning A. Registration, Certifications, Credentialing, Colleges Of Pharmacy, And Accreditation Matters For Pharmacy Professional Staff 26.3 Practice Sites: Inpatient, Ambulatory/Community, Specialty, Long Term Care, and Other (compounding, nuclear) A. Practice settings, Practice site Certification, Pharmacist practice versus the Business of pharmacy, Credentialing, and Accreditation matters 26.4 Issues for Pharmacy Practice, Insurance, and Managed Care In the Near Future A. The landscape of Practice Sites and Changing Business of Health Landscape 26.5 Current and Near Future Issues for Pharmacists A. Landscape of Pharmacy Practice, The Changing Professional Marketplace 26.6 Pharmaceutical Manufacturer Through Wholesaler and Distribution Supply Chain 26.7 Manufacturers: Traditional and Innovative Segments A. Non-Biologic Medications B. Research­Intensive, Biologics, Gene, and Generic Segments 1. Biologic Medications 26.8 Pharmaceutical Manufacturer Customers A. Organization and Operations B. Other Targeted Customer and Class of Trade Segments C. Contracting and Change in the Pharmaceutical Industry 26.9 Health Care Industry Changes in the Near Future 26.10 Summary and Conclusions References Chapter 27: The Pharmacist’s Utilization of the National Patient Safety Goals to Contribute to Safe and Effective Medication Use Jennifer Splawski, Pharm.D., MS, BCPS and Heather Minger, Pharm.D., BCPS 27.1 Introduction A. Overview of ‘The Goals’ 27.2 Goal 3 and the Pharmacist's Role A. NPSG.03.05.01 relating to Anticoagulation 1. Introduction 2. Warfarin Overview 3. Patient monitoring 4. Patient Education 5. Direct Oral Anticoagulant 6. Anticoagulation Reversal Overview 7. Anticoagulation Reversal Programs 8. Patient Education B. NPSG.03.06.01 relating to Reconciling Medication Information 1. Introduction 2. The Process of Medication Reconciliation 3. Improved Accuracy 4. Decreased Mortality 5. Allergy Identification 6. Discharge Medication Reconciliation 7. Utilization of the Pharmacist Extenders in Medication Reconciliation 27.3 Summary and Conclusions References Chapter 28: Pharmacist Malpractice and Liability James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN and James J. O’Donnell III, M.S., Ph.D. 28.1 Introduction 28.2 The Science of Risk Management 28.3 Claims Studies The Pharmacists Mutual Claims Study CNA Claims Study (CNA/HPSO) A. CNA Database and Methodology B. Most Common Categories of Errors C. Claim Analysis by Insurance Source & Licensure Type: Pharmacists v. Technicians D. Factors Affecting Wrong Drug Dispensing Errors E. Drugs Involved in Claims F. Most Common Error: Wrong Drug G. Wrong Drug Strength H. Wrong Directions I. Wrong Route of Administration J. Lack of Drug Review K. Counseling: A Powerful Weapon Against Liability L. Non-Bodily Injury M. Miscellaneous Errors N. Wrong Directions O. Lack of Drug Review P. Avoiding Errors and Malpractice 28.4 Specific Pharmacist Malpractice Case Reports / Topics A. Duty to Warn? B. Wrong Drug C. Quotas and Metrics: Contributing to the Problem? D. Controlled Substances Violations by Pharmacists E. Methotrexate (MTX) errors 28.5 Pharmacists Need to do the Right Thing 28.6 Steps Toward a Better Outcome 28.7 Summary and Conclusions References Chapter 29: Regulation of Pharmacy Practice Ned Milenkovich, Pharm.D., J.D. 29.1 Introduction 29.2 Licensure of Professional Activities A. Boards of Pharmacy – A Closer Look B. National Association of Boards of Pharmacy 29.3 Practice Standards A. Legally Circumscribing Pharmacy Practice 29.4 Licensure Process to Practice Pharmacy A. Licensing B. Licensing of Pharmacists 29.5 The Different Types of Pharmacy Licenses A. Disciplinary Actions B. Causes of Disciplinary Action C. Practice Focus on Licensure D. Ongoing Professional Education E. Support Personnel 29.6 Federal Drug Laws A. Obra ‘90 B. Medicare C. Medicare Part D D. Medicaid E. Prescription Drug Coverage F. Fraud, Waste and Abuse G. 340b Drugs H. Pharmacy Compounding I. FDA Rems J. DEA 29.7 Pharmacy Practice: Putting it Together A. Pharmacy Practice: An Ongoing Progression B. Collaborative Practice Agreements C. Drug Utilization Review (DUR) D. Other Mandates Impacting Pharmacy Practice Quality Assurance Regulations E. Health Insurance Portability and Accountability Act Of 1996, As Amended Chapter 30: Emergency Department Pharmacist Victor Cohen, B.S., Pharm.D., BCPS, CGP, Samantha P. Jellinek-Cohen, Pharm.D., BCPS, CGP, Megan Musselman Pharm.D., M.S., BCPS, BCCP 30.1 Introduction 30.2 Epidemiology of Drug Injury and Contributing Risk Factors A. Contributing Risk Factors 30.3. Etiology and Sources of Drug Injury in the ED 30.4 Clinical Pharmacy in the ED: A Historical Perspective 30.5 The ED Pharmacist Plays a Dual Role at Maimonides Medical Center 30.6 The ED Pharmacist: A Sub-specialist in Emergency Medicine A. Training and Education B. Certification 30.7 The ED Pharmacist as a Generalist 30.8 The ED Pharmacist Ensuring Optimal Continuum of Care A. The ED and Infectious Diseases B. The ED Pharmacist and the Ambulatory Care Interphase C. The ED Pharmacist and Transitions of Care (TOC) 1. Medication admission notes in the ED D. The ED Pharmacist as a Clinical Toxicology Consultant E. The ED Pharmacist and the Cardiology Interface F. The ED Pharmacist and Neurological Emergencies G. The ED Pharmacist and Pulmonary Emergencies H. The ED Pharmacist and Public Health Services in the ED 30.9 Building Layers of Defense Against Drug Injury A. Detecting and Preventing Drug Injury in the ED B. The ED Pharmacist and Community Surveillance for Adverse Drug Reactions 30.10 Pharmacy Practice in the ED: Pharmacotherapy Specialty 30.11 Summary and Conclusions References Chapter 31: Pharmacy Case Law Review Roger N. Morris, R.Ph., J.D., and William J. Stilling, R.Ph., M.S., J.D. 31.1 Administrative Law A. Due Process–Pharmacist Licensure 1. Berjikian, et al. v. Franchise Tax Board et al., No. CV 13–06301 DDP, 2015 WL 1185472 (C.D. Cal. March 12, 2015) 31.2 Antitrust A. State Regulatory Boards Immunity 1. North Carolina Bd. of Dental Examiners. v. Federal Trade Commission, 135 S. Ct. 1101 (Feb. 25, 2015) 31.3 Civil Procedure A. Spoliation of evidence–Pharmacy’s Duty to Maintain Evidence of Misfill 1. Burton v. Walgreen Co., 2015 WL 4228854 (D. Nev. July 10, 2015) 31.4 Conscientious Objection A. Emergency Contraception 1. Stormans, Inc. v. Wiesman, 794 F.3d 1064 (9th Cir. 2015) 31.5 Controlled Substances A. Duty to Verify DEA Registration 1. Farmacia, Yani, 80 Fed. Reg. 29,053 (May 20, 2015) 2. JM Pharmacy Group Inc., d/b/a/ Farmacia Nueva and Best Pharma Corp., 80 Fed. Reg. 28,667 (May 19, 2015) B. Constitutionality 1. McFadden v. United States, 135 S. Ct. 2298 (June 18, 2015) 31.6 Criminal A. Violations of Pharmacy Law Applied to Non-pharmacists 1. Moore v. State of Florida, NO. 1D14-3527, 2015 WL 4464689 (Fla. Dist. Ct. App. July 21, 2015), reh’g denied (Sept. 1, 2015) B. PMP Records 1. Lundy v. State, 26 N.E.3d 656 (Ind. Ct. App. Feb. 20, 2015) C. Second Degree Murder 1. U.S. v. Barry J. Cadden, et al., 2014 WL 7151586 (D. Mass. Dec. 16, 2014) 31.7 Defamation A. Physician against Pharmacist 1. LeFrock v. Walgreen Co., 77 F. Supp.3d 1199 (M.D. Fla. Jan. 16, 2015) B. Duty to Fill 1. Kadambi v. Express Scripts, 2015 WL 475373 (N.D. Ind. February 5, 2015) 31.8 Employment A. Discrimination (Pregnancy) 1. Torres-Skair v. Medco Health Solutions, Inc., 595 F.App’x 847 (11th Cir. Dec., 4, 2014) B. Employment at Will 1. Hoven v. Walgreen Co., 751 F.3d 778 (6th Cir. June 2, 2014) C. Americans with Disability Act 1. Stevens v. Rite Aid Corp., et al., 6:13-cv-00783 (N.D.N.Y., September 23, 2015) D. Overtime Class Action 1. Baugh v. CVS Health, et al., 2:15-cv-00014 (E.D. Penn., July 27, 2015) E. Medical Marijuana 1. Coats v. Dish Network, 350 P. 3d, 849 (Colo. June 15, 2015) 31.9 Fraud and Abuse F. False Claims 1. United States v. Express Scripts, Inc., 602 F. App’x 880 (3rd. Cir. Feb. 20, 2015) G. False Claims–Generic Substitutions 1. Doe v. Houchens Indus., Inc., No. 1:13-CV-00196-RLY, 2015 WL 133706 (S.D. Ind. Jan. 9, 2015) H. False Claims & Anti-Kickback Statute 1. U.S. ex rel. Kester v. Novartis Pharm. Corp., No. 11 CIV. 8196 CM, 2015WL 1650767 (S.D.N.Y. Apr. 10, 2015) I. Consumer Fraud 1. City of Chicago v. Purdue Pharma L.P., 2015 WL 2208423 (N.D. Ill. May 8, 2015) 31.10 Negligence A. Duty to Provide Medication 1. Davies v. Virginia CVS Pharmacy, LLC, et al., 7:14-CV-00175, 2014 WL 6460787 (W.D. Va. Nov. 17, 2014) B. Duty Not to Dispense 1. Oleckna v. Daytona Disc. Pharmacy, 162 So. 3d 178 (Fla. Dist. Ct. App. 2015) 31.11 Privacy C. Patient Privacy–Vicarious Liability 1. Walgreen Co. v. Hinchy, 25 N.E.3d 748 (Ind. Ct. App. Jn. 15, 2015) reh’g of, 21 N.E.3d 99 (Ind. Ct. App. Nov. 14, 2014) D. Text Messages 1. Thompson v. CVS Pharmacy, Inc., 6:204-cv-02081 (M.D. Fla. Dec. 19, 2014) E. Robocalls 1. Kolinek v. Walgreen Co., 2014 WL 3056813, (N.D. Ill. July 7, 2014) 31.12 Product liability A. Learned Intermediary Doctrine 1. Watts v. Medicis Pharm. Corp., 342 P.3d 847 (Ct. App. 2015), review granted in part (Sept. 22, 2015) B. Product Liability (applicability to pharmacists) 1. Randol Mill Pharmacy v. Miller, 465 S.W.3d 612 (Tex. 2015), reh’g denied (Sept. 11, 2015) Chapter 32: Pharmacy Compounding – Patient Injury and Regulatory Compliance Willis C. Triplett, Pharm.D. 32.1 Introduction 32.2 Compounding Trends and Driving Forces 32.3 Optimizing the Regulatory Balance Between “Manufacturing” versus “Compounding” 32.4 Investigations, Indictments, Convictions, and Acquittals after the Fungal Meningitis Outbreak 32.5 Memorandum of Understanding (MOU) 32.6 U SP, NABP, and the State Pharmacy Regulatory Authorities 32.7 Physician and Medical Office Compounding 32.8 Compounding “Center of Excellence” (“COE”) and the Quality Assurance Paradigm Shift 32.9 Conclusions and Forecasts Regarding Patient Injury from Healthcare Compounding 32.10 Recommended Readings CHAPTER 33: Compounding Pharmacy Fraud and Unethical Practices James T. O'Donnell, Pharm.D., M.S., FCP 33.1 Introduction 33.2 Criminal Prosecutions of Pharmacy Compounders 33.3 Over-Prescribing and Over-Charging of Compounded Drugs A. Department of Justice News Releases B. News Reports in Newspapers 33.4 Not Yet Criminal? Insurance Companies Fighting Back A. No-Fault Pain Compounded and Topical Pain Product B. Report Challenging the Pricing and Efficacy of a Compounded Pain Cream Prescription C. Ingredients and Costs of Pain Cream 33.5 General Discussion – Compounded Pain Topical Creams A. Evidence of Efficacy? B. Expensive Ingredients 33.6 Ingredients Review of Efficacy and Mechanism of Action A. Diclofenac B. Menthol (Methyl Salicylate) C. Lidocaine 1. Lidocaine Topical Toxicity D. Amitriptyline E. Cyclobenzaprine F. Dimethylsulfoxide (DMSO) 33.7 Global Opinions for the Prescription CPTM formula 8-NC Claim Challenge 33.8 Discussion and Further Bases of Opinions 33.9 Overbilling of Topical Diclofenac Gels, Lidocaine Creams and Ointments and Patches A. Diclofenac 3” (Solaraze) B. Lidocaine Topical Commercial Products 33.10 Recommendations 33.11 Summary and Conclusions References Part IV: FORENSIC AND TOXICOLOGY ISSUES Chapters 34 – 42 Chapter 34: Alcohol James T. O’Donnell, Pharm.D., M.S.. FCP and James J. O’Donnell III, M.S., Ph.D. 34.1 Introduction 34.2Alcohol Injury Epidemiology 34.3 Alcohol Intoxication Effects in Litigation 34.4 Differences between Civil litigation involving alcohol from Criminal/DUI 34.5 Settings for Alcohol Related Civil Litigation A. Employment 34.6 Police Activities A. Police Pursuit B. Excessive Police Force C. Alcohol Effects on Aggression and Judgment 34.7 Motor Vehicle Collisions A. Vehicle/Vehicle B. Motorcycle Cases C. Boating D. Vehicle/ Pedestrian 34.8 Alcohol and Falls A. Stairs - no alcohol test - fall down bar stairs B. Stairs - Residential Stairs Fall -Adjustment of Calculated BAC due to Morbid Obesity C. Tripped on Threshold – Sued Condominium Association 34.9 Dram Shop (Bar Liability for Serving Intoxicated Persons) 34.10 Biomarkers for Alcohol A. Family Law B. False Positive Alcohol Biomarkers in Diabetes 34.11 Miscellaneous Topics Reports A. Retrograde Extrapolation (See also legal cases Floyd and Cuellar earlier in this chapter. B. Appellate Court reverses Trial Court Barring of BAC 34.13 Summary and Conclusions References Chapter 35: Cocaine James C Norris, Ph.D., D.A.B.T and Rodney G Richmond, R.Ph., MS, CGP, FASCP, FACFE 35.1 Historical Background 35.2 Medical Usages of Cocaine 35.3 Illegal Usage of Cocaine 35.4 Routes of Administration 35.5 Effects of Cocaine 35.6 Psychotic Disorders Induced by Cocaine 35.7 Addiction 35.8 Cognitive Deficits 35.9 Prenatal Cocaine Exposure (PCE) 35.10 Violence 35.11 Tolerance 35.12 Withdrawal or Abstinence Effects 35.13 Mechanisms of Action 35.14 Metabolism 35.15 Blood Levels 35.16 Urine Levels 35.17 Impairment 35.18 Associated Deaths with Cocaine Usage 35.19 Summary and Conclusions References Chapter 36: Marijuana: Pharmacology, Toxicology and Forensic Issues Stephanie E. Tedford, Ph.D., James T. O’Donnell PharmD, MS, FCP, and James J. O’Donnell III MS, Ph.D. 36.1 Introduction 36.2 Federal Law vs. State Law A. Harrison Narcotics Tax Act B. Comprehensive Drug Abuse Control and Prevention Act C. Marijuana Drug Laws at the State Level D. Legalization E. Decriminalization F. Marijuana Policy Project 36.3 Controlled Prescription and Distribution of Medical Marijuana A. Medical Conditions Approved for Treatment with Medical Marijuana B. Marijuana and Epilepsy C. Marijuana and Endometriosis 36.4 Pharmacological Properties of Marijuana A. Active Compounds and Overview of Pharmacology B. Variability in Marijuana Regulation and Content Uniformity C. Routes of Administration D. Pharmacokinetics – Time Course of THC and Metabolites E. Pharmacodynamics F. Vaping vs. Traditional Smoking of Cannabinoids G. Traditional Smoking vs. Ingestion of Cannabinoids H. Pharmacokinetics Applications: Timing of the Peak Euphoric Effect I. Bioavailability 1. Is There a Good Model for Marijuana Ingestion? 2. Overall Advantages of the Oromucosal Route? 3. Can the Effects After Ingestion of Marijuana be Made More Objective? 36.5 Marijuana Safety A. Serious Adverse Effects B. Risk of Psychosis 1. Drug-induced Psychosis: Potential Mechanisms 2. Vaping and Associated Risk for Psychosis C. Pulmonary Function D. Risk of Addiction E. Effect on Brain Development F. Long Term Behavioral Effects G. Age of Onset of Use 36.6 Impact of Legalization A. Hospital Resources B. Driving Under the Influence of Drugs C. Relationship of Marijuana Use and Co-Use with other Substances 36.7 Analysis and Testing for Marijuana Use 36.8 Scientific Data Relating to THC A. Blood THC vs. Brain THC: Any Relationships? B. Relationships Between Percent Plant-THC and Plasma-THC C. Is There a Relationship Between Percent THC in the Smoked Cigarette and Plasma THC? D. Relation Between Degree of “High” and Plasma THC E. Occasional Marijuana Users vs. Practiced Users F. Is THC the Only Psychoactive Cannabinoid? G. Urine Testing for Cannabinoids: Clinical or Evidentiary Value? H. Impairment and Marijuana: Laboratory and On-Road Driving Performance Data I. Hospital and Provider Considerations 36.9 Forensic Case Reports 36.10 Summary and Conclusions References Chapter 37: Drug Evaluation and Classification Program: An Evidence-Based Analysis Fran M. Gengo Pharm.D., FCP and Anna Mattle, Pharm.D., M.S. 37.1 Introduction 37.2 The 12 Steps of DRE Examinations 37.3 Scientific Evaluation of DRE Examinations A. Step 2: Interview of Arresting Officer B. Step 3: Preliminary Examination and Initial Pulse Measurement C. Step 4: Eye Examination D. Step 5: Divided Attention Tests E. Step 6: Second Pulse Reading, Body Temperature, and Blood Pressure Measurement F. Step 7: Eye Examination of Pupil Size in Various Lighting Conditions G. Step 8: Assessment of Muscle Tone H. Step 11: DRE Officer Opinion Statement I. Step 12: Toxicology Sample 37.4 Literature Evaluations And Critiques Of Dre 37.5 Cannabis 37.6 Statistical Validity and Overall Strength of DRE Studies 37.7 DRE Support Literature A. Bigelow et al. 1985 Study B. Heishman et al. 1996 and 1998 Studies C. Smith et al. 2002 Study D. Shinar and Schechtman 2005 Study E. Specific Identification of Drug Class by DRE Officers in Validation Studies 37.9 Summary 37.10 Summary and Conclusions References Chapter 38: Involuntary Intoxication James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN, James J. O’Donnell III, M.S., Ph.D., William Vaughn, J.D. 38.1 Introduction 38.2 Legal Defense Considerations for a Violent Crime 38.3 Confirming That Drugs are Involved in a Violent Crime 38.4 Beyond Pharmacology: The Multifactorial Role of Drugs in Aggression and Violence 38.5 Association of Drugs with Aggression and Violence 38.6 Mechanisms of Drug-Induced Violence 38.7 Intoxication of Victim Defense 38.8 Summary and Conclusions References Chapter 39: Drug-Induced Aggression and Violence Peter D. Anderson, Pharm.D., BCPP 39.1 Classification of Aggression 39.2 Causes of Aggression and Violence A. Neurobiology of Aggression B. Medical and Psychiatric Causes of Aggression 39.3 The Role of Drugs as a Cause of Violence A. Introduction B. Problems with the Literature C. Specific Drugs or Drug Classes that cause aggression 1. Ethanol 2. Lysergic Acid Diethylamide 3. Phencyclidine and Ketamine 4. Anabolic Steroids 5. Insulin 6. Psychostimulants 7. Benzodiazepines 8. Selective Serotonin Reuptake Inhibitors 9. Varenicline 10. Environmental Chemicals 39.4 The Drug-Induced Insanity Defense 39.5 Summary and Conclusions References Chapter 40: Forensic Drug Testing Chapter James J. O’Donnell III, M.S., Ph.D, and James T. O’Donnell, Pharm.D., M.S., FCP, ABCP, FACN 40.1 Introduction 40.2 Non-Regulated Drug Testing 40.3 Regulated Drug Testing 40.4 Voluntary Programs 40.5 Establishment of a Workplace Program A. Written Policy B. Employee Assistance Programs C. Employee Awareness Training D. Supervisor Training E. Drug Testing 40.6 The Drug-Testing Process A. Specimen Collection B. Accessioning C. Drugs to Be Tested D. Screening Tests E. Confirmation Tests F. Reporting and Storage of Samples G. Prevention Against and Detection of Drug Test Cheating 40.7 Additional Program Aspects A. The Medical Review Officer (MRO) B. Public Interest Exclusions (PIE) C. Blind Performance Testing D. Alcohol Testing 40.8 Special Drug-Testing Issues A. Type of Matrix 1. Hair Testing 2. Saliva Testing 3. Sweat Testing 4. Blood 5. Urine B. Alternate Sources of Drug Exposure C. Amphetamine Testing Issues D. Medical Use of Drugs 40.9 Legal Aspects of Workplace Drug-Testing A. Constitutional Issues B. State and Federal Mandates 40.10 Discovery: The “Litigation Package” 40.11 Case Reports 40.12 Summary and Conclusions References Chapter 41: Postmortem Redistribution and Interpretation of Drug Levels Gourang P. Patel Pharm.D., M.Sc., BCPS, BCCCP, FCCM 41.1 Abstract 41.2 Introduction 41.3 Review of a Case File 41.4 Postmortem Considerations A. Physiologic Changes in the Body After Death B. Drug Characteristics 41.5 Analysis of Drug Level Information 41.6 Summary and Conclusions References Chapter 42: Addiction as Mitigation Barry D. Hargan, M.S., MHA and James T. O’Donnell, Pharm.D., M.S., FCP 42.1 Introduction 42.2 Clinical Variables Which Contribute to the Onset of Addiction A. Genetic Predisposition B. Learned Behavior C. Psychopathological Exposure 42.3 Substance/Medication-Induced Mental Disorder A. Executive Summary of Opinion B. Neurotoxicity Mechanisms of Alcohol and Anabolic Steroids in the Developing Brain C. Anabolic Steroid Effects on Brain Structure and Function D. Translational Impact – what does this mean to a teenager abusing large amounts of alcohol and steroids? E. Clinical and Practical Applications of the Basic Neuroscience F. Behavioral Abnormalities Associated with Anabolic Steroid Use G. Defendant’s Alcohol and Anabolic Steroid Use 1. Alcohol H. Expert Opinions Regarding Substance-Induced Brain Damage Affecting Behavior 42.4 The Simplified Version of Neurobiology and the Addicted Brain 42.5 Cocaine 42.6 Expert Testimony Concerning Addictive Disorders A. Role of the Addictions Expert B. Some Testimony Experiences and the Limits of Opinions C. Preparation 42.7 Additional Considerations Concerning Addiction Mitigation A. Neuropsychological Evaluation 42.8 Summary and Conclusions References