Acetaminophen Toxicity
Experimental and Clinical Advances
- 1st Edition - November 21, 2024
- Editors: Barry Rumack, Hartmut Jaeschke, Mitchell McGill
- Language: English
- Paperback ISBN:9 7 8 - 0 - 4 4 3 - 1 5 8 7 7 - 3
- eBook ISBN:9 7 8 - 0 - 4 4 3 - 1 5 8 7 8 - 0
Acetaminophen Toxicity: Experimental and Clinical Advances provides detailed information on the risks of consuming the drug in various situations and effective treatments of toxici… Read more
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Request a sales quoteAcetaminophen Toxicity: Experimental and Clinical Advances provides detailed information on the risks of consuming the drug in various situations and effective treatments of toxicity.
Divided into two parts, the foundational aspects of this book cover the mechanism of toxicity in a detailed manner beginning with the history of acetaminophen to newly explored areas of genetics, proteomics, and metabolomics. The second half goes on to discuss clinical practices and examine where further research and therapeutic approaches may be headed. This part answers key questions about whom to treat, what are the exceptions, how long do you treat, how much antidote do you need, when are other treatments necessary, and what are those other treatments.
With contributions from experts in the field, this book is a thorough, well-researched, and valuable reference for scientists, researchers, and clinicians engaged in pursuing better and more accurate diagnosis and treatment of patients with acetaminophen toxicity.
- Includes comprehensive coverage of fundamental mechanisms of toxicity.
- Provides risk analysis regardless of patient presentation or timing of ingestion or amount with algorithmic support.
- Covers how to determine the level of toxicity and need for liver transplant with algorithmic support.
- Outlines new therapeutic approaches.
Research Toxicologists, Research Pharmacologists, Medical Toxicologists (MD, MD and MPH, MD and PhD), Clinical Toxicologists (RN, BSN, MSN, RPh, PharmD, PhD trained), Medical Toxicology and Emergency Medicine Physician trainees, Emergency Medicine Nurse or Nurse Practitioner Trainees, Poison Control Center Staffs, Pharmacy Students
- Title of Book
- Cover image
- Title page
- Table of Contents
- Copyright
- Dedication
- Foreword
- Part 1. Foundational aspects
- Chapter 1. History of acetaminophen toxicity studies
- Introduction
- Covalent binding and toxicity
- Studies on mechanism of covalent binding
- Acetaminophen free radical
- Mechanisms of detoxification
- Cytochrome P-450 isoforms in APAP Bioactivation
- Proteins adducted in APAP toxicity
- Reactive oxygen/nitrogen in toxicity
- Conclusion
- Chapter 2. Intracellular signaling mechanisms of acetaminophen-induced cell death
- Introduction
- Metabolism and bioactivation of acetaminophen
- Mitochondrial oxidant stress and peroxynitrite formation
- Peroxynitrite
- Nitric oxide synthases
- Mitochondrial dysfunction and nuclear DNA fragmentation
- Summary and conclusion
- Chapter 3. Hepatic MAP kinase signaling pathways in APAP-induced cell death
- Introduction
- MAPK cascades activation in hepatotoxicity
- MAP3K—MLK2/3, ASK1, TAK1
- MKKs—MKK4 and MKK7
- MAP kinases—critical role of JNK versus p38 in APAP-induced hepatotoxicity
- Mechanism and role of sustained P-JNK activation in hepatotoxicity (JNK-SAB-ROS activation loop)
- Modulation of JNK-SAB-ROS activation loop
- Pivotal role of SAB level in APAP induced hepatotoxicity
- JNK weakens the antioxidant defense
- Cross talk of JNK and pathways modulating severity of APAP induced liver injury
- Conclusion
- Chapter 4. Adaptive mechanisms modulating acetaminophen hepatotoxicity
- Introduction
- Modulation of the antioxidant defense system by Nrf2 activation during APAP hepatotoxicity
- Autophagy in APAP-induced liver injury
- Mitophagy
- Removal of APAP-adducts by autophagy
- Mitochondrial biogenesis as adaptive response in APAP-induced liver injury
- Summary and conclusions
- Chapter 5. Cell death in acetaminophen (APAP) toxicity
- Modes of cell death
- Apoptosis
- Necrosis
- Necroptosis
- Autophagy
- Pyroptosis
- Ferroptosis
- Cell death in acetaminophen-induced liver injury (Cell death in acetaminophen toxicity)
- MPT-mediated regulated necrosis in APAP
- Apoptosis in APAP toxicity
- Necroptosis in APAP
- Pyroptosis in APAP
- Ferroptosis in APAP
- Autophagy in APAP
- Conclusion
- Abbreviations
- Chapter 6. Role of sterile inflammation in acetaminophen hepatotoxicity
- Introduction
- Damage-associated molecular patterns and the formation of inflammatory mediators
- Neutrophils
- Cytotoxic versus beneficial effects of neutrophils
- Pleiotropic function of neutrophils
- Liver macrophages
- Kupffer cells
- Monocyte-derived macrophages
- Other immune cells
- NK and NKT cells
- Eosinophils
- Summary and conclusions
- Chapter 7. Liver regeneration after acetaminophen overdose
- Introduction
- Liver regeneration determines the outcome after acute liver injury (ALI)
- Mechanisms of liver regeneration after APAP-induced hepatotoxicity
- Concluding remarks
- Permissions
- Chapter 8. Translation of acetaminophen hepatotoxicity mechanisms from models to humans
- Introduction
- Step 1: Glutathione depletion and protein binding
- Step 2: Mitochondrial damage
- Step 3: Oxidative stress
- Step 4: JNK activation and worsening oxidative stress
- Step 5: Nuclear DNA fragmentation
- Step 6: Cell death
- Step 7: Inflammation
- Step 8: Liver repair
- Other mechanisms that may be involved in APAP hepatotoxicity
- Summary and conclusions
- Chapter 9. Renal toxicity after acetaminophen overdose
- Introduction
- Renal anatomy
- External structure of the kidney
- Internal structures and blood supply of the kidney
- Cortical and juxtamedullary nephrons
- Characteristics of renal physiology
- Renal drug metabolism
- APAP metabolism in the kidneys
- Metabolically active compartments of the kidney
- APAP metabolism has a distinct regional distribution within the kidney when compared to the liver
- Pathophysiology and cell death mechanisms after APAP overdose in the kidney
- Clinical manifestations of APAP-induced nephrotoxicity
- Management strategies for APAP-induced nephrotoxicity
- Summary and conclusion
- Chapter 10. ‘Omics of acetaminophen toxicity
- Introduction
- Genomics
- Proteomics
- Metabolomics
- Other ‘omics
- Summary
- Part 2. Clinical therapeutics
- Chapter 11. Pharmacokinetics and pharmacodynamics of acetaminophen
- Introduction
- Objectives
- The basics
- Pharmacokinetics, pharmacodynamics, toxicokinetics & toxicodynamics
- The toxicodynamic approach
- One-compartment linear open model
- Amount versus concentration—The volume factor
- One Compartment Linear Open Model with First Order Input
- The flip-flop model
- Two-compartment linear model
- Population PK-PD (PopPK-PD) methods
- A glossary of selected pharmacokinetic terms
- Therapeutic use of acetaminophen
- Target concentrations, pharmacokinetics and pharmacodynamics
- IV administration
- Induction of metabolism
- Immediate and prolonged release formulations
- Pediatric patients and pregnancy
- Pediatric patients
- Pregnancy
- Special scenarios
- Elderly patients
- Obese patients
- Acetaminophen overdose
- Overdose toxicokinetics
- Rumack-Matthew nomogram
- Line crossers versus PK
- Overdose toxicodynamics
- Hepatic injury
- Response Surface Representations
- Renal injury
- Extracorporeal treatment
- Appendix A: Development and selection of toxicity models
- Contour plot with smoothing
- Alternative models
- Toxicology models
- Pharmacology models
- Choosing a model
- Chapter 12. Minimally invasive clinical biomarkers for use in acetaminophen hepatotoxicity
- Introduction
- Diagnostic biomarkers
- ALT and AST to detect liver injury
- APAP-protein adducts for diagnosis
- Biomarkers to predict hepatotoxicity
- ALT and AST to predict hepatotoxicity
- The Rumack-Matthew nomogram and other uses of serum APAP
- Emerging risk stratification biomarkers
- Biomarkers to predict death
- ALT, AST, and APAP levels to predict poor clinical outcomes
- Liver function biomarkers and prognostic scores to predict outcome
- Other clinically available biomarkers to predict death
- Recent and emerging biomarkers to predict death
- Conclusions
- Chapter 13. Development of clinical assays for determination of acetaminophen protein adducts
- Introduction
- Development of assays for acetaminophen protein adducts
- Description of the HPLC-EC assay
- Research collaborations enabled through the HPLC-EC assay
- Adduct measurements as a predictor of acute liver injury
- Adduct profiles in other clinical settings
- Development of AcetaSTAT
- Development of the monoclonal antibody based AcetaSTAT
- Chapter 14. The Rumack-Matthew nomogram: Development, evolution, and clinical use
- Original nomogram
- Study design nomogram
- Validation of nomogram
- Safety patients outcome
- Standard Nomogram
- Revised nomogram 2023
- Cautions when utilizing the treatment nomogram
- Chapter 15. Pathophysiology of acetaminophen overdose in patients
- Liver zonation
- Histopathology of liver injury from acetaminophen overdose
- Clinical correlates
- Differential diagnosis
- Chapter 16. Liver transplantation and the Kings College criteria
- Introduction
- Pathogenesis of acetaminophen-induced acute liver failure
- Predicting outcome of acetaminophen-induced acute liver failure
- The King's college criteria
- Meta-analysis of criteria performance
- Issues with clinical application
- Supplementary prognostic markers: Arterial blood lactate
- Impact of improving outcomes with medical therapy
- United Kingdom revised prognostic criteria
- Future directions in prognostic evaluation
- Chapter 17. Sustained-release acetaminophen
- Introduction
- Pharmacokinetics in therapeutic doses
- Human volunteer studies
- Observational studies and case reports
- Extended-release 650mg (50% sustained-release: 50% immediate-release)
- Modified-release acetaminophen 665mg (69% sustained-release: 31% immediate-release)
- Pharmacokinetic models
- Management
- Conclusion
- Chapter 18. Acetaminophen, ethanol and other co-ingestions
- Mechanisms of ethanol potentiation of acetaminophen toxicity
- Ethanol and acetaminophen metabolism in vivo
- Acetaminophen, ethanol and liver injury in humans
- Reports of liver injury at or just above therapeutic doses
- Ethanol and acetaminophen overdose
- Other medications
- Chapter 19. N-acetylcysteine (NAC) treatment of acetaminophen toxicity
- Introduction
- History of approval and studies
- Mechanism of N-acetylcysteine treatment in acetaminophen toxicity
- Pharmacology
- Chemical properties
- Pharmacokinetics
- Absorption
- Distribution
- Metabolism
- Excretion
- Indications
- Role in acetaminophen toxicity
- Role in non-acetaminophen toxicity
- Timing
- Route and adverse effects
- Dosing protocols
- Stop criteria
- Special populations
- Chapter 20. The role of fomepizole in the management of acetaminophen toxicity
- The history of the development of fomepizole
- Fomepizole as an approved treatment for methanol and ethylene glycol poisoning
- Fomepizole in animal models of acetaminophen poisoning
- Clinical experience with fomepizole in the treatment of acetaminophen poisoning
- Future prospects
- Chapter 21. Guidelines for the management of acetaminophen poisoning
- Introduction
- Guideline development
- History of present illness
- Acute versus repeated ingestion
- Out-of-hospital
- Management of acute ingestion of immediate-release acetaminophen products
- High-risk ingestion
- Administration of acetylcysteine
- Revised Rumack-Matthew nomogram
- Acetylcysteine stopping criteria
- Management of acetylcysteine reactions
- Extended release formulations of acetaminophen
- Coingestion of anticholinergic or opioid medications
- Repeated supratherapeutic ingestions (RSTI)
- Patients weighing more than 100kg
- Patients under the age of 6years
- Pregnancy
- Use of enhanced elimination techniques
- Consultation with liver transplant service
- Conclusions
- Chapter 22. Epidemiology of acetaminophen toxicity
- Poisoning registry data
- Public health data
- Acute Liver Failure Study Group
- Prevention
- Summary
- Chapter 23. Acetaminophen use in patients with cirrhosis
- Introduction
- Special considerations
- Pathophysiology of cirrhosis
- How cirrhosis could alter acetaminophen metabolism
- Observations in patients
- Recommendations on safe use of acetaminophen in patients with cirrhosis
- Concluding remarks
- Index
- No. of pages: 514
- Language: English
- Edition: 1
- Published: November 21, 2024
- Imprint: Academic Press
- Paperback ISBN: 9780443158773
- eBook ISBN: 9780443158780
BR
Barry Rumack
Dr. Barry H. Rumack, MD, is currently Professor Emeritus of Pediatrics and Emergency Medicine at the University of Colorado School of Medicine and Director Emeritus of the Rocky Mountain Poison Center of the Denver Department of Health and Hospitals. His research interests include acetaminophen overdose and general medical toxicology. He has published over 250 peer-reviewed articles, authored, or edited numerous books and book chapters. He is or has previously been on the editorial board of a number of journals including Clinical Toxicology and Emergency Medicine, among others. He is a Fellow of the American Academy of Clinical Toxicology, American College of Medical Toxicology, and American Academy of Pediatrics and is or has been a member of Society of Toxicology, American Association of Poison Control Centers, and American College of Emergency Medicine.
HJ
Hartmut Jaeschke
Dr. Hartmut Jaeschke, PhD, is the University Distinguished Professor and Chairman of the Department of Pharmacology, Toxicology, and Therapeutics at the University of Kansas Medical Center, Kansas City, Kansas. He joined KUMC in 2006. He is a Fellow of the Academy of
Toxicological Sciences and Fellow of the American Association for the Study of Liver Diseases. He has published more than 470 peer-reviewed manuscripts, invited reviews, and book chapters in the areas of liver toxicology and liver pathophysiology. He currently serves as an Associate
Editor for Toxicological Sciences, the inaugural Editor-in-Chief of Livers (since 2020), and is a member of 14 editorial boards. In 2019, he was the recipient of the Translational Impact Award from the Society of Toxicology. His major research interests include basic mechanisms and translational aspects of xenobiotic-induced hepatotoxicity and tissue repair with a focus on acetaminophen overdose and mechanisms of inflammatory liver injury in animal models and humans.
MM
Mitchell McGill
Dr. Mitchell R. McGill, PhD, is currently an Associate Professor at the University of Arkansas for Medical Sciences. His primary research interests are 1) fundamental and clinical aspects of acetaminophen toxicity, 2) biomarkers of liver injury for clinical and regulatory applications, and 3) fundamental biological mechanisms of liver repair. He has published more than 100 peer-reviewed articles and has contributed chapters to more than a dozen textbooks. He is also a practicing, board-certified clinical chemist. Outside the university, he is a member of the Hepatotoxicity Working Group of the Critical Path Institute, VP-Elect of the Clinical and Translational Specialty Section of the Society of Toxicology, and serves on the editorial boards of several journals. Finally, he is an active member of the Society of Toxicology, the American Association for the Study of Liver Diseases, and the Association for Diagnostics and Laboratory Medicine.