Pathobiology and Therapeutics

Total Contact Hours:

59 hours

Course Director:

Robert L. Koerker, Ph.D., Associate Progessor of Pharmacology and Toxicology
Paul Koles, M.D., Assistant Professor of Pathology

Course Description:

This course is the introduction to general pathological processes and to basic principles of pharmacology before beginning a detailed study of the physiology, pathology, and pharmacology of each organ system of the human body in the second year.

Course Objectives & Integration with the Educational Objectives:

By the conclusion of this course, the student will demonstrate the ability to:

K1 Recognize the benefits of independent reading in two major textbooks (Robbins and Cotran, Pathologic Basis of Disease; Golan, Principles of Pharmacology), establishing the habit of self-directed, thoughtful study. Such study will broaden and deepen the student's knowledge base in pathology and pharmacology while developing the skills needed for lifelong learning in medicine.

K2 Use the knowledge gained by independent study of textbooks, lectures, and active learning methods to effectively describe the major mechanisms and features of human disease and principles of treatment for those diseases.

K3 Define, recognize, describe, or compare the following pathology-related topics:

• Four major aspects of disease within the scope of pathology
• Five types of adaptations used by cells in response to injury
• Seven categories of stimuli that cause cellular injury
• Five inter-related mechanisms of cellular injury
• Reversible vs. irreversible cellular injury
• Morphologic features of cell necrosis and three kinds of tissue necrosis
• Biochemical and molecular mechanisms of apoptosis
• Five substances that may accumulate within injured but viable cells
• Six kinds of stimuli provoking acute inflammation
• Vascular changes involved in acute inflammation
• Mechanisms of leukocyte extravasation and phagocytosis in acute inflammation
• Chemical mediators of inflammation
• Four morphologic patterns of acute inflammation
• Three types of clinical settings in which chronic inflammation occurs
• Cell types involved in chronic inflammation: three major and two minor
• Histopahtology and diagnostic significance of granulomatous inflammation
• Systemic effects of inflammation and their mechanisms
• Molecular mechanisms controlling normal cell growth, division, and hyperplasia
• Mechanisms of tissue regeneration
• Three groups of macromolecules that comprise the extracellular matrix
• Mechanisms governing interaction of extracellular matrix and cells
• Sequence and mechanisms of three major events in repair by fibrosis
• Two types of wound healing, mechanisms and clinical settings
• Factors influencing wound healing and three aberrant complications of wound healing
• Three potential outcomes of acute and chronic inflammation
• Two major factors governing fluid balance across capillaries
• Five pathophysiologic mechanisms producing edema
• Hyperemia vs. congestion
• Hemorrhage: definition, three terms for sizes, and four terms for specific locations
• Three components of normal hemostasis
• Mechanisms of platelet adhesion, release reaction, and aggregation
• Mechanisms, proteins and co-factors involved, and sequence of coagulation cascade
• Three factors contributing to thrombosis
• Anti-thrombotic mechanisms and events
• Disseminated intravascular coagulation: definition and three laboratory abnormalities
• Embolism: definition and five types
• Infarction: definition, morphologic features, and four major factors determining extent
• Shock: definition, three general categories, and pathogenesis of septic shock
• Mutations: definition and three categories of mutation
• Mendelian disorders: definition and three major transmission patterns
• Biochemical and molecular basis of single-gene disorders: four categories
• Two disorders of defective structural proteins: Marfan & Ehlers-Danlos syndromes
• Familial hypercholesterolemia: pathophysiology and pathologic sequelae
• Three inherited disorders associated with defective enzymes
• Neurofibromatosis 1 and 2: protein defects and pathologic sequelae
• Disorders with multifactorial inheritance
• Normal karyotype: definition and methods of laboratory analysis
• Three trisomies involving autosomes: 21, 18, and 13, with clinical sequelae
• Chromosome 22q11.2 deletion: definition and clinical sequelae
• Two cytogenetic disorders of sex chromosomes: Klinefelter and Turner syndromes
• Single-gene disorders with unusual inheritance mechanisms: triplet-repeat mutations, mutations in mitochondrial genes, genomic imprinting, gonadal mosaicism
• Methods of molecular diagnosis of genetic diseases
• Normal structure and function of the immune system: innate vs. adaptive immunity
• Properties and function of five cells mediating immunity: T lymphocytes, B lymphocytes, macrophages, dendritic cells, and natural killer cells
• Cytokines: general properties and mechanisms of action
• Structure and function of histocompatibility molecules
• Association of HLA alleles with inflammatory disease, autoimmune diseases, and inherited errors of metabolism
• Mechanisms and cells involved in four types of hypersensitivity reactions
• Mechanisms and morphologic classification of three types of transplant rejection
• Normal immunologic tolerance and general mechanisms of autoimmune disorders
• Pathophysiology, pathologic anatomy, and clinical manifestations of seven autoimmune disorders: SLE, rheumatoid arthritis, Sjogren syndrome, systemic sclerosis (scleroderma), inflammatory myopathies, mixed connective tissue disease, and polyarteritis nodosa
• Primary immunodeficiency syndromes (8): modes of inheritance, mechanisms, and clinical manifestations
• AIDS: epidemiology, structure, and properties of HIV; pathogenesis of infection; natural history; and clinical manifestations
• Amyloidosis: pathogenesis, classification, pathologic anatomy, clinical sequelae
• Definition of neoplasm and standard nomenclature for describing neoplasia
• Biology of tumor growth: differentiation vs. anaplasia, rates and mechanisms of tumor cell proliferation, cancer stem cells and lineages, mechanisms of invasion and metastasis, anatomic pathways of spread
• Epidemiology of cancer: incidence, geographic and environmental factors, effect of age
• Genetic predisposition to cancer: mechanisms, tumors observed, clinical features
• Non-hereditary conditions predisposing to cancer, esp. role of chronic inflammation
• Molecular basis of cancer (emphasis on mechanisms and molecules involved):
• Genetic mutations producing malignant transformation of a cell
• Normal cell cycle and altered regulation of cell cycle in neoplasia
• Proto-oncogenes, oncogenes, and oncoproteins
• Tumor suppressor genes
• Evasion of apoptosis
• Defects in DNA repair and genomic instability in cancer cells
• Telomerase and replicative potential
• Sustained angiogenesis
• Invasion and metastasis
• Stromal microenvironment and carcinogenesis
• Dysregulation of cancer-associated genes
• Multistep carcinogenesis: heterogeneity of cells promoting tumor progression
• Carcinogenic agents: chemicals, radiation, and microorgansisms; specific associations of cancer types with offending agent and clinical manifestations
• Immunologic host defenses against neoplasia: tumor antigens, anti-tumor effector mechanisms, immune surveillance
• Clincial features of neoplasia:
• Local and hormonal effects on host
• Cancer cachexia syndrome
• Paraneoplastic syndromes
• Grading and staging: definitions and principles
• Laboratory methods for diagnosis of neoplasia
• Congenital anomalies: definition, five descriptive terms, causes, pathogenesis, clinical manifestations
• Birth weight and gestational age: prematurity, fetal growth restriction, effects of organ immaturity on infant morbidity and mortality, Apgar score
• Birth injuries: types and definitions
• Perinatal infections: transcervical, transplacental, and sepsis
• Neonatal respiratory distress syndrome: pathogenesis, morphology, sequelae
• Necrotizing enterocolitis: pathogenesis, morphology, sequelae
• Fetal hydrops: immune-mediated and non-immune types
• Inborn errors of metabolism: phenylketonuria, galactosemia, cystic fibrosis
• Sudden infant death syndrome
• Common benign and malignant tumors of infancy and childhood: nomenclature, molecular mechanisms, pathologic anatomy, clinical manifestations

K4 Define, recognize, describe, or compare the following pharmacology-related topics:

• Pharmacodynamics, pharmacokinetics, toxicology, pharmacotherapeutics, pharmacology, and pharmacy
• Receptor, agonist, partial agonist, competitive antagonist, non-receptor antagonist, irreversible antagonist, efficacy, intrinsic activity, receptor affinity, and spare receptors
• Mechanisms for down regulating or up regulating receptors
• Attractive and repulsive forces involved in drug-receptor binding; examples of each
• Observations supporting the receptor theory of drug action
• Receptor mediated transmembrane signaling mechanisms
• Advantages of plotting log dose-response curves rather than linear dose-response curves
• How dose-response curves can be used to compare the potency and intrinsic activity of two drugs
• How the slope of the dose-response curve may dictate the therapeutic use of a drug
• How to differentiate competitive from irreversible antagonists
• Graded vs. quantal responses
• ED50, LD50, therapeutic index, and margin of safety
• How drug absorption, metabolism, excretion, and reabsorption influence the onset, duration, and intensity of drug effect
• Characteristics of four membrane transfer mechanisms
• Advantages/disadvantage and characteristics of 10 routes of drug administration
• Newly developed drug delivery systems
• Drug transfer across the blood-brain barrier, choroid plexus, and placenta
• How basic and acidic drugs differ in their volume of distribution
• Zero-order and first-order kinetic processes
• How to calculate the apparent volume of distribution of a drug
• Effects of plasma protein binding on the distribution, metabolism, and excretion of a drug
• How redistribution of a drug will influence its duration of action
• How the dosage regimen will influence the duration of action of a drug
• How to differentiate total, hepatic, and renal clearance of a drug
• How to calculate the maintenance and loading doses needed for steady state concentration as well as GFR and creatinine clearance
• The roles of filtration, secretion, and reabsorption on the renal elimination of drugs
• Metabolic processes of conjugation, hydrolysis, oxidation, and reduction of drugs
• Significance of first pass metabolism
• The role of microsomal cytochrome P-450 on the biotransformation of drugs
• Significance of enzyme induction or inhibition in terms of drug metabolism
• Phase I and Phase II drug metabolic reactions
• Significance of patient variability in drug pharmacokinetics
• The four FDA-mandated phases of new drug development
• Dosage adjustments needed when prescribing drugs to the elderly or to infants compared to normal adults
• Summation, synergism, dispositional vs. functional tolerance, tachyphylaxis, idiosyncrasy, and dependence
• Five schedules of controlled substances and dispensing restrictions for each
• Innate vs. acquired immunity
• Basic physiology and pathophysiology in relation to immunosuppressant therapy
• Three types of solid organ rejection in contrast to non-solid organ rejection
• General approaches to transplantation therapy
• Autoimmunity: explain its mechanism and pathophysiology
• Seven mechanistic approaches for immunosuppression, with examples of drugs that produce each
• How side effects and drug interactions of immunosuppressants relate to their mechanism of action
• Specific TNF-a inhibitors and IL-1 and IL-6 inhibitors used to mediate the immune response
• Use of polyclonal and monoclonal antibodies to deplete the immune system of specific cells, with examples of each
• Specific inhibitors of costimulation to inhibit lymphocyte activation or to induce anergy
• Specific inhibitors of cell adhesion or activation of lymphocyte homing to prevent localization of inflammatory cells
• Drug used to inhibit complement activation
• Pharmacological agents to intervene with cellular and biochemical mechanisms of hemostasis-thrombosis
• Four stages of clot formation and clot limitation
• Role of platelets in coagulation cascade and pharmacologic intervention in coagulation
• Mechanisms of action of four specific anti-platelet agents
• Use of heparins, anti-vitamin K agents (warfarin), direct thrombin inhibitors, and recombinant activated protein C as anticoagulants
• Use of thrombolytic agents or fibrinolytic proteases to lyse thrombi
• Differences between parasympathetic and sympathetic nervous systems in terms of anatomy, neurochemistry, and receptors
• Cholinergic pharmacology of somatic motor nerves
• Effects of specific cholinergic and adrenergic agonists and antagonists on different tissue organs
• Use of specific drugs to alter uptake, synthesis, storage, release, and metabolism adrenergic and cholinergic neurotransmitters
• The goals of cancer chemotherapy
• Cellular and biochemical basis for therapy with prototypic antineoplastic agents
• Mechanisms of initial and acquired resistance to cancer chemotherapeutic agents
• Toxic side effects specific to individual antineoplastic agents
• Strategies for using combination chemotherapies
• Symptoms, causes, and mechanisms of action of drugs used to treat IgE-mediated type I hypersensitivity
• Symptoms, causes, diagnosis, and treatment of asthma, anaphylaxis, and delayed hypersensitivity
• How to differentiate allergies, rhinitis, asthma, and anaphylaxis
• Health consequences of heavy metal poisoning from lead, arsenic, or mercury
• Symptoms, diagnosis, and treatment strategies for poisoning from specific heavy metals
• Treatment strategies for using dimercaprol, succimer, Ca-EDTA, penicillamine, and deferoxamine for chelation therapy
• In Utero pharmacology: delivery to and effects of drugs on the fetus
• Chronological changes in the absorption, binding to plasma proteins, metabolic degradation, and excretion of drugs that occur as one ages from infancy through adulthood to the elderly state
• Consequential or catastrophic drug interactions
• Guidelines for prescribing drugs for elderly patients
• Effects of selected disease states on the absorption, distribution, degradation, and excretion of drugs
• Scope and regulation of the use of herbals, supplements, and vitamins in the U.S.
• Standardization, purity, potency, and marketing of herbals, supplements, and vitamins in the U.S.
• Uses, common adverse effects, contraindications, and consensus expert recommendations for commonly used herbs and supplements
• Rationale and effectiveness of commonly used "natural weight loss" products
• Rationale for use of multivitamins, megavitamins, or mineral supplements

C1 Work effectively in teams by verbalizing knowledge gained through independent study, listening respectfully to and clarifying the communication of team members and faculty, and cooperatively working toward group consensus decisions.

C2 Assist peers to learn during sessions devoted to clarification of difficult concepts by accurately verbalizing areas of confusion or misunderstanding, listening and interpreting the comments of peers, and explaining knowledge gained by independent study.

P1 Emulate professional behaviors of good physicians by:

• Being punctual and attending course learning events
• Developing the skill of independent learning by reading all assignments
• Demonstrating scholarship through preparing conscientiously for all team-based learning modules and collaborating effectively with team members to achieve deeper understanding
• Demonstrating scholarship by preparing thoroughly for major examinations
• Being truthful in all communications
• Practicing integrity, refusing to give or receive help during individually graded exams
• Assisting fellow students with learning during and outside of classes
• Showing respect and courtesy to faculty and fellow students during live lectures by avoiding talking that is unrelated to learning and refraining from the use of cell phones

Learning Activities:

Presentations, Team-Based Learning, Critical Concepts.

Assessment:

One MCQ exam, Team-Based Learning.