Unit 1: Erythrocytes and the mechanics of oxygen transport
-Course introduction, metrics and significance to PharmD program
-Mechanistic levels of drug response
-Review properties of O2 transport in the body, blood constituents and common blood measures
-Erythrocyte development -Erythrocyte abnormalities, unique properties of erythrocytes
-Physical properties of myoglobin and hemoglobin, physical properties of heme
-Introduction to oxygen saturation curves, saturations curves for myoglobin and hemoglobin
-Hill plot basis and theory, introduction to allosterism and cooperativity
-Perutz two state model of oxygen saturation, properties of hemoglobin oxygen binding
-Physical and molecular properties of oxygen binding to hemoglobin
-Electrostatic effects of oxygen loading and unloading
-The Bohr effect and consequences to body physiology
-Globin synthesis during development
Unit 2: Modulation of oxygen transport, keeping RBC oxidation in check
-Isohydric transport and the chloride shift, physiochemical and molecular mechanisms
-Systemic aspects of oxygen delivery
-2,3 Bisphosphoglycerate, synthesis and its effects on oxygen transport
-Physical and molecular properties of 2,3 BPG binding to hemoglobin
-Summative effects of blood pH, carbon dioxide and 2,3 BPG on properties of oxygen delivery
-Summary of energy metabolism from different carbon sources, fed and starvation states
-Glycolysis and its unique role in erythrocyte biology
-Methemoglobin reductase, sodium/potassium and calcium pumps in erythrocytes
-Pharmacologic aspects of sodium/potassium and calcium pumps
-Calcium influx and its role in erythrocyte aging, physiology of erythrocyte elimination
-Glycolytic detours and the role of glycolysis in combating reactive oxygen species
-The pentose monophosphate shunt, NADPH generation, introduction to antioxidative enzymes
-Drugs and toxins which affect erythrocyte function, mechanism of ferric iron reduction
- Physiochemical properties of carbon monoxide and methemoglobinemia (drug promotion)
-Free radical promotion by drugs, leucomethylene blue reduction of methemoglobinemia
-Hemolytic anemia, energy utilization in fast and slow twitch muscles
-Malignant hyperthermia and anesthetic risks
Unit 3: Introduction to the immune system
-Introduction to the immune system, therapeutic aspects, What is the immune system?
-The Immune System: general traits/ functions, Humoral and innate immune function
-Haematopoiesis, development and regulation
-Deficiency or dysfunction of the immune system
-Non-immunological defenses, microbial flora
-Innate versus Adaptive immune functions, natural immunity, Innate immune effector cells
-Recognition of foreign effectors, PAMPS versus DAMPS, cytokines and their roles
-Leukocyte receptors and their activation, different intracellular signaling pathways
-Macrophage tissue variants, TLR therapies
-Components of acute inflammation, Leukocyte Migration from blood vessels
-Mechanism of neutrophil killing
-Acute phase proteins, complement system and pathways, anti-complement treatments
- Macrophage effector mechanisms
-Unresolved inflammation, acute versus chronic inflammation, microbial evasion
-Coordination of innate versus adaptive immunity
-Capture and presentation of antigens by dendritic cells, the CD3 complex
-Antigen processing, CD4 and CD8 T cells, T cell anergy
-Therapeutics: compounds to stimulate T-cells: Anti-Cd80 and CD86: Ipilimumab
-Antigen presenting cells, Th cells and interleukin relationships
-Activation of B lymphocytes, B cell activation
-Cytokine exposure and antibodies, Adaptive immune response: antibodies
Unit 4: More on the Immune System and Its Disorders
-Immunoglobin subtypes and antibody repertoire
-Immunoglobulin rearrangements: VDJ recombination
-Mechanisms of eosinophils
-Basophils and Mast cells, mechanisms of action
-Natural killer cells, humoral immune responses
-Primary and secondary immune responses, Ig class switching
-Neutralization of microbes and toxins by antibodies, opsonization and engulfment
-Cytokine control of phagocytic function
-Antibody-dependent cell mediated cytotoxicity (ADCC)
-Negative lymphocyte selection, programmed cell death in the immune system
-Class I and Class II MHC's, role in physiology and transplantation
-Genetic organization of MHC's, autoimmunity
-Immunity related disorders, transplantation and immunity, allograft rejection
-Acute, hyperacute and chronic rejection
-Immunosuppressive drugs, Calcineurin, MTOR inhibitors, corticosteroids, NSAIDS
-Graft versus Host disease, type I, II, III and IV hypersensitivities
-Allergy and IgE, therapeutic treatments
Unit 5: Immune Disorders, Vaccines, Covid-19 and Drug Sensitivities
-Autoimmunity and tolerance, central and peripheral mechanisms
-Autoimmune diseases and their mechanisms
-Therapeutic antibodies and modulators, immunotherapeutics, limitations
-Antigen specific immunotherapies, clinical experiences
-Congenital immunodeficiencies (SCID and other disorders)
-Disorders in lymphocyte activation
-Management of primary immunodeficiencies, stem cell transplantation
-Secondary immunodeficiencies (HIV)
-HIV therapies, introduction to vaccines, types of vaccinations, schedule consideration
-Coronaviruses, Covid-19 (SARS Cov2), molecular underpinnings, symptoms and diagnosis
-Adaptive immunity, cytokine storm and potential immunotherapeutics for Covid-19, vaccines
-Adverse drug reactions, IDR mechanisms, idiosyncratic drug reactions, skin and liver
Unit 6: Tumor Immunity and Immunotherapy
-Immune cells at the tumor site
-Adaptive T-cell immunity and tumor antigen recognition
-The potential of natural killer cells in cancer immunotherapy
-The tumor microenvironment: The role of tumor-associated macrophages in cancer progression
-Hard and soft loss of MHC class I expression in cancer cells
-Modulation of the adaptive immune system through chronic inflammation and T cell responses
-Triggering death receptors to promote cancer cell death
-Viral antigens as targets for prophylactic and therapeutic intervention in cancer
-HER2/neu as a target for vaccine and antibody-directed therapies
-Tumor-associated antigens characterized in a conceptual framework of biology
-Predictive biomarkers to better select patients for cancer immunotherapy
-Viral platforms for expression of tumor antigens in cancer immunotherapy
-Translating research into clinical practice: lessons from the immunology
Unit 7: The Metabolic Role of Cellular Mitochondria
-Role of endothelial cells in regulating blood pressure
-Biochemistry of smooth muscle contraction, cGMP, Ca2+, cAMP
-Nitric oxide formation, signaling and toxicity
-Use of drugs that generate nitric oxide
-The urea cycle, nitrogen catabolism of amino acids, detoxification of ammonia
-Role of peroxisomes in Intermediary metabolism
-Inborn errors of metabolism
-Synthesis and export of uric acid, proteins, cholesterol, steroids
-Nitrogen catabolism of nucleic acids (uric acid excretion)
-Role in Ischemic Reperfusion Injury (also heart)
-Biochemistry of Gout, Lesch-Nyhan syndrome, drug treatments
Unit 8: Mitochondrial Disorders and their Management
-Purine Nucleotide Biosynthesis and N-catabolism to endogenous toxins
-Drug / Steroid metabolism, detoxification of drugs, steroids and other physiological substrates
-Cytochrome P450 Isozymes and polymorphisms
-Pharmacogenomics, protein synthesis and targeting
-Export of albumin transport proteins and proteins involved in blood clotting (fibrinogens, prothrombin)
-Biochemistry of antithrombotic drugs
-Synthesis and export of cholesterol
-Utilization of cholesterol and fatty acids by extra-hepatic tissues for membrane biosynthesis
-Molecular diseases of cholesterol and lipoproteins
-Mechanism of LDL oxidation in foam cell mediated plaque formation
-Biochemistry of cholesterol lowering drugs (statins and non-statins)
-Synthesis and function of coenzyme Q
Unit 9: Mechanisms of oxidation, drugs, diseases and genes
-Chemistry of oxidative free radicals, Fenton, Haber-Weiss reactions, biologic use of radicals
-Biologic detoxification of free radicals (O2 to water), peroxynitrite and myeloperoxidases
-Glutathione metabolism, synthesis and degradation, actions in drug detoxification
-Acetaminophen, example of detoxification and drug induced necrosis
-Genetic disorders of erythrocyte function, G6PD deficiency
-Genetic drivers of G6PD, oxidative damage, structural mutations and polymorphisms
-G6PD and malaria, molecular interactions
-Drug induced hemolytic anemia, Aniline dyes and Favism
-Sickle cell anemia, molecular mechanisms of action, triggers and treatments
-Alpha and beta thalassemias
Unit 10: Regulation of iron homeostasis, iron supplementation and iron overload
-Introduction to iron reserves, iron requirements and reclamation
-Mucosal iron uptake, export and homeostatic regulation, transport and conversion
-Acute iron regulation, hepcidin, acute phase proteins, DcytB, ferroportin, hephaestin
-Ferritin and transferrin physiochemistry and regulation
-Transferrin receptor, regulation of iron intake by transferrin receptor
-Mechanism of iron responsive elements, molecular integration of iron signaling
-Causes of iron deficiency (dietary and drug induced) and anemias (major classes)
-Medical conditions and drugs which they alter iron uptake / distribution
-Clinical indicators of iron, diagnostic criteria used to identify class and type of iron deficiency
-Iron supplementation (dietary, pharmaceutic, drug interactions)
-Iron overload (environmental, clinical, drug induced, genetic) early indications, mechanisms of iron toxicity
-Therapeutic approaches to iron overload. Diagnostic evaluation critera
Unit 11: B vitamins and mechanisms of methylation
-Folic acid: sources, synthesis and mechanisms of deficiency and clinical pathology
-Biochemistry of tetrahydrafolate: absorption, distribution, metabolic isoforms
-THF cycle I: purine biosynthesis and catabolism
-THF: Chemotherapeutic drugs and mechanisms in 1C metabolism
-THF II and III: The remethylation cycle, transport of 1C units from amino acids
-One carbon pathway interactions, critical role of B vitamins and S-adenosyl methionine
-Regulation of THF cycles (Methionine synthase and the folate trap)
-DNA methylation and cancer, genetic derangements of one carbon metabolism
-Vitamin B12, mechanisms of absorption and distribution, cobalt chemistry
-Clinical pathology of B12 deficiency, pernicious anemia and its treatments
Unit 12: Thyroid function and disease
-The thyroid gland, its interactions and control within the hypothalamic-pituitary axis
-Biochemistry of thyroid hormones, actions and regulation
-Thyroid hormones: synthesis, activation and inactivation
-Metabolic modulation by thyroid hormones, iodine biochemistry
-Pharmaceutics and dietary agents which alter thyroid function (adverse)
-Clinical indicators of thyroid function, biochemistry of thyroid pharmaceutics
-Thyroid syndromes: Hyperthyroidism (Graves disease, thyroid cancer, thyroid storm)
-Thyroid syndromes: Hypothyroidism (Hashimoto's thyroiditis, cretinism)
Unit 13: CNS function and drug modification
-CNS structure and function, principles of neural processing
-Introduction to neurotransmission, molecular actions of excitatory and inhibitory neurotransmitters
-The action potential, introduction to channel modulators, agonists, antagonists
-Biochemistry of mood altering substances: CNS stimulants
-The psychomotor group: caffeine, nicotine, cocaine, amphetamine
-The psychomimetics: LSD, PCP, THC
-Structure function relationships between neurotransmitters and drugs of abuse
-Mechanisms of Anxiolytics (benzodiazepines and non-barbiturate sedatives)
-Mechanisms of Antidepressants (Tricyclics, SSRI's, MAO inhibitors)
