Cellular Regulation PDF

PATHOPHYSIOLOGY & CELLULAR REGULATION Tobi Ajayi  What is Pathophysiology. CONCEPTS OF PATHO Important Concepts. Cell and Tissue Characteristics CELLULAR REGULATION Cellular adaptation, injury and death. Pathphysiology...

PATHOPHYSIOLOGY & CELLULAR REGULATION Tobi Ajayi  What is Pathophysiology. CONCEPTS OF PATHO Important Concepts. Cell and Tissue Characteristics CELLULAR REGULATION Cellular adaptation, injury and death. Pathphysiology of Neoplasia NEOPLASIA Anti-neoplastic Therapy  PATHOPHYSIOLOGY Pathophysiology: the study of the physical and functional changes that occur during a disease process. Etiology: Study of the causes and reasons for a particular disease or injury. Idiopathic: cause is unknown Iatrogenic: resulting from medical treatment. Risk factor: increases likelihood of disease. Understanding the clinical consequences of a particular disease/illness helps understand treatments.  PATHO CONCEPTS Sign: Objective or observed manifestation of disease. (e.g. bruise). Symptom: Subjective feeling of abnormality (e.g. headache). Latent period: time between exposure and first appearance of S & S. Prodromal period: When S&S first appear, indicating onset of disease.  PATHO CONCEPTS Acute phase: Disease/illness is at full intensity. May be short-lived but intense manifestation. Chronic illness: may last months to years, sometimes after an acute course. Exacerbation: A sudden increase in severity of disease or S&S. Remission: decrease in severity, S&S; may indicate disease is cured. Convalescent: stage of recovery after a disease, injury or surgery.  Cultural consideration: each culture defines health Factors affecting 01 and illness in a manner that reflects their experiences. Health and Disease 02 Age differences: a normal value at one age may not be normal at another age. (e.g. infants vs Patient-centered care adults). Gender differences: a normal value for men 03 may not be normal for women or transgender patients, and vice-versa. Situational differences: determine whether a 04 derivation from normal is abnormal or an adaptation mechanism. Also socio-economic context.  Epidemiology Epidemiology is the study of the patterns of disease involving populations. Examines the occurrence, incidence, prevalence, transmission, and distribution of diseases in large groups of populations/people. Endemic disease: is consistently present within a particular geographic area or population. Often associated with specific environmental or social factors. Epidemic: sudden increase in the number of cases of a disease above what is normally expected in a specific region or population. This can be caused by a new strain of a pathogen, changes in the environment, or lapses in vaccination coverage. Pandemic: an epidemic that has spread across multiple countries or continents, affecting a large portion of the global population. It often involves a new pathogen to which most people have little or no immunity. LEVELS OF ORGANIZATION CELL STRUCTURE The cell is the smallest functional living thing. (>30 trillion in the body). 3 main parts: Cell Membrane: encases the cell and regulates the movement of substances in and out of the cell. Nucleus: houses the majority of the cell's DNA/genetic material. Cytoplasm: gel-like fluid inside the cell that contains various cell components with specific functions. Excludes the nucleus.  CELL CYCLE G-0(resting stage): The phase where cells conduct their everyday activities specific to cell type (e.g. metabolism, contraction, etc.). Cells spends most of their lifetime in this phase. G-1: First step after receiving signal to divide. Cell synthesizes ribonucleic acid (RNA), proteins, and other components needed for DNA duplication. S (Synthesis): Cell duplicates its DNA. G-2 (pre-mitotic phase): Cell makes additional proteins and the components necessary for cell division/mitosis. M (Mitosis): Cell undergoes mitosis (prophase, metaphase, anaphase, and telophase). Results in the cell splitting into 2 identical cells.  CELL CYCLE Cell Proliferation: Cells multiply through mitosis, where one cell divides to make two new daughter cells identical to the parent cell. Allows the body to grow, repair and replace cells. Tightly regulated to ensure that cells divide only when necessary. Cell Differentiation: the process by which a cell becomes more specialized with distinct functions and characteristics. Ensures that cells can perform specialized functions necessary for the organism's survival. Stem cells are special cells with the ability to develop into various cell types. During differentiation, they receive signals directing them to become a specific type of cell. Modern stem cell research explores the potential of repairing and regenerating damaged tissues and organs through controlled stem cell differentiation. Possible treatments for conditions such as including Parkinson's disease, heart disease, spinal cord injuries, etc.  Cell types Labile cells: constantly dividing and replacing cells that are lost. E.g. the skin, intestinal epithelial cells. Stable cells: do not divide under normal conditions but can be stimulated to divide after injury. E.g. Hepatocytes and liver regeneration (Zeus Vs Prometheus). Permanent cells: lack regenerative ability. E.g. Cardiac, neural, and skeletal cells. Cardiac tissues don’t heal after MI, causing reduced cardiac capacity.  TISSUES Tissues are a group of cells that work together to perform a specific function. 4 basic types: Epithelial: line all internal and external surfaces. Muscular: specialized for contraction, allowing movement and force generation in the body. Connective: supports, connects, or separates different types of tissues and organs in the body. Nervous: specialized tissues that transmit electrical impulses to coordinate bodily functions by facilitating communication between different body parts.  Cellular Adaptation Cells actively regulate the composition of their surrounding environment and their internal conditions, maintaining a stable range of physiological parameters known as "homeostasis." Cellular adaptation refers to a cell’s ability to adjust in response to different stimuli and challenging environmental conditions that threaten their structure or function. Stimuli could be physiological (e.g. breast during pregnancy) or pathological (e.g. aging). Cells may change in size, number or type, to adapt. The adaptive responses cease once stimuli is removed. If the stress is too severe or the adaptations are not effective, the cell may become injured or die. Cellular Adaptation Atrophy Decreases in cell size leading to tissue degeneration. Hypertrophy Enlargement of cells. Increase in size and functional components. E.g. Bigger muscle = more ATP, Cells might adapt to work demands or threats to Atrophied cells = decrease in more actin and myosin cell content = Reduced oxygen filaments. survival by changing in size. consumption. Hypertrophy results from increased functional demands or Caused by: specific hormonal stimuli. Disuse Denervation E.g. Exercise and muscle mass, Loss of endocrine uterus enlargement in preg stimulation (estr/meno) (physiological), myocardial Inadequate nutrition hypertrophy from hypertension Ischemia (pathological). Cellular Hyperplasia Adaptation Controlled increase in the number of cells in an organ or tissue. Cells might also adapt to work demands or threats Occurs in wound healing with proliferating fibroblasts of connective tissues. to survival by increasing in number. “Plasia” = cell formation or growth” Different from hypertrophy but may occur together. E.g. uterus. E.g. stimulation of endometrium in the follicular stage of menstrual cycle (physiological), Beneign Prostrate Hyperplasia (pathological). Endometrial hyperplasia (pathological)  Metaplasia Cellular Reversible replacement of a mature, differentiated cell- type by another cell-type that is better suited to tolerate Adaptation a particular stimuli or environment. Reprogramming of undifferentiated stem cells present in the tissue., but conversion of cell type remains within boundaries of primary tissue (e.g. epithelial cell cannot be converted to a cardiac cell. E.g. Barrett’s oesophagus- In response to irritation from acid-reflux, normal squamous cells lining the distal esophagus (squamous-flat) are replaced by columnar cells that typically line the stomach and small intestinal. E.g. The replacement of ciliated pseudostratified columnar epithelium in the bronchi with stratified squamous epithelium, r/t smoking. When signals that cause metaplasia persist, they frequently lead to the development of neoplasia. Cellular Dysplasia Adaptation Disordered cell growth in a tissue, resulting in cells that vary in size, shape, and organization. Caused by irritation (e.g. smoke) or inflammation (e.g. UV or x-ray radiation). Radiation causes damages to cell DNA. Mild-moderate cases may regress if underlying cause is alleviated, but severe dysplasia can be a precursor to irreversible malignancy (esp. lungs and cervix).  INTRACELLULAR ACCUMULATION... describes the build-up of substances that the cells cannot immediately used or eliminate. Normal body substance: Substance is produced faster than it can be metabolized or excreted E.g. Obesity = High delivery of free fatty acids from adipose tissues to the liver = Accumulation of FFA = Fatty Liver. Abnormal endogenous products: May result from disorders that disrupt metabolism due to abnormal or missing enzymes. E.g. Von Gierke disease where a deficiency in glucose-6- phosphatase leads to accumulation of glycogen in the liver and kidneys. Exogenous products: Such as environmental agents and pigments. E.g. Accumulation of carbon dust blackens t he lung tissue and may cause serious lung disease. PATHOLOGICAL CALCIFICATIONS... involves abnormal tissue deposition of calcium salts, and other minerals, in tissues. Dystrophic Calcification: Occurs in damaged or necrotic tissues despite normal calcium levels in the blood. Often happens in areas of tissue injury, such as in damaged heart valves, atherosclerotic plaques, or areas of chronic inflammation. Metastatic Calcification: Occurs in healthy tissues due to elevated levels of calcium in the blood (hypercalcemia). Causes of Physical Agents Radiation Cellular Injury Ultraviolet Radiation: Mechanical force: *Photon: is a particle of electromagnetic Trauma due to body’s impact radiation energy. *UV radiation contain high energy photons with external force. that can disrupt release free radicals, damage Split and tear tissues, fracture DNA, and damage melanin-producing processes in skin cells. Cell injury can generally be reversed up to a specific bones, disrupt blood flow, point, after which the damage becomes irreversible, etc. Ionizing Radiation: leading to cell death. *Radiation energy above the ultraviolet (UV) Extremes of Temperature: range. Heat (burns) disrupt cell *I.R photons causes ionization of molecules and atoms in the cell by knocking off electrons membrane. from them. Cold may lead to hypoxic *E.g. Localized irradiation in cancer treatment. The extent of an injury depends on the type of cell, as tissue injury due to well as the duration and intensity of the injury. Nonionizing Radiation: vasoconstriction). *Radiation energy below the ultraviolet (UV) Electrical injuries: range. (E.g. Ultrasound, welding, microwaves) *Uses energy from vibration of atoms and Extensive tissue injury. molecules to generate thermal energy. Disruption of neural and * Resulting thermal energy can disrupt the cell depending on duration and extend of cardiac impulses. exposure (E.g. industrial settings.) Causes of Cellular Injury Chemical Injury Biologic Agents May injure cells membrane, Viruses incorporate block enzymatic pathways, themselves into a cell’s DNA Cell injury can generally be reversed up to a specific disrupt cell metabolism, etc. machinery. point, after which the damage becomes irreversible, Air and water pollutants, leading to cell death. tobacco smoke. Bacteria may release toxins Drugs and alcohol. that increase cardiac Carbon Monoxide permeability, interfere with Lead Toxicity: ATP production or other The extent of an injury depends on the type of cell, as Mercury Toxicity: cellular processes. well as the duration and intensity of the injury. Mechanisms of Free Radical Injury Cellular Injury Free radicals are chemical molecules with an Oxidative stress: when the generation unpaired electron. (Single dancer looking to of free radicals exceeds the ability of the pair up) body to neutralize it. Highly reactive with molecules in their High blood sugar can cause vicinity and can convert other molecules into oxidative stress on blood additional free radicals. vessels. Reactive Oxygen Species (ROS) = Free radical In cancer, oxidative stress in the body (contains O-). damages the DNA in healthy Endogenous: from cell metabolic cells. processes (E.g. ATP production), Also linked to Aging, inflammation. neurodegenerative disease, etc. Exogenous: Cigarette smoke, UV from sun rays. Antioxidants: Vitamins A,C,E, zinc, Exert beneficial in the cellular regulation Beta-carotene, etc. of cell function, immune function, etc. React with proteins, lipids and carbohydrates in cells/tissues, causing membranes damage, inactivation of enzymes, and damage to nucleic acids that make up DNA. Mechanisms of Hypoxic Cell Injury Genetic defect Cellular Injury Oxygen deficiency r/t lack of oxygen in the air, respiratory disease, anemia, ischemia Cause cell injury due to deficiency in functional proteins or the accumulation of damaged DNA or (restriction in blood flow), etc. misfolded proteins. Both trigger cell death when they are beyond Deprives the cell of oxygen, repair. thereby interrupting the Inborn errors of metabolism. generation of ATP, and other E.g. Sickle cell anemia: metabolic processes. decreased life span of red Brain (4-6 minutes) and Heart blood cells caused by a single sensitive to oxygen amino acid substitution in deprivation. hemoglobin. OUTCOME OF CELL INJURY. Injury to a cell either causes reversible cellular damage, apoptosis (programmed cell removal), or cell death (necrosis).  OUTCOME OF CELL INJURY. REVERSIBLE CELL INJURY Cellular Swelling: impairment of the sodium-potassium-ATPase pump leads to accumulation of Na and water inside the cell. Hydropic degeneration. Change is reversible if oxygen delivery resumes alongside ATP production. Fatty changes: Intracellular accumulation of fat, causing small vacuoles of fat to disperse throughout the cell. Accumulation r/t: r/t increased fat load (Obesity). Impairment of fat metabolism. Injury to a cell either causes reversible cellular damage, apoptosis (programmed cell removal), or cell death (necrosis).  CELL DEATH PROGRAMMED CELL DEATH = APOPTOSIS An highly selective process that controls tissue regeneration by eliminating injured and aged cells. Cellular suicide. Severe cell damage triggers cell’s own death. (Cellular suicide). Does not trigger the inflammatory process Is responsible for several physiologic processes: Programmed destruction of cells during embryonic development: Separates webbed fingers and toes in embryo. Hormone-dependent involution of tissue: Endometrial cells during menstrual cycle, regression of breast tissue after breastfeeding. Control of immune cells. Cell death occurs by programmed cell death (Apoptosis) or Necrosis. Interference with Apoptosis is linked to Cancer and other diseases.  CELL DEATH NECROSIS Refers to cell death in an organ or tissue that is still part of a living tissue.Usually due to ischemia or toxic injury. Interferes with cell replacement and tissue regeneration. Triggers inflammatory process. Gangrene: When a considerable mass of tissue undergo necrosis. Necrosis occurs when injury is too severe OUTCOME OF CELL INJURY. NEOPLASM Cells regulate growth ­(proliferation) by turning growth-promoting and growth suppressing genes on and off. Tumor Neoplasia = Abnormal cell proliferation/tissue growth caused by damage or mutation of regulators. Stems from any organ. Metastasis = movement of abnormal cells to other parts of the body, where they populate new tumors. Benign (Non-cancerous): Uncontrolled cell proliferation enclosed in a fibrous capsule and does not infiltrate or affect tissue of origin directly. Slow growing and localized. Does not metastasize and can be removed. E.g. Benign Prostatic Hyperplasia. Malignant tumors (Cancerous): Rapid & uncontrolled cell proliferation that invades the tissue of origin and can invade other remote tissues via lymph or blood. Not enclosed, making it difficult to contain and remove. Always requires treatment.  CANCER CELLS Uncontrolled proliferation De-differentiation: Loss of normal function Invasiveness Metastases: Cancer cells break away (from primary CA) Travel through the blood or lymph system. Form new tumors (metastatic tumors). Metastatic tumor is the same type of cancer as the primary tumor.** Angiogenesis: Formation of new capillaries out of existing blood vessels. Cancer cells establish their own blood supply to bring in ­nutrients and escape during metastasis. CANCER CELLS Telomere: section of DNA that safeguards the chromosome ends from damage and entanglement. They shorten with each cell division and eventually become too short for proper cell division = Cell Death. Telomerase: an enzyme that lengthens the telomere chains and allow continued replication. Found in stem cells. Cancer cells produce large amounts = Indefinite Replication. TYPES OF CANCER Solid Abnormal tissue mass. Difficult to assess in blood at 1st. May release abnormal chemicals detectable in the blood (e.g. PSA). E.g. Breast, Prostate, Lung CA, etc. Hematological Formed in the blood or bone marrow Not a mass (liquid). E.g. Leukemia, Lymphoma Classifications of Cancer Leukemia Cancer of the blood-forming cells in Carcinoma bone marrow; may be acute or chronic Cancer of epithelial tissue; most common type of ­ Myelocytic leukemia, lymphocytic malignant neoplasm; grows rapidly and leukemia metastasizes. Malignant melanoma, renal cell carcinoma, ­ Lymphoma adenocarcinoma, hepatocellular carcinoma Cancer of lymphoid tissue Sarcoma Hodgkin’s disease, lymphoblastic lymphoma Cancer of connective tissue; grows extremely rapidly and metastasizes early Gilioma in the progression of the disease Osteogenic sarcoma, fibrosarcoma, Cancer of glial (interstitial) cells in Kaposi’s sarcoma, angiosarcoma. the brain, spinal cord, and pineal gland. Brainsteam glioma. CAUSES & DIAGNOSTIC TOOLS Carcinogen: an agent or factor, associated with higher risk of developing CA. Lead to abnormal cell growth and the formation of tumors. Chemical: Tobacco smoke = Lung CA Asbestos = Lung CA Physical: Sun’s Uv rays = Skin carcinoma Xrays = Leukemia Biological: Genetic predisposition to damaged growth promoter/suppressor. Viruses. Human papillomavirus (HPV) = Cervical CA Diagnostic Tools Blood Test: CBC & Differential (Hb, WBC, blood smears, etc.) Imaging: Ultrasound, CT Scan, MRI, PET Scans, Mammogram. Others: Biopsy, colonoscopy. EXERT CAUSE WHEN DISCUSSING DIAGNOSIS AND PROGNOSIS WITH PATIENT AND FAMILY....defer to the experts!  CA STAGING Staging: identifies the location and extent of cancer invasion within the body. Assessed at initial diagnosis to help understand the disease's prognosis and the most effective treatment options. CA is assigned values for the tumor (T), node (N), and metastasis (M), after which a stage (I-IV) is assigned. Assigned stage does not change even if CA progresses. E.g. If metastasis later occurs in a Stage 2 CA, it may be called "Stage II with metastasis". Stage 1 (Least invasive, Most favorable outlook): No lymph involvement, No metastasis, tumors are less than 2 cm in size. Stage 2: local lymph involvement, no metastasis, tumors are less than 5 cm in size. Stage 3: Nodal involvement, no metastasis, tumors are over 5 cm Stage 4 (Most aggressive = Least favorable outlook): nodal involvement, metastasis, tumors greater than 5 cm. Specific types of CA might have their own additional subtype staging.  CA STAGING T Category: Describes the primary tumor. TX Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Tumour is confined to the primary area Tumour has invaded areas surrounding the primary T3–T4 tumour N Category: Describes whether the cancer has spread to lymph nodes. NX Nearby lymph nodes cannot be assessed N0 No regional lymph nodes metastasis N1–N3 Primary tumour has spread to regional lymph nodes M Category: Describes whether distant metastases are present. MX Distant metastases cannot be assessed M0 No distant metastases were found M1 Distant metastases are present  CA GRADING Grading (Biopsy): involves examining cancer cells under a microscope and comparing their appearance to that of normal, mature cells it came from. Normal cells resemble their parent cells, and perform similar functions. (E.g. Liver cells Vs. muscle look & work differently). Cancer cells gradually become less differentiated in both structure and function. When fully undifferentiated, cancer cells appear very different from their original parent cells and do not perform the functions of those cells. G1 = differentiated and very similar to the parent cells G4= Very abnormal and different from normal cells. Aggressive CA cells with worst prognosis. Grading has limitations because different cells/sections of the same solid tumour may exhibit varying grades, such as G2 in one area and G4 in another. Unlike staging, grading can change as the tumor evolves over time. Clinical Manifestations Pathophysiologic effects vary with type and location of cancer. Hematologic Anorexia-cachexia Obstruction Alterations Syndrome Impairs functions of blood cells Cachexia (wasting Malignant CA may Leukemia immature leukocytes syndrome): Malnutrition, cause anoxia and cannot perform normal unexplained loss of weight protective functions, necrosis of surrounding and muscle mass. GI tumors: disrupt absorption of tissue, leadin to loss of vitamin B12 and Iron, Neoplastic cells divert function of the involved Tumors deprive bone marrow of nutrition to own use purines and folate Metabolic rate may increase organ or tissue. Renal cell carcinoma: produces Tumor secretes substances its own erythropoietin hormone, causing excessive numbers of that decrease appetite RBCs. GI CA impair nutrient use Clinical Manifestations Pathophysiologic effects vary with type and location of cancer. Paraneoplastic Syndromes Psychological Stress Pain Occurs when a malignant tumor secretes Psychological emotional May be caused by stretching and hormones or proteins that affects organ responses compression of tissues r/t tumor, or systems away from the tumor site. by traumatization of tissue from Can also be a result of the body’s Grief physiological antibodies inadvertently cancer therapies. Guilt Acute attacking normal cells instead of CA cells. May be early warning sign of cancer, or Anger Well-defined pattern of onset suggest return of a malignancy. Fear Common signs and symptoms Isolation Hyperactivity of autonomic Symptoms occur away from site of Body image concerns system. tumor, and depend on organ systems affected Sexual dysfunction Nervous: Dizziness, Diplopia, memory Chronic loss, seizures, etc. > 6 months Endocrine: fatigue, high blood May result in personality pressure, N/V, etc. changes, alterations in functional Skin: itching, redness, thickened skin, abilities, and lifestyle disruptions etc.  Treatments Surgery Radiation Removal of localized, solid tumour and sometimes a portion of normal Aiming high doses of ionizing radiation surrounding tissue. directly at a tumour. Not an option for tumours of blood cells. Effective with localized tumour. Debunking = part of tutor removed. May be use for palliation, to shrink a May also be used tumour that may be pressing on vital For diagnostic purposes organs. To relieve pain, obstruction. Neoadjuvant Chemotherapy Adjuvant Chemotherapy Administration of ­anti-neoplastic drugs Administration of ­antineoplastic drugs before surgery or radiation therapy. after surgery or radiation therapy. Leads to less invasive procedures when Eliminates any remaining cancerous cells removing a tumour that has impacted that were not removed during the surgery, surrounding tissues. and addresses any micro-metastases.  Radiation Electron cell injury Used in >50% of patients with CA https://www.youtube.com/watch?v=V2VGHUjN17w Possible Side effects: Local skin irritation Local hair loss. Inflammatory response around the irradiated site. Brain tumor radiation: loss of hearing, headache, speech impediments. Systemic effects: Nausea, vomiting, diarrhea, etc. Chemotherapy Antineoplastic pharmacotherapy Goal is to kill most possible CA cells and allow immune system to complete process. Challenge is isolating and damaging ONLY neoplastic cells without hurting human cells Cure Control Palliation Greater chance if CA is Preventing growth and Shrinking a tumour to identified and treated when spread of tumour to alleviate pain and other the tumour is small and extend a client’s life. symptoms associated with localized to a well-defined it, thereby enhancing a region. patient's overall quality of E.g. Hodgkin’s lymphoma life.  CELL CYCLE & ANTINEOPLASTICS G-0(resting stage): The phase where cells conduct their everyday activities specific to cell type (e.g. metabolism, contraction, etc.). Cells spends most of their lifetime in this phase. G-1: First step after receiving signal to divide. Cell synthesizes ribonucleic acid (RNA), proteins, and other components needed for DNA duplication. S (Synthesis): Cell duplicates its DNA. G-2 (pre-mitotic phase): Cell makes additional proteins and the components necessary for cell division/mitosis. M (Mitosis): Cell undergoes mitosis (prophase, metaphase, anaphase, and telophase). Note: Chemotherapeutic drugs are less effective Results in the cell splitting into 2 identical cells. on cells in the resting phase, so debulking a tumor may enhance their efficacy. By surgically **Antineoplastic Agents: Cell-cycle specific or Non-cycle-specific. ** removing part of the tumor, the remaining cells enter active phases of mitosis, making them more susceptible to the drugs' effects.  ANTINEOPLASTIC AGENTS 1. Drugs targeting DNA formation/repair: Alkylating drugs: Non-cycle specific: kills cancer cells at any stage of the cell cycle. E.g. Nitrogen Mustards (based on ‘mustard gas’, a World War I chemical agent). Cyclophosphamide Anti-metabolites (-ate/purine, bine): Interrupts S-phase of cell cycle. Disrupts cellular processes in DNA/RNA metabolism & production. E.g. Methotrexate. Cytotoxic Antibiotics (-mycin/bicin): Block DNA replication enzymes, or produce free radicals (oxidative stress = Apoptosis) Often used in combination with other treatments. E.g. Doxorubicin, Daunorubicin, Bleomycin Vinca Alkaloids (Vin-): Targets Mitosis-phase of the cell cycle. E.g. Vincristine, Vinorelbine  ANTINEOPLASTIC AGENTS 2. Hormonal Anti-neoplastic Agents Used to treat cancers that are linked to hormonal stimulation. Prevents cell proliferation by disrupting testosterone/estrogen/progesterone production or their interactions with receptors. E.g. Tamoxifen (Selective Estrogen Receptor Modulator) Fulvestrant (Selective Estrogen Receptor Down-regulator) Relugolix (Gonadotropin Releasing hormone antagonist) Flutamide, Bicalutamide (Anti-androgen)  ANTINEOPLASTIC AGENTS 3. Immunotherapy Immuno-stimulants: Stimulate immune system against certain tumor cells. Drug e.g.: Interferons, Interleukins. Interferon alpha-2b: enhances body’s immune response to tumors or viruses Antibodies: Monoclonal antibodies: Mark CA cells to enhance & direct immune response Immune ‘check-point’ inhibitors: CA cells de-activate the endogenous immune response check-point inhibitors reverse this de-activation enabling the immune system to activate & locate cancer cells. **There are other chemotherapy MoA that attack CA cells differently: E.g. angiogenesis inhibition**  IMPROVING SUCCESS OF CHEMOTHERAPY Combination drugs Dosing schedule Route of Administration  COMBINATION CHEMOTHERAPY Using multiple drugs together with intermittent dosing leads to better outcomes for patients. A cancer treatment protocol describes the specific combination of antineoplastics that will be given, their doses, and the cycles in which they will be administered. Each cancer type has a unique protocol, developed through clinical trials. Benefits of Combination Therapy: Target Multiple Stages: Affects various stages of the cancer cell’s life cycle. Attack Different Clones: Targets different tumor clones through various mechanisms. Increase Efficacy: Enhances the percentage of cancer cell kill. Lower Dosages: Reduces toxicity by using lower doses of each drug (less adverse effects). Slow Resistance: Helps prevent the development of drug resistance. Examples: Breast Cancer: Cyclophosphamide, Methotrexate, Fluorouracil. Lung Cancer: Cyclophosphamide, Doxorubicin, Vincristine.  CHEMOTHERAPY PO vs Topical vs IV vs CVAD administration. CVAD= Central Venous Access Devices (e.g. PICC, Implanted ports) Patients undergoing chemotherapy typically go through multiple treatment cycles over weeks or months. Chemotherapy cycles give normal cells (e.g. neutrophils) time to recovery, and may allow tu,mor cells to re-enter mitosis. E.g. If a chemo treatment requires 4 to 8 cycles and a cycle lasts 4 weeks, the patient may have treatment on the 1st, 2nd and 3rd days then nothing from the 4th to the 28th day. Then the cycle starts again. In theory, curing a cancer patient requires eliminating every single malignant cell, as leaving even one could lead to tumor regrowth. However, achieving this is extremely challenging, so a drug that eradicates a high percentage of cancer cells would be considered highly effective. In each cycle, anti-neoplastic drugs targets and destroys a certain percentage of rapidly dividing cancer cells, with subsequent cycles addressing remaining cells - Cell Kill Hypothesis. Reducing the number of cancer cells significantly allows the client's immune system to manage or eliminate the remaining cells. This highlights the importance of early diagnosis and treatment, when the cancer cell count is lower.  CHEMOTHERAPY TOXICITY Growth Fraction: is the ratio of replicating cells(growth) to resting cells in a tissue. Antineoplastic drugs are more toxic to tissues & tumours with high growth fractions, therefore normal tissues with high growth fractions are sensitive to their effects. Fetal cells Hair follicles: alopecia Testicles and ovaries: may cause sterility and infertility. GI epithelium: Inflammation of GI mucosa (mucositis): Painful ulcers in the mouth and esophagus, difficulties with eating or swallowing, gastrointestinal bleeding, intestinal infections, and severe diarrhea. Nausea: Administer antiemetics 30-60 minutes before initiation of chemotherapy. Constipation/Diarrhea Anorexia may occur due to nausea, vomitting and mucositis. ?Nursing consideration for side effects? HEMATOLOGIC CONSIDERATIONS IN CHEMOTHERAPY Erythrocytes, leukocytes, and platelets have brief lifespans and need continuous replacement by stem cells in the bone marrow. Antineoplastic agents can destroy stem cells, causing bone marrow suppression. Neutrophils: Very Sensitivity to chemotherapy due to need for constant replacement r/t short lifespan of 7-12 hours. Neutropenia: Diagnosed when neutrophil count is below 1500 cells/mL (Infection risk). Neutropenic clients may need reverse isolation to prevent infections. Colony-stimulating factors (e.g., filgrastim can aid in recovery and boost WBC count. Platelets: Lifespan of 7-8 days, requiring constant replenishment. Thrombocytopenia: Diagnosed when platelet count drops below 100,000 per milliliter of blood, often leading to delayed chemotherapy. Low platlets can cause ++ bleeding. Bleeding precautions needed if count falls below 50,000. Platelet infusions and thrombopoietic growth factors (e.g., oprelvekin) may be used. Erythrocytes: Erythrocytes live 90-120 days, so anemia appears later in chemotherapy. Anemia affects oxygen delivery to tissues, potentially impacting all body systems. RBC infusions, and medications like epoetin alfa, may be administered to increase RBC count and hemoglobin.  EXTRAVASATION Extravasation refers to the unintended leakage of blood, lymph, or other fluids, including chemotherapy drugs, from a blood vessel or catheter into the tissue surrounding intravenous (IV) site. Signs range from mild irritation and stiffness to local pain and tissue damage/loss. Chemo drugs classified as: Vesicants, irritants, or non-irritants Vesicants are drugs that have the potential to cause blistering, severe tissue injury, or necrosis when they infiltrate into surrounding tissue. E.g. Doxorubicin. (Nursing consideration: Ensure patent, large bore IV site) Irritants are agents that may cause inflammation (phlebitis) and/or pain at the venipuncture site or along the vein; however, if infiltrated, they do not cause tissue necrosis. Signs of extravasation -pain, swelling, redness, and stinging/ burning sensation at IV site. Blisters and ulcerations are late signs. INFORM MD immediately!  Surgery Radiation Chemotherapy SIDE EFFECT OF TREATMENT Anemia, Pain Inflammation bone marrow suppression Localized Hematomas Fatigue/malaise hair loss Hemorrhage Radiodermatitis Alopecia Risk of Nausea/vomitting infection Risk for Cytotoxicity: Organ atelectasis, toxicities pneumonia, hypoxia Risk for DVT Extravasation  CANCER CELL RESISTANCE Primary or Acquired Reduce uptake of the drug Enhance regenerative enzyme production => repairs DNA Alter enzymatic function Deactivate drug Cross-resistance is present Multi-drug/tx approach attempts to enhance efficacy & decrease resistance  NURSING CONSIDERATION -CYTOTOXIC PRECAUTIONS Cytotoxic = substances that damage or kill cells/tissues. Nurses must follow safety measures when handling cytotoxic drugs and waste (urine, faeces, vomit), to minimize exposure. Note: chemotherapy may stay in the body for 3-7 days. Personal Protective Equipment (PPE): gloves, gowns. Mask and eye protection as needed. Administration: Use infusion pumps and other equipment to prevent accidental spills or leaks. Environmental Cleaning: Ensure that surfaces and equipment are cleaned thoroughly after drug administration. Use appropriate cleaning agents and procedures. Spill Management: Follow protocol for containment, cleanup of any drug spills, and emergency procedures for accidental exposure. Cytotoxic Waste Disposal: Dispose of cytotoxic drug waste in designated hazardous waste containers, following institutional protocols and regulatory guidelines. Hand Hygiene: Wash hands thoroughly after handling cytotoxic drugs or any potentially contaminated materials. No pregnant women LIFESPAN CONSIDERATIONS - CHILDREN & ADOLESCENTS Long-term effects of chemotherapy drugs Developmental stage affects reaction to Cardiomyopathy illness Hearing loss Cataracts, other eye problems Positive relationships with staff is Learning disabilities important Infertility Long-term effects of radiation Cancer treatment may predispose to Impaired growth of bones and teeth secondary cancers Hypothyroidism from head and neck radiation Survivors may have higher rates of Delayed puberty, sterility depression, suicidal ideation Impaired neurocognitive performance Nurses can emphasize positive feelings of Long-term effects of chemotherapy drugs hope, added purpose in life Cardiomyopathy Hearing loss Parents Cataracts, other eye problems Make treatment decisions Learning disabilities Must gather resources to support child Infertility Adjust life to integrate needs of the child with cancer  LIFESPAN CONSIDERATIONS Pregnant Women Older Adults. Some cancers can spread to placenta; most Risks and benefits of cancer screening cannot spread to fetus. Screenings for specific cancers for adults who have life expectancy >10 Delayed diagnosis may occur. years. Treatment approach is especially complex Patients do not respond to treatment the same way younger adults do, and recovery Surgery safest treatment may also be delayed due to: Age-associated physiologic changes Certain types of chemotherapy may be Higher incidence of comorbidities used during second, third trimesters Polypharmacy Radiation avoided because of potential Cancer treatment may worsen chronic harm to fetus health conditions  POPULAR ALTERNATIVE TREATMENTS IN CANCER CARE High Dose IV Vitamin C Also known as ascorbic acid; water soluble vitamin found in many fruits and vegetables. Hypothesized to prevent cancer by reducing oxidative stress. Hypothesized as cancer treatment: Vitamin C plays an important role in the formation of new collagen, which may lead to a reduction in malignant infiltration May also act as carrier for H2O2 to extracellular tissue, generating free radicals that act against cancer cells. WHAT ARE THE SAFETY CONCERNS? Side effects: GI disturbances (nausea, diarrhea, stomach cramps); hemolytic anemia if G6PD deficient Contraindications: kidney stones, renal impairment, hemodialysis, and hematochromatosis Drug-herb interactions: increases iron absorption; interfere with effectiveness of select chemotherapeutic agents (vincristine, doxorubicin, methotrexate, cisplatin, imatinib); enhance cardio-protective action of beta-blockers Lab value interactions: glucose test strips; fecal occult blood  POPULAR ALTERNATIVE TREATMENTS IN CANCER CARE Vitamin D Fat soluble vitamin found in diary, fish and some plants. Also produced through sun exposure. Needed for maintaining calcium and phosphorous levels in the blood and bone formation. Also important for immune system functioning. Hypothesized to have a role in cancer prevention through anti-proliferative and cell differentiating effects (Ali & Vaidya, 2007) SAFETY CONCERNS? Side effects: Side effects are rare, but include gastro-intestinal issues (constipation, cramps, vomiting), hypercalcemia, and headache. Contraindications: kidney stones, renal disease, diseases in which calcium metabolism is disrupted Drug-herb interactions: Increase serum calcium levels with thiazide diuretics; may decrease bioavailability of Lipitor (CYP 3A4); high doses of vit D with digoxin may cause arrhythmias Lab value interactions: may influence blood glucose levels WHAT IS IT? CANNABIS Used for hundreds of years in traditional medicine; more recently has been used recreationally for it’s psychoactive properties. Used by patients to treat variety of conditions: Pain (arthritis), muscle spasms (MS), cachexia (HIV/AIDs), nausea/vomiting (esp. in cancer), and anxiety/depression. WHAT DOES THE EVIDENCE TELL US? Most research has been on pharmaceutical cannabis. Shown to be effective in managing nausea and vomiting (Tramer et al., 2001) and cancer-related pain (e.g., Johnson et al., 2013). Mixed results re: role in cachexia and appetite stimulation. Research suggests THC may down-regulate and control cell invasion. Concern THC may promote cell growth in cancers without cannabinoid receptors (e.g., breast). Lack of epidemiological evidence of a link between cannabis and cancer risk WHAT ARE THE SAFETY CONCERNS? Side effects: Psychoactive response, dry mouth, decreased psychomotor coordination, impairment of short-term memory and concentration, nausea, dizziness, cardiac complications (hypo/hypertension/tachycardia), panic attacks/paranoia Contraindications: Concern about impact on mental health and brain development for youth under 25 years. Drug-herb interactions: Barbiturates, CNS depressants, and anesthesia. May effect drugs metabolized by cytochrome P450 Lab value interactions: impact inter-ocular pressure  TUMERIC WHAT IS IT? A tropical plant that is part of the ginger family. Also called curcumin or Indian saffron and is commonly used as a spice in cooking. Comprised of many curcuminoids, including curcumin, which has been subject to the most research. Has been shown in laboratory studies to have anti-inflammatory and anti-oxidant effects and enhance apoptosis. Note that it also has an anti-platelet effect. Some suggestion it may have chemo/radiosensitivity effects WHAT ARE THE SAFETY CONCERNS? Side effects: Generally well tolerated. Can increase risk of bleeding; may cause GI disturbances; can cause contact dermatitis Contraindications: Bleeding disorders, gallbladder disease, diabetes (may cause hypoglycemia), ulcers and GERD Drug-herb interactions: Can potentiate anti-coagulants, anti-diabetes drugs. Has been shown to inhibit chemotherapy drugs processed by cytochrome P450 enzymes (e.g., cyclophosphamide and doxorubicin) Lab value interactions: Interfere with thioflavin T assays  REVIEW Describe the following concepts: Acute Vs Chronic Endemic Vs Epidemic Vs Pandemic Signs Vs Symptoms Cell proliferation Vs Differentiation Cell cycle and Cell Death Hypertrophy, Hyperplasia, Metaplasia, Dysplasia Neoplasia: Benign vs Malignant  REVIEW Classifications, causes, staging/grading of malignant neoplsams. Cancers are described by their stage and grade. Classes of antineoplastic agents and their MOA Side effects of chemotherapy Lifespan consideartions