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Immunity and Infection: Viruses, Retroviruses & Medications for Immunity The Immune System Physiology • The immune system includes tissue and cells in the lymph system, spleen, liver, lungs, GI tract, and brain. • An integrated immune system response provides the body’s response to invasion. • Anything foreign to the body is an “antigen”: • Antigens are identified as “non-self” by the body thus are in need of attack by the immune system. • Immunizations (vaccinations) utilize live, dead or synthetic viruses to “trick” the immune system into establishing an antigen response. Pathophysiology Four abnormal conditions can weaken the immune system and stimulate the immune response: – Neoplasms (result from the growth of mutant cells, called cancers) – Viral invasion – Autoimmune diseases – Organ transplant rejection Pathophysiology • Viral invasion of a cell changes the cell’s membrane and antigenic action. • In autoimmune diseases, the body responds to specific self-antigens by producing antibodies against the self (autoantibodies). Examples: – Rheumatoid arthritis – Lupus erythematosis • Organ transplantation weakens the immune system as the body reacts to the introduction of foreign cells. Cytokines • Cytokines are chemical mediators released by WBCs in response to antigenic invasion of the blood or tissues. • Cytokines serve to enhance and accelerate the inflammatory and specific responses that will destroy the invading antigen. • Cytokines are generally pro-inflammatory, but many also have antiviral, anti-proliferative, and antineoplastic properties. Prototype drug: interferon alpha-2b (Intron) Produced by recombinant DNA technology using Escherichia coli bacteria. Interferon: Core Drug Knowledge • Pharmacotherapeutics – Some types of cancer and chronic hepatitis • Pharmacodynamics – Inhibits the growth of tumor cells, prevents these cells from multiplying – Stimulates the immune system • Side/Adverse effects – Dizziness, confusion, lethargy, flu-like symptoms, anorexia, nausea, and changes in taste • Minimizing adverse effects – Pre-medicate patients with drugs such as acetaminophen or diphenhydramine to reduce the flu-like adverse effects. Pathophysiology: Rheumatoid Arthritis • A systemic, inflammatory disease. • Effects are not limited to joint destruction. • Affects all age groups. – May onset as early as age 2 years • Believed to be an autoimmune. • Primary characteristics are symmetrical, severe polyarticular inflammation. • Can cause inflammation of glands, the linings of the heart, the lungs, and the vascular system. • RA has a substantial effect on quality of life because of the associated pain, fatigue, and depression, and the increased risk of heart disease. Disease-Modifying Anti-rheumatic Drugs • Disease-modifying anti-rheumatic drugs (DMARDs) are used in conjunction with salicylates and NSAIDs, or as monotherapy. • They are so named because they are capable of arresting the progression of RA and can induce remission in some patients. Prototype drug: methotrexate (Rheumatrex) Methotrexate: Core Drug Knowledge • Pharmacotherapeutics – Used in treating various malignancies (cancers) and rheumatoid arthritis • Pharmacokinetics – Administered: orally or parenterally. Metabolized in the liver, excreted in the kidneys • Pharmacodynamics – Exerts immunosuppressive effects by inhibiting the replication and function of T lymphocytes that stimulate the production of cytokines Methotrexate: Core Drug Knowledge • Contraindications and precautions – – – – Immunosuppression, Blood disorders Pregnancy Category X Lactation • Side effects – Rash, headache, nausea and vomiting, diarrhea, stomach inflammation, alopecia (hair loss) • Adverse effects – Bone Marrow suppression – White blood cell suppression Methotrexate: Planning and Interventions • Maximizing therapeutic effects – Administer medication as ordered. – Drink plenty of water to prevent nephrotoxicity. • Minimizing adverse effects – Folic acid will interfere with effectiveness of drug. – Can cause photosensitivity – Monitor CBC for bone marrow suppression (anemia) – Monitor for opportunistic infections (WBC suppression) What is a Virus? What is a Virus? How does it replicate? http://www.youtube.com/watch?v=L8oHs7G_syI Physiology of Viral Reproduction The reproduction of viruses in humans requires five steps: Adsorption – Attachment to human cells Penetration – Entering human cells Un-coating – Virus sheds its protein coat Replication – Viral RNA converts to DNA by “hijacking” the human DNA Transcription – New viruses are synthesized After this, the cell lyses (splits) and the new viruses are released Viral Reproduction Pathophysiology of Selected Viral Infections Hepatitis – Five types: HAV, HBV, HCV, HDV, and HEV – Most common in the United States: Hepatitis A, B, and C – HAV: spread via oral–fecal route (“food poisoning”) – HBV and HCV: spread via blood or body fluids Symptoms of Hepatitis include jaundice, fatigue, abdominal pain, nausea, and anorexia. Pathophysiology of Selected Viral Infections Herpes simplex (HSV) – Two types: HSV-1 and HSV-2 – Characterized by the formation of painful vesicles: • HSV-1 on or near the mouth • HSV-2 in the genital region HSV Type 1 HSV Type 2 Pathophysiology of Selected Viral Infections Herpes zoster (Chickenpox, Shingles) – Acute segmental inflammation of the peripheral nervous system’s dorsal root ganglia caused by infection with the herpes virus varicella zoster (chickenpox) – Follows along dermatomes of trunk and occasionally on arms and legs • A dermatome is an area of skin in which sensory nerves derive from a single spinal nerve root – Post-herpetic neuralgia (nerve pain) is a common complication. Dermatomes of the Head, Face and Neck Herpes Zoster Virus: Shingles (left) and Chicken Pox (right) Purine Nucleoside Analogue Drugs • The largest group of antiviral drugs are the purine nucleoside analogue drugs. • They have relatively selective toxicity to viruses because viral DNA polymerases are more sensitive than human polymerases to inhibition by these drugs. Prototype drug: acyclovir (Zovirax) Acyclovir: Core Drug Knowledge • Pharmacotherapeutics – Suppress outbreaks of herpes viruses • Pharmacokinetics – Administered: topical, oral, or IV • Pharmacodynamics – In an infected cell, acyclovir is converted by viral enzymes and incorporated into the virus. Once inside, it terminates viral DNA synthesis. Acyclovir: Core Drug Knowledge • Side effects – Light-headedness, anorexia, nausea, vomiting, abdominal pain, and headache • Adverse effects – Risk for confusion, seizures or nephrotoxicity (oral or IV) • Minimizing adverse effects – Advise the patient to drink at least 8-oz glasses of water a day. – Administer IV acyclovir over 60 minutes. Acyclovir: Core Drug Knowledge • Patient and family education – Emphasize that acyclovir does not prevent the transmission of infection to another person and does not cure the infection. • Ongoing assessment and evaluation – Monitor for the effectiveness of therapy – Document new lesions – Assess for possible secondary bacterial infections. Pathophysiology of Selected Viral Infections Influenza – Attacks both the upper and the lower respiratory tracts – A and B are the only types affected by current antiviral medications Drugs Used for Influenza • Influenza can be a debilitating virus though it generally subsides without pharmacotherapy. • Certain populations require treatment due to possible life-threatening symptoms. – Elderly – Infants and children – Immunocompromised persons Prototype Drug : oseltamivir (Tamiflu) Oseltamivir: Core Drug Knowledge • Pharmacotherapeutics – Used to manage influenza A or B virus; drug of choice for H5N1 and H1N1 • Pharmacodynamics – Appears to inhibit the release of viruses from infected cells, reducing spread to adjacent cells • Maximizing therapeutic effects – Works best when started within 48 hrs of onset of symptoms Oseltamivir: Core Drug Knowledge • Side effects – Nausea and vomiting, bronchitis, insomnia, vertigo • Maximizing therapeutic effects – Works best when started within 48 hrs. of onset of symptoms • Minimizing adverse effects – Reduce nausea and vomiting by administrating the drug with milk, a snack, or a meal. Pathophysiology of Selected Viral Infections Respiratory syncytial virus (RSV) – Highest rates of RSV illness occur in infants 2-6 months of age – Symptoms include hacking cough and wheezing on exhalation. Examples: Infant RSV http://www.youtube.com/watch?v=lIE_UElOk3c Retroviruses: Drugs Treating HIV Infection and AIDS Physiology of the Immune System Cells • CD4 cells are receptors on T-cells, a type of white blood cell. • The CD4 site recognizes foreign antigens and infected cells and helps activate the antibodyproducing B lymphocytes. • B lymphocytes then produce natural antibodies that help T-cells to induce immunity. • T-cells are necessary for normal immune function. CD4 T-Cell Function Human immunodeficiency virus – HIV is like all other viruses in physical structure. – HIV has an affinity for CD4 cells. By hijacking CD4 cells, it reduces the development of Tcells and reduces human immunity. – The HIV virus is called a retrovirus. The difference between a virus and a retrovirus is in the genetic material (RNA) Pathophysiology • HIV infection begins when the virus binds to cells that have a CD4 protein receptor site. • Once the virus is bound to the cell, the viral envelope and the plasma membrane fuse (adsorption) • Inside the cell, viral RNA is transcribed into a single strand of viral DNA that then is able to be inserted into the healthy human DNA strand by enzymes such as integrase and protease. • Many anti-HIV drugs act to prevent the enzymes. Diagnosis of HIV and AIDS Diagnosis of HIV infection is usually made by a salivary screening test followed by a confirmatory serum (blood) assay. • Viral load. This test measures the amount of virus in your blood. Studies have shown that people with higher viral loads generally fare more poorly than do those with a lower viral load. • CD4 count. HIV infection progresses to AIDS when your CD4 count dips below 200. The Difficulty in Treating HIV • HIV viruses take over human T-cells and insert themselves into the human DNA • When you attack the HIV, you also attack the host cell • Thus, killing HIV also kills human T-cells. • Drugs work by trying to prevent the HIV from hijacking the host cell’s DNA strand through affecting different enzymes that help the RNA/DNA insertion of the virus. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors • These are the first class of drugs approved to treat HIV infection and AIDS. • These drugs inhibit reverse transcriptase, an enzyme critical to HIV replication. Prototype drug: zidovudine (Retrovir) Zidovudine: Core Drug Knowledge • Pharmacotherapeutics – Epstein-Barr virus, hepatitis B virus, and HIV infection • Side effects – GI symptoms, headache, and sleepiness • Adverse effects – Seizures and hematologic toxicities In-class Quiz #8: The Immune System and Viruses • Complete the proctored, 20 point quiz in class. • You will repeat this quiz in class on 4/13 • 10 participation points will be awarded on 4/8 for completing the quiz. • 10 participation points will be awarded on 4/13 for completing the quiz. • Overall learning of material will be evaluated in the ATI Exam #4.