Biologic Response–Modifying and Antirheumatic Drugs



Biologic Response–Modifying and Antirheumatic Drugs


Objectives


When you reach the end of this chapter, you will be able to do the following:



1 Describe the basic anatomy, physiology, and functions of the immune system.


2 Compare the two major classes of biologic response–modifying drugs: hematopoietic drugs and immunomodulating drugs.


3 Discuss the mechanisms of action, indications, dosages, routes of administration, adverse effects, cautions, contraindications, and drug interactions of the different biologic response–modifying drugs.


4 Describe the pathology associated with rheumatoid arthritis.


5 Discuss the mechanisms of action, indications, dosages, routes of administration, adverse effects, cautions, contraindications, and drug interactions of the different antirheumatic drugs.


6 Develop a nursing care plan that includes all phases of the nursing process for patients receiving biologic response–modifying drugs and for those receiving antirheumatic drugs.


Drug Profiles



Key Terms


Adjuvant A nonspecific immunostimulant that enhances overall immune function, rather than stimulating the function of a specific immune system cell or cytokine through specific chemical reactions. (p. 776)


Antibodies Immunoglobulin molecules (see Chapter 49) that have the ability to bind to and inactivate antigen molecules through formation of an antigen-antibody complex. This process serves to inactivate foreign antigens that enter the body and are capable of causing disease. (p. 765)


Antigen A biologic or chemical substance that is recognized as foreign by the body’s immune system. (p. 764)


Arthritis Inflammation of one or more joints. (p. 777)


Autoimmune disorder A disorder that occurs when the body’s tissues are attacked by its own immune system. (p. 776)


B lymphocytes (B cells) Leukocytes of the humoral immune system that develop into plasma cells, and then produce the antibodies that bind to and inactivate antigens. B cells are one of the two principal types of lymphocytes; T lymphocytes are the other. (p. 765)


Biologic response–modifying drugs A broad class of drugs that includes hematopoietic drugs and immunomodulating drugs. Often referred to as biologic response modifiers (BRMs), they alter the body’s response to diseases such as cancer as well as autoimmune, inflammatory, and infectious diseases. Examples are cytokines (e.g., interleukin, interferons), monoclonal antibodies, and vaccines. They are also called biomodulators or immunomodulating drugs. Biologic response–modifying drugs may be adjuvants, immunostimulants, or immunosuppressants. (p. 764)


Cell-mediated immunity Collective term for all immune responses that are mediated by T lymphocytes (T cells). Also called cellular immunity. Cell-mediated immunity acts in collaboration with humoral immunity. (p. 764)


Colony-stimulating factors Cytokines that regulate the growth, differentiation, and function of bone marrow stem cells. (p. 766)


Complement Collective term for about 20 different proteins normally present in plasma that assist other immune system components (e.g., B cells and T cells) in mounting an immune response. (p. 774)


Cytokines The generic term for nonantibody proteins released by specific cell populations (e.g., activated T cells) on contact with antigens. Cytokines act as intercellular mediators of an immune response. (p. 765)


Cytotoxic T cells Differentiated T cells that can recognize and lyse (rupture) target cells that have foreign antigens on their surfaces. These antigens are recognized by the corresponding antigen receptors that are expressed (displayed) on the cytotoxic T-cell surface. Also called natural killer cells. (p. 765)


Differentiation The process of cellular development from a simplified into a more specialized cellular structure. In hematopoiesis, it refers to the multistep processes involved in the maturation of blood cells. (p. 766)


Disease-modifying antirheumatic drugs (DMARDs) Medications used in the treatment of rheumatic diseases that have the potential to arrest or slow the actual disease process instead of providing only antiinflammatory and analgesic effects. (p. 777)


Hematopoiesis Collective term for all of the body’s processes originating in the bone marrow that result in the formation of various types of blood components (adjective: hematopoietic). It includes the three main processes of differentiation (see earlier): erythropoiesis (formation of red blood cells, or erythrocytes), leukopoiesis (formation of white blood cells, or leukocytes), and thrombopoiesis (formation of platelets, or thrombocytes). (p. 764)


Humoral immunity Collective term for all immune responses that are mediated by B cells, which ultimately work through the production of antibodies against specific antigens. Humoral immunity acts in collaboration with cell-mediated immunity. (p. 764)


Immunoglobulins Complex immune system glycoproteins that bind to and inactivate foreign antigens. The term is synonymous with immune globulins. (p. 765)


Immunomodulating drugs Collective term for various subclasses of biologic response–modifying drugs that specifically or nonspecifically enhance or reduce immune responses. The three major types of immunomodulators, based on mechanism of action, are adjuvants, immunostimulants, and immunosuppressants (see Chapter 48). (p. 764)


Immunostimulant A drug that enhances immune response through specific chemical interactions with particular immune system components. An example is interleukin-2. (p. 776)


Immunosuppressant A drug that reduces immune response through specific chemical interactions with particular immune system components. An example is cyclosporine (see Chapter 48). (p. 769)


Interferons One type of cytokine that promotes resistance to viral infection in uninfected cells and can also strengthen the body’s immune response to cancer cells. (p. 768)


Leukocytes The collective term for all subtypes of white blood cells. Leukocytes include the granulocytes (neutrophils, eosinophils, and basophils), monocytes, and lymphocytes (B cells and T cells). Some monocytes also develop into tissue macrophages. (p. 766)


Lymphokine-activated killer (LAK) cell Cytotoxic T cells that have been activated by interkeukin-2 and therefore have a stronger and more specific response against cancer cells. (p. 774)


Lymphokines Cytokines that are produced by sensitized T lymphocytes on contact with antigen particles. (p. 765)


Memory cells Cells involved in the humoral immune system that remember the exact characteristics of a particular foreign invader or antigen for the purpose of expediting immune response in the event of future exposure to this antigen. (p. 765)


Monoclonal Denoting a group of identical cells or organisms derived from a single cell. (p. 765)


Plasma cells Cells derived from B cells that are found in the bone marrow, connective tissue, and blood. They produce antibodies. (p. 765)


Rheumatism General term for any of several disorders characterized by inflammation, degeneration, or metabolic derangement of connective tissue structures, especially joints and related structures. (p. 776)


T helper cells Cells that promote and direct the actions of various other cells of the immune system. (p. 765)


T lymphocytes (T cells) Leukocytes of the cell-mediated immune system. Unlike B cells, they are not involved in the production of antibodies but instead occur in various cell subtypes (e.g., T helper cells, T suppressor cells, and cytotoxic T cells). They act through direct cell-to-cell contact or through production of cytokines that guide the functions of other immune system components (e.g., B cells, antibodies). (p. 765)


T suppressor cells Cells that regulate and limit the immune response, balancing the effects of T helper cells. (p. 766)


Tumor antigens Chemical compounds expressed on the surfaces of tumor cells. They signal to the immune system that these cells do not belong in the body, labeling the tumor cells as foreign. (p. 764)


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http://evolve.elsevier.com/Lilley



Anatomy, Physiology, and Pathophysiology Overview


Overview of Immunomodulators


Over the last two decades, medical technology has developed a group of drugs whose primary site of action is the immune system. This has resulted in new additions to the class of drugs known as biologic response–modifying drugs, or biologic response modifiers(s). These drugs alter the body’s response to diseases such as cancer and autoimmune, inflammatory, and infectious diseases. These drugs can enhance or restrict the patient’s immune response to disease, can stimulate a patient’s hematopoietic (blood-forming) function, and can prevent disease. Hematopoiesis is the collective term for all of the blood component–forming processes of the bone marrow. Two broad classes of biologic response–modifying drugs are hematopoietic drugs and immunomodulating drugs. Subclasses of immunomodulating drugs include interferons, monoclonal antibodies, interleukin receptor agonists and antagonists, and miscellaneous drugs. Disease-modifying antirheumatic drugs are drugs that are used to treat rheumatoid arthritis, which is discussed later in the chapter.


Immunomodulating drugs therapeutically alter a patient’s immune response. In cancer treatment, they make up the fourth type of cancer therapy, along with surgery, chemotherapy, and radiation. The human immune system is most commonly viewed as the body’s natural defense against pathogenic bacteria and viruses. However, it also has effective antitumor capabilities. An intact immune system can identify cells as malignant and destroy them. In contrast to chemotherapeutic drugs, a healthy immune system can distinguish between tumor cells and normal body tissues. Normal cells are recognized as “self” and are not damaged, whereas tumor cells are recognized as “foreign” and are destroyed. People develop cancerous cells in their bodies on a regular basis. Normally the immune system is able to eliminate these cells before they multiply to uncontrollable levels. It is only when the natural immune responses fail to keep pace with these initially microscopic cancer cell growths that a person develops a true “cancer” requiring clinical intervention.


In terms of their activity against cancer cells, biologic response–modifying drugs work by one of three mechanisms: (1) enhancement or restoration of the host’s immune system defenses against the tumor; (2) direct toxic effect on the tumor cells, which causes them to lyse, or rupture; or (3) adverse modification of the tumor’s biology, which makes it harder for the tumor cells to survive and reproduce.


Some immunomodulating drugs are used to treat autoimmune, inflammatory, and infectious diseases. In these instances, the drug functions either to reduce the patient’s inappropriate immune response (in the case of inflammatory and autoimmune diseases such as rheumatoid arthritis) or to strengthen the patient’s immune response against microorganisms (especially viruses) and cancer cells. To better understand these complex drugs, a review of immune system physiology is beneficial.


Immune System


The immune system is an intricate biologic defense network of cells that are capable of distinguishing an unlimited variety of substances as either foreign (“nonself”) or a natural part of the host’s body (“self”). When a foreign substance such as a bacteria or virus enters the body, the immune system recognizes it as being foreign and mounts an immune response to eliminate or neutralize the invader. Tumors are not truly foreign substances because they arise from cells of normal tissues whose genetic material (deoxyribonucleic acid [DNA] and ribonucleic acid [RNA]) has somehow mutated. Tumor cells express chemical compounds on their surfaces that signal the immune system that these cells are a threat. These chemical markers are called tumor antigens or tumor markers, and they label the tumor cells as abnormal cells. An antigen is any substance that the body’s immune system recognizes as foreign. Recognition of antigens varies among individuals, which is why some people are more prone than others to immune-related diseases such as allergies, inflammatory diseases, and cancer.


The two major components of the body’s immune system are humoral immunity, mediated by B-cell functions (primarily antibody production), and cell-mediated immunity, which is mediated by T-cell functions. These two systems work together to recognize and destroy foreign particles and cells in the blood or other body tissues. Communication between these two divisions is vital to the success of the immune system as a whole. Attack against tumor cells by antibodies produced by the B lymphocytes (B cells) of the humoral immune system prepares those tumor cells for destruction by the T lymphocytes (T cells) of the cell-mediated immune system. This is just one example of the effective way that the two divisions of the immune system communicate with each other for a collaborative immune response.


Humoral Immune System


The functional cells of the humoral immune system are the B lymphocytes. They are also called B cells because they originate in the bone marrow. The B cells that are capable of generating a particular antibody normally remain dormant until the corresponding antigen is detected. When an antigen binds to receptors located on the B cells, a biochemical signal is sent to the B lymphocytes. These B cells then mature or differentiate into plasma cells, which in turn produce antibodies. Antibodies are immunoglobulins (large glycoprotein molecules; glyco = sugar; protein = amino acid chain) that bind to specific antigens, forming an antigen-antibody complex that inactivates disease-causing antigens.


The immune system in a healthy individual is genetically preprogrammed to be able to mount an antibody response against literally millions of different antigens. This ability results from the individual’s lifetime antigen exposure and is further developed through exposure to new antigens and passed down through many generations. Antibodies that a single plasma cell makes are all identical. They are therefore called monoclonal antibodies. Since the 1980s, monoclonal antibodies have also been prepared synthetically using recombinant DNA technology, which has resulted in newer drug therapies.


There are five major types of naturally occurring immunoglobulins in the body: immunoglobulins A, D, E, G, and M. These unique types have different structures and functions and are found in various areas of the body. During an immune response, when B lymphocytes differentiate into plasma cells, some of these B cells become memory cells. Memory cells “remember” the exact characteristics of a particular foreign invader or antigen, which allows a stronger and faster immune response in the event of reexposure to the same antigen. The cells of the humoral immune system are shown in Figure 47-1.



Cell-Mediated Immune System


The functional cells of the cell-mediated (as opposed to antibody-mediated) immune system are the T lymphocytes. They are also referred to as T cells because they mature in the thymus. There are three distinct populations of T cells: cytotoxic T cells, T helper cells, and T suppressor cells (Figure 47-2). They are distinguished by the different functions that they perform. Cytotoxic T cells directly kill their targets by causing cell lysis or rupture. T helper cells are considered the master controllers of the immune system. They direct the actions of many other immune components, such as lymphokines and cytotoxic T cells. Cytokines are nonantibody proteins that serve as chemical mediators of various physiologic functions. Lymphokines are a subset of cytokines. They are released by T lymphocytes upon contact with antigens and serve as chemical mediators of the immune response. T suppressor cells have an effect on the immune system that is opposite to that of T helper cells and serve to limit or control the immune response. A healthy immune system has about twice as many T helper cells as T suppressor cells at any given time.



The major cells involved in the destruction of cancer cells are part of the cell-mediated immune system (see Figure 47-2). The cancer-killing cells of the cellular immune system are the macrophages (derived from monocytes), natural killer (NK) cells (another type of lymphocyte), and polymorphonuclear leukocytes (not lymphocytes), which are also called neutrophils. In contrast, T suppressor cells have an important negative influence on antitumor actions of the immune system. Overactive T suppressor cells may be responsible for clinically significant cancer cases by permitting tumor growth beyond the immune system’s control.


Pharmacology Overview


Therapy with biologic response–modifying drugs combines the knowledge of several disciplines, including general biology, genetics, immunology, pharmacology, medicine, and nursing. The general therapeutic effects of these drugs are as follows:



Box 47-1 lists the currently available biologic response–modifying drugs used in the treatment of cancer and other illnesses that have varying levels of immune system–related pathophysiology. The drugs are classified according to their biologic effects.



Hematopoietic Drugs


Hematopoietic drugs include several medications developed over the past 10 to 15 years. Falling into this category are two erythropoietic drugs (epoetin alfa and darbepoetin alfa), three colony-stimulating factors (filgrastim, pegfilgrastim, and sargramostim), and one platelet-promoting drug (oprelvekin). All of these drugs promote the synthesis of various types of major blood components by promoting the growth, differentiation, and function of their corresponding precursor cells in the bone marrow.


Mechanism of Action and Drug Effects


Although the hematopoietic drugs are not toxic to cancer cells, they do have beneficial effects in the treatment of cancer. All hematopoietic drugs have the same basic mechanism of action. They decrease the duration of chemotherapy-induced anemia, neutropenia, and thrombocytopenia and enable higher dosages of chemotherapy to be given; decrease bone marrow recovery time after bone marrow transplantation or irradiation; and stimulate other cells in the immune system to destroy or inhibit the growth of cancer cells, as well as virus- or fungus-infected cells.


All of these drugs are produced by recombinant DNA technology, which allows them to be essentially identical to their endogenously produced counterparts. These substances work by binding to receptors on the surfaces of specialized progenitor cells in the bone marrow. Progenitor cells are responsible for the production of three particular cell lines: red blood cells (RBCs), white blood cells (WBCs), and platelets. When a hematopoietic drug binds to a progenitor cell surface, the immature progenitor cell is stimulated to mature, proliferate (reproduce itself), differentiate (transform into its respective type of specialized blood component), and become functionally active. Hematopoietic drugs may enhance certain functions of mature cell lines as well.


Epoetin alfa is a synthetic derivative of the human hormone erythropoietin, which is produced primarily by the kidney. It promotes the synthesis of erythrocytes (RBCs) by stimulating RBC progenitor cells in the bone marrow. Darbepoetin alfa is a longer-acting form of epoetin alfa. These drugs are discussed in detail in Chapter 54. Filgrastim is a colony-stimulating factor that stimulates progenitor cells for the subset of WBCs (leukocytes) known as granulocytes (including basophils, eosinophils, and neutrophils). For this reason, it is also commonly called granulocyte colony-stimulating factor (G-CSF). Pegfilgrastim is a longer-acting form of filgrastim. Sargramostim is also a colony-stimulating factor that works by stimulating the bone marrow precursor cells that synthesize both granulocytes and the phagocytic (cell-eating) cells known as monocytes, some of which become macrophages. For this reason, it is also called granulocyte-macrophage colony-stimulating factor (GM-CSF). Oprelvekin is classified as an interleukin, namely, interleukin-11 (IL-11). Other interleukins are discussed later in the chapter. Oprelvekin stimulates the bone marrow cells, specifically megakaryocytes that eventually give rise to platelets.


Indications


Neutrophils are the most important granulocytes for fighting infection. Infections often appear in patients who have experienced destruction of bone marrow cells as a result of chemotherapy. Colony-stimulating factors stimulate neutrophils to grow and mature and thus directly oppose the detrimental bone marrow actions of chemotherapy. Because these drugs reduce the duration of low neutrophil counts, they reduce the incidence and duration of infections. Colony-stimulating factors also enhance the functioning of mature cells of the immune system, such as macrophages and granulocytes. This increases the ability of the body’s immune system to kill cancer cells, as well as virus- and fungus-infected cells. Ultimately these properties allow patients to receive higher dosages of chemotherapy. Similar benefits occur with epoetin alfa and oprelvekin with regard to RBC and platelet counts, respectively.


The effect of hematopoietic drugs on the bone marrow cells also reduces the recovery time after bone marrow transplantation and radiation therapy. Dosages of chemotherapy used in bone marrow transplantation are often much higher than those used in conventional chemotherapy. Both the chemotherapy and radiation therapy are toxic to the bone marrow. When one or more colony-stimulating factors are administered as part of the drug therapy for bone marrow transplantation, bone marrow cell counts return to normal in a drastically shortened time. This helps to increase the likelihood of a successful bone marrow transplantation and therefore patient survival. Specific drug indications are listed in the Dosages table on this page.


Contraindications


Contraindications for all these drugs include drug allergy. Use of filgrastim, sargramostim, and pegfilgrastim is contraindicated in the presence of more than 10% myeloid blasts (immature tumor cells in the bone marrow), because colony-stimulating factors may stimulate malignant growth of these myeloid tumor cells.


Adverse Effects


Adverse effects associated with the use of hematopoietic drugs are mild. The most common are fever, muscle aches, bone pain, and flushing. Table 47-1 lists additional adverse effects.



Interactions


Filgrastim and sargramostim have significant drug interactions when these two drugs are given with myelosuppressive (bone marrow depressant) antineoplastic drugs. Remember that these two drugs are administered to enhance the production of bone marrow cells; therefore, when myelosuppressive antineoplastics are given with them, the drugs directly antagonize each other. Typically filgrastim and sargramostim are not given within 24 hours of administration of myelosuppressive antineoplastics. However, they are given soon after this time to help prevent the WBC nadir from dropping to dangerous levels and also to speed WBC recovery. It is also recommended that these drugs be used with caution or not be given with other medications that can potentiate their myeloproliferative (bone marrow–stimulating) effects. Two examples are lithium and corticosteroids.


Dosages


For dosage information on hematopoietic drugs, see the table on this page.



Drug Profiles


♦ filgrastim


Filgrastim (Neupogen) is a synthetic analogue of human granulocyte colony-stimulating factor and is commonly referred to as G-CSF. Filgrastim promotes the proliferation, differentiation, and activation of the cells that make granulocytes. Granulocytes are the body’s primary defense against bacterial and fungal infections. Filgrastim has the same pharmacologic effects as endogenous human G-CSF, which is normally secreted by specialized leukocytes known as monocytes, macrophages, and mature neutrophils. Filgrastim is indicated to prevent or treat febrile neutropenia in patients receiving myelosuppressive antineoplastics for nonmyeloid (non–bone marrow) malignancies. It must be given before a patient develops an infection, but not within 24 hours before or after myelosuppressive chemotherapeutic drugs. Pegfilgrastim (Neulasta) is a long-acting form of filgrastim that reduces the number of injections required. Both drugs are available for injection only. These drugs are usually discontinued when a patient’s absolute neutrophil count (ANC) rises above 10,000 cells/mm3. However, some prescribers will stop it when the ANC is between 1000 and 2000 cells/mm3



♦ sargramostim


Sargramostim (Leukine) is a synthetic analogue of human granulocyte-macrophage colony-stimulating factor and is commonly referred to as GM-CSF. There are three major subsets of leukocytes: granulocytes, monocytes, and lymphocytes (B cells and T cells). Granulocytes are further subdivided into basophils, eosinophils, and neutrophils. Neutrophils are the most important in fighting infection. Macrophages are tissue-based (as opposed to circulating) cells that are derived from monocytes, which circulate in the blood. Neutrophils, monocytes, and macrophages make up the three main categories of phagocytic (cell-eating) blood cells, and they literally ingest foreign cells and other antigens as part of their immune system function. Sargramostim has the same pharmacologic effects as endogenous human GM-CSF. It stimulates the proliferation, differentiation, and activation of the cells in the bone marrow that eventually become granulocytes, monocytes, and macrophages.


Sargramostim is indicated for promoting bone marrow recovery after autologous (own marrow) or allogenic (donor marrow) bone marrow transplantation in patients with various types of leukemia and lymphoma. This drug is available for injection only.



♦ oprelvekin


Oprelvekin (Neumega) is both a hematopoietic drug and one of the interleukins. However, its function is similar to that of the colony-stimulating factors (filgrastim and sargramostim) in that it enhances synthesis of a specific blood component—in this case, the platelets. Oprelvekin is indicated for the prevention of chemotherapy-induced severe thrombocytopenia and avoidance of the need for platelet transfusions. Its use is contraindicated in cases of known drug allergy. It is available for injection only.



Interferons


Interferons are proteins that have three basic properties: they are antiviral, antitumor, and immunomodulating. There are three different groups of interferon drugs—the alpha, beta, and gamma interferons—each with its own antigenic and biologic activity. Interferons are most commonly used in the treatment of certain viral infections and certain types of cancer.


Mechanism of Action and Drug Effects


Interferons are recombinantly manufactured substances that are identical to the interferon cytokines that are naturally present in the human body. In the body, interferons are produced by activated T cells and by other cells in response to viral infection. Interferons protect human cells from virus attack by enabling the human cells to produce enzymes that stop viral replication and prevent viruses from penetrating into healthy cells. Interferons prevent cancer cells from dividing and replicating and also increase the activity of other cells in the immune system, such as macrophages, neutrophils, and natural killer cells. Their effect on cancer cells is caused by a combination of direct inhibition of DNA and protein synthesis within cancer cells (antitumor effects) and multiple immunomodulatory effects on the host’s immune system. Interferons increase the cytotoxic activity of natural killer cells and the phagocytic ability of macrophages. Interferons also increase the expression of cancer cell antigens on the cell surface, which enables the immune system to recognize cancer cells more easily, specifically marking them for destruction.


Overall, interferons have three different effects on the immune system. They can (1) restore its function if it is impaired, (2) augment (amplify) the immune system’s ability to function as the body’s defense, and (3) inhibit the immune system from working. This latter function may be especially useful when the immune system has become dysfunctional, causing an autoimmune disease. This is believed to be the case in multiple sclerosis. Two interferons (interferon beta-1a and interferon beta-1b) are specifically indicated for treatment of multiple sclerosis. Inhibiting the dysfunctional immune system prevents further damage to the body from the disease process.


Indications


The beneficial actions of interferons (antiviral, antineoplastic, and immunomodulatory) make them excellent drugs for the treatment of viral infections, various cancers, and some autoimmune disorders. Currently accepted indications for interferons are listed in the Dosages table on this page.


Contraindications


Contraindications to the use of interferons include known drug allergy and may include autoimmune disorders, hepatitis or liver failure, concurrent use of immunosuppressant drugs, Kaposi’s sarcoma related to acquired immunodeficiency syndrome (AIDS), and severe liver disease.


Adverse Effects


The most common adverse effects can be broadly described as flulike symptoms: fever, chills, headache, malaise, myalgia, and fatigue. The major dose-limiting adverse effect of interferons is fatigue. Patients taking high dosages become so exhausted that they are often confined to bed. Other adverse effects of interferons are listed in Table 47-2.


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May 9, 2017 | Posted by in NURSING | Comments Off on Biologic Response–Modifying and Antirheumatic Drugs

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