Chapter 54: Biological Response–Modifying and Antirheumatic Drugs

Lilley’s Pharmacology for Canadian Health Care Practice, 4^th Canadian Edition

Chapter 54: Biological Response–Modifying and Antirheumatic Drugs

Chapter Summary

OVERVIEW

• Cancer treatment has traditionally involved surgery, radiation, and chemotherapy. Surgery and radiation are usually local or regional therapies. Chemotherapy is generally systemic, but it often does not completely eliminate all of the cancer cells in the body. Adjuvant therapy is frequently used to destroy undetected distant micrometastases.

• 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. The humoral and cellular immune systems act together to recognize and destroy foreign particles and cells in the blood or other body tissues. The humoral immune system is composed of lymphocytes that are known as B cells until they are transformed into plasma cells when they come in contact with an antigen (foreign substance). The plasma cells then manufacture antibodies to that antigen.

• The development of drugs whose primary site of action is the immune system has resulted in new additions to the drugs known as biological response–modifying drugs. These drugs alter the body’s response to diseases such as cancer and autoimmune, inflammatory, and infectious diseases and can enhance or restrict the patient’s immune response to disease, stimulate a patient’s hematopoietic function, and prevent disease.

• Biological response–modifying drugs provide another treatment option for patients who have malignancies and are receiving chemotherapy and need to boost blood cell counts.

• Two broad classes of biological 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 used to treat rheumatoid arthritis.

• Immunomodulating drugs therapeutically alter a patient’s immune response.

• An intact immune system can identify cells as malignant and destroy them; a healthy immune system can distinguish between tumour cells and normal body tissues.

• 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. Only when the natural immune responses fail to keep pace with these initially microscopic cancer cell growths does a person develop a true “cancer” requiring clinical intervention.

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

• Some immunomodulating drugs are used to treat autoimmune, inflammatory, and infectious diseases. They either reduce the patient’s inappropriate immune response (as in rheumatoid arthritis) or strengthen the immune response against microorganisms and cancer cells.

Immune System

• Tumour cells express chemical compounds on their surfaces that signal the immune system that these cells are a threat. These chemical markers are called tumour antigens or markers.

• 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.

• Humoral immunity is mediated by B-cell functions (primarily antibody production), and cell-mediated immunity is mediated by T-cell functions.

• Attack against tumour cells by antibodies produced by the B lymphocytes of the humoral immune system prepares those tumour cells for destruction by the T lymphocytes.

• The immune system in a healthy individual is genetically preprogrammed to be able to mount an antibody response against literally millions of different antigens resulting from the individual’s lifetime antigen exposure and through exposure to new antigens that are passed down.

• Antibodies that a single plasma cell makes are all identical and are called monoclonal. Monoclonal antibodies have also been prepared synthetically using recombinant deoxyribonucleic acid (DNA) technology, which has resulted in newer drug therapies.

• When B lymphocytes differentiate into plasma cells, some of these B cells become memory cells that “remember” the exact characteristics of a particular foreign antigen, allowing a stronger and faster immune response upon re-exposure to the same antigen.

• The functional cells of the cell-mediated immune system are the T lymphocytes, which mature in the thymus. T cells include cytotoxic T cells, T-helper cells, and T-suppressor cells.

• Cytotoxic T cells kill their targets directly 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 serving as chemical mediators of physiological functions.

• Lymphokines are a subset of cytokines released by T lymphocytes upon contact with antigens; they 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 that serves 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 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, which are not lymphocytes and which are also called neutrophils.

• In contrast, T-suppressor cells have an important negative influence on antitumour actions of the immune system. Overactive T-suppressor cells may be responsible for clinically significant cancer cases by permitting tumour growth beyond the immune system’s control.

BIOLOGICAL RESPONSE MODIFIERS 

• Therapeutic effects of the biological response–modifying drugs include enhancement of hematopoietic function, regulation or enhancement of the immune response, inhibition of metastases, prevention of cell division, and inhibition of cell maturation.

Hematopoietic Drugs

• Erythropoietic drugs (epoetin alfa and darbepoetin alfa), two colony-stimulating factors (filgrastim and pegfilgrastim), and one platelet-promoting drug (oprelvekin) are not available in Canada. All of these drugs promote the synthesis of various types of major blood components promoting the growth, differentiation, and function of their corresponding precursor cells in the bone marrow.

• All hematopoietic drugs decrease the duration of chemotherapy-induced anemia, neutropenia, and thrombocytopenia and allow higher dosages of chemotherapy to be given. They 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.

• Neutrophils are the most important granulocytes for fighting infection. Colony-stimulating factors stimulate neutrophils to grow and mature and thus directly oppose the detrimental bone marrow actions of chemotherapy.

• Colony-stimulating factors, such as macrophages and granulocytes, also enhance the functioning of mature cells of the immune system. This increases the ability of the body’s immune system to kill cancer cells, as well as virus- and fungus-infected cells.

• Filgrastim has significant drug interactions when these two drugs are given with myelosuppressive antineoplastic drugs. When myelosuppressive antineoplastics are given with them, the drugs directly antagonize each other. Filgrastim and sargramostim are not given within 24 hours of administration of myelosuppressive antineoplastics.

Interferons

• Interferons are proteins with three basic properties: (1) antiviral, (2) antitumour, and (3) immunomodulating. There are three different groups of interferon drugs—interferons alpha, beta, and gamma—each with its own antigenic and biological activity.

• Interferons are most commonly used in the treatment of certain viral infections and types of cancer.

• Interferons are recombinantly manufactured substances that are identical to the interferon cytokines that are naturally present in the human body.

• 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, which is useful when the immune system has become dysfunctional, causing autoimmune disease such as multiple sclerosis (MS).

• The beneficial actions of interferons make them excellent drugs for the treatment of viral infections, various cancers, and some autoimmune disorders.

• The most commonly used interferon products are in the alfa class and are referred to as leukocyte interferons because they are produced from human leukocytes. Two newer types of interferon alfa include peginterferon alfa-2a and peginterferon alfa-2b.

• 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.

• The most common adverse effects can be broadly described as flulike symptoms: fever, chills, headache, malaise, myalgia, and fatigue.

• Patients taking high dosages become so exhausted that they are often confined to bed.

Monoclonal Antibodies

• Monoclonal antibodies are becoming standards of therapy in many areas, including the treatment of cancer, rheumatoid arthritis and other inflammatory diseases, MS, and organ transplantation. They can specifically target cancer cells with minimal effect on healthy cells.

• Many, if not most, patients receiving these potent drugs manifest acute symptoms that are comparable with classic allergy or flulike symptoms, such as fever, dyspnea, and chills. The primary objective is to adminis­ter the medication and control such symptoms.

• Because the mechanisms of action of these drugs work through augmentation or inhibition of the human immune response, they can have a variety of adverse effects— some mild, some severe—that affect several body systems.

Interleukins and Related Drugs

• Interleukins are a natural part of the immune system and are classified as lymphokines, soluble proteins that are released from activated lymphocytes, such as NK cells.

• Interleukins cause multiple effects in the immune system, one of which is antitumour action.

• The interleukin (IL)-2 derivative aldesleukin acts indirectly to stimu­late or restore immune response. Aldesleukin binds to receptor sites on T cells, which stimulates the T cells to multiply.

• Anakinra is a recombinant form of the natural human IL-1 receptor antagonist. It competitively inhibits the binding of IL-1 to its corresponding receptor sites, which are expressed in many different tissues and organs. Tocil­izumab is a recombinant form of the natural IL-6 receptor antagonist.

• Therapy with aldesleukin is commonly complicated by severe toxicity. A syndrome known as capillary leak syndrome is responsible for the severe toxicities of aldesleukin.

• Anakinra has a much milder adverse effect profile that includes local reactions at the injection site, various respiratory tract infections, and headache.

• Tocilizumab use poses a high risk of causing anaphylaxis.

Miscellaneous Immunomodulating Drugs

• Several additional medications can be broadly classified as miscellaneous immunomodulating drugs.

• A special term used for immunostimulant drugs that work by a nonspecific mechanism is adjuvant.

Rheumatoid Arthritis

• Rheumatism is a general term for any of several disorders characterized by inflammation, degeneration, or metabolic derangement of connective tissue structures, especially joints and related structures such as muscles, tendons, bursae, fibrous tissue, and ligaments.

• Rheumatoid arthritis is a chronic autoimmune disorder that commonly causes inflammation and tissue damage in joints. It can also cause anemia and diffuse inflammation in the lungs, eyes, and pericardium of the heart, and subcutaneous nodules under the skin.

Disease-Modifying Antirheumatic Arthritis Drugs

• Disease-modifying antirheumatic drugs (DMARDs) not only provide analgesic effects but can arrest or slow the disease processes associated with arthritis. They exhibit anti-inflammatory, antiarthritic, and immunomodulating effects and work by inhibiting the movement of various cells into an inflamed and damaged area, such as a joint.

• DMARDs often have a slow onset of action of several weeks versus minutes to hours for nonsteroidal anti-inflammatory drugs; thus, these drugs are sometimes also referred to as slow-acting antirheumatic drugs.

• Nonbiological DMARDs include methotrexate, leflunomide, hydroxychloroquine sulfate, sodium auro­thiomalate, cyclosporine, azathioprine, and sulfasalaz­ine.

• The biological DMARDs include adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, adalimumab, abata­cept, rituximab, tocilizumab, and tofacitinib.

• DMARDs are not used in patients with active bacterial infection, active herpes zoster, active or latent tuberculosis, or acute or chronic hepatitis B or C.

• Etanercept, infliximab, and adalimumab are not to be used in patients with heart failure, lymphoma, or MS.

• Methotrexate, tofacitinib, and leflunomide are to be avoided during pregnancy and lactation.

• The guidelines recommend starting with methotrexate alone or with another DMARD in most patients.

• Use of other drugs, including the biological DMARDs, is gener­ally reserved for those patients who do not respond to methotrexate or combination DMARDs.

NURSING PROCESS

Assessment

• Before administering these medications, document baseline assessments of vital signs, skin turgor and intactness, bowel sounds and patterns, and breath sounds.

• Assess potential intravenous and subcutaneous sites, and if appropriate, note the chemotherapy-induced absolute neutrophil nadir (low point).

• When filgrastim is used, watch for any existing joint or bone pain due to the possible adverse effect of mild to severe bone pain. Do not administer filgrastim and sargramostim within 24 hours of giving a myelosuppressive antineoplastic, and follow the time frame for their use as prescribed, whether in an inpatient or home setting.

• With biological response–modifying drugs, note the presence of any conditions that represent contraindications or cautions to their administration.

• Assess these four systems:

  • Respiratory system (rate, rhythm, and depth, as well as breath sounds and any adventitious [abnormal] sounds)

  • Cardiac system (vital signs, heart sounds, heart rate and rhythm, and oxygen saturation levels, as well as edema or shortness of breath, the presence of cyanotic discoloration around the mouth or nail beds, and any chest pain)

  • Central nervous system (baseline mental status, as well as assessment of any seizure-like activity or central nervous system abnormalities)

  • Immune system (history of chronic illnesses, ability to fight off infections, and history of suppressed immunity)

• Before interferons are given, assess the patient’s history of drug allergies as well as any history of autoimmune disorders, hepatitis, liver failure, or AIDS.

• Prior to the use of DMARDs, perform a close assess­ment of any past or present medical conditions as well as a thorough assessment of allergies. Compile a com­plete and thorough medication profile, listing prescrip­tion drugs, natural health products, and over-the-counter drugs. Note the specific type of DMARD prescribed, because there are nonbiological and biological DMARDS. Check the contraindications to the use of DMARDs, such as active bacterial infections, active herpes, active or latent tuberculosis, and acute or chronic hepatitis B or C.

• Before the initiation of therapy with leflunomide, perform a complete assessment of hepatic functioning as well as baseline blood cell counts. Because of the possible adverse effects of diarrhea and respiratory infections, assess GI functioning and bowel patterns.

• Etanercept is to be avoided in patients with sepsis and active infections, so conduct a thorough assessment of white blood cell (WBC) counts and document any signs and symptoms of infection or any history of infection. Some dosage forms may contain latex, so it is critical to also assess for latex allergy.

Implementation

• Premedication with acetaminophen and diphenhydramine may be deemed necessary to help minimize any allergic-type reaction when any of the biological response–modifying drugs are administered.

• With some of the biological response–modifying drugs, treatment with opioids, other antihistamines, or anti-inflammatory drugs may be required for the management of bone pain and chills if treatment with acetaminophen or diphenhydramine is not successful.

• Antiemetics may also be needed for any drug-related nausea or vomiting and may be given before the administration of the specific biological response–modifying drug.

Evaluation

• Because infection is a concern with many biological response−modifying drugs, monitor the patient’s vital signs, with attention to temperature, and also note any occurrence of chills and headache.

• With monoclonals, serious infections are a major concern.

• The variety of therapeutic responses to biological response–modifying drugs include a decrease in the growth of the lesion or mass, a decreased tumour size, and an easing of symptoms related to the tumour or disease process. Other therapeutic effects are an improvement in WBC, red blood cell, and platelet counts or the return of blood counts to normal levels, and the absence of infection, anemias, and hemorrhage.

• DMARDs are expected to show therapeutic results within a documented time frame (often weeks). The patient experiences an increased ability to move joints, less discomfort, and an overall increased sense of improvement and well-being.

• The toxicity of these drugs may be manifested by liver, renal, and respiratory dysfunction and, in the case of methotrexate, bone marrow suppression.

• Nursing management associated with the administration of biological response–modifying drugs focuses on the use of careful aseptic technique and other measures to prevent infection; proper nutrition; oral hygiene; monitoring of blood counts; and management of adverse effects, including joint or bone pain and flulike symptoms.