Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 55–7 Actions of some monoclonal antibodies (shown in red). CTLA-4-lgFc fusion protein (CTLA-4-lg, abatacept) binds to CD80/86 on DC and inhibits T-cell costimulation. Alefacept inhibits activation of T cells by blocking the interaction of LFA-3 and CD2. Basiliximab and daclizumab block IL-2 from binding to the IL-2 receptor (CD25) on T cells, preventing activation; CD25 is also important for the survival of T regulatory cells. T-cell activation can be maintained or restored if CTLA-4 interaction with CD80/86 is blocked using an anti–CTLA-4 antibody (ipilimumab); ipilimumab inhibits CTLA-4 signaling and prolongs activation. Pembrolizumab and nivolumab bind to PD-1, while atezolizumab binds to PD-L1. Each of these three Mabs inhibits the negative signal delivery by PD-1, also prolonging T cell activation. release of IL-1β, causing autoimmune inflammation resulting in fever, urticarial-like rash, arthralgia, myalgia, fatigue, and conjunctivitis.


Pharmacology_Katzung

Pharmacology_Katzung. release of IL-1β, causing autoimmune inflammation resulting in fever, urticarial-like rash, arthralgia, myalgia, fatigue, and conjunctivitis. Natalizumab is a humanized IgG4 monoclonal antibody that binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surfaces of all leukocytes except neutrophils. It inhibits the α4-mediated adhesion of leukocytes to their cognate receptor. It is indicated for patients with multiple sclerosis and Crohn’s disease who have not tolerated or had inadequate responses to conventional treatments. Natalizumab should not be used with any of the anti-TNF-α drugs listed above. Natalizumab increases risk of progressive multifocal leukoencephalopathy.


Pharmacology_Katzung

Pharmacology_Katzung. Omalizumab is an anti-IgE recombinant humanized monoclonal antibody that is approved for the treatment of allergic asthma in adult and adolescent patients whose symptoms are refractory to inhaled corticosteroids (see Chapter 20). The drug is also approved for chronic urticaria. The antibody blocks the binding of IgE to the high-affinity Fcε receptor on basophils and mast cells, which suppresses IgE-mediated release of type I allergy mediators such as histamine and leukotrienes. Total serum IgE levels may remain elevated in patients for up to 1 year after administration of omalizumab.


Pharmacology_Katzung

Pharmacology_Katzung. Ustekinumab is a human IgG1 monoclonal antibody that binds to the p40 subunit of IL-12 and IL-23 cytokines. It blocks IL-12 and IL-23 from binding to their receptors, therefore inhibiting receptor-mediated signaling in lymphocytes. Ustekinumab is indicated for adult patients with moderate to severe plaque psoriasis either alone or with methotrexate. The advantage of ustekinumab over antiTNF-α drugs for psoriasis is faster and longer-term improvement in symptoms along with very infrequent dosing. Vedolizumab is a humanized monoclonal antibody that targets the α4β7 integrin in the gastrointestinal tract. It does not appear to induce systemic immunosuppression of other α4β7 integrin-binding antibodies such as natalizumab because it does not bind to the majority of α4β7 integrin on lymphocytes. It has been recommended for approval for the treatment of adults with Crohn’s disease and ulcerative colitis.


Pharmacology_Katzung

Pharmacology_Katzung. Abciximab is a Fab fragment of a murine-human monoclonal antibody that binds to the integrin GPIIb/IIIa receptor on activated platelets and inhibits fibrinogen, von Willebrand factor, and other adhesion molecules from binding to activated platelets, thus preventing their aggregation. It is indicated as an adjunct to percutaneous coronary intervention in combination with aspirin and heparin for the prevention of cardiac ischemic complications. See Chapter 34 for additional details.


Pharmacology_Katzung

Pharmacology_Katzung. Alirocumab and Evolocumab are anti-cholesterol Mabs (see Chapter 35). They lower LDL levels by blocking proprotein convertase subtilisin/kexin type 9 (PCSK9) from binding to LDL receptors (LDRL) and causing LDL receptor degradation. Therefore, these Mabs have the effect of increasing LDLR on hepatocytes, which lowers LDL levels in circulation. They are approved as an adjunct to diet and maximally tolerated statin therapy in adults with homoor heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease who require additional lowering of LDL-C.


Pharmacology_Katzung

Pharmacology_Katzung. Denosumab is a human IgG2 monoclonal antibody specific for human RANKL (receptor activator of nuclear factor kappa-B ligand; see Chapter 42). By binding RANKL it inhibits the maturation of osteoclasts, the cells responsible for bone resorption. Denosumab is indicated for treatment of postmenopausal women with osteoporosis at high risk for fracture. Before starting denosumab, patients must be evaluated to be sure they are not hypocalcemic. During treatment, patients should receive supplements of calcium and vitamin D.


Pharmacology_Katzung

Pharmacology_Katzung. Eculizumab is a humanized IgG monoclonal antibody that binds the C5 complement component, inhibiting its cleavage into C5a and C5b thereby inhibiting the terminal pore-forming lytic activity of complement. Eculizumab is approved for patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). It dramatically reduces the need for red blood cell transfusions. It prevents PNH symptoms of anemia, fatigue, thrombosis, and hemoglobinemia by inhibiting intravascular hemolysis. Similarly in aHUS eculizumab prevents complement-mediated thrombotic microangiopathy. Clinicians must be aware of increased risk of meningococcal infection in patients receiving this anti-C5 monoclonal antibody.


Pharmacology_Katzung

Pharmacology_Katzung. Palivizumab is a humanized IgG1 monoclonal antibody that binds to the fusion protein of respiratory syncytial virus (RSV), preventing serious lower respiratory tract disease. It is used in neonates at risk for this viral infection and reduces the frequency of infection and hospitalization by about 50% (see Chapter 49). Ranibizumab is a recombinant human IgG1 Fab that binds to VEGF-A. It prevents new blood vessel formation by blocking VEGF from binding to its receptor. Ranibizumab is approved for intravitreal injection in patients with neovascular age-related macular degeneration, diabetic macular edema, and sudden blurring or vision loss secondary to macular edema following retinal vein occlusion. Pegaptanib is a pegylated oligonucleotide that binds extracellular VEGF and is also given by intravitreous injection to slow macular degeneration.


Pharmacology_Katzung

Pharmacology_Katzung. Obiltoxaximab and raxibacumab are FDA-approved Mabs for treatment of patients after inhalation exposure to Bacillus anthracis spores. Both Mabs block the binding of B anthracis “protective antigen” to its cellular receptor, preventing entry of anthrax lethal and edema factors into cells. They are approved for the treatment or prophylaxis of adults and children with inhalational anthrax in combination with appropriate antibacterial drugs. Interestingly, these Mabs were not tested in humans because exposing a control cohort to inhalational anthrax is unethical and there are too few naturally infected persons to conduct a proper clinical trial. Immunosuppressive agents are commonly used in two clinical circumstances: transplantation and autoimmune disorders. The agents used differ somewhat for the specific disorders treated (see specific agents and Table 55–1), as do administration schedules.


Pharmacology_Katzung

Pharmacology_Katzung. Because autoimmune disorders are very complex, optimal treatment schedules have yet to be established in many of them.


Pharmacology_Katzung

Pharmacology_Katzung. In organ transplantation, tissue typing—based on donor and recipient histocompatibility matching with the human leukocyte antigen (HLA) haplotype system—is required. Close histocompatibility matching reduces the likelihood of graft rejection and may also reduce the requirements for intensive immunosuppressive therapy. Prior to transplant, patients may receive an immunosuppressive regimen, including antithymocyte globulin, daclizumab, or basiliximab. Four types of rejection can occur in a solid organ transplant recipient: hyperacute, accelerated, acute, and chronic. Hyperacute rejection is due to preformed antibodies against the donor organ, such as anti– blood group antibodies. Hyperacute rejection occurs within hours of the transplant and cannot be stopped with immunosuppressive drugs. It results in rapid necrosis and failure of the transplanted organ. Accelerated rejection is mediated by both antibodies and T cells, and it also cannot be stopped by immunosuppressive drugs. Acute


Pharmacology_Katzung

Pharmacology_Katzung. It results in rapid necrosis and failure of the transplanted organ. Accelerated rejection is mediated by both antibodies and T cells, and it also cannot be stopped by immunosuppressive drugs. Acute rejection of an organ occurs within days to months and involves mainly cellular immunity. Reversal of acute rejection is usually possible with general immunosuppressive drugs such as azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, glucocorticoids, cyclophosphamide, methotrexate, and sirolimus. Recently, biologic agents such as anti-CD3 monoclonal antibodies have been used to stem acute rejection. Chronic rejection usually occurs months or even years after transplantation. It is characterized by thickening and fibrosis of the vasculature of the transplanted organ, involving both cellular and humoral immunity. Chronic rejection is treated with the same drugs as those used for acute rejection.


Pharmacology_Katzung

Pharmacology_Katzung. Allogeneic hematopoietic stem cell transplantation is a well-established treatment for many malignant and nonmalignant diseases. An HLA-matched donor, usually a family member, is located, patients are conditioned with high-dose chemotherapy and/or radiation therapy, and then donor stem cells are infused. The conditioning regimen is used not only to kill cancer cells in the case of malignant disease, but also to totally suppress the immune system so that the patient does not reject the donor stem cells. As patients’ blood counts recover (after reduction by the conditioning regimen) they develop a new immune system that is created from the donor stem cells. Rejection of donor stem cells is uncommon and can only be treated by infusion of more stem cells from the donor.


Pharmacology_Katzung

Pharmacology_Katzung. GVH disease, however, is very common, occurring in the majority of patients who receive an allogeneic transplant. GVH disease occurs because donor T cells fail to recognize the patient’s skin, liver, and gut (usually) as self and attack those tissues. Although patients are given immunosuppressive therapy (cyclosporine, methotrexate, and others) early in the transplant course to help prevent this development, it often occurs despite these medications. Acute GVH disease occurs within the first 100 days and is usually manifested as a skin rash, severe diarrhea, or hepatotoxicity. Additional medications are added, invariably starting with high-dose corticosteroids and adding drugs such as mycophenolate mofetil, sirolimus, tacrolimus, daclizumab, and others, with variable success rates. Patients generally progress to chronic GVH disease (after 100 days) and require therapy for variable periods thereafter. Unlike solid-organ transplant patients, however, most stem cell transplant patients


Pharmacology_Katzung

Pharmacology_Katzung. generally progress to chronic GVH disease (after 100 days) and require therapy for variable periods thereafter. Unlike solid-organ transplant patients, however, most stem cell transplant patients are able to eventually discontinue immunosuppressive drugs as GVH disease resolves (usually 1–2 years after their transplant).


Pharmacology_Katzung

Pharmacology_Katzung. The effectiveness of immunosuppressive drugs in autoimmune disorders varies widely. Nonetheless, with immunosuppressive therapy, remissions can be obtained in many instances of autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, type 1 diabetes, Hashimoto’s thyroiditis, and temporal arteritis. Improvement is also often seen in patients with systemic lupus erythematosus, acute glomerulonephritis, acquired factor VIII inhibitors (antibodies), rheumatoid arthritis, inflammatory myopathy, scleroderma, and certain other autoimmune states. Immunosuppressive therapy is utilized in chronic severe asthma, where cyclosporine is often effective and sirolimus is another alternative (see Chapter 20). Omalizumab (anti-IgE antibody) has been approved for the treatment of severe asthma (see previous section). Tacrolimus is currently under clinical investigation for the management of autoimmune chronic active hepatitis and of multiple sclerosis, where IFN-β has a definitive role.


Pharmacology_Katzung

Pharmacology_Katzung. The development of agents that modulate the immune response rather than suppress it has become an important area of pharmacology. The rationale underlying this approach is that such drugs may increase the immune responsiveness of patients who have either selective or generalized immunodeficiency. The major potential uses are in immunodeficiency disorders, chronic infectious diseases, and cancer. The AIDS epidemic has greatly increased interest in developing more effective immunomodulating drugs.


Pharmacology_Katzung

Pharmacology_Katzung. The cytokines are a large and heterogeneous group of proteins with diverse functions. Some are immunoregulatory proteins synthesized by leukocytes and play numerous interacting roles in the function of the immune system and in the control of hematopoiesis. The cytokines that have been clearly identified are summarized in Table 55–2. In most instances, cytokines mediate their effects through receptors on relevant target cells and appear to act in a manner similar to the mechanism of action of hormones. In other instances, cytokines may have antiproliferative, antimicrobial, and antitumor effects. The first group of cytokines discovered, the interferons (IFNs), were followed by the colony-stimulating factors (CSFs, discussed TABLE 55–2 The cytokines. Note: Many interleukin activities overlap and are influenced by each other. HCF, hematopoietic cofactor; LAK, lymphokine-activated killer cell.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 55–2 The cytokines. Note: Many interleukin activities overlap and are influenced by each other. HCF, hematopoietic cofactor; LAK, lymphokine-activated killer cell. in Chapter 33). The latter regulate the proliferation and differentiation of bone marrow progenitor cells. Most of the more recently discovered cytokines have been classified as interleukins (ILs) and numbered in the order of their discovery. Pharmaceutical cytokines are produced using gene cloning techniques. Most cytokines (including TNF-α, IFN-γ, IL-2, G-CSF, and granulocyte-macrophage colony-stimulating factor [GM-CSF]) have very short serum half-lives (minutes). The usual subcutaneous route of administration provides slower release into the circulation and a longer duration of action. Each cytokine has its own unique toxicity, but some toxicities are shared. For example, IFN-α, IFN-β, IFN-γ, IL-2, and TNF-α all induce fever, flu-like symptoms, anorexia, fatigue, and malaise.


Pharmacology_Katzung

Pharmacology_Katzung. Interferons are proteins that are currently grouped into three families: IFN-`, IFN-a, and IFN-f. The IFN-α and IFN-β families constitute type I IFNs, ie, acid-stable proteins that bind to the same receptor on target cells. IFN-γ, a type II IFN, is acid-labile and binds to a separate receptor on target cells. Type I IFNs are usually induced by virus infections, with leukocytes producing IFN-α. Fibroblasts and epithelial cells produce IFN-β. IFN-γ is usually the product of activated T lymphocytes.


Pharmacology_Katzung

Pharmacology_Katzung. IFNs interact with cell receptors to produce a wide variety of effects that depend on the cell and IFN types. IFNs, particularly IFN-γ, display immune-enhancing properties, which include increased antigen presentation and macrophage, NK cell, and cytotoxic T-lymphocyte activation. IFNs also inhibit cell proliferation. In this respect, IFN-α and IFN-β are more potent than IFN-γ. Another striking IFN action is increased expression of MHC molecules on cell surfaces. While all three types of IFN induce MHC class I molecules, only IFN-γ induces class II expression. In glial cells, IFN-β antagonizes this effect and may, in fact, decrease antigen presentation within the nervous system.


Pharmacology_Katzung

Pharmacology_Katzung. IFN-α is approved for the treatment of several neoplasms, including hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma, and Kaposi’s sarcoma, and for treatment of hepatitis B and C infections. It has also shown activity as an anti-cancer agent in renal cell carcinoma, carcinoid syndrome, and T-cell leukemia. IFN-β is approved for use in relapsing-type multiple sclerosis. IFN-γ is approved for the treatment of chronic granulomatous disease and IL-2, for metastatic renal cell carcinoma and malignant melanoma. Clinical investigations of other cytokines, including IL-1, -3, -4, -6, -10, -11, and -12, are ongoing. Toxicities of IFNs, which include fever, chills, malaise, myalgias, myelosuppression, headache, and depression, can severely restrict their clinical use.


Pharmacology_Katzung

Pharmacology_Katzung. TNF-α has been extensively tested in the therapy of various malignancies, but results have been disappointing due to dose-limiting toxicities. One exception is the use of intra-arterial high-dose TNF-α for malignant melanoma and soft tissue sarcoma of the extremities. In these settings, response rates greater than 80% were noted. Denileukin diftitox is IL-2 fused to diphtheria toxin, used for the treatment of patients with CD25+ cutaneous T-cell lymphomas. IL-12 and GM-CSF have also shown adjuvant effects with vaccines. GM-CSF is of particular interest because it promotes recruitment of professional antigen-presenting cells such as the dendritic cells required for priming naive antigen-specific T-lymphocyte responses. There are some reports that GM-CSF can itself stimulate an antitumor immune response, resulting in tumor regression in melanoma and prostate cancer.


Pharmacology_Katzung

Pharmacology_Katzung. It is important to emphasize that cytokine interactions with target cells often result in the release of a cascade of different endogenous cytokines, which exert their effects sequentially or simultaneously. For example, IFN-γ exposure increases the number of cell-surface receptors on target cells for TNF-α. Therapy with IL-2 induces the production of TNF-α, while experimental therapy with IL-12 induces the production of IFN-γ.


Pharmacology_Katzung

Pharmacology_Katzung. The basic immune mechanism and the ways in which it can be suppressed or stimulated by drugs have been discussed in previous sections of this chapter. Drugs also activate the immune system in undesirable ways that are manifested as adverse drug reactions. These reactions are generally grouped in a broad classification as “drug allergy.” Indeed, many drug reactions such as those to penicillin, iodides, phenytoin, and sulfonamides are allergic in nature. These drug reactions are manifested as skin eruptions, edema, anaphylactoid reactions, glomerulonephritis, fever, and eosinophilia. Drug reactions mediated by immune responses can have several different mechanisms. Thus, any of the four major types of hypersensitivity discussed earlier in this chapter (pages 981–983) can be associated with allergic drug reactions:


Pharmacology_Katzung

Pharmacology_Katzung. I: IgE-mediated acute allergic reactions to stings, pollens, and drugs, including anaphylaxis, urticaria, and angioedema. IgE is fixed to tissue mast cells and blood basophils, and after interaction with antigen the cells release potent mediators. II: Drugs often modify host proteins, thereby eliciting antibody responses to the modified protein. These allergic responses involve IgG or IgM in which the antibody becomes fixed to a host cell, which is then subject to complement-dependent lysis or to antibody-dependent cellular cytotoxicity. III: Drugs may cause serum sickness, which involves immune complexes containing IgG complexed with a foreign antigen and is a multisystem complement-dependent vasculitis that may also result in urticaria. IV: Cell-mediated allergy is the mechanism involved in allergic contact dermatitis from topically applied drugs or induration of the skin at the site of an antigen injected intradermally.


Pharmacology_Katzung

Pharmacology_Katzung. IV: Cell-mediated allergy is the mechanism involved in allergic contact dermatitis from topically applied drugs or induration of the skin at the site of an antigen injected intradermally. In some drug reactions, several of these hypersensitivity responses may occur simultaneously. Some adverse reactions to drugs may be mistakenly classified as allergic or immune when they are actually genetic deficiency states or are idiosyncratic and not mediated by immune mechanisms (eg, hemolysis due to primaquine in glucose-6-phosphate dehydrogenase deficiency, or aplastic anemia caused by chloramphenicol). See Figure 55–6.


Pharmacology_Katzung

Pharmacology_Katzung. Type I (immediate) sensitivity allergy to certain drugs occurs when the drug, not capable of inducing an immune response by itself, covalently links to a host carrier protein (hapten). When this happens, the immune system detects the drug-hapten conjugate as “modified self” and responds by generating IgE antibodies specific for the drug-hapten. It is not known why some patients mount an IgE response to a drug while others mount IgG responses. Under the influence of IL-4, -5, and -13 secreted by Th2 cells, B cells specific for the drug secrete IgE antibody. The mechanism for IgE-mediated immediate hypersensitivity is diagrammed in Figure 55–5.


Pharmacology_Katzung

Pharmacology_Katzung. Fixation of the IgE antibody to high-affinity Fc receptors (FcεRs) on blood basophils or their tissue equivalent (mast cells) sets the stage for an acute allergic reaction. The most important sites for mast cell distribution are skin, nasal epithelium, lung, and gastrointestinal tract. When the offending drug is reintroduced into the body, it binds and cross-links basophil and mast cell-surface IgE to signal release of the mediators (eg, histamine, leukotrienes; see Chapters 16 and 18) from granules. Mediator release is associated with calcium influx and a fall in intracellular cAMP within the mast cell. Many of the drugs that block mediator release appear to act through the cAMP mechanism (eg, catecholamines, glucocorticoids, theophylline), others block histamine release, and still others block histamine receptors. Other vasoactive substances such as kinins may also be generated during histamine release. These mediators initiate immediate vascular smooth muscle relaxation, increased


Pharmacology_Katzung

Pharmacology_Katzung. block histamine receptors. Other vasoactive substances such as kinins may also be generated during histamine release. These mediators initiate immediate vascular smooth muscle relaxation, increased vascular permeability, hypo-tension, edema, and bronchoconstriction.


Pharmacology_Katzung

Pharmacology_Katzung. Drug Treatment of Immediate Allergy One can test an individual for possible sensitivity to a drug by a simple scratch test, ie, by applying an extremely dilute solution of the drug to the skin and making a scratch with the tip of a needle. If allergy is present, an immediate (within 10–15 minutes) wheal (edema) and flare (increased blood flow) will occur. However, skin tests may be negative in spite of IgE hypersensitivity to a hapten or to a metabolic product of the drug, especially if the patient is taking steroids or antihistamines.


Pharmacology_Katzung

Pharmacology_Katzung. Drugs that modify allergic responses act at several links in this chain of events. Prednisone, often used in severe allergic reactions, is immunosuppressive; it blocks proliferation of the IgE-producing clones and inhibits IL-4 production by T helper cells in the IgE response, since glucocorticoids are generally toxic to lymphocytes. In the efferent limb of the allergic response, isoproterenol, epinephrine, and theophylline reduce the release of mediators from mast cells and basophils and produce bronchodilation. Epinephrine opposes histamine; it relaxes bronchiolar smooth muscle and contracts vascular muscle, relieving both bronchospasm and hypotension. As noted in Chapter 8, epinephrine is the drug of choice in anaphylactic reactions. The antihistamines competitively inhibit histamine, which would otherwise produce bronchoconstriction and increased capillary permeability in end organs. Glucocorticoids may also act to reduce tissue injury and edema in the inflamed tissue, as well as


Pharmacology_Katzung

Pharmacology_Katzung. which would otherwise produce bronchoconstriction and increased capillary permeability in end organs. Glucocorticoids may also act to reduce tissue injury and edema in the inflamed tissue, as well as facilitating the actions of catecholamines in cells that may have become refractory to epinephrine or isoproterenol. Several agents directed toward the inhibition of leukotrienes may be useful in acute allergic and inflammatory disorders (see Chapter 20).


Pharmacology_Katzung

Desensitization to Drugs

Pharmacology_Katzung. Desensitization to Drugs


Pharmacology_Katzung

Pharmacology_Katzung. When reasonable alternatives are not available, certain drugs (eg, penicillin, insulin) must be used for life-threatening illnesses even in the presence of known allergic sensitivity. In such cases, desensitization (also called hyposensitization) can sometimes be accomplished by starting with very small doses of the drug and gradually increasing the dose over a period of hours or days to the full therapeutic range (see Chapter 43). This practice is hazardous and must be performed under direct medical supervision with epinephrine available for immediate injection, as anaphylaxis may occur before desensitization has been achieved. It is thought that slow and progressive administration of the drug gradually binds all available IgE on mast cells, triggering a gradual release of granules. Once all of the IgE on the mast cell surfaces has been bound and the cells have been degranulated, therapeutic doses of the offending drug may be given with minimal further immune reaction. Therefore, a


Pharmacology_Katzung

Pharmacology_Katzung. all of the IgE on the mast cell surfaces has been bound and the cells have been degranulated, therapeutic doses of the offending drug may be given with minimal further immune reaction. Therefore, a patient is desensitized only during administration of the drug.


Pharmacology_Katzung

Pharmacology_Katzung. Certain autoimmune syndromes can be induced by drugs. Examples include systemic lupus erythematosus following hydralazine or procainamide therapy, “lupoid hepatitis” due to cathartic sensitivity, autoimmune hemolytic anemia resulting from methyldopa administration, thrombocytopenic purpura due to quinidine, and agranulocytosis due to a variety of drugs. As indicated in other chapters of this book, a number of drugs are associated with type I and type II reactions. In these drug-induced autoimmune states, IgG antibodies bind to drug-modified tissue and are destroyed by the complement system or by phagocytic cells with Fc receptors. Fortunately, autoimmune reactions to drugs usually subside within several months after the offending drug is withdrawn. Immunosuppressive therapy is warranted only when the autoimmune response is unusually severe.


Pharmacology_Katzung

Pharmacology_Katzung. Immunologic reactions to drugs resulting in serum sickness are more common than immediate anaphylactic responses, but type II and type III hypersensitivities often overlap. The clinical features of serum sickness include urticarial and erythematous skin eruptions, arthralgia or arthritis, lymphadenopathy, glomerulonephritis, peripheral edema, and fever. The reactions generally last 6–12 days and usually subside once the offending drug is eliminated. Antibodies of the IgM or IgG class are usually involved. The mechanism of tissue injury is immune complex formation and deposition on basement membranes (eg, lung, kidney), followed by complement activation and infiltration of leukocytes, causing tissue destruction. Glucocorticoids are useful in attenuating severe serum sickness reactions to drugs. In severe cases plasmapheresis can be used to remove the offending drug and immune complexes from circulation.


Pharmacology_Katzung

Pharmacology_Katzung. Immune vasculitis can also be induced by drugs. The sulfonamides, penicillin, thiouracil, anticonvulsants, and iodides all have been implicated in the initiation of hypersensitivity angiitis. Erythema multiforme is a relatively mild vasculitic skin disorder that may be secondary to drug hypersensitivity. Stevens-Johnson syndrome is probably a more severe form of this hypersensitivity reaction and consists of erythema multiforme, arthritis, nephritis, central nervous system abnormalities, and myocarditis. It frequently has been associated with sulfonamide therapy. Administration of nonhuman monoclonal or polyclonal antibodies such as rattlesnake antivenom may cause serum sickness.


Pharmacology_Katzung

Pharmacology_Katzung. Type IV hypersensitivity occurs 24–48 hours after exposure to the allergen and therefore is called delayed type hypersensitivity (DTH). Like other drug hypersensitivities, the drug may chemically react with host tissue to create a new antigen. Upon first exposure to the allergen (drug), antigen-presenting cells stimulate a T-cell response specific for that allergen. This takes 1–2 weeks. Upon second and all subsequent exposures, tissue-derived antigen-presenting cells that come in contact with the new antigen (allergen-modified host protein) secrete chemokines and cytokines that attract memory T cells to the site of allergen re-exposure. This takes only 24–48 hours. Lymphocytes and antigen-presenting cells such as macrophages accumulate at the site, causing induration, erythema, and swelling. Contact hypersensitivity is a form of DTH and occurs when an allergen elicits DTH on the skin, resulting in spongiosis such as when an ointment containing an allergen is applied to skin.


Pharmacology_Katzung

Pharmacology_Katzung. GENERIC NAME AVAILABLE AS Abatacept Orencia Abciximab ReoPro Adalimumab Humira Ado-trastuzumab emtansine Kadcyla Alefacept Amevive Alemtuzumab Campath Alirocumab Praluent Anakinra Kineret GENERIC NAME AVAILABLE AS Etanercept Enbrel Afinitor, Zortress Evolocumab Repatha Gilenya Glatiramer acetate Copaxone Simponi Ibritumomab tiuxetan Zevalin Various Azathioprine Generic, Imuran Cyclosporine Generic, Sandimmune, Restasis Interferon beta-1a Avonex, Rebif Interferon beta-1b Betaseron, Extavia Interleukin-2 (IL-2, aldesleukin) Proleukin Mycophenolate mofetil Generic, CellCept


Pharmacology_Katzung

Pharmacology_Katzung. Interferon beta-1b Betaseron, Extavia Interleukin-2 (IL-2, aldesleukin) Proleukin Mycophenolate mofetil Generic, CellCept GENERIC NAME AVAILABLE AS Pegademase bovine (bovine adenosine deaminase) Adagen Pegaptanib Macugen Peginterferon alfa-2a Pegasys Peginterferon alfa-2b PEG-Intron Pembrolizumab Keytruda Pertuzumab Perjeta Pomalidomide Pomalyst Ramucirumab Cyramza Ranibizumab Lucentis Raxibacumab ABthrax Reslizumab Cinqair Rho(D) immune globulin micro-dose RhoGam, others GENERIC NAME AVAILABLE AS Rilonacept Arcalyst Rituximab Rituxan Scorpion antivenom (equine (Fab)¢2) Anascorp Siltuximab Sylvant Sirolimus Generic, Rapamune Tacrolimus (FK 506) Generic, Prograf, others Teriflunomide Aubagio Thalidomide Thalomid Tocilizumab Actemra Trastuzumab Herceptin UstekinumabStelaraVedolizumabEntyvio*Several drugs discussed in this chapter are available as orphan drugs but are not listed here. Other drugs not listed here will be found in other chapters (see Index).


Pharmacology_Katzung

Pharmacology_Katzung. Levinson WE: Review of Medical Microbiology and Immunology, 13th ed. McGraw-Hill, 2014. Lubberts E: The IL-23–IL-17 axis in inflammatory arthritis. Nat Rev Rheumatol 2015;11:415. Murphy KM, Travers P, Walport M (editors): Janeway’s Immunobiology, 9th ed. Garland Science, 2016. Sharma P, Allison JP: The future of immune checkpoint therapy. Science 2015;348:56. Borroni RG: Role of dermatology in pharmacogenomics: Drug-induced skin injury. Pharmacogenomics 2015;16:401. De Groot AC: New contact allergens: 2008 to 2015. Dermatitis 2015;26:199. Aytan J: Use of biologics in SLE: A review of the evidence from a clinical perspective. Rheumatology 2016;55:775 Cantini F et al: Tailored first-line biologic therapy in patient with rheumatoid arthritis, spondyloarthritis, and psoriatic arthritis. Semin Arthritis Rheum 2016;45:519. Marzano AV et al: Immune-mediated inflammatory reactions and tumors as skin side effects of inflammatory bowel disease therapy. Autoimmunity 2014;47:146.


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Pharmacology_Katzung. Marzano AV et al: Immune-mediated inflammatory reactions and tumors as skin side effects of inflammatory bowel disease therapy. Autoimmunity 2014;47:146. Tiligada E et al: The expanding role of immunopharmacology: IUPHAR review 16. Br J Pharmacol 2015;172:4217. Sriaroon P, Ballow M: Immunoglobulin replacement therapy for primary immunodeficiency. Immunol Allergy Clin North Am 2015;35:713. Capron A et al: Intra-cellular immunosuppressive drug monitoring: A step forward towards better therapeutic efficacy after organ transplantation? Pharmacol Res 2016;111:610. Choi WE, Reddy P: Current and emerging strategies for the prevention of graftversus-host disease. Nat Rev Clin Oncol 2014;11:536. Lee JH et al: A comprehensive review of the treatment of atopic eczema. Allergy Asthma Immunol Res 2016;8:181. Sharma P, Scott DG: Optimizing methotrexate treatment in rheumatoid arthritis: Prior to biologics. Drugs 2015;75:1953.


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Pharmacology_Katzung. Sharma P, Scott DG: Optimizing methotrexate treatment in rheumatoid arthritis: Prior to biologics. Drugs 2015;75:1953. Waldner M et al: New perspectives on mTOR inhibitors (rapamycin, rapalogs, and TORKinibs) in transplantation. Br J Clin Pharmacol 2016;82:1158. Costa AG, Bilezikian JP: How long to treat with Denosumab. Curr Osteoporos Rep 2015;13:415. Cummings SR: Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756. Spain L et al: Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 2013;44:51. Wolf M et al: Peripheral administration of antithymocyte globulins: A review of current literature. Transplant Rev (Orlando) 2013;27:17. Akdis M et al: Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β and TNF-α: Receptors, functions and roles in diseases. J Allergy Clin Immunol 2016;138:984.


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Pharmacology_Katzung. Akdis M et al: Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β and TNF-α: Receptors, functions and roles in diseases. J Allergy Clin Immunol 2016;138:984. Khan DA: Hypersensitivity and immunologic reactions to biologics: Opportunities for the allergist. Ann Allergy Asthma Immunol 2016;117:115. Macy E: Practical management of patients with a history of immediate hypersensitivity to common non-beta-lactam drugs. Curr Allergy Asthma Rep 2016;16:4. Wickner PG, Hong D: Immediate drug hypersensitivity Curr Allergy Asthma Rep 2016;16:49.


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Pharmacology_Katzung. Wickner PG, Hong D: Immediate drug hypersensitivity Curr Allergy Asthma Rep 2016;16:49. Glucocorticoids (steroids) are first-line treatment for acute graft-vs-host disease. Acute graft-vs-host disease is the pro-cess of donor T cells attacking host recipient tissues (includ-ing skin), despite ongoing immunosuppressive therapy such as tacrolimus. Adding a steroid (eg, prednisone) can amelio-rate the T-cell response of graft-vs-host disease in most cases of grade II disease. See section in this chapter on Clinical Uses of Immunosuppressive Drugs. Introduction to Toxicology: Occupational & Environmental Daniel T. Teitelbaum, MD*


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Pharmacology_Katzung. Introduction to Toxicology: Occupational & Environmental Daniel T. Teitelbaum, MD* A 6-year-old girl is brought to the emergency department by her parents. She is comatose, tachypneic (25 breaths per minute), and tachycardic (150 bpm), but she appears flushed, and fingertip pulse oximetry is normal (97%) breathing room air. Questioning of her parents reveals that they are homeless and have been living in their car (a small van). The nights have been cold, and they have used a small char-coal burner to keep warm inside the vehicle. What is the most likely diagnosis? What treatment should be instituted immediately? If her mother is pregnant, what additional measures should be taken?


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Pharmacology_Katzung. Humans live in a chemical world. They inhale, ingest, and absorb through the skin many of these chemicals. The occupational-environmental toxicologist is primarily concerned with adverse effects in humans resulting from exposure to chemicals encountered at work or in the general environment. In clinical practice, the occupational-environmental toxicologist must identify and treat the adverse health effects of these * The author thanks the late Gabriel L. Plaa, PhD, previous author of this chapter, for his enduring contributions. exposures. In addition, the trained occupational-environmental toxicologist will be called upon to assess and identify hazards associated with chemicals used in the workplace or introduced into the human environment.


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Pharmacology_Katzung. Occupational and environmental toxicology cases present unusually complex problems. Occupational and environmental exposure is rarely limited to a single type of molecule. Most workplace or environmental materials are compounds or mixtures, and the ingredients are often poorly described in the documentation that is available for physician review. Moreover, although regulatory agencies in many countries have requirements for disclosure of hazardous materials and their health impacts, proprietary information exclusions often make it difficult for those who treat occupationally and environmentally poisoned patients to understand the nature and scope of the presenting illness. Because many of these illnesses have long latency periods before they become manifest, it is often a matter of detective work, when patients finally present with disease, to ascertain past exposure and relate it to present clinical effect. Monitoring of exposure concentrations both in the workplace and in the


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Pharmacology_Katzung. detective work, when patients finally present with disease, to ascertain past exposure and relate it to present clinical effect. Monitoring of exposure concentrations both in the workplace and in the general environment has become more common, but it is far from widespread, and so it is often very difficult to establish the extent of exposure, its duration, and its dose rate when this information is critical to the identification of the toxic disorder and its management.


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Pharmacology_Katzung. Occupational toxicology deals with the chemicals found in the workplace. The major emphasis of occupational toxicology is to identify the agents of concern, identify the acute and chronic diseases that they cause, define the conditions under which they may be used safely, and prevent absorption of harmful amounts of these chemicals. The occupational toxicologist will also be called upon to treat the diseases caused by these chemicals if he or she is a physician. Occupational toxicologists may also define and carry out programs for the surveillance of exposed workers and the environment in which they work. They frequently work hand in hand with occupational hygienists, certified safety professionals, and occupational health nurses in their activities.


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Pharmacology_Katzung. Regulatory limits and voluntary guidelines have been elaborated to establish safe ambient air concentrations for many chemicals found in the workplace. Governmental and supragovernmental bodies throughout the world have generated workplace health and safety rules, including shortand long-term exposure limits for workers. These permissible exposure limits (PELs) have the power of law in the United States. Copies of the US Occupational Safety and Health Administration (OSHA) standards may be found on OSHA’s website at http://www.osha.gov. Copies of the US Mine Safety and Health Administration (MSHA) standards may be found at http://www.msha.gov. In addition to the PELs that appear in the OSHA publications and on the website, OSHA promulgates standards for specific materials of particularly serious toxicity. These standards are developed following extensive scientific study, stakeholder input at hearings, public comment, and other steps such as publication in the Federal Register. Such


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Pharmacology_Katzung. serious toxicity. These standards are developed following extensive scientific study, stakeholder input at hearings, public comment, and other steps such as publication in the Federal Register. Such standards have the force of law and employers who use these materials are obligated to comply with the standards. OSHA standards may be found in full on the OSHA website at http:// www.osha.gov.


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Pharmacology_Katzung. Voluntary organizations, such as the American Conference of Governmental Industrial Hygienists (ACGIH), periodically prepare lists of recommended threshold limit values (TLVs) for many chemicals. These guidelines are periodically updated. Regulatory imperatives in the United States may also be updated from time to time when new information about toxicity becomes available. However, this process is slow and requires input from many sources except under certain extraordinary circumstances. In those cases, emergency alterations to standards may be made and an emergency temporary standard may be promulgated after appropriate regulatory procedures. The ACGIH TLV guidelines are useful as reference points in the evaluation of potential workplace exposures. Compliance with these voluntary guidelines is not a substitute for compliance with the OSHA requirements in the United States. TLVs do not have the force of law. Current TLV lists may be obtained from the ACGIH at http://www.acgih.org.


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Pharmacology_Katzung. Environmental toxicology deals with the potentially deleterious impact of chemicals, present as pollutants of the environment, on living organisms. The term environment includes all the surroundings of an individual organism, but particularly the air, soil, and water. Although humans are considered a target species of particular interest, other species are of considerable importance as potential biologic targets. Scientific study of signal occurrences in animals often provides early warning of impending human events as a result of ecotoxic impacts.


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Pharmacology_Katzung. Air pollution is usually a product of industrialization, technologic development, and increased urbanization. On rare occasions, natural phenomena such as volcanic eruptions may result in air pollution with gases, vapors, or particulates that are harmful to humans. Humans may also be exposed to chemicals used in the agricultural environment as pesticides or in food processing that may persist as residues or ingredients in food products. Air contaminants are regulated in the United States by the Environmental Protection Agency (EPA) based on both health and esthetic considerations. Tables of primary and secondary regulated air contaminants and other regulatory issues that relate to air contaminants in the United States may be found at http://www.epa.gov. Many states within the USA also have individual air contaminant regulations that may be more rigorous than those of the EPA. Many other nations and some supragovernmental organizations regulate air contaminants. In the case of


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Pharmacology_Katzung. also have individual air contaminant regulations that may be more rigorous than those of the EPA. Many other nations and some supragovernmental organizations regulate air contaminants. In the case of adjoining countries, transborder air and water pollution problems have been of concern in recent years. Particulates, radionuclides, acid rain, and similar problems have resulted in cross-contamination of air and water in different countries. Maritime contamination, too, has raised concern about oceanic pollution and has had an impact on the fisheries of some countries. This type of pollution is now the subject of much research and of new international treaties.


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Pharmacology_Katzung. The United Nations Food and Agriculture Organization and the World Health Organization (FAO/WHO) Joint Expert Commission on Food Additives adopted the term acceptable daily intake (ADI) to denote the daily intake of a chemical from food that, during an entire lifetime, appears to be without appreciable risk. These guidelines are reevaluated as new information becomes available. In the United States, the Food and Drug Administration (FDA) and the Department of Agriculture are responsible for the regulation of contaminants such as pesticides, drugs, and chemicals in foods. Major international problems have occurred because of traffic among nations in contaminated or adulterated foods from countries whose regulations and enforcement of pure food and drug laws are lax or nonexistent. Recently, for example, both human and animal illnesses have resulted from ingestion of products imported from China that contained melamine.


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Pharmacology_Katzung. Ecotoxicology is concerned with the toxic effects of chemical and physical agents on populations and communities of living organisms within defined ecosystems; it includes the transfer pathways of those agents and their interactions with the environment. Traditional toxicology is concerned with toxic effects on individual organisms; ecotoxicology is concerned with the impact on populations of living organisms or on ecosystems. Ecotoxicology research has become one of the foremost areas of study for toxicologists. Hazard is the ability of a chemical agent to cause injury in a given situation or setting; the conditions of use and exposure are primary considerations. To assess hazard, one needs to have knowledge about both the inherent toxicity of the substance and the amounts to which individuals are liable to be exposed. Hazard is often a description based on subjective estimates rather than objective evaluation.


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Pharmacology_Katzung. Risk is defined as the expected frequency of the occurrence of an undesirable effect arising from exposure to a chemical or physical agent. Estimation of risk makes use of dose-response data and extrapolation from the observed relationships to the expected responses at doses occurring in actual exposure situations. The quality and suitability of the biologic data used in such estimates are major limiting factors. Risk assessment has become an integral part of the regulatory process in most countries. However, many of the assumptions of risk assessment scientists remain unproven, and only long-term observation of population causes and outcomes will provide the basis for validation of newer risk assessment technologies. Routes of Exposure


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Pharmacology_Katzung. Routes of Exposure The route of entry for chemicals into the body differs in different exposure situations. In the industrial setting, inhalation is the major route of entry. The transdermal route is also quite important, but oral ingestion is a relatively minor route. Consequently, primary prevention should be designed to reduce or eliminate absorption by inhalation or by topical contact. Atmospheric pollutants gain entry by inhalation and by dermal contact. Water and soil pollutants are absorbed through inhalation, ingestion, and dermal contact. Quantity, Duration, & Intensity of Exposure


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Pharmacology_Katzung. Toxic reactions may differ depending on the quantity of exposure, its duration, and the rate at which the exposure takes place. An exposure to a toxic substance that is absorbed by the target human or animal results in a dose. Acute exposure indicates a single exposure or multiple exposures that occur over a brief period from seconds to 1–2 days. Intense, rapidly absorbed acute doses of substances that may ordinarily be detoxified by enzymatic mechanisms in small doses may overwhelm the body’s ability to detoxify the substance and may result in serious or even fatal toxicity. The same amount of the substance, absorbed slowly, may result in little or no toxicity. This is the case with cyanide exposure. Rhodanese, a mitochondrial enzyme present in humans, effectively detoxifies cyanide to relatively nontoxic thiocyanate when cyanide is presented in small amounts, but the enzyme is overwhelmed by large, rapidly encountered cyanide doses, with lethal effect.


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Pharmacology_Katzung. Single or multiple exposures over a longer period of time represent chronic exposure. In the occupational setting, both acute (eg, accidental discharge) and chronic (eg, repetitive handling of a chemical) exposures occur. Exposures to chemicals found in the environment such as air and water pollutants are often chronic, resulting in chronic disease, as in the Minamata Bay, Japan, methyl mercury disaster. Sudden large chemical releases may result in acute massive population exposure with serious or lethal consequences. The tragedy in Bhopal, India, was such an event, in which methyl isocyanate was released into a crowded population area, resulting in almost 4000 deaths and more than half a million injuries. The release of dioxin in Seveso, Italy, contaminated a populated area with a persistent organic chemical having both acute and long-term chronic effects. More recently, the massive oil spill caused by the explosion of BP’s Deepwater Horizon drilling rig in the Gulf of Mexico


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Pharmacology_Katzung. persistent organic chemical having both acute and long-term chronic effects. More recently, the massive oil spill caused by the explosion of BP’s Deepwater Horizon drilling rig in the Gulf of Mexico highlighted the potential for long-term ecotoxic impacts involving widespread geographic areas.


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Pharmacology_Katzung. Certain chemical and physical characteristics are important for the estimation of the potential hazard of environmental toxicants. Data on toxic effects of different organisms, along with knowledge about degradability, bioaccumulation, and transport and biomagnification through food chains, help in this estimation. (See Box: Bioaccumulation & Biomagnification for a classic example involving the Great Lakes.) Poorly degraded chemicals (by abiotic or biotic pathways) exhibit environmental persistence and can accumulate. Such chemicals include the persistent organic pollutants (POPs), polychlorinated biphenyls, dioxins and furans, and similar substances. Lipophilic substances such as the largely banned or abandoned organochlorine pesticides tend to bioaccumulate in body fat. This results in tissue residues that are slowly released over time. These residues and their metabolites may have chronic adverse effects such as endocrine disruption. When the toxicant is incorporated into the food


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Pharmacology_Katzung. tissue residues that are slowly released over time. These residues and their metabolites may have chronic adverse effects such as endocrine disruption. When the toxicant is incorporated into the food chain, biomagnification occurs as one species feeds on others. This concentrates the chemical in organisms higher on the food chain. Humans stand at the apex of the food chain. They may be exposed to highly concentrated pollutant loads as bioaccumulation and biomagnification occur. The pollutants that have the widest environmental impact are poorly degradable; are relatively mobile in air, water, and soil; exhibit bioaccumulation; and also exhibit biomagnification.


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Pharmacology_Katzung. If the intake of a long-lasting contaminant by an organism exceeds the latter's ability to metabolize or excrete the sub-stance, the chemical accumulates within the tissues of the organ-ism. This is called bioaccumulation. Although the concentration of a contaminant may be virtu-ally undetectable in water, it may be magnified hundreds or thousands of times as the contaminant passes up the food chain. This is called biomagnification. The biomagnification of polychlorinated biphenyls (PCBs) in the Great Lakes of North America is illustrated by the follow-ing residue values available from a classic Environment Canada report published by the Canadian government, and elsewhere. The biomagnification for this substance in the food chain, begin-ning with phytoplankton and ending with the herring gull, is nearly 50,000-fold. Domestic animals and humans may eat fish from the Great Lakes, resulting in PCB residues in these species as well. Source PCB Concentration (ppm)1 Concentration Relative


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Pharmacology_Katzung. gull, is nearly 50,000-fold. Domestic animals and humans may eat fish from the Great Lakes, resulting in PCB residues in these species as well. Source PCB Concentration (ppm)1 Concentration Relative to Phytoplankton Phytoplankton 0.0025 1 Zooplankton 0.123 49.2 Rainbow smelt 1.04 416 Lake trout 4.83 1,932 Herring gull 124 49,600 1Sources: Environment Canada, The State of Canada's Environment, 1991, Government of Canada, Ottawa; and other publications.


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Pharmacology_Katzung. Air pollution may result from vapors, aerosols, smokes, particulates, and individual chemicals. Five major substances have been said to account for about 98% of air pollution: carbon monoxide (about 52%); sulfur oxides (about 14%); hydrocarbons (about 14%); nitrogen oxides (about 14%) and ozone, their breakdown product; and particulate matter (about 4%). Agriculture, especially industrial-scale farming, contributes a variety of air pollutants: dusts as particulates, pesticidal chemicals, hydrogen sulfide, and others. Sources of pollutants include fossil fuel burning, transportation, manufacturing, other industrial activities, generation of electric power, space heating, refuse disposal, and others. Studies in Helsinki and other cities have shown that uncatalyzed automobile traffic emissions are larger contributors to ground-level air pollution than any other source. The introduction of catalytic converters on automobiles and their mandatory use in many countries has greatly reduced


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Pharmacology_Katzung. are larger contributors to ground-level air pollution than any other source. The introduction of catalytic converters on automobiles and their mandatory use in many countries has greatly reduced automobile-released air pollution. In addition, the ban on tetraethyl lead in gasoline has eliminated a major source of lead contamination and childhood lead poisoning in urban environments. In emerging economies, the use of transport based on two-cycle engines creates heavy ground-level air pollution in very crowded cities. The introduction of “clean, low-sulfur” diesel fuels is helping to reduce urban and highway pollutants such as sulfur oxides.


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Pharmacology_Katzung. Sulfur dioxide and smoke from incomplete combustion of coal have been associated with acute adverse effects among children, the elderly, and individuals with preexisting cardiac or respiratory disease. Ambient air pollution has been implicated as a cause of cardiac disease, bronchitis, obstructive ventilatory disease, pulmonary emphysema, bronchial asthma, and airway or lung cancer. Extensive basic science and clinical epidemiologic literature on air pollutant toxicology has been published and has led to modifications of regulatory standards for air pollutants. EPA standards for these substances apply to the general environment, and OSHA standards apply to workplace exposure. Ambient air standards for carbon monoxide and five other harmful pollutants—particulate matter, nitrogen dioxide, ozone, sulfur dioxide, and lead—may be found at https://www.epa.gov/criteria-air-pollutants.


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Pharmacology_Katzung. Carbon monoxide (CO) is a colorless, tasteless, odorless, and nonirritating gas, a byproduct of incomplete combustion. The average concentration of CO in the atmosphere is about 0.1 ppm; in heavy traffic, the concentration may exceed 100 ppm. Current recommended permissible exposure limit (PEL) values are shown in Table 56–1 (see also http://www.osha.gov, Standard Number 1910.1000, Table Z-1). 1.


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Pharmacology_Katzung. 1. Mechanism of action—CO combines tightly but reversibly with the oxygen-binding sites of hemoglobin and has an affinity for hemoglobin that is about 220 times that of oxygen. The product formed—carboxyhemoglobin—cannot transport oxygen. Furthermore, the presence of carboxyhemoglobin interferes with the dissociation of oxygen from the remaining oxyhemoglobin as a result of the Bohr effect. This reduces the transfer of oxygen to tissues. Organs with the highest oxygen demand (the brain, heart, and kidneys) are most seriously affected. Normal nonsmoking adults have carboxyhemoglobin levels of less than 1% saturation (1% of total hemoglobin is in the form of carboxyhemoglobin); this has been attributed to the endogenous formation of CO from heme catabolism. Smokers may exhibit 5–10% CO saturation. The level depends on their smoking habits. A person who breathes air that contains 0.1% CO (1000 ppm) would have a carboxyhemoglobin level of about 50% in a short period of time. 2.


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Pharmacology_Katzung. 2. Clinical effects—The principal signs of CO intoxication are those of hypoxia. They progress in the following sequence: (1) psychomotor impairment; (2) headache and tightness in the temporal area; (3) confusion and loss of visual acuity; TABLE 56–1 Examples of permissible exposure limit values (PELs) of some common air pollutants and solvents in parts per million (ppm).1 1These exposure limits can be found at http://www.osha.gov, 1910.1000, Tables Z-1 and Z-2. The OSHA standards are updated frequently and readers are referred to the website for the most current information. 2PELs are 8-hour TWA (time-weighted average) values for a normal 8-hour workday to which workers may be repeatedly exposed without adverse effects.


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Pharmacology_Katzung. (4) tachycardia, tachypnea, syncope, and coma; and (5) deep coma, convulsions, shock, and respiratory failure. There is great variability in individual responses to carboxyhemoglobin concentration. Carboxyhemoglobin levels below 15% may produce headache and malaise; at 25% many workers complain of headache, fatigue, decreased attention span, and loss of fine motor coordination. Collapse and syncope may appear at around 40%; and with levels above 60%, death may ensue as a result of irreversible damage to the brain and myocardium. The clinical effects may be aggravated by heavy labor, high altitudes, and high ambient temperatures. CO intoxication is usually thought of as a form of acute toxicity. There is evidence that chronic exposure to low CO levels may lead to adverse cardiac effects, neurologic disturbance, and emotional disorders. The developing fetus is quite susceptible to the effects of CO exposure. Exposure of a pregnant woman to elevated CO levels at critical periods of fetal


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Pharmacology_Katzung. disturbance, and emotional disorders. The developing fetus is quite susceptible to the effects of CO exposure. Exposure of a pregnant woman to elevated CO levels at critical periods of fetal development may cause fetal death or serious and irreversible but survivable birth defects.


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Pharmacology_Katzung. 3. Treatment—Patients who have been exposed to CO must be removed from the exposure source immediately. Respiration must be maintained and high flow and concentration of oxygen—the specific antagonist to CO—should be administered promptly. If respiratory failure is present, mechanical ventilation is required, High concentrations of oxygen may be toxic and may contribute to the development of acute respiratory distress syndrome. Therefore, patients should be treated with high concentrations only for a short period. With room air at 1 atm, the elimination half-time of CO is about 320 minutes; with 100% oxygen, the half-time is about 80 minutes; and with hyperbaric oxygen (2–3 atm), the half-time can be reduced to about 20 minutes. Although some controversy exists about hyperbaric oxygen for CO poisoning, it may be used if it is readily available. It is particularly recommended for the management of pregnant women exposed to CO. Hypothermic therapy to reduce metabolic demand of the brain


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Pharmacology_Katzung. CO poisoning, it may be used if it is readily available. It is particularly recommended for the management of pregnant women exposed to CO. Hypothermic therapy to reduce metabolic demand of the brain has also been useful. Cerebral edema that results from CO poisoning does not seem to respond to either mannitol or steroid therapy and may be persistent. Progressive recovery from treated CO poisoning, even of a severe degree can be complete but some patients manifest neuropsychological and motor dysfunction for a long time after recovery from acute CO poisoning.


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Pharmacology_Katzung. Sulfur dioxide (SO2) is a colorless irritant gas generated primarily by the combustion of sulfur-containing fossil fuels. The current OSHA PEL (Table 56–1) is given on the OSHA website (see http://www.osha.gov, Standard Number 1910.1000, Table Z-1). 1.


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Pharmacology_Katzung. Mechanism of action—At room temperature, the solubility of SO2 is approximately 200 g SO2/L of water. Because of its high solubility, when SO2 contacts moist membranes, it transiently forms sulfurous acid. This acid has severe irritant effects on the eyes, mucous membranes, and skin. Approximately 90% of inhaled SO2 is absorbed in the upper respiratory tract, the site of its principal effect. The inhalation of SO2 causes bronchial constriction and produces profuse bronchorrhea; parasympathetic reflexes and altered smooth muscle tone appear to be involved. The clinical outcome is an acute irritant asthma. Exposure to 5 ppm SO2 for 10 minutes leads to increased resistance to airflow in most humans. Exposures of 5–10 ppm are reported to cause severe bronchospasm; 10–20% of the healthy young adult population is estimated to be reactive to even lower concentrations. The phenomenon of adaptation to irritating concentrations has been reported in workers. However, current studies have not


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Pharmacology_Katzung. adult population is estimated to be reactive to even lower concentrations. The phenomenon of adaptation to irritating concentrations has been reported in workers. However, current studies have not confirmed this phenomenon. Asthmatic individuals are especially sensitive to SO2.


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Pharmacology_Katzung. 2.


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Pharmacology_Katzung. Clinical effects and treatment—The signs and symptoms of intoxication include irritation of the eyes, nose, and throat, reflex bronchoconstriction, and increased bronchial secretions. In asthmatic subjects, exposure to SO2 may result in an acute asthmatic episode. If severe exposure has occurred, delayed-onset pulmonary edema may be observed. Cumulative effects from chronic low-level exposure to SO2 are not striking, particularly in humans, but these effects have been associated with aggravation of chronic cardiopulmonary disease. When combined exposure to high respirable particulate loads and SO2 occurs, the mixed irritant load may increase the toxic respiratory response. Treatment is not specific for SO2 but depends on therapeutic maneuvers used to treat irritation of the respiratory tract and asthma. In some severely polluted urban air basins, elevated SO2 concentrations combined with elevated particulate loads has led to air pollution emergencies and a marked increase in cases of


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Pharmacology_Katzung. and asthma. In some severely polluted urban air basins, elevated SO2 concentrations combined with elevated particulate loads has led to air pollution emergencies and a marked increase in cases of acute asthmatic bronchitis. Children and the elderly seem to be at greatest risk. The principal source of urban SO2 is the burning of coal, both for domestic heating and in coal-fired power plants. High-sulfur transportation fuels also contribute. Both also contribute to the respirable fine particulate load and to increased urban cardiorespiratory morbidity and mortality.


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Pharmacology_Katzung. Nitrogen dioxide (NO2) is a brownish irritant gas sometimes associated with fires. It is formed also from fresh silage; exposure of farmers to NO2 in the confines of a silo can lead to silo-filler’s disease, a severe and potentially lethal form of acute respiratory distress syndrome. The disorder is uncommon today. Miners who are regularly exposed to diesel equipment exhaust have been particularly affected by nitrogen oxide emissions with serious respiratory effects. Today, the most common source of human exposure to oxides of nitrogen, including NO2, is automobile and truck traffic emissions. Recent air pollution inventories in cities with high traffic congestion have demonstrated the important role that internal combustion engines have in the increasing NO2 urban air pollution. A variety of disorders of the respiratory system, cardiovascular system, and other problems have been linked to NO2 exposure. 1.


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Pharmacology_Katzung. Mechanism of action—NO2 is a relatively insoluble deep lung irritant. It is capable of producing pulmonary edema and acute adult respiratory distress syndrome (ARDS). Inhalation damages the lung infrastructure that produces the surfactant necessary to allow smooth and low-effort lung alveolar expansion. The type I cells of the alveoli appear to be the cells chiefly affected by acute low to moderate inhalation exposure. At higher exposure, both type I and type II alveolar cells are damaged. If only type I cells are damaged, after an acute period of severe distress, it is likely that treatment with modern ventilation equipment and medications will result in recovery. Some patients develop nonallergic asthma, or “twitchy airway” disease, after such a respiratory insult. If severe damage to the type I and type II alveolar cells occurs, replacement of the type I cells may be impaired; progressive fibrosis may ensue that eventually leads to bronchial ablation and alveolar collapse. This can


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Pharmacology_Katzung. type I and type II alveolar cells occurs, replacement of the type I cells may be impaired; progressive fibrosis may ensue that eventually leads to bronchial ablation and alveolar collapse. This can result in permanent restrictive respiratory disease. In addition to the direct deep lung effect, long-term exposure to lower concentrations of nitrogen dioxide has been linked to cardiovascular disease, increased incidence of stroke, and other chronic disease.


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Pharmacology_Katzung. The current PEL for NO2 is given in Table 56–1. Exposure to 25 ppm of NO2 is irritating to some individuals; 50 ppm is moderately irritating to the eyes and nose. Exposure for 1 hour to 50 ppm can cause pulmonary edema and perhaps subacute or chronic pulmonary lesions; 100 ppm can cause pulmonary edema and death. 2. Clinical effects—The signs and symptoms of acute exposure to NO2 include irritation of the eyes and nose, cough, mucoid or frothy sputum production, dyspnea, and chest pain. Pulmonary edema may appear within 1–2 hours. In some individuals, the clinical signs may subside in about 2 weeks; the patient may then pass into a second stage of abruptly increasing severity, including recurring pulmonary edema and fibrotic destruction of terminal bronchioles (bronchiolitis obliterans). Chronic exposure of laboratory animals to 10–25 ppm NO2 has resulted in emphysematous changes; thus, chronic effects in humans are of concern. 3.


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Pharmacology_Katzung. 3. Treatment—There is no specific treatment for acute intoxication by NO2; therapeutic measures for the management of deep lung irritation and noncardiogenic pulmonary edema are used. These measures include maintenance of gas exchange with adequate oxygenation and alveolar ventilation. Drug therapy may include bronchodilators, sedatives, and antibiotics. New approaches to the management of NO2-induced ARDS have been developed and considerable controversy now exists about the precise respiratory protocol to use in any given patient.


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Pharmacology_Katzung. Ozone (O3) is a bluish irritant gas found in the earth’s atmosphere, where it is an important absorbent of ultraviolet light at high altitude. At ground level, ozone is an important pollutant. Atmospheric ozone pollution is derived from photolysis of oxides of nitrogen, volatile organic compounds, and CO. These compounds are produced primarily when fossil fuels such as gasoline, oil, or coal are burned or when some chemicals (eg, solvents) evaporate. Nitrogen oxides are emitted from power plants, motor vehicles, and other sources of high-heat combustion. Volatile organic compounds are emitted from motor vehicles, chemical plants, refineries, factories, gas stations, paint, and other sources. More information on ground-level ozone and its sources and consequences may be found at https://www.epa.gov/arc-x/ climate-adaptation-ground-level-ozone-and-health.


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Pharmacology_Katzung. Ozone can be generated in the workplace by high-voltage electrical equipment, and around ozone-producing devices used for air and water purification. Agricultural sources of ozone are also important. There is a near-linear gradient between exposure to ozone (1-hour level, 20–100 ppb) and bronchial smooth muscle response. See Table 56–1 for the current PEL for ozone.


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Pharmacology_Katzung. 1. Mechanism of action and clinical effects—Ozone is an irritant of mucous membranes. Mild exposure produces upper respiratory tract irritation. Severe exposure can cause deep lung irritation, with pulmonary edema when inhaled at sufficient concentrations. Ozone penetration in the lung depends on tidal volume; consequently, exercise can increase the amount of ozone reaching the distal lung. Some of the effects of O3 resemble those seen with radiation, suggesting that O3 toxicity may result from the formation of reactive free radicals. The gas causes shallow, rapid breathing and a decrease in pulmonary compliance. Enhanced sensitivity of the lung to bronchoconstrictors is also observed. Exposure around 0.1 ppm O3 for 10–30 minutes causes irritation and dryness of the throat; above 0.1 ppm, one finds changes in visual acuity, substernal pain, and dyspnea. Pulmonary function is impaired at concentrations exceeding 0.8 ppm.


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Pharmacology_Katzung. Airway hyperresponsiveness and airway inflammation have been observed in humans. The response of the lung to O3 is a dynamic one. The morphologic and biochemical changes are the result of both direct injury and secondary responses to the initial damage. Long-term exposure in animals results in morphologic and functional pulmonary changes. Chronic bronchitis, bronchiolitis, fibrosis, and emphysematous changes have been reported in a variety of species, including humans, exposed to concentrations above 1 ppm. Increased visits to hospital emergency departments for cardiopulmonary disease during ozone alerts have been reported. A study of the basic physiologic responses of humans to ozone exposure and the biomarkers evoked provides useful insight into the fundamental toxicologic impacts of ozone.


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Pharmacology_Katzung. 2. Treatment—There is no specific treatment for acute O3 intoxication. Management depends on therapeutic measures used for deep lung irritation and noncardiogenic pulmonary edema that have resulted in ARDS. Current national ambient air quality standards for ozone are listed at https://www.epa.gov/ criteria-air-pollutants.


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Pharmacology_Katzung. These “halohydrocarbon” agents once found wide use as industrial solvents, degreasing agents, and cleaning agents. The substances include carbon tetrachloride, chloroform, trichloroethylene, tetrachloroethylene (perchloroethylene), and 1,1,1-trichloroethane (methyl chloroform). Many halogenated aliphatic hydrocarbons are classified as known or probable human carcinogens. Carbon tetrachloride and trichloroethylene have largely been removed from the workplace. Perchloroethylene and trichloroethane are still in use for dry cleaning and solvent degreasing, but it is likely that their use will be very limited in the future. In 2016, the National Institute of Environmental Sciences (NIEHS) listed trichloroethylene as a known carcinogen. The EPA now considers perchloroethylene a likely human carcinogen. The EPA data sheet may be found at https://www.epa.gov/haps/health-effectsnotebook-hazardous-air-pollutants. Dry cleaning as an occupation is listed as a class 2B carcinogenic activity by the


Pharmacology_Katzung

Pharmacology_Katzung. The EPA data sheet may be found at https://www.epa.gov/haps/health-effectsnotebook-hazardous-air-pollutants. Dry cleaning as an occupation is listed as a class 2B carcinogenic activity by the International Agency for Research on Cancer (IARC). The Canadian Center for Occupational Health and Safety lists occupations and exposures to occupational carcinogens at http://www.ccohs.ca/oshanswers/ diseases/carcinogen_occupation.html.


Pharmacology_Katzung

Pharmacology_Katzung. Fluorinated aliphatics such as the freons and closely related compounds have also been used in the workplace, in consumer goods, and in stationary and mobile air conditioning systems. Because of the severe damage they cause to the ozone layer in the troposphere, their use has been limited or eliminated by international treaty agreements. The common halogenated aliphatic solvents also create serious problems as persistent water pollutants. They are widely found in both groundwater and drinking water as a result of poor disposal practices. Table 56–1 includes recommended OSHA PELs for several of these compounds (see also http://www.osha.gov, Table Z-1).


Pharmacology_Katzung

Pharmacology_Katzung. Table 56–1 includes recommended OSHA PELs for several of these compounds (see also http://www.osha.gov, Table Z-1). 1. Mechanism of action and clinical effects—In laboratory animals, the halogenated hydrocarbons cause central nervous system (CNS) depression, liver injury, kidney injury, and some degree of cardiotoxicity. Several are also carcinogenic in animals and are considered probable human carcinogens. Trichloroethylene and tetrachloroethylene are listed as “reasonably anticipated to be a human carcinogen” by the US National Toxicology Program, and as class 2A probable human carcinogens by IARC. These substances are depressants of the CNS in humans. Chronic workplace exposure to halogenated hydrocarbon solvents can cause significant neurotoxicity with impaired memory and peripheral neuropathy. All halohydrocarbon solvents can cause cardiac arrhythmias in humans, particularly in situations involving sympathetic excitation and norepinephrine release.


Pharmacology_Katzung

Pharmacology_Katzung. Hepatotoxicity is also a common toxic effect that can occur in humans after acute or chronic halohydrocarbon exposures. Nephrotoxicity can occur in humans exposed to carbon tetrachloride, chloroform, and trichloroethylene. Chloroform, carbon tetrachloride, trichloroethylene, and tetrachloroethylene carcinogenicity have been observed in lifetime exposure studies performed in rats and mice and in some human epidemiologic studies. Dichloromethane (methylene chloride) is a potent neurotoxin, a generator of CO in humans, and a probable human carcinogen. It has been widely used as a paint stripper, plastic glue, and for other purposes. Epidemiologic studies of workers who have been exposed to aliphatic hydrocarbon solvents that include dichloromethane, trichloroethylene, and tetrachloroethylene have found significant associations between the agents and renal, prostate, and testicular cancer. Trichloroethylene is now considered a class 1, known human carcinogen by IARC; renal cancers and


Pharmacology_Katzung

Pharmacology_Katzung. have found significant associations between the agents and renal, prostate, and testicular cancer. Trichloroethylene is now considered a class 1, known human carcinogen by IARC; renal cancers and non-Hodgkin’s lymphoma have been reported. Other cancers are increased but their incidence has not reached statistical significance.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Treatment—There is no specific treatment for acute intoxication resulting from exposure to halogenated hydrocarbons. Management depends on the organ system involved. Benzene is used for its solvent properties and as an intermediate in the synthesis of other chemicals. It remains an important component of gasoline. Benzene may be found in premium gasolines at concentrations of about 1.5%. In cold climates such as Alaska, benzene concentrations in gasoline may reach 5% in order to provide an octane boost. It is one of the most widely used industrial chemicals in the world. The current PEL is 1.0 ppm in the air (see Table 56–1 and http://www.osha.gov, Table Z-1), and a 5 ppm limit is recommended for skin exposure. The National Institute for Occupational Safety and Health (NIOSH) and others have recommended that the exposure limits for benzene be further reduced to 0.1 ppm because excess blood cancers occur at the current PEL.


Pharmacology_Katzung

Pharmacology_Katzung. The acute toxic effect of benzene is depression of the CNS. Exposure to 7500 ppm for 30 minutes can be fatal. Exposure to concentrations greater than 3000 ppm may cause euphoria, nausea, locomotor problems, and coma. Vertigo, drowsiness, headache, and nausea may occur at concentrations ranging from 250 to 500 ppm. No specific treatment exists for the acute toxic effect of benzene. Chronic exposure to benzene can result in very serious toxic effects, the most significant of which is bone marrow injury. Aplastic anemia, leukopenia, pancytopenia, and thrombocytopenia occur, as does leukemia. Chronic exposure to low levels of benzene has been associated with leukemia of several types as well as lymphomas, myeloma, and myelodysplastic syndrome. Recent studies have shown the occurrence of leukemia following exposures as low as 2 ppm-years. The pluripotent bone marrow stem cells appear to be targets of benzene or its metabolites and other stem cells may also be targets.


Pharmacology_Katzung

Pharmacology_Katzung. Benzene has long been known to be a potent clastogen, ie, a mutagen that acts by causing chromosomal breakage. Recent studies have suggested specific chromosome reorganization and genomic patterns that are associated with benzene-induced leukemia. Epidemiologic data confirm a causal association between benzene exposure and leukemia and other bone marrow cancers in workers. IARC classifies benzene as a class 1, known human carcinogen. Most national and international organizations classify benzene as a known human carcinogen.


Pharmacology_Katzung

Pharmacology_Katzung. Toluene (methylbenzene) does not possess the myelotoxic properties of benzene, nor has it been associated with leukemia. It is not carcinogenic and is listed as class 3 by IARC. It is, however, a CNS depressant and a skin and eye irritant. It is also fetotoxic. See Table 56–1 and OSHA Tables Z-1 and Z-2 (http:// www.osha.gov) for the PELs. Exposure to 800 ppm can lead to severe fatigue and ataxia; 10,000 ppm can produce rapid loss of consciousness. Chronic effects of long-term toluene exposure are unclear because human studies indicating behavioral effects usually concern exposures to several solvents. In limited occupational studies, however, metabolic interactions and modification of toluene’s effects have not been observed in workers also exposed to other solvents. Less refined grades of toluene contain benzene. If technical grade toluene is to be used where there is human contact or exposure, analysis of the material for benzene content is advisable.


Pharmacology_Katzung

Pharmacology_Katzung. Xylene (dimethylbenzene) has been substituted for benzene in many solvent degreasing operations. Like toluene, the three xylenes do not possess the myelotoxic properties of benzene, nor have they been associated with leukemia. Xylene is a CNS depressant and a skin irritant. Less refined grades of xylene contain benzene. Estimated TLV–time-weighted average and TLV–short-term exposure limit are 100 and 150 ppm, respectively. The current OSHA PELs may be found at http://www. osha.gov, Table Z-1. TABLE 56–2 Organochlorine pesticides.


Pharmacology_Katzung

Pharmacology_Katzung. These agents are usually classified into four groups: DDT (chlorophenothane) and its analogs, benzene hexachlorides, cyclodienes, and toxaphenes (Table 56–2). They are aryl, carbocyclic, or heterocyclic compounds containing chlorine substituents. The individual compounds differ widely in their biotransformation and capacity for storage in tissues; toxicity and storage are not always correlated. They can be absorbed through the skin as well as by inhalation or oral ingestion. There are, however, important quantitative differences between the various derivatives; DDT in solution is poorly absorbed through the skin, whereas dieldrin absorption from the skin is very efficient. Organochlorine pesticides have largely been abandoned because they cause severe environmental damage. They are now known to be endocrine disrupters in animals and humans. DDT continues to have very restricted use for domestic mosquito elimination in malaria-infested areas of Africa. This use is controversial, but it


Pharmacology_Katzung

Pharmacology_Katzung. to be endocrine disrupters in animals and humans. DDT continues to have very restricted use for domestic mosquito elimination in malaria-infested areas of Africa. This use is controversial, but it is very effective and is likely to remain in place for the foreseeable future. Organochlorine pesticide residues in humans, animals, and the environment present long-term problems that are not yet fully understood.


Pharmacology_Katzung

Pharmacology_Katzung. 1. Human toxicology—The acute toxic properties of all the organochlorine pesticides in humans are qualitatively similar. These agents interfere with inactivation of the sodium channel in excitable membranes and cause rapid repetitive firing in most neurons. Calcium ion transport is inhibited. These events affect repolarization and enhance the excitability of neurons. The major effect is CNS stimulation. With DDT, tremor may be the first manifestation, possibly continuing to convulsions, whereas with the other compounds convulsions often appear as the first sign of intoxication. There is no specific treatment for the acute intoxicated state, and management is symptomatic.


Pharmacology_Katzung

Pharmacology_Katzung. The potential carcinogenic properties of organochlorine pesticides have been extensively studied, and results indicate that 1Toxicity rating: Probable human oral lethal dosage for class 3 = 500−5000 mg/kg, class 4 = 50−500 mg/kg, and class 5 = 5−50 mg/kg. (See Gosselin et al, 1984.) 2ADI, acceptable daily intake (mg/kg/d).


Pharmacology_Katzung

Pharmacology_Katzung. chronic administration to laboratory animals over long periods results in enhanced carcinogenesis. Endocrine pathway disruption is the postulated mechanism. Numerous mechanisms for xenoestrogen (estrogen-like) carcinogenesis have been postulated. To date, however, several large epidemiologic studies in humans have not found a significant association between the risk of cancer and specific compounds or serum levels of organochlorine pesticide metabolites. The results of a case-control study conducted to investigate the relation between dichlorodiphenyldichloroethylene (DDE, the primary metabolite of DDT) and DDT breast adipose tissue levels and breast cancer risk did not confirm a positive association. In contrast, recent work supports an association between prepubertal exposure to DDT and brain cancer. Recent studies also suggest that the risk of testicular cancer and non-Hodgkin’s lymphoma is increased in persons with elevated organochlorine levels. Noncancer end points are also of


Pharmacology_Katzung

Pharmacology_Katzung. brain cancer. Recent studies also suggest that the risk of testicular cancer and non-Hodgkin’s lymphoma is increased in persons with elevated organochlorine levels. Noncancer end points are also of concern. Recent work associates cryptorchidism and hypospadias in newborns with maternal adipose levels of chlordane metabolites. These residues are also linked to testicular cancer.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Environmental toxicology—The organochlorine pesticides are considered persistent chemicals. Degradation is quite slow when compared with other pesticides, and bioaccumulation, particularly in aquatic ecosystems, is well documented. Their mobility in soil depends on the composition of the soil; the presence of organic matter favors the adsorption of these chemicals onto the soil particles, whereas adsorption is poor in sandy soils. Once adsorbed, they do not readily desorb. These compounds induce significant abnormalities in the endocrine balance of sensitive animal and bird species, in addition to their adverse impact on humans. Since the early 1960s, when Rachel Carson’s work and subsequent book, Silent Spring, brought attention to the issue, the organochlorine pesticides have been recognized as pernicious environmental toxins. Their use is banned in most jurisdictions.


Pharmacology_Katzung

Pharmacology_Katzung. These agents, some of which are listed in Table 56–3, are used to combat a large variety of pests. They are useful pesticides when in direct contact with insects or when used as plant systemics, where the agent is translocated within the plant and exerts its effects on insects that feed on the plant. The many varieties currently in use are applied by spray techniques including hand, tractor, and aerial methods. They are often spread widely by wind and weather and are subject to widespread drift. The organophosphate pesticides are based on compounds such as soman, sarin, and tabun, which were developed for use as war gases. Some of the less toxic organophosphorus compounds are used in human and veterinary medicine as local or systemic antiparasitics (see Chapters 7 and 53). The compounds are absorbed by the skin as well as by the respiratory and gastrointestinal tracts. Biotransformation is rapid, particularly when compared with the rates observed with the chlorinated hydrocarbon


Pharmacology_Katzung

Pharmacology_Katzung. are absorbed by the skin as well as by the respiratory and gastrointestinal tracts. Biotransformation is rapid, particularly when compared with the rates observed with the chlorinated hydrocarbon pesticides. Storm and collaborators reviewed current and suggested human inhalation occupational exposure limits for 30 organophosphate pesticides (see References).


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 56–3 Organophosphorus pesticides. Trichlorfon 4 0.01 1Toxicity rating: Probable human oral lethal dosage for class 4 = 50–500 mg/kg, class 5 = 5–50 mg/kg, and class 6 = ≤5 mg/kg, ;—, data not found. (See Gosselin et al, 1984.) 2ADI, acceptable daily intake (mg/kg/d).


Pharmacology_Katzung

Pharmacology_Katzung. 1. Human toxicology—In mammals as well as insects, the major effect of these agents is inhibition of acetylcholinesterase through phosphorylation of the esteratic site. The signs and symptoms that characterize acute intoxication are due to inhibition of this enzyme and accumulation of acetylcholine; some of the agents also possess direct cholinergic activity. Specific treatment with antidotes and useful antagonists is available. In addition, pretreatment with physostigmine and other short-acting compounds may provide protection against these pesticides or their war gas analogs if used in timely fashion. These effects and their treatment are described in Chapters 7 and 8 of this book. Altered neurologic and cognitive functions, as well as psychological symptoms of variable duration, have been associated with exposure to these pesticides. Furthermore, there is some indication of an association of low arylesterase activity with neurologic symptom complexes in Gulf War veterans.


Pharmacology_Katzung

Pharmacology_Katzung. In addition to—and independently of—inhibition of acetylcholinesterase, some of these agents are capable of phosphorylating another enzyme present in neural tissue, the so-called neuropathy target esterase (NTE). This results in progressive demyelination of the longest nerves. Associated with paralysis and axonal degeneration, this lesion is sometimes called organophosphorus ester-induced delayed polyneuropathy (OPIDP). Delayed central and autonomic neuropathy may occur in some poisoned patients. Hens are particularly sensitive to these properties and have proved very useful for studying the pathogenesis of the lesion and for identifying potentially neurotoxic organophosphorus derivatives. There is no specific treatment for NTE toxicity.


Pharmacology_Katzung

Pharmacology_Katzung. In humans, progressive chronic axonal neurotoxicity has been observed with triorthocresyl phosphate (TOCP), a noninsecticidal organophosphorus compound. It is also thought to occur with the pesticides dichlorvos, trichlorfon, leptophos, methamidophos, mipafox, trichloronat, and others. The polyneuropathy usually begins as burning and tingling sensations, particularly in the feet, with motor weakness occurring a few days later. Sensory and motor difficulties may extend to the legs and hands. Gait is affected, and ataxia may be present. Central nervous system and autonomic changes may develop still later. There is no specific treatment for this form of delayed neurotoxicity. The long-term prognosis of NTE inhibition is highly variable. Reports of this type of neuropathy (and other toxicities) in pesticide manufacturing workers and in agricultural pesticide applicators have been published (see References).


Pharmacology_Katzung

Pharmacology_Katzung. Recent clinical observation has also defined an intermediate syndrome in severely organophosphate-poisoned patients. This syndrome is characterized by neuromuscular transmission failure, and cardiac failure more typical of nicotinic than muscarinic poisoning. Progressive neuromuscular failure leads to weakness of the respiratory muscles and eventually to death. The physiologic abnormalities are complex but involve a progressive decrement in neuromuscular junction transmission efficiency. Patients who develop this intermediate syndrome are at great risk of cardiorespiratory failure and may require mechanical ventilation. Because organophosphorus poisoning frequently occurs in less developed parts of the world where medical resources are very limited, the development of the intermediate syndrome is frequently a lethal complication. It is not effectively treated with the usual management protocol for organophosphate pesticide poisoning.


Pharmacology_Katzung

Pharmacology_Katzung. 2. Environmental toxicology—Organophosphorus pesticides are not considered to be persistent pesticides. They are relatively unstable and break down in the environment as a result of hydrolysis and photolysis. As a class they are considered to have a small permanent impact on the environment, in spite of their acute effects on organisms. These compounds (Table 56–4) inhibit acetylcholinesterase by carbamoylation of the esteratic site. Thus, they possess the toxic properties associated with inhibition of this enzyme as described TABLE 56–4 Carbamate pesticides. 1Toxicity rating: Probable human oral lethal dosage for class 4 = 50−500 mg/kg, class 5 = 5−50 mg/kg, and class 6 = ≤ 5 mg/kg. (See Gosselin et al, 1984.) 2ADI, acceptable daily intake (mg/kg/d), data not found.


Pharmacology_Katzung

Pharmacology_Katzung. for the organophosphorus pesticides. However, as described in Chapters 7 and 8, the binding is relatively weak, dissociation occurs after minutes to hours, and clinical effects are of shorter duration than those observed with organophosphorus compounds. Spontaneous reactivation of cholinesterase is more rapid after inhibition by the carbamates. The therapeutic index, the ratio of the doses that cause severe toxicity or death to those that result in minor intoxication, is larger with carbamates than with the organophosphorus agents. Although the clinical approach to carbamate poisoning is similar to that for organophosphates, the use of pralidoxime is not recommended. The carbamates are considered to be nonpersistent pesticides. They exert only a small impact on the environment.


Pharmacology_Katzung

Pharmacology_Katzung. The carbamates are considered to be nonpersistent pesticides. They exert only a small impact on the environment. Pesticides derived from natural sources include nicotine, rote-none, and pyrethrum. Nicotine is obtained from the dried leaves of Nicotiana tabacum and N rustica. It is rapidly absorbed from mucosal surfaces; the free alkaloid, but not the salt, is readily absorbed from the skin. Nicotine reacts with the acetylcholine receptor of the postsynaptic membrane (sympathetic and parasympathetic ganglia, neuromuscular junction), resulting in depolarization of the membrane. Toxic doses cause stimulation rapidly followed by blockade of transmission. These actions are described in Chapter 7. Treatment is directed toward maintenance of vital signs and suppression of convulsions. Nicotine analogs (neonicotinoids) have been developed for use as agricultural pesticides and have been accused of a role in bee colony collapse.


Pharmacology_Katzung

Pharmacology_Katzung. Rotenone (Figure 56–1) is obtained from Derris elliptica, D mallaccensis, Lonchocarpus utilis, and L urucu. The oral ingestion of rotenone produces gastrointestinal irritation. Conjunctivitis, dermatitis, pharyngitis, and rhinitis can also occur. Treatment is symptomatic.


Pharmacology_Katzung

Pharmacology_Katzung. Pyrethrum consists of six known insecticidal esters: pyrethrin I (Figure 56–1), pyrethrin II, cinerin I, cinerin II, jasmolin I, and jasmolin II. Synthetic pyrethroids account for an increasing percentage of worldwide pesticide usage. Pyrethrum may be absorbed after inhalation or ingestion. When absorbed in sufficient quantities, the major site of toxic action is the CNS; excitation, convulsions, and tetanic paralysis can occur. Voltage-gated sodium, calcium, and chloride channels are considered targets, as well as peripheral-type benzodiazepine receptors. Treatment of exposure is usually directed at management of symptoms. Anticonvulsants are not consistently effective. The chloride channel agonist, ivermectin is of use, as are pentobarbital and mephenesin. The pyrethroids are highly irritating to the eyes, skin, and respiratory tree. They may cause irritant asthma and, potentially, reactive airways dysfunction syndrome (RADS) and even anaphylaxis. The most common injuries reported


Pharmacology_Katzung

Pharmacology_Katzung. to the eyes, skin, and respiratory tree. They may cause irritant asthma and, potentially, reactive airways dysfunction syndrome (RADS) and even anaphylaxis. The most common injuries reported in humans result from their allergenic and irritant effects on the airways and skin. Cutaneous paresthesias have been observed in workers spraying synthetic pyrethroids. The use of persistent synthetic pyrethroids to exterminate insects on aircraft has caused respiratory and skin problems as well as some neurologic complaints in flight attendants and other aircraft workers. Severe occupational exposures to synthetic pyrethroids in


Pharmacology_Katzung

Pharmacology_Katzung. CH3N+2CI–Paraquat dichloride H3C+NCIDichlorodiphenyltrichloroethane (DDT) CICCCI3H2,3,7,8-Tetrachlorodibenzodioxin (TCDD) CICIOOCICI2,4-Dichlorophenoxyacetic acid (2,4-D) CIOCH2COOHCICIOCH2COOHCIOCH3OOOOHOHCCH2H Rotenone 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) FIGURE 56–1 Chemical structures of selected herbicides and pesticides. China resulted in marked effects on the CNS, including convulsions. Other previously unreported toxic manifestations have been observed in pyrethrin-exposed individuals.


Pharmacology_Katzung

Pharmacology_Katzung. 2,4-Dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and their salts and esters have been used as herbicides for the destruction of weeds (Figure 56–1). These compounds are of relatively low acute human toxicity. However, despite their low acute hazard, they cause serious longterm human and environmental toxicity. 2,4-D remains in wide commercial and domestic use for lawn weed control. 2,4,5-T had similar uses but was infamously incorporated into Agent Orange, used as a defoliant during the Vietnam conflict. Agent Orange was contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (a potent animal carcinogen and likely human carcinogen) and other toxic, persistent, and undesirable polychlorinated compounds. When this toxicity was discovered, the US Department of Agriculture canceled the domestic pesticide registrations for trichlorophenoxy herbicides, and these compounds are no longer used. However, other, less thoroughly studied compounds, eg, chlorinated


Pharmacology_Katzung

Pharmacology_Katzung. Agriculture canceled the domestic pesticide registrations for trichlorophenoxy herbicides, and these compounds are no longer used. However, other, less thoroughly studied compounds, eg, chlorinated xanthenes, are present in both the dichlorophenoxy and trichlorophenoxy herbicides (see below).