Pharmacology Ii Exam 2 - Born

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Natural Defense Mechanism of the Body

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Humans are constantly exposed to a variety of microorganisms (bacteria, viruses, fungi, etc.) in the course of their daily existence. In addition, they are intermittently exposed to potentially highly pathogenic microorganisms. Yet in spite of this overwhelming exposure to potentially disease-causing organisms, humans experience relatively little illness in their lifespan. This is a result of development of efficient, effective host defense mechanisms.

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Nonspecific Mechanisms

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1. The skin - acts as a mechanical barrier; has secretions capable of inhibiting growth of microorganisms; has a pH unsuitable for many MO; has a normal microflora
2. Mucous membranes - barrier, secretions (mucus, IgA), cilia, microflora
3. GI Tract - barrier, microflora, secretions, movement, acid
4. GU Tract - barrier, microflora, secretions, pH, washing action of urine
5. Tears, Saliva - washing action, secretions
6. Nonspecific phagocytosis - by neutrophils

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Specific Mechanisms

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1. Humoral Immunity
2. Cellular Immunity
-It is important to remember that the integrity and function of these host defense mechanisms are as important or more important than drug therapy in preventing human morbidity and mortality due to infectious microorganisms.

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It is especially important to avoid medications and factors that injure or impair the function of the natural defense mechanisms. Among these are:

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1. Injuries to the skin and mucous membranes
2. Malnutrition
3. Inappropriate antibiotics
4. Diabetes
5. Corticosteroids/Immunosuppressives
6. Infancy
7. Alcohol/smoking/tobacco
8. Old age
9. Cancer/Anticancer cytotoxic drugs

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Antigens

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An antigenic material must contain chemical groupings on it surface that are recognized as foreign by the immunologically competent cells of the host. Most naturally occuring complete antigens are proteins or polysaccharides. Most microorganisms contain 10 to 1000 antigens on their surfaces. In addition to complete antigens, incomplete antigens (or haptens) are also well known. These are usually compounds of low MW, such as drugs. When combined with a carrier protein, haptens are capable of inducing antibody formation. That portion of an antigen recognized as foreign is called the "determinant group". A determinant group is usually on the order of a penta- or hexapeptide.

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Antibodies

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Antibodies (or immunoglobulins) are proteins ith two identical combining sites that react specifically with and have a structure that is complementary to a particular determinant group on an antigen. Since there are two combining sites, an antibody is capable of combining with two antigen molecules. There are five classes of antibodies: immunoglobulins (Ig) G; A; M; D; E. Each has specific functions, distribution, etc. Quantitatively, each antigen molecule may stimulate production of up to 100,000 Ig molecules. Antibody production may start within 20 minutes after antigen exposure and those produced are secreted into plasma. None is stored.

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Antibody Production (type and quantity)

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-The type and quantity of antibody produced depends on a number of factors including: dose of antigen; form of antigen; and previous exposure. Usually, the 1st antibody produced in response to a threshold dose of antigen is IgM. As the dose is increased, production of IgG is stimulated. IgM will appear after about 4 days (primary response) or 1 day (2ndary response). IgG appears after 7-8 days (1 response) or 1-2 days (2 response). Blood titers of IgG (at maximum) are usually much higher than those of IgM (at max).

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Antibody Production (form)

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The form of antigen administration is also important. "Particulate antigen" (antigen adsorbed on Al[OH]3 or Al[PO4]) is a more effective stimulant of antibody production than is "fluid" (soluble) antigen. Usually, larger doses of particulate antigen than fluid antigen can be administered and it is absorbed over a prolonged period.

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Antibody Production (previous exposure)

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Previous exposure to a particular antigen also influences antibody response. On first exposure to a antigen, a primary response occurs. This is characterized by development of relatively low titers of antibody which appear after 7-10 days and persist for weeks or a few months. Second and subsequent exposures should prodcue a secondary response. Antibody levels of the secondary response appear sooner, rise much higher, and persist for long periods.

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There are several types of disorders in which the immune system participates. These include:

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1. hypersensitivity (allergy) reactions
2. autoimmune disorders
3. rejection of organ transplants

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Hypersensitivity

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Type I Reactions - also called immediate, atopic, or anaphylactic reactions. Types include hay fever, urticaria, angioedema, and anaphylactic shock
Type II Reactions - also called cytotoxic reactions. Types include hemolysis and thrombocytopenia
Type III Reactions - also called immune complex reactions. Types include serum sickness, joint reactions, and glomerulus.
Type IV Reactions - also called delayed hypersensitivity or cell-mediated hypersensitivity. Types include graft rejection and contact dermatitis.
*Types I-III are antibody mediated

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Autoimmune Disorders

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Normally we have immunological tolerance. When tolerance fails, the results can be disastrous. Some proposed mechanisms for tolerance failure:
1. Breakdown of T-cell anergy - when antigens are presented with certain costimulatory molecules - multiple sclerosis, rheumatoid arthritis, type I DM
2. Failure of activation-induced cell death - no examples
3. Failure of T cell-mediated suppression - loss of CD8+ which suppress autoreactive B and T cells
4. Molecular mimicry - a foreign antigen closely resembling a self-antigen generates a cros-reaction - rheumatic heart disease, MS
5. Polyclonal lymphocyte activation - produced by a "superantigen" - activates many clones, including anergic clones
6. Release of sequestered antigens - cornea or testes

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Examples of Autoimmune Disease

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Myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, IDDM, thyroiditis (Grave's disease), pernicious anemia

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Immunosuppressive Agents - General

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Drugs altering immune responses in diseases with suspected involvement of pathological immune or inflammatory reactions. Their use is somewhat controverial because:
a. disease origins are sometimes obscure
b. immunosuppressives are non-specific
c. immunosuppressives have limited margins of safety
This leads to endless tinkering with regimens, schedules and doses

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Effects of Glucocorticoids

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NFkB is a factor for transcription of inflammatory mediators. It is normally found in the cytoplasm bound to an inhibitor - IkB. Glucocorticoids combine with a cytoplasmic receptor, enter the nucleus and increase production of the inhibitor (IkB). This is responsible for most of the anti-inflammatory effect.

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Actions of Glucocorticoids

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1. prevent production of IL-1 by APCs and IL-6
2. other lymphokines inhibited or blocked (IL-2, MIF, TNF, Interferon)
3. Phospholipase A2 inhibited
4. Stabilizes lysosomal membranes
5. Phagocytes display poor chemotaxis/inhibited degranulation
6. Apoptosis of activated cells
7. Depresses cellular immunity much more than humoral immunity

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Uses of Glucocorticoids

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Maintenance and pulse dosing in organ transplant and autoimmune disease

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Regimen of Glucocorticoids

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Prednisone or other short t1/2 glucocorticoid is DOC.
1. Start with large dose
2. Taper rapidly
3. Give in AM
4. Give QOD if possible
5. Plan to DC eventually

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Problems of Glucocorticoids

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Rule of Thumb: a single dose, no matter how large, almost never produces adverse reactions. Chronic dosage, no matter how small, almost always produces adverse reactions.
1. Suppression of HT-P-A axis
2. Antianabolic
3. Increase capillary fragility
4. Osteoporosis
5. Retention of Na+ and water
6. Hyperglycemia
7. Increase in infections and malignancies

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Calcineurin Inhibitors

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1. Cyclosporine
2. Tacrolimus

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Actions of Cyclosporine

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A cyclic peptide with 11 amino acid residues. It inhibits a protein phosphatase that dephosphorylates proteins that would otherwise enter the nucleus an dincrease transcription of cytokine genes. Cyclosporine is effective in activated T-lymphocytes. Little effect on humoral immunity:
Cyclosporine has two properties which make it especially valuable:
1. readily reversible actions
2. minimal effect on formed elements (no thrombocytopenia or neutropenia)

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Uses of Cyclosporine

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1. in combination with prednisone to prevent rejection of renal, heaptic or cardiac transplants; considered the most effective immunosuppresant in routine use
2. In treatment of a variety of autoimmune/inflammatory diseases (psoriasis, rheumatoid arthritis)

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Toxicity of Cyclosporine

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1. dose-related nephrotoxicity - in up to 75% of patients, usually reversible when therapy DC, but if you are working with only one kidney, and a transplanted one at that, it is a high risk. Usually DC therapy when toxicity appears.
2. Hypertension in 50% of renal patients, 100% of cardiac patients
3. Neurotoxicity - seizures in 5%, tremors in 50%
4. Hepatotoxicity - 50% have elevated levels of hepatic enzymes in serum
5. Diabetogenic, especially with glucocorticoids
6. Increase in infectious episodes/tumors

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Drug Interactions of Cyclosporine

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Metabolized by liver MFO system (CYP3A), therefore agents stimulating/impairing MFO system will predicatbly alter blood levels of cyclosporine.

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MOA of Tacrolimus

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A macrolide which inhibits T-cell activation in the same manner as cyclosporine.

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Toxicity of Tacrolimus

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Nephrotoxicity, Neuro (tremor, headache, seizures), hypertension, hyperglycemia, diabetes, additive toxicity

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Uses of Tacrolimus

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Prophylaxis of solid-organ allograft rejection; rescue therapy with rejection episode despite therapeutic levels of cyclosporine

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Antiproliferative and Antimetabolic Drugs - General

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These agents were originally developed as anticancer agents, and therefore have the ability to kill or inhibit reproduction of rapidly reproducing cells. Since immune system cells are among the most rapidly reproducing cells of the body, they are greatly affected by the cytotoxic drugs.

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Antiproliferative and Antimetabolic Drugs - Examples

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1. Sirolimus
2. Azathioprine
3. Methotrexate
4. Mycophenolate
5. Thalidomide

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Actions of Sirolimus

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Binds to the same intracellular receptor as tacrolimus but inhibits a kinase (mTOR) resulting in blocking cell-cycle progression at the G1/S transition. Used in combinations with glucocorticoid and calcineurin inhibitor to prevent solid-organ allograft rejection.

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Actions of Azathioprine

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Azathioprine is converted in the body to mercaptopurine, which in turn inhibits synthesis of RNA/DNA of actively reproducing cells. A standard agent in renal transplant and is used in other transplants. usually it is used in combination with prednisone.

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Actions of Methotrexate

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Methotrexate inhibits the human enzyme dihydrofolate reductase, inhibiting folate synthesis and those pathways requring folate. Special uses of methotrexate are psoriasis and severe, active rheumatoid arthritis.

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Actions of Mycophenolate Mofetil

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Antimetabolite which inhibits synthesis of guanine nucleotides - an especially important process in lymphocytes. Used in renal transplant and in psoriasis; may be useful in liver and heart transplants as well; commonly used in combination with glucocorticoid or calcineurin inhibitor.

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Thalidomide

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-antiinflammatory, immunomodulatory; inhibits angiogenesis
-in clinical trials for treatment of many disorders
-highly effective in multiple myeloma, especially when combine with dexamethasone
-also for leprosy and some skin disorders
-adv effects include teratogenesis, perpheral neuropathy, constipation, rash, fatigue, hypothyroidism, deep vein thrombosis

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Antibody Reagents

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1. Muromonab - combines with CD-3 receptor on T-cells
2. Antithymocyte Globulin - provides antibodies against a number of T-cell surface proteins and HLA proteins
3. Basiliximab and Daclizumab - bind IL-2 receptor
4. Infliximab - anti-TNF-alpha MAB
5. Etanercept - anti-TNF-alpha
6. Alemtuzumab - binds to CD 52+ on the surface of some leukemic WBCs

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Monoclonal Antibody nomenclature

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-"monab" or "mab" are monoclonal antibodies often of mouse origin and provoking allergic response
-"humanized" antibodies have most of the mouse amino acids replaced with human amino acids. "umab" or "zumab"
-chimeric antibodies have less complete replacement of mouse amino acids; "imab" or "ximab"