Basic Pharmacology Mod 4: Immune System PDF

BASIC PHARMACOLOGY 09/01/2024. MOD 4: IMMUNE SYSTEM Charles C. Monsada,...

BASIC PHARMACOLOGY 09/01/2024. MOD 4: IMMUNE SYSTEM Charles C. Monsada, MD Trans Group/s: 9B I. IMMUNOSUPPRESSIVE AGENTS 4 Betamethasone Drugs that suppress the immune response Majority are immunomodulating pharmaceuticals, 5 Dexamethasone cytotoxic drugs originally applied in cancer therapy Most are used as an effective treatment for Reduces inflammation via suppressive effects on the autoimmune and inflammatory diseases concentration, distribution, and function of These agents block lymphocyte activation and peripheral leukocytes, inflammatory cytokines, and proliferation chemokines. Reduce acute transplant rejection by suppressing Mainstay in the treatment of inflammatory diseases cellular immunity (used as prophylaxis) such as SLE (systemic lupus erythematosus) and Frequently combined to achieve greater efficacy with bronchial asthma. decreased toxicity ○ Associated with many side effects and toxicities Chronic suppression increases risk of infection 1. MECHANISM OF ACTION Inhibition of Phospholipase A2 ○ Phospholipase A2: part of the arachidonic acid pathway which is most primarily involved in the process of inflammation Suppression of inflammatory cytokine production (IL-1, IL-2, TNF-a, IFN-v) Downregulation of destructive enzymes and collagenase production Summary of the actions of the different immunosuppressants. Calcineurin inhibitors, cyclosporine and tacrolimus, will bind with cyclophilin. Once they bind with cyclophilin, they will then be able to block the T cell activation by preventing IL 2 transcription. Corticosteroids suppress both B and T cell function by decreasing transcription of many cytokines via alteration of the glucocorticoid response element (GRE). ○ GRE is specifically present on the regulatory region of the gene and regulates the transcription by RNA polymerase II and associated transcription factors. Sirolimus (Rapamycin) and everolimus are proliferation signal inhibitors. Specifically, they inhibit your mTOR (Molecular Target of Rapamycin). ○ mTOR is a key component of a complex in the cellular signaling pathway involved in different cellular responses. ○ Blockade of mTOR will then lead to inhibition of Molecular level mechanism of action of corticosteroids. interleukin driven T-cell proliferation. Azathioprine, an antimetabolite, is a precursor of the 2. EFFECT OF STEROIDS 6-mercaptopurine and will inhibit lymphocyte The adverse effects of steroids are directly linked to the proliferation by blocking the nucleotide synthesis. general effect of steroids. Increasing serum glucose, a steroid effect, may be A. GLUCOCORTICOIDS translated to developing hyperglycemia in patients. Steroids may also increase fat deposition → weight 1 Hydrocortisone gain, buffalo hump, and moon facies, which is a characteristic of Cushing syndrome. 2 Prednisone Steroids may also cause catabolism in the lymphoid, connective muscle, peripheral fat, and skin → 3 Triamcinolone Pharmacology - Mod # Topic Title 1 of 4 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  muscle wasting, thinning of skin, impaired wound Anti–idiotypic activity or inhibition of cytokine healing, osteoporosis, and growth suppression. synthesis/action It may also reduce manifestations of inflammation, which is the preferred effect primarily in the context of 1.2 Clinical Use immunopharmacology. Usually varies, but it can be utilized primarily in: ○ Reduced manifestations of inflammation → ○ Immunoglobulin deficiencies immunosuppression, and patients will actually be ○ Autoimmune diseases more at risk of different infections. ○ Bone marrow transplantation Some patients may also have behavioral changes when taking steroids → insomnia, euphoria, or 2. HYPERIMMUNE GLOBULINS depression. Steroids are directly related to mineralocorticoids IGIV preparations made from pools of selected (e.g. aldosterone) → hypertension, hypokalemia, and human or animal donors with high titers of edema when these steroids stimulate mineralocorticoid antibodies from a particular virus or toxin receptors. IV administration reduces risk of severity of infection In the long term effect of steroids, it may cause adrenal suppression. 2.1 Clinical Use Respiratory syncytial virus GLUCOCORTICOIDS Cytomegalovirus Varicella zoster General Effects Adverse Effects Human herpes virus 3 Hepatitis B virus Increase serum glucose Hyperglycemia, Diabetes Rabies Mellitus Tetanus Digoxin overdose Net increase fat deposition Weight gain, buffalo hump, moon facies — Cushing C. CALCINEURIN INHIBITORS syndrome 1. CYCLOSPORINE Catabolism in lymphoid, Muscle wasting, thinning of Differ with tacrolimus primarily on their binding site connective muscle, skin, impaired wound peripheral fat, and skin healing, osteoporosis, 1.1 Mechanism of Action growth suppression Binds to cyclophilin to act as a calcineurin inhibitor Inhibits gene transcription of IL-2, IL-3, and IFN-𝛄 Reduced manifestations of Immunosuppression, Regarding the binding site of distrons, they block inflammation Peptic Ulcer Disease specifically the T cell activation → inhibit gene transcription Behavioral changes Insomnia, euphoria → depression 1.2 Clinical Use May stimulate Hypertension, Given orally or via IV, for tissue transplantation mineralocorticoid receptors hypokalemia, edema Used in combination with methotrexate ○ Standard prophylactic regimen to prevent graft versus host disease May induce adrenal Autoimmune disorders (e.g., uveitis, rheumatoid suppression arthritis, psoriasis) B. IMMUNOSUPPRESSIVE ANTIBODIES 1.3 Adverse Effect 1. IMMUNE GLOBULIN INTRAVENOUS (IGIV) Nephrotoxicity ○ One of the limiting factors for the use of the drug Prepared from pooled plasma of thousands of ○ Most important and limiting adverse effect healthy donors, and NO single specific antigen is the Hypertension target of the antibody. Liver dysfunction Predominantly contains monomeric IgG, with limited Hyperkalemia amounts of dimers. Altered mental status Provides intact and functional IgG molecules, which Seizure can provide the patient with broad spectrum antibodies Hirsutism and anti-idiotypes that contain different Gingival hyperplasia immunomodulatory and not neutralizing antibodies. The pool of different antibodies will have a normalizing 2. TACROLIMUS effect on the patient’s immune network. 2.1 Mechanism of Action 1.1 Mechanism of Action Binds to the FK506 binding protein (FKBP) → Reduction of T helper cells prevents IL-2 transcription → blocks T-cell Increase of regulatory T cells → suppress the activation (similar to cyclosporine) immune response 10 to 100 times more potent than cyclosporine in Decreased spontaneous immunoglobulin production inhibiting immune response Fc receptor blockade Ointment used in therapy for atopic dermatitis and ○ Fc: fragment crystallizable region psoriasis Increased antibody catabolism 2.2 Adverse Effect Pharmacology - Mod 4 🏠 Immune System 2 of 4 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Similar to cyclosporine but it may also cause 2.1 Clinical Use hypoglycemia and neurotoxicity In contrast with cyclosporin, it does NOT have gingival In smaller doses: hyperplasia or hirsutism ○ Autoimmune disorder (SLE) Both are notorious for their nephrotoxic effect ○ Acquired factor XIII antibodies ○ Autoimmune hemolytic anemia ○ Antibody-induced pure red cell aplasia D. PROLIFERATION SIGNAL INHIBITORS ○ Wegener granulomatosis 1. SIROLIMUS, EVEROLIMUS 2.2 Adverse Effect 1.1 Mechanism of Action Hematologic, gastrointestinal and mucocutaneous mTOR inhibitor. toxicity are common Binds FKPB Hemorrhagic cystitis: most notable adverse effect of Blocks T-cell activation and B-cell differentiation by Cyclophosphamide preventing response to IL-2 MESNA: antidote of Cyclophosphamide Cardiac toxicity 1.2 Clinical Use Electrolyte disturbance Kidney transplant rejection prophylaxis Use as prophylaxis for steroid-refractory acute and 3. PYRIMIDINE SYNTHESIS INHIBITORS chronic GVHD in hematopoietic stem cell transplant recipients Leflunomide, Teriflunomide Leflunomide: prodrug 1.3 Adverse Effects ○ Once metabolized in the body, the principal active metabolite will be Teriflunomide Myelosuppression (especially thrombocytopenia) Hepatotoxicity 3.1 Mechanism of Action Diarrhea Hypertriglyceridemia Reversibly inhibit mitochondrial enzyme Pneumonitis dihydroorotate dehydrogenase (involved in pyrimidine Renal toxicity is less common with proliferation signal synthesis) → decreased pyrimidine synthesis → inhibitors decreased lymphocyte activation E. CYTOTOXIC AGENTS 3.2 Clinical Use 1. AZATHIOPRINE CLINICAL USE OF PYRIMIDINE SYNTHESIS INHIBITORS Prodrug of 6-mercaptopurine Leflunomide Teriflunomide Inactivated by xanthine oxidase — patients receiving Allopurinol for hyperuricemia should have the dose of Approved for rheumatoid For relapsing remitting Azathioprine reduced to 1/4 or 1/3 the usual amount to arthritis multiple sclerosis prevent toxicity Should be started with Does not require a loading 1.1 Mechanism of Action loading dose dose. Produce immunosuppression by interfering with purine nucleic acid metabolism at steps that are required for the wave of lymphoid cell proliferation after 3.3 Adverse Effects antigenic stimulation Elevation of liver enzymes 1.2 Clinical Use Leukopenia Renal impairment Rheumatoid arthritis Thrombocytopenia Crohn's disease Teratogenic: should not be given primarily to pregnant Multiple sclerosis patients. Prednisone-resistant antibody-mediated idiopathic thrombocytopenic purpura Autoimmune hemolytic anemia F. MONOCLONAL ANTIBODIES Humanized and chimeric monoclonal antibodies 1.3 Adverse Effect directed against a wide array of therapeutic targets Chimeric antibodies typically contain antigen-binding Bone marrow suppression (causes pancytopenia) murine variable regions and human constant Skin rashes regions Fever Most have a suffix -mab Nausea and vomiting Most are given primarily for cancer therapy Gastrointestinal symptoms (higher dosage) Other uses: utilized primarily for autoimmune disease Hepatic dysfunction (high serum alkaline therapy phosphatase) 2. CYCLOPHOSPHAMIDE MONOCLONAL ANTIBODIES FOR CANCER THERAPY Alkylating agent Agent Target Clinical Use Destroys proliferating lymphoid cells and alkylate some resting cells Alemtuzumab CD52 CLL, MS Pharmacology - Mod 4 🏠 Immune System 3 of 4 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.  Metastatic colorectal RSV F RSV prophylaxis for Palivizumab cancer, Renal cell protein high-risk infants carcinoma, Bevacizumab VEGF non-squamous Ranibizumab, non-small cell lung Bevacizumab VEGF Neovascular … cancer (Avastin) Head and neck cancer; KRAS II. IMMUNOSTIMULANT AGENTS Cetuximab EGFR negative, EGFR Drugs that increase the immune responsiveness of positive metastatic patients who have either selective or generalized colorectal cancer immunodeficiency Major potential uses include immunodeficiency B cell non-Hodgkin disorders, chronic infectious diseases, and cancer lymphoma CLL, Rituximab CD20 A. CYTOKINES rheumatoid arthritis, ITP A large and heterogenous group of proteins with diverse functions Breast cancer, Immunoregulatory proteins synthesized by leukocytes Trastuzumab Her2/neu and play numerous roles in the function of the gastric cancer immune system Able to mediate their effect to receptors of relevant Monoclonal antibodies also have other applications that cells, appear to act similarly to hormones are not specific to autoimmune diseases. In other instances, cytokines may have antiproliferative, antimicrobial, and antitumor effects OTHER APPLICATIONS OF MONOCLONAL ANTIBODIES CLINICAL USE Agent Target Clinical Use Hairy cell leukemia, chronic myelogenous Adalimumab, INF α leukemia, malignant melanoma, and IBD, rheumatoid Certolizumab, Soluble Kaposi sarcoma arthritis, ankylosing Golimumab, TNF-alpha spondylitis, psoriasis Infliximab INF B Relapsing-type multiple sclerosis CD25 (part INF γ Chronic granulomatous disease Relapsing multiple Daclizumab of IL-2 sclerosis receptor) Metastatic renal carcinoma and malignant IL-2 melanoma Paroxysmal Complement Eculizumab nocturnal protein C5 hemoglobinuria TOXICITIES Multiple sclerosis, Natalizumab α4-integrin Fever Crohn disease Malaise Psoriasis, psoriatic Ustekinumab IL-12/IL-23 arthritis Myalgias MONOCLONAL ANTIBODIES FOR AUTOIMMUNE DISEASE Myelosuppression THERAPY Agent Target Clinical Use Antiplatelet agent for prevention of ischemic Platelet complications in Abciximab glycoproteins patients undergoing IIb/IIa percutaneous coronary intervention Osteoporosis; inhibits osteoclast Denosumab RANKL maturation (mimics osteoprotegerin) Refractory allergic Omalizumab IgE asthma Pharmacology - Mod 4 🏠 Immune System 4 of 4 The use of trans, practice questions, and evals ratio must be used discreetly and social media/public exposure of the aforementioned shall be strictly prohibited.