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 CONTENT ADDITIONAL INFO RESOURCES 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 OUTLINE decreasing transcription of many cytokines via alteration - of the glucocorticoid response element (GRE). ○ GRE is specifically present on the regulatory region I. Immunosuppressive Agents of the gene and regulates the transcription by RNA A. Glucocorticoids polymerase II and associated transcription factors. B. Immunosuppressive Antibodies - Sirolimus (Rapamycin) and everolimus are C. Calcineurin Inhibitors proliferation signal inhibitors. Specifically, they inhibit D. Proliferation Signal Inhibitors your mTOR (Molecular Target of Rapamycin). E. Cytotoxic Agents ○ mTOR is a key component of a complex in the F. Monoclonal Antibodies cellular signaling pathway involved in different II. Immunostimulant Agents cellular responses. A. Cytokines ○ Blockade of mTOR will then lead to inhibition of interleukin driven T-cell proliferation. References - Azathioprine, an antimetabolite, is a precursor of the - - - - - 6-mercaptopurine and will inhibit lymphocyte proliferation by blocking the nucleotide synthesis. LEARNING OBJECTIVES 1. Classify the immunomodulators A. GLUCOCORTICOIDS CH P , T B D) 2. Give the drug prototype for each classification , ,. 3. Discuss the pharmacodynamics and pharmacokinetics of drug prototypes 1 Hydrocortisone 4. Understand clinical uses 5. Understand adverse effects and drug interactions of 2 Prednisone medications 3 Triamcinolone 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 autoimmune Reduces inflammation via suppressive effects on the and inflammatory diseases concentration, distribution, and function of peripheral These agents block lymphocyte activation and leukocytes, inflammatory cytokines, and chemokines. proliferation Mainstay in the treatment of inflammatory diseases such Reduce acute transplant rejection by suppressing as-SLE (systemic lupus erythematosus) and Bronchial cellular immunity (used as prophylaxis) Asthma. Frequently combined to achieve greater efficacy with - ○ Associated with many side effects and toxicities decreased toxicity Chronic suppression increases risk of infection 1. MECHANISM OF ACTION Inhibition of 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) · & Down regulation of destructive enzymes, collagenase - production Summary of the actions of the different immunosuppressants. First Aid for the USMLE Step 1, 2015 edition Calcineurin inhibitors, cyclosporine and tacrolimus, - will bind with cyclophilin. Once they bind with cyclophilin, Pharmacology - Mod # Topic Title 1 of 6 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.  GLUCOCORTICOIDS General Effects Adverse Effects vIncrease serum glucose Hyperglycemia, Diabetes Mellitus WNet increase fat deposition Weight gain, buffalo hump, moon facies WCatabolism in lymphoid, Muscle wasting, thinning of connective muscle, skin, impaired wound peripheral fat, and skin healing, osteoporosis, growth suppression ~Reduce manifestations of Immunosuppression, inflammation Peptic Ulcer Disease ↓ acid production WBehavioral changes Insomnia, euphoria → depression Molecular level mechanism of action of corticosteroids. rMay stimulate mineralocorticoid receptors Hypertension, hypokalemia, edema Katzung's Basic & Clinical Pharmacology, 16th edition May induce adrenal 2. EFFECT OF STEROIDS suppression The adverse effects of steroids are directly linked to the general effect of steroids. B. IMMUNOSUPPRESSIVE ANTIBODIES Increasing serum glucose, a steroid effect, may be boost of translated to developing hyperglycemia in patients. 1. IMMUNE GLOBULIN INTRAVENOUS (IGIV) giveody -> from heat a Steroids may also increase fat deposition → weight people Prepared from pooled plasma of thousands of healthy gain, buffalo hump, and moon facies, which is a - - donors, and no single specific antigen is the target of the characteristic of Cushing syndrome. antibody. Steroids may also cause catabolism in the lymphoid, Predominantly contains - monomeric IgG, with limited connective muscle, peripheral fat, and skin → muscle amounts of dimers. wasting, thinning of skin, impaired wound healing, -... Provides intact and functional IgG molecules, which can osteoporosis, and growth suppression. - - provide the patient with broad spectrum antibodies and It may also reduce manifestations of inflammation, which anti-idiotypes that contain different immunomodulatory is the preferred effect primarily in the context of and not neutralizing antibodies. immunopharmacology. Reduced manifestations of The pool of different antibodies will have a normalizing inflammation → immunosuppression, and patients will actually be more at risk of different infections. Be effect on the patient’s immune network. Some patients may also have behavioral changes when 1.1 Mechanism of Action taking steroids → insomnia, euphoria, or depression. Steroids are directly related to mineralocorticoids (e.g. ↓ Reduction of T helper cells T-helper activate other immure system : ↑ Increase of regulatory T cells regulator - - aldosterone) → hypertension, hypokalemia, and edema - when these steroids stimulate mineralocorticoid ○ Suppress the immune response prevent for aggressive receptors. ↓ Decreased spontaneous immunoglobulin production immure system ⑧ - - In the long term effect of steroids, it may cause adrenal Fc receptor blockade present binding to antibodies easily -> - ○ Fc - fragment crystallizable region - suppression. ↑ Increased antibody catabolism "breakdown" of unnecessary antibodies - Anti–idiotypic activity or inhibition of cytokine neutralize har -> synthesis/action bodies - 1.2 Clinical Use Usually varies, but it can be utilized primarily in: ○ v Immunoglobulin deficiencies - 3 · ○ WAutoimmune diseases - 110 ○- Bone marrow transplantation 2. HYPERIMMUNE GLOBULINS ins IGIV preparations made from pools of selected human or animal donors with - high titers of antibodies from a particular virus or toxin IV administration reduces risk of severity of infection 2.1 Clinical Use Respiratory syncytial virus Cytomegalovirus · Pharmacology - Mod 4 Immune System 2 of 6 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.  IGIU vs. Ha -mix antibodies specialized antibodies - specific infutions - -more general -broad antibodies Varicella zoster targeted protation Use as prophylaxis for - steroid-refractory acute and - -variety of infX Human herpes virus 3 - chronic GVH disease in hematopoetic stem cell. Hepatitis B virus transplant recipients Rabies Tetanus 1.3 Adverse Effects Digoxin overdose ~ Myelosuppression (especially thrombocytopenia) ~ Hepatotoxicity C. CALCINEURIN INHIBITORS Diarrhea I Hypertriglyceridemia En 1. CYCLOSPORINE ~Pneumonitis #Renal Toxicity is less common with proliferation signal Differ with tacrolimus primarily on their binding site inhibitors 1.1 Mechanism of Action E. CYTOTOXIC AGENTS Binds to-cyclophilin to act as a calcineurin inhibitor Inhibits gene transcription of00 IL-2, IL-3, and⑧ IFN-𝛄 1. AZATHIOPRINE Regarding the binding site of distrons, they block specifically the T cell activation E Prodrug of mercaptopurine - - ○ Hence, inhibit gene transcription Inactivated by- Xanthine Oxidase - Patients receiving Allopurinol for hyperuricemia should have the dose of - 1.2 Clinical Use Azathioprine reduced to 1/4 or 1/3 the usual amount to prevent toxicity -- Given orally or via IV, for tissue transplantation Used in combination with methotrexate 1.1 Mechanism of Action ○ standard prophylactic regimen to prevent graft - versus host disease Produce Immunosuppression by interfering with purine Autoimmune disorders nucleic acid metabolism at steps that are required for ○ - - uveitis, rheumatoid - arthritis, psoriasis the wave of lymphoid cell proliferation after antigenic stimulation 1.3 Adverse Effect * Nephrotoxicity 1.2 Clinical Use ○ one of the limiting factors for the use of the drug ~Rheumatoid arthritis * ○ most important and limiting adverse effect WCrohn's disease* * Hypertension WMultiple sclerosis * Liver dysfunction ~Prednisone-resistant antibody-mediated idiopathic Hyperkalemia thrombocytopenic purpura Altered mental status WAutoimmune hemolytic anemia * * Seizure Hirsutism 1.3 Adverse Effect ⑭ Gingival hyperplasia I Bone marrow suppression (causes pancytopenia) & standard Asean Skin rashes 2. TACROLIMUS + WFever WNausea and vomiting 2.1 Mechanism of Action v Gastrointestinal symptoms (higher dosage) Mechanisms of action: Binds to the FK506 binding W Hepatic dysfunction (high serum alkaline phosphatase immunophic protein & (FKBP) blocks T-cell activation (similar to cyclosporin) by preventing IL-2 transcription 2. CYCLOPHOSPHAMIDE 10 to 100 times more potent than cyclosporine in inhibiting immune response -Alkylating agent Ointment used in therapy for - - atopic dermatitis and Destroys proliferating lymphoid cells but also alkylate - psoriasis & some resting cells 2.2 Adverse Effect 2.1 Clinical Use Similar to cyclosporine but it may also cause In Smaller doses: hypoglycemia and> - neurotoxicity ⑰ W Autoimmune disorder (SLE) In contrast with cyclosporin, it does NOT have gingival - ~ Acquired factor XIII antibodies hyperplasia or hirsutism ⑦ - ~Autoimmune hemolytic anemia Both are notorious for their- - - nephrotoxic effect ~ Antibody-induced pure red cell aplasia - W Wegener granulomatosis D. PROLIFERATION SIGNAL INHIBITORS 2.2 Adverse Effect Eeee 1. SIROLIMUS, EVEROLIMUS Hematologic, gastrointestinal and mucocutaneous 1.1 Mechanism of Action - - - toxicity are common mTOR inhibitor. Binds FKPB -- Hemorrhagic Cystitis - Most notable adverse effect of Blocks T-cell activation and B-cell differentiation by Cyclophosphamide - Antidote⑱MESNA O preventing response to IL-2 Cardiac toxicity Electrolyte disturbance 1.2 Clinical Use Kidney transplant rejection - prophylaxis Professor’s Notes: Pharmacology - Mod 4 Immune System 3 of 6 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.  In the exam if you are asked what is the antidote of Cyclophosphamide you need to answer MESNA MONOCLONAL ANTIBODIES FOR CANCER THERAPY ⑧ Agent Target Clinical Use 3. PYRIMIDINE SYNTHESIS INHIBITORS Alemtuzumab CD52 CLL, MS -> leukemia multiple sclerosis Leflunomide, Teriflunomide Chronic lympholitic ; ○ Leflunomide - prodrug Bevacizumab VEGF Metastatic colorectal Once metabolized in the body, the principal cancer, Renal cell Not administered : active metabolite will be Teriflunomide · carcinoma, 3.1 Mechanism of Action post-surgery non-squamous Reversibly inhibit mitochondrial enzyme dihydroorotate non-small cell lung dehydrogenase (involved in pyrimidine synthesis) → cancer decreased lymphocyte activation Cetuximab EGFR Head and neck 3.2 Clinical Use cancer; KRAS negative, EGFR CLINICAL USE OF PYRIMIDINE SYNTHESIS INHIBITORS positive metastatic colorectal cancer - Leflunomide Teriflunomide Rituximab CD20 B cell non-Hodgkin -- Approved for rheumatoid For relapsing remitting lymphoma CLL, earthritis multiple sclerosis rheumatoid arthritis, Should be started with Does not require a ITP loading dose loading dose. Trastuzumab Her2/neu Breast cancer, gastric cancer 3.3 Adverse Effects · Note: Dr. Monsada made a table but make sure to read ADVERSE EFFECTS OF PYRIMIDINE SYNTHESIS the books also. INHIBITORS ~ Elevation of liver enzymes WLeukopenia Monoclonal antibodies also have other applications that are not specific to autoimmune diseases ~ Renal impairment WThrombocytopenia OTHER APPLICATIONS OF MONOCLONAL ANTIBODIES Teratogenic ⑧* ○ should not be given primarily to pregnant patients. Agent Target Clinical Use Adalimumab, Soluble IBD, rheumatoid F. MONOCLONAL ANTIBODIES Certolizumab, TNF-alpha arthritis, ankylosing Humanized and chimeric monoclonal antibodies directed Golimumab, spondylitis, psoriasis against a wide array of therapeutic targets Infliximab - Chimeric antibodies typically contain antigen-binding murine variable regions and human constant regions Daclizumab CD25 (part Relapsing multiple Most have a suffixC -mab of IL-2 sclerosis Most are given primarily for cancer therapy receptor) ○ Other uses: utilized primarily for autoimmune disease therapy Eculizumab Complement Paroxysmal protein nocturnal C5 hemoglobinuria Natalizumab α4-integrin Multiple sclerosis, Crohn disease Ustekinumab IL-12/IL-23 Psoriasis, psoriatic arthritis MONOCLONAL ANTIBODIES FOR AUTOIMMUNE DISEASE > THERAPY Agent Target Clinical Use Abciximab Platelet Antiplatelet agent for glycoproteins prevention of IIb/IIa ischemic complications in patients undergoing percutaneous Pharmacology - Mod 4 Immune System 4 of 6 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.  coronary intervention Denosumab RANKL Osteoporosis; inhibits osteoclast maturation (mimics osteoprotegerin) Omalizumab IgE Refractory allergic asthma Palivizumab RSV F RSV prophylaxis for protein high-risk infants Ranibizumab, VEGF Neovascular … Bevacizumab (Avastin) II. IMMUNOSTIMULANT AGENTS Drugs that increase the immune responsiveness of patients who have either selective or generalized immunodeficiency Major potential uses include immunodeficiency disorders, chronic infectious diseases, and cancer A. CYTOKINES A large and heterogenous group of proteins with diverse functions Immunoregulatory proteins synthesized by leukocytes and play numerous roles in the function of the immune system Able to mediate their effect to receptors of relevant cells, appear to act similarly to hormones In other instances, cytokines may have antiproliferative, antimicrobial, and antitumor effects CLINICAL USE INF α Hairy cell leukemia, chronic myelogenous leukemia, malignant melanoma, and Kaposi sarcoma INF B Relapsing-type multiple sclerosis INF γ Chronic granulomatous disease IL-2 Metastatic renal carcinoma and malignant melanoma TOXICITIES Fever Malaise Myalgias Myelosuppression REFERENCES Katzung B, Vanderah T. Basic and Clinical Pharmacology. 15th Edition. McGraw-hIll Lange. 2021 Brunton L, Hilal-Dandan R, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 13th Edition, McGraw-H Pharmacology - Mod 4 Immune System 5 of 6 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.  PRACTICE QUESTIONS Reminder: each individual is assigned to make two (2) practice questions each, with respective rationales. DISCLAIMER: Practice questions WERE NOT fact-checked and DID NOT undergo proofreading. Please be advised. You may comment on the specific question if you have any corrections. TITLE OF THE TOPIC QUESTION RATIONALE ANSWER Which among the following are pyrimidine synthesis E inhibitors? A. Leflunomide B. Teriflunomide C. Alemtuzumab D. All of the above E. Only two among the choices Which among the following monoclonal antibodies Trastuzumab targets Her2/neu and is used primarily in C targets Her2/neu and is commonly used in breast patients with breast cancer. cancer therapy? Reference: Video Lecture A. Rituximab B. Eculizumab C. Trastuzumab D. Alemtuzumab TRUE or FALSE: Aside from being mediators of Cytokines may also have antiproliferative, A immune function, cytokines may also have antimicrobial antimicrobial, and antitumor effects. effects Reference: Video Lecture A. TRUE B. FALSE Pharmacology - Mod 4 Immune System 6 of 6 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.