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Naglaa F.El-Orabi, Ph D, MSc, B Pharm Sc Assistant professor Department of Pharmacology &Toxicology College of Pharmacy, Girls section King Saud University, Riyadh, KSA Immune system : The importance of the immune system is to protect the body against harmful foreign molecules (living and nonliving pathogens) and defend against diseases. Components of immune system: 1- Lymphoid organs and tissues 2- Leukocytes (WBCs) 3- Soluble proteins: Immune system (cont’d) 1- Lymphoid organs and tissues Immune system (cont’d) 2- Leukocytes lymphocytes granulocytes Monocytes (Phagocytes) Immune system (cont’d) 3- Soluble proteins: - Complement system. - Acute phase proteins. - Antibodies. - Cytokines.(are soluble , signaling proteins that produced by various population of immune cells and other cells to interact with cell surface receptors on a variety of affecter cells and they play many roles as pro-inflammatory, anti-nflammatory, growth regulation and others). Cytokines include ◦ Interleukins (ILs) ◦ Interferons (IFNs), ◦ Tumor Necrosis Factors (TNFs), ◦ Transforming Growth Factors (TGFs) ◦ Colony-stimulating factors (CSFs). Innate immunity Acquired immunity Passive immunity Innate immunity Non First No specific, constitutive. line of defense. Present from birth. immunologic memory. Innate Immunity Includes physical, chemical and biochemical barriers. Innate Immunity Includes physical, chemical and biochemical barriers. •Microbes. •Microbial products. •Tissue damage. Inflammation It is secondary to the innate response. Adaptive and specific. Recognition ( self/ non-self or pathogenic discrimination). Essential to the development of specific immunity is the recognition of antigen. Immunological memory (long lasting). Two types of specific immune response: - Cell-mediated immunity (CMI): All immunologic activities in which cellular elements play a direct role e.g. activation of antigen-specific T-lymphocytes. Abnormal cell e.g cancer cell, infected cell Killer T-cell recognises antigen Antigen Clones of killer T-cell attach to antigen Killer T-cells release perforin pores Normal cell Helper T-cell stimulates correct killer T-cell to multiply Destruction of abnormal cell - Humoral immunity (HI): It is directly dependent on the production of antigen –specific antibody by B lymphocytes and involve the coordinated interaction of antigen-presenting cells, T lymphocytes and Blymphocytes. Function of T helper cells: Acquired Immunity Antigen presenting cells (APCs) present antigen on their Class II MHC molecules (MHC2). Helper T cells recognize these, with the help of their expression of CD4 co-receptors (CD4+, CD3+,……). The activation of a resting helper T cell causes it to release cytokines and other stimulatory signals (green arrows) that stimulate the activity of macrophages, killer T cells and B cells, the latter producing antibodies. The stimulation of B cells and macrophages succeeds a proliferation of T helper cells. It is a form of induced immunity. Antibodies are borrowed from another sources. It usually gives short-term resistance (2 weeks – 6 months). Two types are recognized: Natural Passive e.g. Baby in uterus (placenta) and Breast-fed babies (milk) Artificial Passive e.g. Gamma globulin injection Extremely fast, but short lived (e.g. snake venom) In some instances, the response of immune system can result in serious problems. For example, the introduction of an allograft (that is, the graft of an organ or tissue from one individual to another who is not genetically identical) can elicit a damaging immune response, causing rejection of the transplanted tissue. Transplantation of organs and tissues (for example, kidney, heart, or bone marrow) has become routine due to improved surgical techniques and better tissue typing. Another immune-related problem is the problem associated with autoimmune diseases (e.g. SLE, RA, MS, autoimmune hemolytic anemia, acute glomerulonephritis), when the immune system fail to recognize the self antigen and attack it. Immunosuppressant drug are now utilized to inhibit rejection of transplanted tissues and to treat the autoimmune diseases. Because of their severe toxicities when used as monotherapy, a combination of immunosuppressive agents (2-4 agents with different mechanisms of action), usually at lower doses, is generally employed. I. Immunophilin-binding drugs (act as inhibitors of cytokine production or function): 1Calcineurin inhibitors •Cyclosporine •Tacrolimus (FK506) 2) Antiproliferative drugs • Sirolimus (Rapamycin). •Everolimus, Biolimus A9 Novolimus,and Zotarolimus (umirolimus), Myolimus, II. Corticosteroides (mainly act by alteration of gene expression of many immune-regulating proteins like cytokines and others) ◦ Corticosteroids (Prednisone, Prednisolone, Methylprednisolone, Dexamethasone) III. Cytotoxic/Cytostatic drugs • Inhibitors of purine or pyrimidine synthesis (Antimetabolites): ◦ Azathioprine ◦ Myclophenolate Mofetil ◦ Leflunomide ◦ Methotrexate • Alkylating agents: Cyclophosphamide IV. Immunosuppressive antibodies that block T cell surface molecules involved in signaling immunoglobulins ◦ antilymphocyte globulins (ALG). ◦ antithymocyte globulins (ATG). ◦ Rho (D) immunoglobulin. ◦ Basiliximab ◦ Daclizumab ◦ Muromonab-CD3 V. Miscellanous: e.g. Interferons, opoids, Fingolimod, …. Immunophilins are abundant endogenous cytosolic proteins that catalyze the cis‐trans isomerization of proline residues within proteins, generally to aid in protein folding. Immunophillins (e.g. FKBP-12, and cyclophillin) are the intracellular binding proteins of several immunosuppressive drugs. Immunophilin-binding drugs act mainly as inhibitors of cytokine gene expression or cytokine function. Cytokines are soluble, antigennonspecific, signaling proteins that bind to cell surface receptors on a variety of cells. Of particular interest when discussing immunosuppressive drugs is IL-2 cytokine, a growth factor that stimulates the proliferation of antigenprimed (helper) T cells, which subsequently produce more IL-2, IFNɣ, and TNFα. These cytokines collectively activate natural killer cells, macrophages, and cytotoxic T lymphocytes. Drugs that interfere with the production of IL-2, such as cyclosporine, and Tacrolimus (FK506) are also known as calcineurin inhibitors . Example of drugs that inhibit IL-2 action is sirolimus (rapamycin) Cyclosporin Cyclosporin (Sandimmune) Cyclosporine (CsA) is a lipophillic cyclic polypeptide composed of 11 amino acids that is extracted from a soil fungus (Tolypocladium inflatum). Cyclosporin (cont’d) Mechanism of action: Cyclosporine preferentially suppresses cell-mediated immune reactions, whereas humoral immunity is affected to a far lesser extent. It acts by blocking activation of T cells by inhibiting interleukin-2 production (IL-2). It also decreases proliferation and differentiation of T cells. After diffusing into the T cell, CsA binds to cytosolic protein known as cyclophilin (immunophilin) that acts as CsA intracellular receptors. Cyclosporine-immunophilin complex inhibits calcineurin, a phosphatase necessary for dephosphorylation of transcription factor NFATc (cytosolic Nuclear Factor of Activated T cells). required for interleukins synthesis (IL-2). Inhibition of NFATc dephosphorylation suppresses cell-mediated immunity. Cyclosporin (cont’d) Pharmacokinetics: ⁻ Can be given orally or I.V. infusion. It is slowly and incompletely absorbed from GIT. ⁻ Peak levels is reached after 2– 4 hours, elimination half life is 24 h. ⁻ Oral absorption is delayed by fatty meal. CsA is usually available in soft gelatin capsules, microemulsion that has higher bioavailabilityis not affected by food. ⁻ 50 – 60% of cyclosporine accumulates in blood (erythrocytes & lymphocytes). ⁻ CsA is extensively metabolized by liver CYP-450, primarily by hepatic CYP3A4. ⁻ Excreted mainly through the biliary route, and about 6% is excreted in urine. Cyclosporin (cont’d) Therapeutic Uses: CsA is used to prevent rejection of kidney, liver, and cardiac allogeneic transplants. CsA is most effective in preventing acute rejection of transplanted organs when combined in a double-drug or triple-drug regimen with corticosteroids and an antimetabolite such as mycophenolate mofetil. CsA is used for the treatment autoimmune disorders like severe, active rheumatoid arthritis, and recalcitrant psoriasis that does not respond to other therapies. Cyclosporin (cont’d) Adverse Effects: Many of the adverse effects caused by CsA are dose dependent; therefore, it is important to monitor blood levels of the drug Nephrotoxicity; critical to monitor kidney function. Reduction of the CsA dosage can result in reversal of nephrotoxicity in most cases, although nephrotoxicity may be irreversible in 15% of patients. Symptoms of nephrotoxicity is enhanced by coadministeration with NSAIDs and aminoglycosides antibiotics. Liver dysfunction. Hypertension, hyperkalemia.(K-sparing diuretics should not be used). Hyperglycemia. Multiple infections especially viral infections (Herpes cytomegalovirus). Cyclosporin (cont’d) Adverse Effects (cont’d): ◦ ◦ ◦ ◦ ◦ Lymphoma (Predispose recipients to cancer). Hirsutism Neurotoxicity (tremor). Gum hyperplasia. Anaphylaxis may experienced after I.V. Drug Interactions Clearance of cyclosporine is enhanced by co-administration of CYP450 inducers (Phenobarbitone, Phenytoin & Rifampin ) rejection of transplant. Clearance of cyclosporine is decreased when it is co-administered with cimetidine, erythromycin or Ketoconazole, Grapefruit juice cyclosporine toxicity. Additive nephrotoxicity: NSAIDs, aminoglycosides. Tacrolimus (FK506) Tacrolimus (Prograft, Protopic) Tacrolimus (TAC, originally called FK506) is a macrolide antibiotic that is isolated from a soil actinobacteria (Streptomyces tsukubaensis) Tacrolimus (cont’d) Mechanism of action: TAC exerts its immunosuppressive effect in the same mechanism as CsA, except that it binds to a different immunophilin protein , FKBP-12 (FK506-binding protein-12) creating a new complex (tacrolimusFKBP12 complex) that inhibits calcineurin. Tacrolimus (cont’d) Pharmacokinetics: TAC may be administered orally , I.V., or some topical preperations (ointment). GI absorptin of TAC is incomplete and variable, reduced by fat and carbohydrate meals. TAC is from 10- to 100-fold more potent than CsA. It has half-life after I.V. adminsteration is 9-12 hours. It is highly bound to plasma proteins and is also concentrated in erythrocytes. It is undergoes hepatic metabolism by the CYP3A4 isozyme; thus, the same drug interactions with CsA occur. At least one metabolite of TAC has been shown to have immunosuppressive activity. Excreted mainly in bile and minimally in urine. Tacrolimus (cont’d) Therapeutic Uses: as cyclosporine Organ and stem cell transplantation Prevention of rejection of liver and kidney transplants (given with a corticosteroids and/or an antimetabolite). TCA is also used in treatment of dermal symptoms associated with some autoimmune disorders (e.g. dermatitis and psoriasis). Tacrolimus (cont’d) Adverse Effects: Nephrotoxicity (more than CsA) Neurotoxicity; tremor, seizures, and hallucinations, (more than CsA) insulin-dependent diabetes mellitus GIT disturbances Hperkalemia Mild hypertension Anaphylaxis NO hirsutism or gum hyperplasia Drug interactions: as CsA Tacrolimus (cont’d) What are the differences between CsA and TAC ? TAC is more favorable than CsA due to: TAC is 10 – 100 times more potent than CsA in immunosupression capacity. TAC has decreased episodes of rejection. TAC is combined with lower doses of glucocorticoids. TAC has also been found to have a lower incidence of cardiovascular toxicities such as hypertension and hyperlipidemia, both of which are common disease states found in kidney transplant recipients. But, TAC is more nephrotoxic and neurotoxic. Sirolimus (rapamycin) Sirolimus (Rapamune) Sirolimus (SRL) is macrolide antibiotic It was first discovered as a product of the bacterium (Streptomyces hygroscopicus ) in a soil sample from a pacific island known as Rapa Nui, hence it was initially marketed under the name Rapamycin Sirolimus (cont’d) Mechanism of action: Sirolimus is to bind the cytosolic protein FKBP12 (in a manner similar to tacrolimus), but instead of inhibition of calcineurin, Sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin1 (mTOR). mTOR is a serine-threonine kinase that is essential for many cellular functions, such as cell-cycle progression, DNA repair, and regulation of protein translation Binding of Sirolimus-FKBP12 complex to mTOR blocks the activated T -cells proliferation, B cell proliferation & immunoglobulin production. Unlike CsA and TAC, SRL does not owe its effect to lowering IL-2 production but, rather, to inhibiting the cellular responses to IL-2. Sirolimus (cont’d) Pharmacokinetics: The drug is available only as oral preparations. It is readily absorbed from GIT (rate is decreased by high-fat meals) A loading dose is required at the time of initiation of therapy. SRL is extensively bound to plasma proteins (~ 92%) and has a long half-life (57-63 hours) compared to those of CsA and TAC. SRL is metabolized by the CYP3A4 isozyme and has the same drug-drug interactions as CsA and TAC. Due to competition in protein binding sites, SRL increases the drug concentrations of CsA, and careful blood level monitoring of both agents must be employed to avoid harmful drug toxicities uppon combined therapy. SRL and its metabolites are predominantly eliminated in the feces. Sirolimus (cont’d) Therapeutic Uses: SRL has both anti-proliferative and immunosuppressive effects (equipotent to CsA). In renal transplantation(used mainly combined with CsA and corticosteroids) To limit the long-term side effects of the calcineurin inhibitor, SRL is often utilized in calcineurin inhibitor withdrawal protocols in patients who remain rejection free during the first 3 months posttransplant. Heart allografts In halting graft vascular disease (SRL-coated stents inserted into the cardiac vasculature inhibit neointimal vascular hyperplasia and restenosis of the blood vessels by reducing proliferation of the endothelial cells). Hematopoietic stem cell transplant recipients. Sirolimus (cont’d) Adverse Effects: Hyperlipidemia (elevated cholesterol and triglycerides), The combination of CsA and SRL or TAC and SRL are more nephrotoxic than CsA or TAC alone headache, nausea and diarrhea, leukopenia, and thrombocytopenia. Impaired wound healing especially in obese and diabetic patients which may represents a problem immediately following the transplant surgery. II. Corticosteroids The corticosteroids were the first pharmacologic agents to be used as immunosuppressives both in transplantation and in various autoimmune disorders. They have both anti-inflammatory action and immunosuppressant effects. They are still one of the mainstays for attenuating rejection episodes. The most common agents are Prednisone, prednisolone, methylprednisolone, and betamethasone dexamethasone Pridinsone Pridinsolone Dexamethasone Corticosteroids Mechanism of action: On entering cells, they bind to the glucocorticoid receptor (GR). The glucocorticoid-GR complex translocates into the nucleus and interacts with DNA to regulates the gene transcription of . Among the genes affected are those involved in inflammatory responses. ◦ Decrease production of inflammatory mediators as prostaglandins, leukotrienes, histamine, PAF, bradykinin mainly by their stimulatory action on annexin-1 (a phoshplipase A inhibitor). ◦ Decrease production of a wide array of proinflammatory cytokines like IL-1, IL-2,IL-3,…, TNF-, GM-CSF. ◦ Stabilize lysosomal membranes. ◦ Decrease generation of IgG, and nitric oxide. ◦ Inhibit antigen processing by macrophages. ◦ Suppress T-cell helper function ◦ Decrease T-lymphocyte proliferation. Corticosteroids (cont’d) Pharmacokinetics: - - - - Corticosteroids may be administered by a variety of routes. Most are active when given orally, and parentrally . In addition topical preparations, eye/ear/ nasal drops and aerosoles are also available. Corticosteroids (~90%) bind to corticosteroid-binding globulin (CBG) and to albumin with variable tendencies. Plasma half-life 2-8 hours, with variable durations depending on preparation ;(8-12 hrs for SAGCs e.g. Cortisol, 18-36 hrs for IAGCs e.g. Predinsolne, and 36-54 hrs for LAGCs e.g. Dexamethasone, Betamethasone). Generally GCs are metabolized in the liver by both microsomal (mainly CYP3A4 & CYP2D6) and non-microsomal enzymes, where they are reduced and conjugated (glucourinate and sulfate), forming inactive water-soluble metabolites that are excreted by the kidney (~75%) in addition to ~25% are execreted in feces. Some GCs are bioactivated after adminstration like Prednisone that is converted in vivo to active metabolite prednisolone. Corticosteroids (cont’d) Therapeutic Uses: Corticosteroids are first line therapy for solid organ allografts & haematopoietic stem cell transplantation to attenuating rejection episodes. Acute or chronic rejection of solid organ allografts (given with TAC/CsA and/or an antimetabolite). Autoimmune diseases as refractory rheumatoid arthritis, systemic lupus erythematosus, temporal arthritis, and asthma. Corticosteroids (cont’d) Adverse Effects: The use of these agents is associated with numerous adverse effects. For example, ◦ Hypercholesterolemia ◦ Hyperglycemia ◦ Hypertension ◦ Cataract ◦ Osteoporosis ◦ Increase liability to infection ◦ Adrenal suppression III. Cytotoxic agents ◦ ◦ ◦ ◦ Alkylating agents e.g. Cyclophosphamide Inhibitors of purine or pyrimidine synthesis (Antimetabolites): Azathioprine Mycophenolate Mofetil Leflunomide Methotrexate Cyclophosphamide Cyclophosphamide (Cytoxan) Cyclophosphamide is a cytotoxic agent acts by alkaylation of the DNA. Cyclophosphamide is a prodrug that is undergo some modification by the effect of multiple liver CYP450 to form the active compounds, phosphoramide mustard and acrolein. Reaction of the phosphoramide mustard with DNA is considered to be the cytotoxic step especialy to those rapidly deviding cells like neoplastic cells, proliferating lymphoid cells and germ cells. Cyclophosphamide (cont’d) • It is administered orally& intravenously • Cyclophosphamide is converted by mixed-function oxidase enzymes (cytochrome P450 system) in the liver to active metabolites. The main active metabolite is 4hydroxycyclophosphamide, and aldophosphamide. Most of the aldophosphamide is oxidised by the enzyme aldehyde dehydrogenase (ALDH) to make carboxyphosphamide. A small proportion of aldophosphamide freely diffuses into cells, it is decomposed into two compounds, phosphoramide mustard and acrolein. • The execretion occurs equally between renal and biliary routs. Cyclophosphamide (cont’d) Therapeutic Uses: It is widely utilized in treatment of a wide variety of neoplastic diseases (anticancer), such as lymphoma and breast cancer. Immunosupressant in autoimmune disorders such as rheumatoid arthritis , systemic lupus erythrematosus, Autoimmune hemolytic anemia Adverse effects: ◦ Alopecia and GIT disorders (Nausea -vomiting-diarrhea) ◦ Bone marrow suppression ◦ Hemorraghic cystitis , which can lead to fibrosis of the bladder. The latter toxicity has been attributed to acrolein which is toxic to the bladder epithelium. This can be prevented through the use of aggressive hydration and/or MESNA (sodium 2-mercaptoethane sulfonate), which neutralizes the toxic metabolites, minimizes this problem. ◦ Sterility (testicular atrophy and aspermia in male& amenorrhea in females) ◦ Veno-occlusive disease of the liver Antimetabolites 1- Azathioprine Azathioprine (Imuran) • It is a purine analogue immunosuppressive drug that was the first agent to achieve widespread use in organ transplantation. • It is a prodrug that is converted first to 6mercaptopurine (6-MP) and then to the corresponding nucleotide, thioinosinic acid. Azathioprine (cont’d) Mechanism of action: • The immunosuppressive effects of azathioprine are due to this nucleotide analog; thioinosinic acid. • Because of their rapid proliferation in the immune response, lymphocytes (B &T) are predominantly affected by the cytotoxic effects of azathioprine. • Azathioprine Inhibits de novo synthesis of purines required for lymphocytes proliferation. Pharmacokinetics: ◦ It is administered orally or intravenously. ◦ Widely distributed but does not cross BBB. ◦ Metabolized in the liver to 6-mercaptopurine or to thiouric acid (inactive metabolite) by xanthine oxidase. ◦ Excreted primarily in urine. Azathioprine (cont’d) Therapeutic Uses: It is used to prevent organ rejection following organ transplantation To treat a vast array of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus inflammatory bowel diseases (such as Crohn's disease and ulcerative Colitis), multiple scleroses, autoimmune hepatitis, atopic dermatitis, myasthenia gravis, acute glomerulonephritis, and others. Azathioprine (cont’d) Adverse effects: Bone marrow suppression (leukopenia & thrombocytopenia). Nausea , vomiting and diarrhea Hepatotoxicity. Increased risk of infections and mutagencity (Lymphoma) Drug Interactions: Concomitant use with ACE inhibitors in renal transplant patients can lead to an exaggerated leukopenic response. Allopurinol, an inhibitor of xanthine oxidase that is used to treat gout, significantly inhibits the metabolism of azatihioprine; therefore, the dose of azathioprine must be reduced by 60 to 75 %. 2- Mycophenolate Mofetil Mycophenolate Mofetil (Mycept) • It is a semisynthetic derivative of mycophenolic acid from fungus source. • Prodrug; it is rapidly hydrolyzed in the gastrointestinal tract to mycophenolic acid (MPA) Mechanism of action: ◦ Inhibits de novo synthesis of purines. ◦ mycophenolic acid is a potent inhibitor of inosine monophosphate dehydrogenase (IMP), crucial for purine synthesis deprivation of proliferating T and B cells of nucleic acids. Mycophenolate Mofetil (cont’d) Pharmacokinetics: ◦ It is given orally, I.V or I.M. Dose 2-3 g/day. ◦ Rapidly and completely absorbed after oral administration. ◦ It undergoes first-pass metabolism to give the active moiety, mycophenolic acid (MPA). ◦ MPA is extensively bound to plasma protein. ◦ metabolized in the liver by glucuronidation. ◦ Excreted in urine as glucuronide conjugate Mycophenolate Mofetil (cont’d) Therapeutic uses: Solid organ transplants (heart, kidney, and liver transplants). Steroid-refractory hematopoietic stem cell transplant patients. Combined with prednisone as alternative to CSA or tacrolimus. Rheumatoid arthritis & dermatologic disorders. Adverse effects & drug interaction: ◦ ◦ ◦ ◦ ◦ GIT toxicity: Nausea, Vomiting, diarrhea, abdominal pain. Leukopenia, neutropenia & anemea Higher risk of CMV infection. It is CI to be administered during pregnancy Concomitant administration with antacids containing Mg2+ or Al 3+, or with cholestyramine, can decrease absorption of the drug. 3- Leflunamide Leflunamide (Arava) • • • Leflunomide is a synthetic disease-modifying antirheumatic group of drugs- antimetabolite immunosupressant (DMARD). It acts by inhibiting dihydroorotate dehydrogenase (an enzyme involved in de novo pyrimidine synthesis) It is a prodrug ,following oral administration, leflunomide is metabolized to teriflunomide, which is responsible for all of the drug's activity in vivo. Luflunamide (cont’d) Pharmacokinetics: • The drug is given orally. It is rapidly metabolized to its pharmacologically- active metabolite teriflunomide. • Teriflunomide is metabolized in the liver and excreted as well renally and biliary. • After oral administration, peak plasma levels of teriflunomide occurred between 6 and 12 hours after dosing. Due to its very long half-life (approximately 2 weeks), a loading dose of 100 mg for 3 days is required to reach steady-state levels quickly. Therapeutic uses: - Leflunomide has both immunosuppressant and anti-inflammatory effects. Leflunomide has been approved for the treatment of rheumatoid arthritis or psoriatic arthritis. It slows the progression of the disease and relief the associated symptoms such as joint tenderness and decreased joint and general mobility in human patients. Luflunamide (cont’d) Adverse effects: • Elevation of liver enzymes • Renal impairment • Teratogenicity (Women or men should not have babies before 2 years after termination of therapy have elapsed or undergo a rapid wash-out procedure like an eleven-day scheme with oral cholestyramine or the use of activated charcoal is indicated and will soon decrease plasma levels below the critical limit of 0.02 mg/l ). • Cardiovascular effects (tachycardia). • Leflunomide has the potential to promote myeloid/lymphatic malignancies or solid cancers 4- Methotrexate Methteraxate ◦ Methotrexate (MTX) is synthetic antimetabolite used mainly in treatment of cancer, and autoimmune diseases ◦ It acts by inhibiting the metabolism of folic acid. It Inhibits DHFR enzyme required for folic acid activation (tetrahydrofolic) and as a result Inhibition of DNA, RNA & protein synthesis occur. ◦ Methotrexate (cont’d) Pharmacokinetics: ◦ It can be taken orally or administered by injection (I.M., I.V., S.C., or I.T.). Methotrexate is metabolized by intestinal bacteria to the inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA), which accounts for less than 5% loss of the oral dose ◦ Oral doses are taken weekly. ◦ It is excreted in urine. Therapeutic uses: Cancer Chemotherapy: In the treatment of a number of cancers including: breast, head and neck, leukemia, lymphoma, lung, osteosarcoma, and bladder. Autoimmune disorders: It is used as a treatment for some autoimmune diseases including: psoriasis and psoriatic arthritis, Crohn's disease, and rheumatoid arthritis. Pregnancy termination: Methotrexate is commonly used (generally in combination with misoprostol) to terminate pregnancies during the early stages (i.e., as an abortifacient). It is also used to treat ectopic pregnancies. Methotrexate (cont’d) Adverse effects & drug interaction: ◦ Nausea, vomiting, diarrhea, abdominal pain, ulcerative stomatitis. ◦ Fatigue, fever, and dizziness ◦ Alopecia ◦ Bone marrow depression (leukocytopenia) ◦ Predisposition to multiple infection ◦ Pulmonary fibrosis ◦ Renal & hepatic disorders ◦ Methotrexate is a highly teratogenic drug and contrindicated during pregnancy.