IMMUNO PHARM Flashcards
Capecitabine
Mechanism:
Prodrug of 5-fluorouracil.
Inhibit thymidylate synthase –> decrease dTMP –> decrease DNA synthesis.
S-phase specific
5-FUcan bind tothymidylate synthaseonly in the presence ofmethylene-tetrahydrofolate, which a derivative offolic acidand acofactorofthymidylate synthase.
Administration of folic acid (leucovorin) concurrently with 5-FU or capecitabine augments the effects of these drugs by increasing their binding to thymidylate synthase and simultaneously increases the risk of adverse effects (e.g., myelotoxicity).
Clinical Use:
Advanced breast, colorectal, gastric cancer, basal cell carcinoma (topical), actinic keratosis
Adverse Effects:
Myelosuppression, palmar-plantar erythrodysesthesia (hand-foot syndrome).
5-FU
A cytostatic/cytotoxic antimetabolite in the subgroup of pyrimidine antagonists.
Mechanism:
Inhibits thymidylate synthase to block synthesis of thymidine, thus halting DNA replication and promoting cell death. 5-FUcan bind tothymidylate synthaseonly in the presence ofmethylene-tetrahydrofolate, which a derivative offolic acidand acofactorofthymidylate synthase.
S- phase specific
Also inhibits protein synthesis.
Administration of folic acid concurrently with 5-FU or capecitabine augments the effects of these drugs by increasing their binding to thymidylate synthase and simultaneously increases the risk of adverse effects (e.g., myelotoxicity).
Clinical Use:
Colon cancer, pancreatic cancer, actinic keratosis, basal cell carcinoma (topical).
Adverse Effects:
Myelosuppression, palmar-plantar erythrodysesthesia (hand-foot syndrome).
Methotrexate
Mechanism:
Folic acid antagonist (antimetabolite)
Competitively inhibits dihydrofolate reductase and AICAR transformylase → ↓ pyrimidine and purine nucleotide synthesis → ↓ DNA synthesis
Suppress cell mediated and humoral immunity
Folic acid administration would decrease the risk of methotrexate toxicity (leucovorin rescue).
Clinical Use:
Severe psoriasis, rheumatoid arthritis, ectopic pregnancy, medicaI abortion (with misoprostol)
In neoplastic diseases like gestational choriocarcinoma, chorioadenoma, and hydatidiform mole
Adverse Effects: Myelosuppression Hepatotoxicity Mucositis (eg, mouth ulcers). Gastrointestinal side effects (e.g., nausea and vomiting) Diarrhea Pulmonary fibrosis and toxicity Rash Hair loss Increased risk of lymphoproliferative disorders Teratogenicity Folate deficiency, which may be teratogenic (neural tube defects) without supplementation. Nephrotoxicity.
Mycophenolate mofetil
Mechanism:
Reversible inhibition of inosine monophosphate dehydrogenase (enzyme that is responsible for guanosine synthesis) → blockade of purine synthesis → selective inhibition of lymphocyte proliferation
Suppress cell mediated and humoral immunity
Clinical Use:
Most commonly used to prevent graft rejection in renal transplant recipients.
Lupus nephritis
Used in combination with cyclosporine or tacrolimus as transplant rejection prophylaxis
Toxicity: GI upset, pancytopenia, hypertension, hyperglycemia. Vomiting and diarrhea Comparatively low neurotoxicity and nephrotoxicity Peripheral edema ↑ Blood urea nitrogen Hypercholesterolemia Back pain Cough Associated with invasive CMV infection.
Azathioprine
Mechanism:
Metabolized to 6-mercaptopurine, which requires further metabolism to thio-inosine monophosphate (TIM) by HGPRT; TIM then directly acts as a cytotoxic agent
An antimetabolite (purine analog) that impairs cell replication. 6-MP inhibits the enzyme PRPP amidotransferase, which normally converts PRPP to 5-phosphoribosyl-1-amine.
Suppress cell mediated and humoral immunity
Clinical Use:
Prophylaxis against renal transplant rejection
Autoimmune disease treatment (e.g., rheumatoid arthritis, Crohn disease, glomerulonephritis)
To wean patients off long-term steroid therapy
Steroid-refractory disease
Adverse Effects:
Myelosuppression
GI, liver toxicity.
Malignancies, including cervical cancer, lymphoma, squamous cell carcinoma, melanoma (rare)
Acute pancreatitis
Azathioprine and 6-MP are metabolized by xanthine oxidase; thus both have increase risk of toxicity with allopurinol or febuxostat.
Leflunomide
Mechanism:
Reversibly inhibits dihydroorotate dehydrogenase (which is an enzyme of the pyrimidine ribonucleotide synthesis pathway that converts dihydroorotate to orotic acid) → impaired pyrimidine synthesis → inhibits proliferation of T cells
Clinical Use:
Rheumatoid arthritis
Psoriatic arthritis
Adverse E:ffects:
Gastrointestinal symptoms, hypertension, hepatotoxicity and teratogenicity.
Tacrolimus
Mechanism:
Calcineurin inhibitor
Binds FK506 binding protein (FKBP).
Blocks the translocation of nuclear factor of activated T-cells (NFAT), resulting in reduced transcription of IL-2.
Blocks T-cell activation by preventing IL-2 transcription.
Clinical Use:
Indications for systemic administration include prevention of organ rejection after allogeneic transplantation and ulcerative colitis.
Indications for topical administration include immune-mediated disorders, such as atopic dermatitis and cutaneous graft versus host disease.
Toxicity:
Similar to cyclosporine (nephrotoxicity, hypertension, hyperlipidemia, neurotoxicity)
NO gingival hyperplasia or hirsutism
Increase risk of diabetes and neurotoxicity
Highly nephrotoxic, especially in higher doses or in patients with decreased renal function.
Can inducenephrotoxicity, which is caused by glomerularand tubular dysfunction and manifests with a slow decrease of renal function.Biopsytypically shows tubular vacuolization. In addition,glomerularscarring andfocal segmental glomerulosclerosismay also be present.
Sirolimus (rapamycin)
Mechanism:
Binds to the immunophilin FK binding protein (FKBP), forming a complex that inhibits mTOR. This leads to interrumption of IL-2 signal transduction, preventing G1 to S phase progression and lymphocyte proliferation.
Blocks T-cell activation and B-cell differentiation by preventing response to IL-2.
Synergistic with cyclosporine.
Clinical Use:
Immunosuppresant also used in kidney transplant rejection prophylaxis specifically.
Also used in drug-eluting stents to reduce the rate of restenosis.
Adverse Effects: Pancytopenia Insulin resistance Hyperlipidemia No nephrotoxicity Infection (e.g., respiratory or urinary tract) Peripheral edema Hypertension Stomatitis
Basiliximab
Chimeric monoclonal antibodies against alpha chain (CD25 antigen) of the IL-2 receptor of T cells
Clinical Use:
Escalation therapy of multiple sclerosis
Formerly used for the prevention of kidney rejection post transplantation (in combination with cyclosporine and glucocorticoids)
Toxicity: Tremor, shaking Hypertension Edema Allergic reaction Nausea, vomiting
2-mercaptoethanesulfonate (mesna)
Mechanism:
Deactivatesacroleinand increase the urinary excretion ofcysteine, afree radicalscavenger
Adequate hydration and frequent voiding are additional measures that can decrease the risk of developinghemorrhagic cystitis.
Clinical Use:
Prevent hemorrhagic cystitis in patients receiving chemotherapy with cyclophosphamide or ifosfamide.
Rituximab
Chimeric type
An anti-CD-20 monoclonal antibody that targets B-cells.
Clinical Use:
Rheumatoid arthritis
Immune thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura (TTP)
Multiple sclerosis
Autoimmune hemolytic anemia (AIHA)
B-cell non-Hodgkin lymphomas (NHL): e.g., chronic lymphocytic leukemia (CLL)
Symptomatic Waldenstrom macroglobulinemia
Adverse Effects:
Increase risk of progressive multifocal leukoencephalopathy.
Romiplostim
Mechanism:
Thrombopoietin agonist that increases platelet production by stimulating megakaryocytes in the bone marrow.
Clinical Use:
ITP and in certain thrombocytopenias of other origins.
Cyclosporine
Mechanism: Calcineurin inhibitor Binds cyclophilin. Blocks T-cell activation by preventing IL-2 transcription. Suppress cell mediated immunity
Clinical Use:
Immunosuppresant also used for psoriasis and rheumatoid arthritis. Transplant rejection prophylaxis (in combination with other immunosuppresants)
Toxicity:
Nephrotoxicity, hypertension, hyperlipidemia, tremors, hyperuricemia, neurotoxicity, gingival hyperplasia, hypertrichosis, hirsutism, elevated liver enzymes.
Highly nephrotoxic, especially in higher doses or in patients with decreased renal function.
Decrease in P-170-related multidrug resistance (e.g., in AML); increase in the toxic side effects of the cytostatic agent
Increase in the risk of squamous cell carcinoma by 50% in patients who are on simultaneous treatment with PUVA during psoriasis treatment
Pimecrolimus
Mechanism:
Calcineurin inhibitor
Binds FK506 binding protein (FKBP).
Blocks the translocation of nuclear factor of activated T-cells (NFAT), resulting in reduced transcription of IL-2.
Blocks T-cell activation by preventing IL-2 transcription.
Suppress cell mediated immunity
Clinical Use:
Indications for topical administration include immune-mediated disorders, such as atopic dermatitis and cutaneous graft versus host disease.
Toxicity:
Similar to cyclosporine (nephrotoxicity, hypertension, hyperlipidemia, neurotoxicity), No gingival hyperplasia or hirsutism
Increase risk of diabetes and neurotoxicity
Highly nephrotoxic, especially in higher doses or in patients with decreased renal function.
Everolimus
Mechanism:
Binding to FKBP → inhibition of mTOR kinase → inhibition of the IL-2-mediated cell cycle → ↓ response to IL-2 → ↓ T-cell activation and B-cell differentiation → ↓ IgM, IgG, and IgA production
Prevent G1 to S phase progression and lymphocyte proliferation.
Suppress cell mediated and humoral immunity
Clinical Use:
Rejection prophylaxis in liver and renal transplant (in combination with other immunosuppressants)
Adverse Effects: Pancytopenia Insulin resistance Hyperlipidemia No nephrotoxicity Infection (e.g., respiratory or urinary tract) Peripheral edema Hypertension Stomatitis
Cyclophosphamide
Mechanism:
Alkylating agent
Cross-link DNA at guanine → cross-linking and strand breaks → impaired DNA synthesis
Require bioactivation by liver.
A nitrogen mustard.
Suppress cell mediated and humoral immunity
Clinical Use:
Solid tumors, leukemia, lymphomas, rheumatic disease (eg, SLE, granulomatosis with polyangiitis), autoimmune hemolytic anemias
Adverse Effects:
Myelosuppression; SIADH; Fanconi syndrome (ifosfamide); hemorrhagic cystitis and bladder cancer, prevented with mesna (sulfhydryl group of mesna binds toxic metabolites) and adequate hydration.
Infliximab
Chimeric anti-TNF-α monoclonal antibody
TNF-α inhibition
Clinical Use:
Refractory-therapy for chronic inflammatory systemic diseases
Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis, psoriatic arthritis
Crohn disease, ulcerative colitis (except for etanercept, which is not effective in the treatment of inflammatory bowel disease)
Adverse Effects:
Predisposition to infection, including reactivation of latent TB, since TNF is important in granuloma formation and stabilization.
Can also lead to drug-induced lupus
Contraindications to anti-TNF-α treatment:
Pregnancy
Immunosuppressed individuals
Systemic or localized infections
Chronic infections, particularly tuberculosis (rule out latent tuberculosis before starting therapy (the activity of TNF-α plays a major role in formation and stabilization of granulomas against Mycobacterium tuberculosis)).
Multiple sclerosis (Studies have shown that anti-TNF-α treatment has a negative effect on patient outcome and accelerates disease progression.)
Malignancy (increased risk of various malignancies, particularly lymphomas)
Moderate to severe heart failure (NYHA class III/IV)
Adalimumab
Humanized anti-TNF-α monoclonal antibody
TNF-α inhibition
Clinical Use:
Refractory-therapy for chronic inflammatory systemic diseases
Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis, psoriatic arthritis
Crohn disease, ulcerative colitis (except for etanercept, which is not effective in the treatment of inflammatory bowel disease)
Adverse Effects:
Predisposition to infection, including reactivation of latent TB, since TNF is important in granuloma formation and stabilization.
Can also lead to drug-induced lupus.
Contraindications to anti-TNF-α treatment:
- Pregnancy
- Immunosuppressed individuals
- Systemic or localized infections
- Chronic infections, particularly tuberculosis (rule out latent tuberculosis before starting therapy (the activity of TNF-α plays a major role in formation and stabilization of granulomas against Mycobacterium tuberculosis)).
- Multiple sclerosis (Studies have shown that anti-TNF-α treatment has a negative effect on patient outcome and accelerates disease progression.)
- Malignancy (increased risk of various malignancies, particularly lymphomas)
- Moderate to severe heart failure (NYHA class III/IV)
Golimumab
Humanized anti-TNF-α monoclonal antibody
TNF-α inhibition
Clinical Use:
Refractory-therapy for chronic inflammatory systemic diseases
Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis, psoriatic arthritis
Crohn disease, ulcerative colitis (except for etanercept, which is not effective in the treatment of inflammatory bowel disease)
Adverse Effects:
Predisposition to infection, including reactivation of latent TB, since TNF is important in granuloma formation and stabilization.
Can also lead to drug-induced lupus.
Certolizumab
Humanized anti-TNF-α monoclonal antibody
TNF-α inhibition
Clinical Use:
Refractory-therapy for chronic inflammatory systemic diseases
Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis, psoriatic arthritis
Crohn disease, ulcerative colitis (except for etanercept, which is not effective in the treatment of inflammatory bowel disease)
Adverse Effects:
Predisposition to infection, including reactivation of latent TB, since TNF is important in granuloma formation and stabilization.
Can also lead to drug-induced lupus.
Etanercept
Fusion protein synthesized by recombinant DNA
Etanercept is not a monoclonal antibody but a decoy receptor that binds to TNF-α and IgG1 Fc. This leads to a reduction of the effect of naturally present TNF. Etanercept is therefore a TNF inhibitor.
Clinical Use:
Refractory-therapy for chronic inflammatory systemic diseases
Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis, psoriatic arthritis
Crohn disease, ulcerative colitis (except for etanercept, which is not effective in the treatment of inflammatory bowel disease)
Adverse Effects:
Predisposition to infection, including reactivation of latent TB, since TNF is important in granuloma formation and stabilization.
Can also lead to drug-induced lupus.
Contraindications to anti-TNF-α treatment:
Pregnancy
Immunosuppressed individuals
Systemic or localized infections
Chronic infections, particularly tuberculosis (rule out latent tuberculosis before starting therapy (the activity of TNF-α plays a major role in formation and stabilization of granulomas against Mycobacterium tuberculosis)).
Multiple sclerosis (Studies have shown that anti-TNF-α treatment has a negative effect on patient outcome and accelerates disease progression.)
Malignancy (increased risk of various malignancies, particularly lymphomas)
Moderate to severe heart failure (NYHA class III/IV)
Panitumumab
Mechanism:
Humanized monoclonal antibodies against EGFR.
Clinical Use:
Stage IV colorectal cancer (wiId-type KRAS), head and neck cancer.
Adverse Effects:
Rash, elevated LFTs, diarrhea.
Cetuximab
Mechanism:
Chimeric monoclonal antibodies against Epidermal growth factor receptor (EGFR inhibitor)
Clinical Use:
Stage IV colorectal cancer (wiId-type KRAS), head and neck cancer.
Adverse Effects:
Rash, elevated LFTs, diarrhea.
Alemtuzumab
Target:
Humanized monoclonal antibodies against CD52
On binding to CD52, initiates a direct cytotoxic effect through complement fixation and antibody-dependent, cell mediated cytotoxicity.
Clinical Use:
Chronic lymphoid leukemia (CLL)
Escalation therapy of multiple sclerosis
Natalizumab
Target:
Humanized monoclonal antibodies against α4-integrin (important for WBC adhesion and migration)
Clinical Use:
Escalation therapy of multiple sclerosis
Crohn disease
Risk of PML in patients with JC virus
Omalizumab
Mechanism:
Humanized monoclonal antibodies against IgE
Binds mostly unbound serum IgE and blocks binding to FcεRI.
Clinical Use:
Severe persistent allergic asthma (resistant to inhaled steroids and long-acting β2-agonists) with ↑ IgE
Abciximab
Chimeric monoclonal antibodies against GP IIb/IIIa receptors
Clinical Use:
Antiplatelet agent, especially for patients undergoing percutaneous coronary intervention
Muromonab
Mouse-antibody against CD3 from T cells to trigger apoptosis, reducing T lymphocyte count and IL-2 activity
There is no direct effect on B lymphocytes, but B lymphocyte activity is reduced due to decreased activation by T lymphocytes.
Clinical Use:
Steroid-resistant acute rejection post transplantation
Daclizumab
Humanized monoclonal antibodies against alpha chain (CD25 antigen) of the IL-2 receptor of T cells
Clinical Use:
Escalation therapy of multiple sclerosis
Formerly used for the prevention of kidney rejection post transplantation (in combination with cyclosporine and glucocorticoids)
Adverse Effects:
Rash, dermatitis
Formation of anti-drug antibodies (especially for adalimumab and infliximab): can manifest with a decrease in clinical response (e.g., recurrence of symptoms), low drug levels, and/or allergic reactions.
Flu-like symptoms
↑ ALT, ↑ AST
Lymphadenopathy
Infections (e.g., nasopharyngitis)
Gastrointestinal symptoms (e.g., diarrhea)
Leukocytosis or leukopenia, thrombocytopenia, anemia
Depression
Trastuzumab
Humanized monoclonal antibodies against HER2/neu (c-erbB2), a tyrosine kinase receptor
Inhibits HER2-initiated cellular signaling and antibody-dependent cytotoxicity
Clinical Use:
HER2/neu-positive breast cancer
Stomach cancer with overexpression of HER2/neu
Adverse Effects:
Dilated cardiomyopathy
Cardiotoxicity because HER2 signaling plays a rone in minimizing oxidative stress on cardiomyocytes and preserving cardiomyocyte function. Decrease in myocardial contractility without cardiomyocyte destruction or myocardial fibrosis.
Bevacizumab
Humanized monoclonal antibodies against VEGF (inhibits angiogenesis)
Clinical Use: Neovascular (wet) age-related macular degeneration (off-label use in the US), macular edema Proliferative diabetic retinopathy Solid tumors Non-small cell lung cancer Colorectal cancer Renal cell carcinoma
Adverse Effects: Gastrointestinal perforation Hemorrhages (e.g., GI bleeding) Wound healing complications Thrombosis
Eculizumab
Humanized monoclonal antibodies against complement protein C5
Clinical Use:
Paroxysmal nocturnal hemoglobinuria
Adverse Effects:
Loss of the rapid complement-mediated killing of Gram negative bacteria, especially Neisseria meningitidis. Therefore, patients should be immunized against N meningitidis and be given appropiate antibiotic prophylaxis (eg, penicillin).
