Page 1Page 2Page 3Page 4Page 5Page 6Page 7Page 8Page 91PHARMACOLOGY OF IMMUNOSUPPRESSIVE AND ANTIVIRAL DRUGSI. Immunosuppressive AgentsA. Four major classes of agents employed in immunosuppressive therapy1. Corticosteroids2. Cytotoxic Agents3. T-cell suppressive agents4. AntibodiesB. Simplified model of the immune responseC. Corticosteroids: Prednisone (DELTASONE) and Prednisolone (HYDELTRASOL)Mechanisms of actiona. Lysis of lymphocytesb. Suppress mitosis of lymphocytesD. Cytotoxic Agents: Cyclophosphamide and Azathioprine (IMURAN)Mechanism of action: suppress bone marrow function21. Cyclophosphamidea. Primarily suppresses B-cell production; lowers humoral immunitya. Used to treat severe rheumatoid arthritisb. Not normally used for graft rejection2. Azathioprinea Primarily suppresses T-cell productionb. Used for graft rejectionc. Normally used in combination with corticosteroids3. Mycophenolate Mofetil (CELLCEPT)a. Mechanism of action: inhibits inosine monophosphate dehydrogenase; an enzymerequired for de novo purine synthesisb. Selective because T and B cells rely on de novo pathwayc. Suppresses lymphocyte proliferation and B-cell antibody productiond. Can be used to inhibit transplant rejectionE. T-Cell Suppressor Agents1. Cyclosporine (SANDIMMUNE) and Tacrolimus (PROGRAF, FK506)a. Mechanism of action: block proliferative response of T-cells to antigen by inhibitingcalcineurin activityb. Have little myelotoxicityc. Used in combination with corticosteroids for organ transplantsd. Variable oral absorptione. Extensively metabolizedf. Metabolite excreted in urineg. Cause renal toxicity in up to 75% of patients; frequently responsible for stoppingtherapy3F. Antibodies 1. Selective antibodies against lymphocytes and thymocytes have been used asimmunosuppressantsa. Antithymocyte Globulin (ATGAM)i. Polyclonal antibody, binds T-lymphocytesii. Primary use: graft rejection during acute phaseiii. Side effects: allergic reactions; consequences of immune suppressionb. Muromonoab-CD3 (ORTHOCLONE OKT3)i. Monoclonal antibody, binds to T-lymphocytesii. Primary use: acute graft rejectioniii. Side effects: cytokine release syndrome (can be fatal); allergic reactions;consequences of immune suppressionII. Antiviral AgentsA. Background1. Three approaches to antiviral therapya. Immunological controlb. Chemotherapyc. Stimulation of natural host resistance mechanismsB. Viral replication4C. Anti-influenza Agents1. Amantadine (Symmetrel) and Rimantadinea. Primary use: respiratory infections caused by influenza Ab. Mechanism of action: inhibits viral uncoatingc. Good oral absorption; excreted by kidney unmetabolizedd. Minor dose-related CNS effects (less with Rimantadine) and GI effects2. Zanamivir & Oseltamivira. Primary use: Treatment of uncomplicated influenza infection; types A & B b. Mechanism of action: Inhibit neuraminidase which is required for viralreplication and releasec. Side effects: Well tolerated D. Anti-herpes and anti-CMV AgentsNucleoside Analogs:S Analogs of naturally occuring nucleosidesS Must be converted to the triphosphate analog in order to be activeS Triphosphate competes with native nucleoside for incorporation into viral DNAS Triphosphate inhibits viral DNA polymeraseS Frequently cause DNA chain termination Anti-herpes Agents1. Acyclovir (Zovirax)a. Guanosine analog used against herpes simplex 1 and 2 and varicella-zosterb. Mechanism of action: the dGTP analog and is incorporated into DNA and causesDNA chain termination; the terminated chain inhibits viral DNA polymerase5c. Primary uses:Topically: primary mucotaneous herpes; genital herpes (less effective thansystemic); ineffective in recurrent herpes simplex keratitisOrally: severe primary & recurrent genital herpes; varicella-zoster (children)Intravenous: Treatment of choice for herpes encephalitis and neonatal herpes;severe mucotaneous herpesSide effects: local irritation with topical use; headache, nausea and vomiting withoral use; and nephrotoxicity with intravenous useResistance: Lack of thymidine kinase for activation2. Valacyclovir: Analog of acyclovir; converted to acyclovir in the body3. Ganciclovira. Structurally related to acyclovirb. Mechanism of action: Same as acyclovirc. Primary uses: 100x more active than acyclovir against cytomegalovirus (CMV)d. Side effects: Can produce serious myelosuppression4. Penciclovir and Famciclovira. Mechanism: Converted to the triphosphate form which inhibits viral DNApolymeraseb. Penciclovir is used topically for genital herpesc. Famciclovir is given orally and is converted to penciclovir in the bodyd. Primary uses: recurrent genital herpes, localized herpes zoster and acute zostere. Side effects: headache, diarrhea and nausea Other Nucleoside Analogs: 5. Cidofovira. Cytosine analogb. Primary uses: I.V. use approved for CMV retinitisc. Side effects: Nephrotoxicity 6. Idoxuridinea. Iodinated thymidine analogb. Primary use: herpes keratitis (topically)c. Side effects: Pain, inflammation7. Vidarabinea. Adenosine analogb. Primary uses: I.V. for herpes encephalitis and neonatal herpes (most of uses havebeen replaced by acyclovir)c. Side effects: Nephrotoxicity68. Trifluridinea. Fluorinated pyrimidine nucleoside analogb. Primary use: Topically effective against herpes simplex 1 & 2c. Side effects: local irritationOther Derivatives:1. Foscarneta. Synthetic non-nucleoside analog of pyrophosphateb. Mechanism: Inhibits herpes DNA polymerase, RNA polymerase and HIV reversetranscriptase by directly binding to the pyrophosphate binding site;does not require prior activationc. Primary uses: Given I.V. for acyclovir resistant herpes and CMV retinitisd. Side effects: Nephrotoxicity, CNS toxicity2. Fomivirsena. Antisense oligonucleotideb. Mechanism: Binds to mRNA; inhibits protein synthesis and viral replicationc. Primary use: Intravitreal injection for CMV retinitis in AIDS patientsd. Side effects: Increased ocular pressure, ititis & vitreitis E. Anti-HIV Agents Nucleoside Reverse Transcriptase Inhibitors (NRTIs):S Are analogs of naturally occuring nucleotidesS Require phosphorylation to triphosphate formS Competitively inhibit HIV-1 (and usually HIV-2) reverse transcriptase (RT)S Are incorporated into viral DNA and cause chain terminationS Net effect is inhibition of viral DNA synthesisS Block acute infection but are much less active against chronically infected cellsS Usually used in combination with other anti-HIV drugs S Resistance usually due to viral mutation1. Zidovudine