Chapter IV Immunopharmacology YEAR III Pharm.D Dr. V. Chitra. The Immune Response - why and how ?...
Transcript of Chapter IV Immunopharmacology YEAR III Pharm.D Dr. V. Chitra. The Immune Response - why and how ?...
The Immune Response - why and how ?
Discriminate: Self / Non selfDestroy:
Infectious invadersDysregulated self (cancers)
Immunity:Innate, NaturalAdaptive, Learned
Who are involved ?
InnateComplementGranulocytesMonocytes/macrophagesNK cellsMast cellsBasophils
Adaptive:B and T lymphocytesB: antibodiesT : helper, cytolytic, suppressor.
Immunosuppressants
Organ transplantationAutoimmune diseases
Life long useInfection, cancersNephrotoxicityDiabetogenic
Problem
ImmunosuppressantsGlucocorticoids Calcineurin inhibitors
CyclosporineTacrolimus
Antiproliferative / antimetabolic agentsSirolimusEverolimusAzathioprineMycophenolate MofetilOthers – methotrexate, cyclophosphamide, thalidomide and chlorambucil
AntibodiesAntithymocyte globulinAnti CD3 monoclonal antibody
Muromonab
Anti IL-2 receptor antibody –Daclizumab, basiliximab
Anti TNF alpha – infliximab, etanercept
Glucocorticoids
Induce redistribution of lymphocytes –decrease in peripheral blood lymphocyte counts Intracellular receptors – regulate gene transcription Down regulation of IL-1, IL-6Inhibition of T cell proliferation Neutrophils, Monocytes display poor chemotaxisBroad anti-inflammatory effects on multiple components of cellular immunity
USES - Glucocorticoids
Transplant rejectionGVH – BM transplantationAutoimmune diseases – RA, SLE, Hematological conditionsPsoriasisInflammatory Bowel Disease, Eye conditions
Toxicity
Growth retardationAvascular Necrosis of BoneRisk of InfectionPoor wound healingCataractHyperglycemiaHypertension
Calcineurin inhibitors
CyclosporineTacrolimus
Most effective immunosuppressive drugsTarget intracellular signaling pathwaysBlocks Induction of cytokine genes
CyclosporineMore effective against T-cell dependent immune mechanisms – transplant rejection, autoimmunityIV, Oral
UsesOrgan transplantation: Kidney, Liver, HeartRheumatoid arthritis, IBD, uveitisPsoriasisAplastic anemiaSkin Conditions- Atopic dermatitis, Alopecia Areata, Pemphigus vulgaris, Lichen planus, Pyoderma gangrenosum
Toxicity : Cyclosporine
Renal dysfunctionTremorHirsuitismHypertensionHyperlipidemiaGum hyperplasiaHyperuricemia – worsens goutCalcineurin inhibitors + Glucocorticoids = Diabetogenic
Drug Interaction : Cyclosporine
CYP 3A4Inhibitors: CCB, Antifungals, Antibiotics, HIV PI, Grape juiceInducers: Rifampicin, Phenytoin
Additive nephrotoxicity: NSAIDs
Tacrolimus
Inhibits T-cell activation by inhibiting calcineurinUse
Prophylaxis of solid-organ allograft rejection
Toxicity - TacrolimusNephrotoxicityNeurotoxicity-Tremor, headache, motor disturbances, seizuresGI ComplaintsHypertensionHyperglycemiaRisk of tumors, infections
Drug interactionSynergistic nephrotoxicity with cyclosporineCYP3A4
Antiproliferative and Antimetabolic drugs
SirolimusEverolimusAzathioprineMycophenolate MofetilOthers:
MethotrexateCyclophosphamideThalidomideChlorambucil
Sirolimus
Inhibits T-cell activation and ProliferationComplexes with an immunophilin, Inhibits a key enzyme in cell cycle progression – mammalian target of rapamycin (mTOR)
SirolimusUses
Prophylaxis of organ transplant rejection along with other drugs
ToxicityIncrease in serum cholesterol, TriglyceridesAnemiaThrombocytopeniaHypokalemiaFeverGI effects Risk of infection, tumors
Drug Interactions: CYP 3A4
Everolimus
Shorter half life compared to sirolimusShorter time taken to reach steady stateSimilar toxicity, drug interactions
AzathioprinePurine antimetaboliteIncorporation of false nucleotide
6 Thio-IMP 6Thio-GMP 6Thio-GTP
Inhibition of cell proliferationImpairment of lymphocyte function
UsesPrevention of organ transplant rejectionRheumatoid arthritis
Toxicity - Azathioprine
Bone marrow suppression-leukopenia, thrombocytopenia, anemiaIncreased susceptibility to infectionHepatotoxicityAlopeciaGI toxicity
Drug interaction: Allopurinol
Mycophenolate Mofetil
Prodrug Mycophenolic acid Inhibits IMPDH – enzyme in guanine synthesisT, B cells are highly dependent on this pathway for cell proliferationSelectively inhibits lymphocyte proliferation, function – Antibody formation, cellular adhesion, migration
Uses - Mycophenolate Mofetil
Prophylaxis of transplant rejectionCombination: Glucocorticoids
Calcineurin Inhibitors
ToxicityGI, Hematological
Diarrhea, Leucopenia
Risk of Infection
Drug Interaction
Decreased absorption when co-administered with antacidsAcyclovir, Gancyclovir compete with mycophenolate for tubular secretion
FTY720
S1P-R agonist – sphingosine 1 receptorReduce recirculation of lymphocytes from lymphatic system to blood and peripheral tissues“Lymphocyte homing” – periphery into lymph nodeProtects graft from T-cell-mediated attack UsesCombination immunosuppression therapy in prevention of acute graft rejection
Antibodies
Antithymocyte GlobulinMonoclonal antibodies
Anti-CD3 Monoclonal antibody (Muromonab-CD3)Anti-IL-2 Receptor antibody (Daclizumab, Basiliximab)Campath-1H (Alemtuzumab)
Anti-TNF AgentsInfliximabEtanerceptAdalimumab
LFA-1 Inhibitor (lymphocyte function associated)Efalizumab
Anti-thymocyte Globulin
Purified gamma globulin from serum of rabbits immunized with human thymocytesCytotoxic to lymphocytes & block lymphocyte function
UsesInduction of immunosuppression –transplantationTreatment of acute transplant rejection
ToxicityHypersensitivity Risk of infection, Malignancy
Anti-CD3 Monoclonal Antibody
Muromonab-CD3Binds to CD3, a component of T-cell receptor complex involved in
antigen recognitioncell signaling & proliferation
Muromonab-CD3
Antibody treatment
Rapid internalization of T-cell receptor
Prevents subsequent antigen recognition
Uses
Treatment of acute organ transplant rejection
Toxicity“Cytokine release syndrome”High fever, Chills, Headache, Tremor, myalgia, arthralgia, weaknessPrevention: Steroids
Anti-IL-2 Receptor Antibodies
Daclizumab and BasiliximabBind to IL-2 receptor on surface of activated T cells Block IL-2 mediated T-cell activation
UsesProphylaxis of Acute organ rejection
ToxicityAnaphylaxis, Opportunistic Infections
Campath-1H (Alemtuzumab)
Targets CD52 – expressed on lymphocytes, monocytes, MacrophagesExtensive lympholysis – Prolonged T & B cell depletion
UsesRenal transplantation
Infliximab
UsesRheumatoid arthritisChron’s disease – fistulaePsoriasisPsoriatic arthritis Ankylosing spondylosis
ToxicityInfusion reaction – fever, urticaria, hypotension, dyspnoeaOpportunistic infections – TB, RTI, UTI
EtanerceptFusion proteinLigand binding portion of Human TNF-αreceptor fused to Fc portion of human IgG1
UsesRheumatoid arthritis
LFA-1 Inhibitor - Efalizumab
Monoclonal Ab Targeting Lymphocyte Function Associated AntigenBlocks T-cell Adhesion, Activation, Trafficking
UsesOrgan transplantationPsoriasis
Sites of Action of Selected Immunosuppressive Agents on T-Cell Activation
DRUG SITE OF ACTIONGlucocorticoids Glucocorticoid response elements in
DNA (regulate gene transcription)Muromonab- CD3T-cell receptor complex (blocks
antigen recognition)Cyclosporine Calcineurin (inhibits phosphatase
activity)Tacrolimus Calcineurin (inhibits phosphatase
activity)Azathioprine Deoxyribonucleic acid (false
nucleotide incorporation)Mycophenolate Mofetil Inosine monophosphate
dehydrogenase (inhibits activity)Daclizumab, Basiliximab IL-2 receptor (block IL-2-mediated
T-cell activation)Sirolimus Protein kinase involved in cell-cycle
progression (mTOR) (inhibits activity)
Levamisole
AntihelminthicRestores depressed immune function of B, T cells, Monocytes, MacrophagesAdjuvant therapy with 5FU in colon cancer
ToxicityAgranulocytosis
Thalidomide
Birth defectContraindicated in women with childbearing potentialEnhanced T-cell production of cytokines – IL-2, IFN-γNK cell-mediated cytotoxicity against tumor cells
USE:Multiple myeloma
Bacillus Calmette-Guerin
Live, attenuated culture of BCG strain of Mycobacterium BovisCarcinoma Bladder
Adverse Effects HypersensitivityShockChills
Interferons
AntiviralImmunomodulatory activityBind to cell surface receptors –initiate intracellular events
Enzyme inductionInhibition of cell proliferationEnhancement of immune activitiesIncreased Phagocytosis
Interferon alpha-2b
Hairy cell leukemiaMalignant melanomaKaposi sarcomaHepatitis B
Adverse reactionsFlu-like symptoms – fever, chills, headacheCVS- hypotension, ArrhythmiaCNS- depression, confusion
Interleukin-2 (aldesleukin)
Proliferation of cellular immunity –Lymphocytosis, eosinophilia, release of multiple cytokines – TNF, IL-1, IFN-γ
UsesMetastatic renal cell carcinomaMelanomaToxicityCardiovascular: capillary leak syndrome, Hypotension
Active immunization
VaccinesAdministration of antigen as a whole, killed organism, or a specific protein or peptide constituent of an organismBooster dosesAnticancer vaccines – immunizing patients with APCs expressing tumor antigen.
Immune Globulin
IndicationsIndividual is deficient in antibodies – immunodeficiencyIndividual is exposed to an agent, inadequate time for active immunization
RabiesHepatitis B
Nonspecific immunoglobulinsAntibody-deficiency disorders
Specific immune globulinsHigh titers of desired antibodyHepatitis B, Rabies, Tetanus