Chapter IV
Immunopharmacology
YEAR III Pharm.D
Dr. V. Chitra
The Immune Response - why and how ?
{ Discriminate: Self / Non self
{ Destroy:
z Infectious invaders
z Dysregulated self (cancers)
{ Immunity:
z Innate, Natural
z Adaptive, Learned
Who are involved ?
{ Innate { Adaptive:
z Complement z B and T
z Granulocytes lymphocytes
z Monocytes/macrophages z B: antibodies
z NK cells z T : helper,
z Mast cells cytolytic,
suppressor.
z Basophils
IMMUNE MODIFIERS
Immunosuppressants Immunostimulants
? Immune tolerance
Immunosuppressants
{ Organ transplantation
Problem
{ Autoimmune diseases
{ Life long use
{ Infection, cancers
{ Nephrotoxicity
{ Diabetogenic
Immunosuppressants
{ Glucocorticoids
{ Calcineurin inhibitors
z Cyclosporine
z Tacrolimus
{ Antiproliferative / antimetabolic agents
z Sirolimus
z Everolimus
z Azathioprine
z Mycophenolate Mofetil
z Others – methotrexate, cyclophosphamide,
thalidomide and chlorambucil
{ Antibodies
z Antithymocyte globulin
z Anti CD3 monoclonal antibody
{ Muromonab
z Anti IL-2 receptor antibody –
{ Daclizumab, basiliximab
z 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-6
{ Inhibition of T cell proliferation
{ Neutrophils, Monocytes display poor
chemotaxis
{ Broad anti-inflammatory effects on
multiple components of cellular immunity
USES - Glucocorticoids
{ Transplant rejection
{ GVH – BM transplantation
{ Autoimmune diseases – RA, SLE,
Hematological conditions
{ Psoriasis
{ Inflammatory Bowel Disease, Eye
conditions
Toxicity
{ Growth retardation
{ Avascular Necrosis of Bone
{ Risk of Infection
{ Poor wound healing
{ Cataract
{ Hyperglycemia
{ Hypertension
Calcineurin inhibitors
z Cyclosporine
z Tacrolimus
{ Most effective immunosuppressive
drugs
{ Target intracellular signaling
pathways
{ Blocks Induction of cytokine genes
Cyclosporine
{ More effective against T-cell dependent
immune mechanisms – transplant rejection,
autoimmunity
{ IV, Oral
Uses
{ Organ transplantation: Kidney, Liver, Heart
{ Rheumatoid arthritis, IBD, uveitis
{ Psoriasis
{ Aplastic anemia
{ Skin Conditions- Atopic dermatitis, Alopecia
Areata, Pemphigus vulgaris, Lichen planus,
Pyoderma gangrenosum
Toxicity : Cyclosporine
{ Renal dysfunction
{ Tremor
{ Hirsuitism
{ Hypertension
{ Hyperlipidemia
{ Gum hyperplasia
{ Hyperuricemia – worsens gout
{ Calcineurin inhibitors + Glucocorticoids =
Diabetogenic
Drug Interaction : Cyclosporine
{ CYP 3A4
z Inhibitors: CCB, Antifungals,
Antibiotics, HIV PI, Grape juice
z Inducers: Rifampicin, Phenytoin
{ Additive nephrotoxicity: NSAIDs
Tacrolimus
{ Inhibits T-cell activation by
inhibiting calcineurin
{ Use
z Prophylaxis of solid-organ allograft
rejection
Toxicity - Tacrolimus
{ Nephrotoxicity
{ Neurotoxicity-Tremor, headache, motor
disturbances, seizures
{ GI Complaints
{ Hypertension
{ Hyperglycemia
{ Risk of tumors, infections
{ Drug interaction
z Synergistic nephrotoxicity with cyclosporine
z CYP3A4
Antiproliferative and Antimetabolic
drugs
{ Sirolimus
{ Everolimus
{ Azathioprine
{ Mycophenolate Mofetil
{ Others:
z Methotrexate
z Cyclophosphamide
z Thalidomide
z Chlorambucil
Sirolimus
{ Inhibits T-cell activation and
Proliferation
{ Complexes with an immunophilin,
Inhibits a key enzyme in cell cycle
progression – mammalian target of
rapamycin (mTOR)
Sirolimus
Uses
{ Prophylaxis of organ transplant rejection
along with other drugs
Toxicity
{ Increase in serum cholesterol, Triglycerides
{ Anemia
{ Thrombocytopenia
{ Hypokalemia
{ Fever
{ GI effects
{ Risk of infection, tumors
{ Drug Interactions: CYP 3A4
Everolimus
{ Shorter half life compared to
sirolimus
{ Shorter time taken to reach steady
state
{ Similar toxicity, drug interactions
Azathioprine
{ Purine antimetabolite
{ Incorporation of false nucleotide
6 Thio-IMP 6Thio-GMP 6Thio-GTP
{ Inhibition of cell proliferation
{ Impairment of lymphocyte function
Uses
{ Prevention of organ transplant
rejection
{ Rheumatoid arthritis
Toxicity - Azathioprine
{ Bone marrow suppression-
leukopenia, thrombocytopenia,
anemia
{ Increased susceptibility to infection
{ Hepatotoxicity
{ Alopecia
{ GI toxicity
{ Drug interaction: Allopurinol
Mycophenolate Mofetil
{ Prodrug Æ Mycophenolic acid
{ Inhibits IMPDH – enzyme in guanine
synthesis
{ T, B cells are highly dependent on
this pathway for cell proliferation
{ Selectively inhibits lymphocyte
proliferation, function – Antibody
formation, cellular adhesion,
migration
Uses - Mycophenolate Mofetil
{ Prophylaxis of transplant rejection
{ Combination: Glucocorticoids
Calcineurin Inhibitors
{ Toxicity
{ GI, Hematological
z Diarrhea, Leucopenia
{ Risk of Infection
Drug Interaction
{ Decreased absorption when co-
administered with antacids
{ Acyclovir, Gancyclovir compete with
mycophenolate for tubular secretion
FTY720
{ S1P-R agonist – sphingosine 1 receptor
{ Reduce recirculation of lymphocytes from
lymphatic system to blood and peripheral
tissues
{ “Lymphocyte homing” – periphery into
lymph node
{ Protects graft from T-cell-mediated attack
Uses
{ Combination immunosuppression therapy
in prevention of acute graft rejection
Toxicity
{ Lymphopenia
{ Negative chronotropic effect
z S1P-receptor on human atrial myocytes
Antibodies
{ Against
lymphocyte cell-
surface antigens
{ Polyclonal /
Monoclonal
Antibodies
{ Antithymocyte Globulin
{ Monoclonal antibodies
z Anti-CD3 Monoclonal antibody (Muromonab-CD3)
z Anti-IL-2 Receptor antibody (Daclizumab,
Basiliximab)
z Campath-1H (Alemtuzumab)
{ Anti-TNF Agents
z Infliximab
z Etanercept
z Adalimumab
{ LFA-1 Inhibitor (lymphocyte function associated)
z Efalizumab
Anti-thymocyte Globulin
{ Purified gamma globulin from serum of
rabbits immunized with human thymocytes
{ Cytotoxic to lymphocytes & block lymphocyte
function
Uses
{ Induction of immunosuppression –
transplantation
{ Treatment of acute transplant rejection
Toxicity
{ Hypersensitivity
{ Risk of infection, Malignancy
Anti-CD3 Monoclonal Antibody
{ Muromonab-CD3
{ Binds to CD3, a component of T-cell
receptor complex involved in
z antigen recognition
z cell 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,
weakness
{ Prevention: Steroids
Anti-IL-2 Receptor Antibodies
{ Daclizumab and Basiliximab
{ Bind to IL-2 receptor on surface of
activated T cells Æ Block IL-2 mediated
T-cell activation
Uses
{ Prophylaxis of Acute organ rejection
Toxicity
{ Anaphylaxis, Opportunistic Infections
Campath-1H (Alemtuzumab)
{ Targets CD52 – expressed on
lymphocytes, monocytes, Macrophages
{ Extensive lympholysis – Prolonged T &
B cell depletion
Uses
{ Renal transplantation
Anti-TNF Agents
{ TNF – Cytokine at site of inflammation
{ Infliximab
{ Etanercept
{ Adalimumab
Infliximab
Uses
{ Rheumatoid arthritis
{ Chron’s disease – fistulae
{ Psoriasis
{ Psoriatic arthritis
{ Ankylosing spondylosis
Toxicity
{ Infusion reaction – fever, urticaria,
hypotension, dyspnoea
{ Opportunistic infections – TB, RTI, UTI
Etanercept
{ Fusion protein
{ Ligand binding portion of Human TNF-α
receptor fused to Fc portion of human
IgG1
Uses
{ Rheumatoid arthritis
Adalimumab
Recombinant human anti-TNF mAb
Moderate to severely active crohn’s disease
LFA-1 Inhibitor - Efalizumab
{ Monoclonal Ab Targeting
Lymphocyte Function Associated
Antigen
{ Blocks T-cell Adhesion, Activation,
Trafficking
Uses
{ Organ transplantation
{ Psoriasis
Sites of Action of Selected Immunosuppressive Agents on
T-Cell Activation
DRUG SITE OF ACTION
{ Glucocorticoids 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)
Immunostimulants
{ Levamisole
{ Thalidomide
{ BCG
{ Recombinant Cytokines
z Interferons
z Interleukin-2
Levamisole
{ Antihelminthic
{ Restores depressed immune
function of B, T cells, Monocytes,
Macrophages
{ Adjuvant therapy with 5FU in colon
cancer
Toxicity
{ Agranulocytosis
Thalidomide
{ Birth defect
{ Contraindicated in women with
childbearing potential
{ Enhanced T-cell production of
cytokines – IL-2, IFN-γ
{ NK cell-mediated cytotoxicity against
tumor cells
USE:
{ Multiple myeloma
Bacillus Calmette-Guerin
{ Live, attenuated culture of BCG
strain of Mycobacterium Bovis
{ Carcinoma Bladder
Adverse Effects
z Hypersensitivity
z Shock
z Chills
Interferons
{ Antiviral
{ Immunomodulatory activity
{ Bind to cell surface receptors –
initiate intracellular events
z Enzyme induction
z Inhibition of cell proliferation
z Enhancement of immune activities
z Increased Phagocytosis
Interferon alpha-2b
{ Hairy cell leukemia
{ Malignant melanoma
{ Kaposi sarcoma
{ Hepatitis B
Adverse reactions
{ Flu-like symptoms – fever, chills,
headache
{ CVS- hypotension, Arrhythmia
{ CNS- depression, confusion
Interleukin-2 (aldesleukin)
{ Proliferation of cellular immunity –
Lymphocytosis, eosinophilia, release of
multiple cytokines – TNF, IL-1, IFN-γ
Uses
{ Metastatic renal cell carcinoma
{ Melanoma
{ Toxicity
{ Cardiovascular: capillary leak syndrome,
Hypotension
Immunization
{ Vaccines
{ Immune Globulin
{ Rho (D) Immune
Globulin
Immunization
{ Active – Stimulation with an Antigen
{ Passive – Preformed antibody
Active immunization
Vaccines
{ Administration of antigen as a
whole, killed organism, or a specific
protein or peptide constituent of an
organism
{ Booster doses
{ Anticancer vaccines – immunizing
patients with APCs expressing
tumor antigen.
Immune Globulin
Indications
{ Individual is deficient in antibodies
– immunodeficiency
{ Individual is exposed to an agent,
inadequate time for active
immunization
z Rabies
z Hepatitis B
{ Nonspecific immunoglobulins
z Antibody-deficiency disorders
{ Specific immune globulins
z High titers of desired antibody
z Hepatitis B, Rabies, Tetanus
Rho (D) Immune Globulin
{ Antibodies against Rh(D)
antigen on the surface of
RBC
{ Rh-negative women may be
sensitized to “Foreign” Rh
antigen on fetal RBC
{ Anti-RH Antibodies
produced in mother can
damage subsequent fetuses
by lysing RBC’s
{ Hemolytic disease of
newborn
