Transcript Immunosuppressants and Immunomodulatory drugs

Immunomodulators
(drugs that modulate immune response)
Dr. Kaukab Azim
Drug List
Cytotoxic Drugs
Lymphoid drugs
Azathioprine
Cyclophosphamide
Methotrexate
Corticosteroids
Antithymocyte immunoglobulin
Muromonab – CD3
Drugs acting on a
subpopulation of
immunocompetent cells
Drugs acting on cytokines
Other immunosuppressives
Cyclosporine
Tacrolimus
Sirolimus
Mycophenolate mofetil
Daclizumab
Infliximab
Etanercept
Thalidomide
RhO (D) immune globulin
Immune System
• Functions to protect the host from harmful
foreign molecules
• Inappropriate activation of immune cells can
result in autoimmune disorders
• Allograft introduction can elicit a damaging
immune response
• Immune system include two main arms
1) Cell –mediated immunity
2) Humoral (antibody –mediated immunity)
Cytokines
• Cytokines are soluble signaling proteins that
bind to cell surface receptors on a variety of
cells
• Cytokines include
– Interleukins (IL)
– Interferons (IFNs)
– Tumor Necrosis Factors (TNFs)
– Transforming Growth Factors (TGFs)
– Colony-stimulating factors (CSFs)
• IL-2 stimulates the proliferation of antigenprimed (helper) T cells.
Cell-mediated Immunity
• Activate
– NK cells (kill tumor & virus-infected cells).
– Cytotoxic T cells (kill tumor & virusinfected cells).
– Macrophages (kill bacteria).
Humoral Immunity
B-lymphocytes
TH2 produces
(interleukins) IL-4 & IL-5 which in turn
causes:
• B cells proliferation & differentiation
into
– memory B cells
– Antibody secreting plasma cells
Immunosuppressant Drugs
General Features
• Immunosuppressant drugs suppress primary immune
responses (i.e antigen processing, cell proliferation,
lymphokine synthesis, etc.) more effectively than
secondary immune responses (i.e. those related to reencountering antigen, that is those related to immunologic
memory)
• Immunosuppressant drugs are highly effective in treating
conditions such as organ transplant rejection and severe
autoimmune disorders.
• Immunosuppressant drugs work better if they are given
before rather than after the exposure of the body to the
antigen (unfortunately most autoimmune diseases are
treated after autoimmunity is established).
• Therapies with these drugs often require lifelong use, so
exposing the patient to increased risk of infections and
some cancers (lymphomas, Kaposi’s sarcoma, skin cancer).
CYCLOSPORINE
Mechanism of action
• The drug binds to cyclophilin to form a complex
which in turn binds to calcineurin, a cytoplasmic
phosphatase, and inhibits its action.
• Since calcineurin regulates the ability of a nuclear
factor of activated T cells (NFAT) to translocate to
the nucleus and increase the production of
interleukin-2, the production of IL-2 is
suppressed.
• As a consequence T-helper cells cannot
proliferate and die by apoptosis.
Pharmacokinetics
• The drug is given PO or IV.
• It is totally metabolized by the CYP3A system (its
metabolism is affected by a lot of drugs that
inhibit or induce the p450 system).
• Toxicity
• Nephrotoxicity (up to 80%).
• Neurotoxicity, including paresthesias (up to 50%)
tremor (up to 55%), hallucinations and seizures
• Hypertension (up to 50%)
• Hirsutism (common), gingival hyperplasia (up to
20%)
Therapeutic uses
Clinical uses
• Organ transplantation (to prevent rejection)
(Graft-versus-host disease).
• Selected autoimmune disorders ( psoriasis,
rheumatoid arthritis, IBD, SLE)
TACROLIMUS (FK506)
• a fungal macrolide antibiotic.
• Chemically not related to cyclosporine
• both drugs have similar mechanism of action.
• The internal receptor for tacrolimus is
immunophilin ( FK-binding protein, FK-BP).
• Tacrolimus-FKBP complex inhibits
calcineurin.
Sirolimus (Rapamycin)
Mechanism of action
• The drug resembles tacrolimus and binds to the
same intracellular Fk binding proteins. However,
whereas tacrolimus and cyclosporine block IL-2
gene transcription, sirolimus acts later to block IL2 dependent lymphocyte proliferation.
• This blockade is likely due to the inhibition of
mammalian kinase, an enzyme which is essential
for cell-cycle progression. Therefore the drug
inhibits substantially T and B cell proliferation.
Sirolimus
Pharmacokinetics
• The drug is given orally.
• It is totally metabolized by the CYP3A4 system.
Toxicity
• Hyperlipidemia (up to 50%).
• Hypertension(up to 50%).
• Anemia, leukopenia, thrombocytopenia.
Clinical uses
• Organ transplantation (to prevent rejection)
• Atopic dermatitis, psoriasis
Cytotoxic drugs
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Inhibitors of purine or pyrimidine synthesis
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(Antimetabolites):
Azathioprine
Myclophenolate Mofetil
Leflunomide
Methotrexate
AZATHIOPRINE
CHEMISTRY:
– Derivative of mercaptopurine.
– Prodrug.
– Cleaved to 6-mercaptopurine then to
6-mercaptopurine nucleotide, thioinosinic
acid (nucleotide analog).
– Inhibits de novo (new) synthesis of purines
required for lymphocytes proliferation.
– Prevents clonal expansion of both B and T
lymphocytes.
Pharmacokinetics
– 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.
Drug Interactions
– Co-administration of allopurinol with
azathioprine may lead to toxicity due to
inhibition of xanthine oxidase by allopurinol.
USES
• Acute glomerulonephritis
• Systemic lupus erythematosus
• Rheumatoid arthritis
• Crohn’ s disease.
Adverse Effects
• Bone marrow depression: leukopenia,
thrombocytopenia.
• Gastrointestinal toxicity.
• Hepatotoxicity.
• Increased risk of infections.
MYCOPHENOLATE MOFETIL
– Is a semisynthetic derivative of mycophenolic
acid from fungus source.
– Prodrug; is hydrolyzed to mycophenolic acid.
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.
Pharmacokinetics:
– Given orally, i.v. or i.m.
– rapidly and completely absorbed after oral
administration.
CLINICAL USE:
– Solid organ transplants for refractory rejection.
– Steroid-refractory hematopoietic stem cell
transplant patients.
– Combined with prednisone as alternative to
cyclosporine or tacrolimus.
– Rheumatoid arthritis, & dermatologic
disorders.
ADVERSE EFFECTS:
– GIT toxicity: > 10%. nausea, vomiting,
diarrhea, abdominal pain.
– Bone marrow suppression > 20%
Contraindicated during pregnancy
Antibodies
Block T cell surface molecules involved in
signaling immunoglobulins
– antilymphocyte globulins (ALG).
– antithymocyte globulins (ATG).
– Rho (D) immunoglobulin.
– Basiliximab
– Daclizumab
Muromonab – CD3
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Is a murine monoclonal antibody
Prepared by hybridoma technology
Directed against glycoprotein CD3 antigen
of human T cells.
Given I.V.
Metabolized and excreted in the bile.
Mechanism of action
• The drug binds to CD3 proteins on T
lymphocytes (antigen recognition site) leading
to disruption of T-lymphocyte function, their
depletion and decreased immune response.
• Prednisolone, diphenhydramine are given to
reduce cytokine release syndrome.
Uses
• Used for treatment of acute renal allograft
rejection & steroid-resistant acute allograft
• To deplete T cells from bone marrow donor
prior to transplantation.
Adverse effects
• Anaphylactic reactions (infusion related).
• Pulmonary edema
• Secondary malignancy
• Infection
• Cytokine release syndrome (Flu-like illness to
shock like reaction).
Rho (D) immune globulin
• Rho (D) is a concentrated solution of human
IgG containing higher titer of antibodies
against Rho (D) antigen of red cells.
• Given to Rh-negative mother within 24-72
hours after delivery of Rh positive baby (2 ml,
I.M.) to prevent hemolytic disease of the next
Rh positive babies (erythroblastosis fetalis).
Adverse Effects
– Local pain
– Fever
Thalidomide
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A sedative drug.
Teratogenic
Can be given orally.
Has immunomodulatory actions
Inhibits TNF-α
Reduces phagocytosis by neutrophils
Increases IL-10 production
Inhibits angiogenesis.
Used in multiple myeloma
USES
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Myeloma
Rheumatoid arthritis
Graft versus host disease.
Leprosy reactions
treatment of skin manifestations of lupus
erythematosus
CLINICAL USES OF
IMMUNOSUPPRESSIVE AGENTS
DISEASE
Autoimmune Disease:
Acute glomerulonephritis
Autoimmune haemolytic
anaemia.
AGENT USED
Prednisone,
mercaptopurine.
Cyclophosphamide.
Prednisone,
cyclophosphamide,
mercaptopurine,
azathioprine, high dose globulin.
Organ transplant:
• Renal
• Heart
Cyclosporine, Azathioprine,
Prednisone, ALG
(antilymphocyte globlin),
Tacrolimus.
• Liver
Cyclosporine, Prednisone,
Azathioprine, Tacrolimus.
• Bone marrow
Cyclosporine,
Cyclophosphamide,
Prednisone, Methotrexate,
ALG, total body radiation.
Immunostimulants
INTERFERONS
Three families:
• Type I IFNs ( IFN-α, β ):
• Acid-stable proteins
• induced by viral infections
• leukocyte produces IFN-α
• Fibroblasts & endothelial cells produce IFN-β
• Type II IFN (IFN-γ):
• Acid-labile
• Produced by Activated T lymphocytes.
Interferon Effects:
IFN- γ : Immune Enhancing
– increased antigen presentations with
macrophage, natural killer cell, cytotoxic T
lymphocyte activation
IFN- α, β :
– effective in inhibiting cellular proliferation
(more effective than IFN- γ in this regard)
INTERFERONS
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Recombinant DNA cloning technology.
Antiproliferative activity.
Antiviral action
Immunomodulatory effect.
USES:
– Treatment of certain infections e.g.
Hepatitis C (IFN- α ).
– Autoimmune diseases e.g. Rheumatoid
arthritis.
– Certain forms of cancer e.g. melanoma,
renal cell carcinoma.
– Multiple sclerosis (IFN- β): reduced rate of
exacerbation.
SE:
– Fever, chills, myelosuppression.
Aldesleukin
Mode of action
• The drug is a recombinant version of interleukin-2.
• It induces proliferation of B and T cells (including cytotoxic T cells)
and activation of natural killer cells and lymphokine-activated killer
cells.
• The mechanism of antitumor activity is unknown but is probably
related to the activation of cytotoxic T cells.
Toxicity
• Hypotension (70%),sinus tachycardia (70%), pulmonary congestion
(50%) and edema (50%).
• Acute renal failure(60%)
• Mental status changes (70%)
• Nausea/vomiting and diarrhea (70%)
• Anemia, thrombocytopenia (70%).
Clinical uses
• Renal cell carcinoma, malignant melanoma
Disease modifying anti-rheumetic
drugs (DMARDs)
• DMARDs are used in the treatment of
Rheumotoid arthritis (RA) and have been
shown to slow the course of the disease and
prevent further destruction of the joints and
involved tissues
LEFLUNOMIDE
• A prodrug
• Active metabolite undergoes enterohepatic
circulation.
• Has long duration of action.
• Can be given orally
• antimetabolite immunosuppressant.
• Pyrimidine synthesis inhibitor
• Approved only for rheumatoid arthritis
Adverse effects
1. Elevation of liver enzymes
2. Renal impairment
3. Teratogenicity
4. Cardiovascular effects (tachycardia).
Methotrexate
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a folic acid antagonist
Orally, parenterally (I.V., I.M).
Excreted in urine.
Inhibits dihydrofolate reductase required for
folic acid activation (tetrahydrofolic)
Inhibition of DNA, RNA & protein synthesis
Interferes with T cell replication.
Rheumatoid arthritis & psoriasis and Crohn
disease
Graft versus host disease
Adverse effects
– Nausea-vomiting-diarrhea
– Alopecia
– Bone marrow depression
– Pulmonary fibrosis
– Renal & hepatic disorders
Hydroxychloroquine
• Used for early, mild RA and has relatively few
side effects
• Does not slow joint damage, therefore it is
often used in combination with methotrexate
• Mechanism of action may include inhibition of
phospholipase A2 , platelet aggregation and
effects on the immune system
Gold Salts
• Cannot repair existing damage, only prevent further
injury
• Gold compounds are used infrequently due to
constant monitoring for serious toxicity
• Currently available gold preparation is auranofin,
given orally
• Auranofin is taken up by macrophages and
suppresses phagocytosis and lysosomal enzyme
activity resulting in slower progression of bone and
articular destruction
Biological therapies in RA
• IL-1 and TNF-a are proinflammatory cytokines
involved in the pathogenesis of RA
• TNF inhibitors (etanercept, adalimumab and
infliximab)
• IL-1 receptor antagonist (anakinra)
Infliximab
• Monoclonal antibody that binds specifically to
TNF-a, thereby neutralizing the cytokine
• Approved for use in combination in patients
with RA who have had inadequate response to
methotrexate monotherapy
• Not indicated for use alone, because it allows
the body to develop anti-infliximab antibodies
which reduces efficacy