Immunosuppressants

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• Immunosuppressants
• Prof. Alhaider, 1431 H
• Definition
• Clinical Uses (Organ transplants Autoimmune
  diseases)
• Pre-requisite to understand immunosuppressive
  drugs (Basic immunology).
• Review of immune system (see Table 56-1)
• Cell mediated vs humoral immunity
• Importance of cytokines
• Immunophilins
• Calcineurin

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Classification of Immunosuppressant (Based on
Mechanism of Action)

• A) Antiprolifirative Agents
• 1) Drugs Acting on Immunophilins
• a) Selective Inhibitors of Cytokine
  production ) (Calcineurin Inhibitors) (e.g
  Cyclosporine Tacrolimus)
• b) Inhibitor of cytokine function (e.g.
  Sirolimus).
• 3) Antimetabolites (Azathioprine Mycophenolate
  Mofetil)
• 4) Alkylating Agents (Cyclophosphamide)
• B) Lymphocyte Depletion Agents
• 1) Corticosteroids
• 2. Immunosuppressive Antibodies
• a) Polyclonal Antibodies (Antilymphocyte
  Globulin)
• b) Monoclonal Antibodies (Selective inhibitors
  of IL2 (Basiliximab Daclizumab)

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Immunosuppressant Classes

• Non-selective
• Corticosteroids
• Prednisone (PO) Methylprednisolone (IV)
• Antimetabolite (DNA synthesis inhibitors)
• Azathioprine Myclophenolate mofetil
• Immunoglobulins
• Anti-lymphocyte antibodies

• Selective
• Calcineurin Inhibitors
• Cyclosporine
• Tacrolimus (Rapamycin)
• Selective IL-2 Receptor antagonists
• Basiliximab, Daclizumab Infliximab
• Mamalian target of Rapamycin (mTOR) inhibitors
• Sirolimus

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Selective Inhibitors of Cytokine Production
(Drugs Acting on Immunophilins)

• 1) Cyclosporine (Cyclic peptide from Soil
  Fungus (1971)
• MOA (See Figure 40.4)
• CsA binds to cyclophillin forming a comlex
  Bind to Calcineurin dephosphorylation
  NFATc Synthesis of IL 2
  proliferation of T cells
• Thus, decreases the level of IL-2, the primary
  chemical stimulus for increasing the number of T
  lymphocytes
• Note Suppress only cell immunity with no effect
  on humoral immunity.

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• PK
• CsA available as oral (capsule) or parental (i.v)
• Oral bioavailability (20-50), it undergoes
  extensive hepatic metabolism by CytP450 (CYP3A4)
  (Affected by some drugs EXAMPLES) and mainly
  excreted in the bile.

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• Clinical Uses of Cyclosporine
• 1) Drug of choice for preventing organ transplant
  rejection in combination with steroids and other
  immunosuppressants.
• 2) Severe active rheumatoid arthritis, as
  alternative for methotrexate
• 3) Lower doses (7.5 mg/kg/d) for autoimmune
  diseases (Uveitis RA early Rx of DM 1)
• 3) Psoriasis and asthma ?.
• Side Effects (remember most immunosuppressant are
  very toxic)
• Dose-dependent nephrotoxicity ( Risk of
  Rejection) enhanced of given with other
  nephrotoxic drugs (Aminoglycosides NSADs)
• Hepatotoxicity
• Neurotoxicity as tremor and hallucination
• Infection How?
• Lymphoma and cancer How?
• Hypertension hyperlipedemia Hyperkalemia D.M
  Osteoporosis Hirsutism and gum hyperplacia (So
  What)

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• 2. Tacrolimus (FK 506)
• More potent than Cyclosporine
• MOA Similar to Cyclosporine (Calcineurin
  Antagonist) but it bind to different
  immunophilin (FKBP) Figure 40.6.
• PK Almost Similar to Cyclosporine
• Side Effects differ from Cyclosporine, that it
  ((Tac) has no hirsutism or gum hyperplasia but
  may show more hyperglycemia than cyclosporine.
• Note It is like cyclosporine, could lead to
  nephrotoxicity and hyperglycemia (more
  hyperglycemia than cyclosporine) , and
  hyperlipedemia.

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• Clinical uses of Tacrolimus
• Preferred over CsA because
• of more potency (50-100 times more potent than
  cyclosporine).
• lower rejection episodes,
• and lower doses of glucocorticoids are used with
  lower side effects
• Better first choice for woman?
• Severe refractory atopic dermatitis, local
  application of an ointment
• An ointment for psoriasis.
• 3. Sirolimus (Rapamycin Maclolides)
• MOA
• 1) Binds to the same immunophilin as Tacrolimus,
  but does not form a complex with calcineurin,
  instead, it binds to mTOR (Mammalian Target of
  Rapamycin) which is essential for many cellular
  functions (See Figure 40.6)
• 2) Potent inhibitor of B-cell proliferation and
  immunoglobulin production (humor immunity)

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• 3. Sirolimus (Rapamycin Maclolides)
• MOA
• 1) Binds to the same immunophilin as Tacrolimus,
  but does not form a complex with calcineurin,
  instead, it binds to mTOR (Mammalian Target of
  Rapamycin) which is essential for many cellular
  functions (See Figure 40.6)
• 2) Sirolimus does not affect IL-2 production,
  unlike CsA TAc, rather inhibits T-cell
  response to it (Blocks cytokine-stimulated cell
  proliferation)
• 3) Potent inhibitor of B-cell proliferation and
  immunoglobulin production (humor immunity)

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• Uses of Sirolimus
• 1) can be used together with cyclosporine (to
  increases the activity of cyclosporine for organ
  transplanted patients.
• 2) As replacement of cyclosporine if transplanted
  patient developed cancer of skin or lips.
• 3) used in cardiac catheter stint to prevent
  stenosis??
• 4) as an ointment for atopic dermatitis and
  psoriasis
• Side Effects
• 1) Pneumonitis
• 2) hyperlipedemia (more then calcineurin-antagoni
  st)

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• Antiproliferatives (Continue)
• 2. Antimetabolites (Cytotoxic Drugs)
• 1) Azathioprine is a prodrug of mercaptopurine.
• Cytotoxic, rarely used as chemotherapeutic drug,
  but commonly used for immunosuppression.
• It is a pro-drug converted in the body to the
  active metabolite, 6-mercaptopurine and
  thioinosinic acid.
• MOA (see Figure)
• Simply, it inhibits purine synthesis
  (antimetabolite), thus interfering with nucleic
  acid metabolism and lead to inhibition of the
  proliferation of leukocytes and lymphocytes.
• Why it is considered as cytotoxic agent?
• Because the purine analog of Azathioprine can
  destroy lymphoids cells.
• Why it is very important to know the structure of
  azathioprine?.

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Metabolic pathway for azathioprine

• 
  6-thiouracil
• 
  (-)
• Xanthine
  Alloburinol
• 
  Oxidase
• 
  Nonenzymatic HPRT
• AZA
  6-MP thioiosinic acid
  6-thioguanine
• (TIMP)
  ( 6-TG)
• TPMT
  TPMT
• 
  6-MMP 6-MMP
• ribonucleides

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• Cliniclal Uses of Azathioprine (ImuranR)
• 1) maintenance of renal allograft and other
  transplantations together with steroids and
  cyclosporine.
• 2) Can be used for glomerulonephtitis and SLE
  RA Crohns disease and multiple sclerosis.
• Side Effects
• 1) it is like cyclosporine, not teratogenic
  (Unlike TAC or Siro) but carcinogenic if given
  together with alkylating agents. (here higher
  doses are used as compared to autoimmune
  diseases.
• 2) strong bone marrow suppression (Leucopenia
  anemia thrombocytopenia How?
• 3) Hepatic dysfunction as increase AP and mild
  jaundice.
• 4) Hypersensitivity reactions (as rashes, fever,
  diarrhea) Why?.

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• Adverse Effects bone marrow suppression
  (leukopenia, thrombocytopenia, anemia),
  hepatotoxicity,
• Combination with ACEIs or cotrimoxazole can cause
  severe leukopenia in renal transplants
• It can be given both orally and by IV

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• 2) Mycophenolate Mofetil (CellceptR)
• The most important discovery among the
  immunosuppressant agents.
• MOA (See Figure)
• Mycophenolic acid acts as non-competitive,
  selective 7 reversible inhibitor of inosine
  monophosphate dehydrogenase
• Decreases GMP, which is a key enzyme in the de
  novo pathway of purine synthesis. This leads to
  suppression of both B and T lymphocyte
  activation.
• PK Good oral absorption
• Side Effects
• Less than azathioprine, Bone marrow suppresion
  (leukopenia and anemia) NV and diarrhea
  (decresed by Enteric-coated form).
• Unlike azathiorine it is teratogenic.

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• Clinical Uses
• 1) As a replacement for the more cytotoxic drug,
  azathioprine in renal allograft patients as well
  as liver, heart et act. Why?
• As replacement of azathioprine or
  cyclophosphamide for autoimmune diseases (RA, SLE
  (especialy before lupus nephritis)
  Glomerulonephritis
• Has good oral bioavailability
• Note in renal or liver transplant, patients may
  take the followings
• Corticosteriods as prednisolone (Low dose)
  cyclosporine or Tac Mycophenolate Mofetil

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• 3. Lefunomide
• - A Pro-drug of an inhibitor ofn PYRIMIDINE
  synthesis rather than purine like azathioprine
  and mycophenolate.
• Orally active used only for RA
• Side effects Alopecia increase LFT,
  nephrotoxicity, teratogenicity.
• 3. Alkylating Agents (e.g. Cyclophosphamide)
• The most potent immunosuppressant
• Destroys proliferating lymphoid cells (cytotoxic
  agent) also alkylate some resting cells (Thus, it
  is very toxic)
• Clinical Uses
• Before the discovery of Mycophenolate,
  cyclophosphamide was the drug of choice for
  treatment of many autoimmune diseases like SLE
  autoimmune hemolytic diseases and RA.
• Side Effects
• Pancytopenia
• Hemorrhagic cystitis
• Infertility
• Teratogenic

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• B) Lymphocyte Depletion Agents
• 1. Corticosteroids
• The most commonly used immunosuppressant
• MOA
• At biochemical level act on gene expression,
  which lead to decrease synthesis of PGs LKTs
  cytokines and other signaling molecules that
  participate in immune response.
• At the cellular level they inhibit the
  proliferation of T lymphocytes (cell mediated)
  and slightly dampen humoral immunity (by
  increasing the catabolism of immunoglobulins).
• At immunosuppressive doses, Corticosteroids are
  cytotoxic and continuous uses lowers IgG.

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• Uses
• In combination with other immunossppressants for
  transplanted patients (To prepare the patients as
  well as maintenance).
• To Rx acute rejection episodes (high doses)
• To Rx undesirable immunoreactions (to drugs or
  asthma).
• To autoimmune diseases (ITP IBD RA SLE GN)
• Side Effects

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• Adverse effects (revise endocrine system)
• Increased blood pressure How?
• hyperglycemia due to increased gluconeogenesis,
  insulin resistance, and impaired glucose
  tolerance ("steroid diabetes")
• Osteoporosis
• Visceral and truncal fat deposition (central
  obesity) and appetite stimulation
• Weight gain (water salt retention) How?
• Muscle breakdown (proteolysis), weakness reduced
  muscle mass and repair
• Increased skin fragility, easy bruising
• Cataracts
• Adrenal cortex suppression (NO ABRUPT WITHDRAWAL)
• Increase tendency to infections How?

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• 2. Immunosuppressive Antibodies
• a) Polyclonal Antibodies (Antilymphocyte
  Globulins)
• Definition Thymocytes are considered as T-cell
  precursors.
• What are the differences between polyclonal and
  monoclonal antibodies?
• 1) Antithymocyte (Antilymphocyte) Globulins
  (ALG) this antisera can be obtained by
  immunization of large animals (e.g.rabbits) with
  human lymphoid cells.
• MOA Antibodies bind to the surface of
  circulating T lymphocytes forming a comlex. This
  complex will be phagocytosed in liver or spleen
  and leading to destruction or inactivation of T
  cells.
• ALG mainly affects the cellular immunity with no
  effect on humoral, resulting in antibodies
  against these foreign proteins.
• PK Administered by IM or slow IV infusion with
  long half-life of 3-9 days
• Side Effects
• 1) Mainly result from the introduction of
  foreign proteins obtained from heterogeneous
  serum (Anaphylactic and serum sickness reactions
  Local pain and erythema at site of injection).
• 2) Chills fever and Leukopenia
  thrombocytopenia
• 3) Viral infections and skin rashes
• 4) Lymphoma and cancer

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• Polyclonal Antibodies (continue)
• Clinical Uses of ALG
• 1) Rx of hyperacute phase of allograft
  rejection
• 2) To prepare the bone marrow transplanted
  patient (Large doses of ALG for 7 days)
• 2) Immune globulin Intravenous (IGIV)
• - Prepared from a pool of thousands of healthy
  donors.
• Uses
• 1) Refractory ITP
• Advantages Has no antigenicity

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• B) Monoclonal Antibodies (Muromonab Basiliximab
  Abciximab Daclizumab.
• 1) Muromonab-CD3 (IL-2-antagonist)
• From its name, it is murine monoclonal antibody
  that prepared by hypridoma technology and
  directed against the glycoprotien CD3 antigen of
  human T cells. Used mainly for cases of acute
  allograft rejections of kidney, heart and liver.
• it is also used to deplete T cells from donor
  bone marrow before transplantation.
• Advantage over ALG More specific and T
  lymphocytes return to normal within 24 hr.
• Side Effects
• 1) Cytokine release syndrome (Anaphylactoid
  reactions) Why and seizure (contraindication)
• Therefore it is not used.

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Side Effect of Muromonab

• Its use has been declined much because of
  multiple side effects and the emergence of newer
  and more selective antibodies therapy
• Anaphylaxis may occur
• Cytokine release syndrome, flu-like to dangerous
  shock-like reactions can occur, high fever
• CNS Seizures, encephalopathy, cerebral edema
  headache
• Infection like CMV
• Contraindicated with pregnancy, breast feeding,
  history of seizures, uncompensated heart failure

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• 2) Modified Types of monoclonal antibodies (e.g
  Selective Inhibitors of IL2)
• Note Monoclonal Antibodies are not limited for
  immunosuppression but could be utilized for other
  purposes (See Table 56-3)
• By using the genetic engineering, most murine
  amino acids of Muromonab have been replaced by
  human ones producing monoclonal antibody
  designated humanized (e.g. Daclizumab
  Transtuzumab). While the chimeric (Mixed)
  antibodies contain XI in their name (e.g.
  Abciximab Infliximab Rutuximab).
• Clinical Uses See Table 56-3
• Advantages over polyclonal antibodies

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B- Selective IL-2 Receptor Antagonists
Basiliximab Daclizumab

• Basiliximab is a chimeric antibody composed of
  25 murine 75 human protein. Block IL
• Daclizumab is humanized antibody composed of 90
  human protein
• Therapeutic Use
• Prophylaxis against acute rejection of kidney
  transplantation
• Used in combination with steroids or CsA

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Selective IL-2 Receptor Antagonists Basiliximab
Daclizumab (Continue)

• Mechanism of action
• They are anti-CD25 antibodies
• They bind to the ?-chain of the IL-2R (CD25 or
  TAC subunit) on the activated T-cells
• Then, IL-2 binding to IL-2R is prohibited
  T-cell activation and proliferation are
  suppressed

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VI- Selective IL-2 Receptor Antagonists
Basiliximab Daclizumab (Continue...)

• Pharmacokinetics Given by IV route
• Daclizumab has serum half-life of 20 days
  receptor blockade for 120 days
• Administered in 5 doses the first 24 hours
  before transplantation and next 4 doses at
  14-days intervals
• Basiliximab has serum half-life of 7 days
• Administered in two doses the first at 2-hours
  before transplantation the second at 4 days
  after surgery

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Selective IL-2 Receptor Antagonists Contiue..))
Basiliximab Daclizumab

• Adverse Effects
• Both are well-tolerated
• Gastrointestinal toxicity is the major one
• NO antibodies, of clinical relevance, to the
  drugs are produced
• Infection malignancy are not reported

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• Alemtuzumab
• Humanized monoclonal antibody directed against
  CD-52, and produce profound depletion of T cells.
• Used for refractory B- cell chronic lymphocytic
  leukemia. However, it is currently in use for
  organ transplant.

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3- RhoD Immunoglobulin

• Rho(D) Immune Globulin (Rhogam)
• Rhogam is an immunoglobulin that recognizes the
  Rho(D) antigen
• Prepared from pooled sera from Rho-negative
  volunteers immunized with D erythrocytes
• It prevents erythroblastosis fetalis or hemolytic
  disease of the newborn
• When a Rho(D)-negative mother carries a
  Rho(D)-positive fetus, mother becomes sensitized
• Subsequent pregnancies can strengthen response
  increasing chance of Ab transfer to fetus

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RhoD Immunoglobulin

• It is usually given to the mother within 72 hours
  after the birth of Rh-positive baby
• This would prevent hemolytic anemia that may
  occur in subsequent pregnancies
• Adverse Effects
• Chills
• Fever
• Anaphylaxis (rare)

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• Rho(D) Immune Globulin
• Used to prevent Rh hemolytic disease in newborn.
• Thus, Rho(D) Immune Globulin antibodies are given
  to the mother within 72 Hrs after birth of Rh
  positive baby.
• Uses
• Erythroblastosis Faetalis
• Miscarriages