Immunosuppressants

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• Immunosuppressants
• Prof. Alhaider, 1432 H
• Definition
• Clinical Uses (Organ transplants Autoimmune
  diseases)
• Pre-requisite to understand immunosuppressive
  drugs (Basic immunology).
• Review of immune system (read Table 56-1, next
  slide)
• Cell mediated vs humoral immunity
• Importance of cytokines
• Immunophilins
• Calcineurin

Pharma Team
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MOA next slide
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Classification of Immunosuppressant (Based on
Mechanism of Action)

• A) Antiprolifirative Agents
• I) Drugs Acting on Immunophilins (most
  importanat )
• a) Selective Inhibitors of Cytokine production
  (Calcineurin Inhibitors)
• e.g Cyclosporine Tacrolimus
• b) Inhibitor of cytokine function (e.g.
  Sirolimus).
• II) Antimetabolites (Azathioprine
  Mycophenolate Mofetil)
• III ) Alkylating Agents
  (Cyclophosphamide)
• B) Lymphocyte Depleting Agents
• Corticosteroids (Prednisone (orall)
  Methylprednisolone (IV) )
• Immunosuppressive Antibodies
• a) Polyclonal Antibodies (Antilymphocytic
  Globulins)
• 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 (CsA) (Cyclic peptide from Soil
  Fungus (1971)
• MOA (See slide 5)
• CsA binds to cyclophillin forming a comlex ? Bind
  to Calcineurin ? dephosphorylation NFATc ?
  Synthesis of IL-2 ? cell-mediated
  immune response (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-mediated immunity with
  no effect on B lymphocytes/humoral immunity.

NFATc cytosolic nuclear factor of activated T
cells
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• PK
• CsA available as oral (capsule) or parentral
  (i.v)
• Oral bioavailability (20-50),
• It undergoes extensive hepatic metabolism by Cyt
  P450 (CYP3A4) (Affected by drugs affecting the
  microenzymes cimetidine, rifampin, cefaporazone)
• 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 an
  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 ? Not used anymore

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• Side Effects (remember most immunosuppressant
  are very toxic)
• Dose-dependent nephrotoxicity ( Risk of
  Rejection) enhanced when given with other
  nephrotoxic drugs (Aminoglycosides NSIADs,
  amphotericin B)
• Hepatotoxicity
• Neurotoxicity as tremor and hallucination
• Infection, opportunistic
• Lymphoma and cancer How? immunity
• Hypertension hyperlipidemia Hyperkalemia DM
  osteoporosis, hirsutism, and gum hyperplasia (So
  What?
• ? dont prescribe it to female patints)

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• 2. Tacrolimus (FK 506)
• More potent than Cyclosporine
• MOA Similar to Cyclosporine (Calcineurin
  Antagonist) but it bind to a different
  immunophilin (FKBP) slide 14
• PK Almost Similar to Cyclosporine
• Side Effects differ from Cyclosporine, that it
  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
  hyperlipidemia.

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• Clinical uses of Tacrolimus
• Preferred over CsA for
• Its greater potency (50-100 times more potent
  than cyclosporine)
• lower rejection episodes
• lower doses of glucocorticoids are used with
  lower side effects
• Better first choice for women, can you tell why?
  Less hirsutism and gum hyperplasia
• Severe refractory atopic dermatitis, local
  application of an ointment
• An ointment for psoriasis.

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Five year renal allograft survival in patients
with cyclosporin or tacrolimus
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• 3. Sirolimus (Rapamycin Macrolides)
• MOA see next slide
• 1) Binds to the same immunophilin Tacrolimus
  binds to 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-cells
  response to IL-2 (Blocks cytokine-stimulated cell
  proliferation)
• 3) Potent inhibitor of B-cell proliferation and
  immunoglobulin production (decreases the humoral
  immunity)

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• Uses of Sirolimus
• 1) can be used together with cyclosporine to
  increases the activity of cyclosporine for organ
  transplantion. Why not tacrolimus? Because it
  shares the same MOA.
• 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) Hyperlipidemia (even more than
  calcineurin-antagonists)

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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 prodrug, converted in the body to the
  active metabolite, 6-mercaptopurine and
  thioinosinic acid.
• MOA (see next slide Figure)
• It inhibits purine synthesis (antimetabolite),
  thus interfering with nucleic acid metabolism of
  leukocytes and lymphocytes leading to the
  inhibition of proliferation.
• Why it is considered as cytotoxic agent?
• Because the purine analog of Azathioprine can
  destroy lymphoids cells.
• Why is it very important to know the structure of
  azathioprine?.

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Metabolic pathway for azathioprine

• 
  6-thiouracil
• 
  (-)
• Xanthine
  Allopurinol
• 
  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
  transplants together with steroids and
  cyclosporine.
• 2) Can be used for glomerulonephtitis and SLE
  RA Crohns disease and multiple sclerosis (MS).
• PKIt can be given both orally and IV
• Side Effects
• 1) Like cyclosporine, is not teratogenic (Unlike
  TAC and Siro) but carcinogenic if given together
  with alkylating agents. Here, higher doses are
  used for immunosuppression as compared to its use
  in autoimmune diseases.
• 2) Strong bone marrow suppression (Leukopenia
  anemia thrombocytopenia How?
• 3) Hepatic dysfunction as increase ALP and mild
  jaundice.
• 4) Hypersensitivity reactions (as rashes, fever,
  diarrhea) Why?.

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• Drug interactions
• Combination with ACEIs or cotrimoxazole can cause
  severe leukopenia in renal transplants

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• 2) Mycophenolate Mofetil (CellceptR)
• The most important discovery among the
  immunosuppressant agents.
• MOA (See Figure in the coming 2nd slide)
• Mycophenolic acid acts as non-competitive,
  selective 7 reversible inhibitor of inosine
  monophosphate dehydrogenase (IMD)
• 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, Reversible bone marrow
  suppresion (leukopenia and anemia) N/V and
  diarrhea (decresed by Enteric-coated form).
• Unlike azathioprine it is teratogenic.

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• Clinical Uses
• 1) Drug of choice for preventing vasculopathy in
  cardiac transplants
• 2)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
  (especially 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 Prodrug of an inhibitor of PYRIMIDINE
  synthesis rather than purine-like azathioprine
  and mycophenolate mofetil.
• Orally active used only for RA
• Side effects Alopecia raised LFT,
  nephrotoxicity, teratogenicity.

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3. Alkylating Agents

• e.g. Cyclophosphamide
• The most potent immunosuppressant
• Destroys proliferating lymphoid cells (cytotoxic
  agent) also alkylates some resting cells?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? a unique Adverse effect
• Infertility
• Teratogenic

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• B) Lymphocyte Depleting Agents
• 1. Corticosteroids
• The most commonly used immunosuppressant
• MOA
• At the biochemical level act on gene
  expression, which leads to decrease synthesis of
  PGs Leukotrienes, cytokines, and other signaling
  molecules which participate in the 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 causes lowering of
  IgGs.

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• Uses
• In combination with other immunossppressants for
  transplanted patients (To prepare the patients as
  well as maintenance).
• To treat acute rejection episodes (high doses)
• To treat undesirable immunoreactions (to drugs or
  asthma).
• For autoimmune diseases (idiopathic
  thrompocytopenic purpura inflammatory bowel
  diease rheumatoid arthritis systemic lupus
  erythematosus and glomerulonephritis)

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• Adverse effects
• Increased blood pressure How? By their
  aldostrone-like moiety
• 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?
  Answered above!
• Muscle breakdown (proteolysis), weakness reduced
  muscle mass and repair
• Increased skin fragility, easy bruising
• Cataracts
• Adrenal cortex suppression (Avoid abrupt
  withdrawl)
• Increase tendency to infections

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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 the liver or
  spleen 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.

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• 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 the 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 patient undergoing bone
  marrow
• translpant (Give
  large doses of ALG for 7 days)
• 2) Immune globulin Intravenous (IGIV)
• - Prepared from a pool of thousands of healthy
  donors.
• Uses
• 1) Refractory Idipathic Thrombocutopenic
  Purpura
• 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
  prepared by hybridoma technology and directed
  against the glycoprotien CD3 antigen of human T
  cells. Used mainly for cases of acute allograft
  rejections of the 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 hours.
• Side Effects
• 1) Cytokine release syndrome (Anaphylactoid
  reactions) and seizure (contraindication)
• Therefore, it is less used nowadays.

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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 IL-2)
• 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 a.a. producing humanized designated
  monoclonal antibodies (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? Are less
  immunoantigenic.

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B- Selective IL-2 Receptor Antagonists
Basiliximab Daclizumab

• Basiliximab is a chimeric antibody composed of
  25 murine 75 human protein. Blocks
• IL-2 of activated lymphocytes
• Daclizumab is humanized antibody composed of 90
  human protein
• Therapeutic Use
• Prophylaxis against acute rejection of kidney
  transplantation
• Used in combination with steroids and CsA

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Selective IL-2 Receptor Antagonists Basiliximab
Daclizumab (Continue)

• Mechanism of action
• They are anti-CD25 and IL-2 antibodies
• They bind to the ?-chain of the IL-2 R (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
  antibodies are produced
• Infection malignancy were not reported

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

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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 (hemolytic
  disease of the newborn)
• When a Rho(D)-negative mother carries a
  Rho(D)-positive fetus, the mother becomes
  sensitized
• Subsequent pregnancies can strengthen response
  increasing chance of Ab transfer to the fetus in
  the last trimester

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How Does Rho(immunoglobulin work)

• The potion is a solution of IgG anti-D
  (anti-RhD) antibodies that bind to, and lead to
  the destruction of, fetal Rh D positive red blood
  cells that have passed from the fetal
  circulation to the maternal circulation.
  Therefore, Rho in a Rhesus negative mother it can
  prevent sensitization of the maternal immune
  system to Rh D antigens, which can cause rhesus
  disease in the current or in subsequent
  pregnancies. Note With the widespread use of Rho
  (D) Immune Globulin, Rh disease of
  the fetus and newborn has almost disappeared.

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RhoD Immunoglobulin

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