PH 1.50 Drugs acting as immunosuppressants and immunostimulant

1. PH 1.50
Describe mechanisms of action, types, doses, side
effects, indications, and contraindications of
immunomodulators and management of organ
transplant rejection
DR. MANI BHARTI
ASSISTANT PROFESSOR, PHARMACOLOGY
NDMC, MEDICAL COLLEGE, DELHI

2. Learning objectives
At the end of the session phase, II MBBS students shall be able to
 Differentiate between Immuno-suppressants and immuno-stimulants
 Define immunosuppressants & Classify immuno-suppressants
 Describe the mechanisms of action of Calcineurin inhibitors
 Enlist m-Tor inhibitors and antiproliferative agents used as immunosuppressants
 Enlist Biological agents used as immunosuppressants
 Enumerate the adverse effects of immunosuppressants
 Enlist clinical uses of immunosuppressants

3. Drugs for immunomodulation
 All drugs which modify immune response are generally
categorised as immunomodulators.
 These can either function as immunosuppressants or
immunostimulants.

4. Immunosuppressants
 Immunosuppressants are drugs that inhibit cellular/humoral or
both types of immune responses and have their major use in organ
transplantation and autoimmune diseases

5. Immune system
 Is designed to protect the host from harmful foreign molecules.
 Allograft introduction can elicit a damaging immune response.
 Immune system include two main arms
1) Cell–mediated immunity.
2) Humoral (antibody–mediated immunity).

11. 1) Calcineurin inhibitors
Cyclosporine ,Tacrolimus
CYCLOSPORINE
Chemistry
Cyclosporine is a fungal polypeptide composed of 11 amino acids
Mechanism of action
 Acts by blocking the activation of T cells by inhibiting interleukin-2 production (IL-2).
 Decreases proliferation and differentiation of T- cells.

13. Pharmacokinetics
 Can be given orally or i.v. infusion
 Orally (25 or 100 mg) soft gelatin capsules, microemulsion.
 Orally, it is slowly and incompletely absorbed.
 Peak levels is reached after 1– 4 hours, elimination half-life 24 h.
 Oral absorption is delayed by fatty meal (gelatin capsule formulation)
 50 – 60% of cyclosporine accumulates in the blood (erythrocytes – lymphocytes).
 Metabolized by CYT-P450 system (CYP3A4).
 Excreted mainly through bile into feces, about 6% is excreted in the urine.

14. Therapeutic Uses of Cyclosporine
Organ transplantation (kidney, liver, heart) either alone or with other
immunosuppressive agents (Corticosteroids).
Autoimmune disorders (low dose 7.5 mg/kg/d). e.g. endogenous uveitis,
rheumatoid arthritis, active Crohn’s disease, psoriasis, nephrotic
syndrome, severe corticosteroid-dependent asthma, and early type I
diabetes.
Graft-versus-host disease after stem cell transplants

15. Adverse Effects of cyclosporine (Dose-dependent)
Therapeutic monitoring is essential
 Nephrotoxicity (increased by NSAIDs and aminoglycosides).
 Liver dysfunction.
 Hypertension, hyperkalemia.
(K-sparing diuretics should not be used).
 Hyperglycemia.
 Viral infections (Herpes - cytomegalovirus).

16.  Lymphoma (Predispose recipients to cancer).
 Hirsutism
 Neurotoxicity (tremor).
 Gum hyperplasia.
 Anaphylaxis after I.V.
Adverse Effects of Cyclosporine (Dose-dependent) cont..

17. TACROLIMUS
 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.

19. Kinetics of Tacrolimus
 Given orally or i.v or topically (ointment).
 Oral absorption is variable and incomplete, reduced by fat and
carbohydrate meals.
 Half-life after I.V. form is 9-12 hours.
 Highly bound with serum proteins and concentrated in erythrocytes.
 metabolized by P450 in liver.
 Excreted mainly in bile and minimally in urine.

20. USES as cyclosporine
 Organ and stem cell transplantation
 Prevention of rejection of liver and kidney
transplants (with glucocorticoids).
 Atopic dermatitis and psoriasis (topically).

21. Toxic effects
 Nephrotoxicity (more than CsA)
 Neurotoxicity (more than CsA)
 Hyperglycemia ( require insulin).
 GIT disturbances
 Hyperkalemia
 Hypertension
 Anaphylaxis
NO hirsutism or gum hyperplasia
 Drug interactions as cyclosporine.

22. Differences between CsA and TAC ?
TAC is more favorable than CsA due to:
 TAC is 10 – 100 times more potent than CsA in inhibiting immune
responses.
 TAC has decreased episodes of rejection.
 TAC is combined with lower doses of glucocorticoids.
But
 TAC is more nephrotoxic and neurotoxic.

23. 2)M-TOR inhibitor
Sirolimus , Everolimus
Sirolimus (Rapamycin)
 SRL is macrolide antibiotic.
 SRL is derived from fungus.
 It binds to FKBP and the formed complex binds to mTOR (mammalian
Target Of Rapamycin).
 mTOR is serine-threonine kinase essential for cell cycle progression, DNA
repairs, protein translation.

24.  SRL blocks the progression of activated T cells from G1 to S phase of cell
cycle (Antiproliferative action).
 It Does not block IL-2 production but blocks T cell response to cytokines.
 Inhibits B-cell proliferation & immunoglobulin production.
Sirolimus (Rapamycin) Contd..

26. Pharmacokinetics of Sirolimus
 Given orally and topically, reduced by fat meal.
 Extensively bound to plasma proteins
 metabolized by CYP3A4 in liver.
 Excreted in feces.
Pharmacodynamics
 Immunosuppressive effects
 Anti- proliferative action.
 Equipotent to CsA.

27. USES OF SIROLIMUS
 Solid organ allograft
 Renal transplantation alone or combined with (CSA, tacrolimus, steroids, and
mycophenolate).
 Heart allografts
 In halting graft vascular disease.
 Hematopoietic stem cell transplant recipients.
 Topically with cyclosporine in uveoretinitis.
 Synergistic action with CsA

28. Toxic effects Sirolimus
 Hyperlipidemia (cholesterol, triglycerides).
 Thrombocytopenia
 Leukopenia
 Hepatotoxicity
 Hypertension
 GIT dysfunction

29. Inhibitors of cytokine gene expression
Corticosteroids
 Prednisone
 Prednisolone
 Methylprednisolone
 Dexamethasone
They have both anti-inflammatory action and
immunosuppressant effects.

30. Mechanism of action
 Bind to glucocorticoid receptors and the complex interacts with DNA to inhibit
gene transcription of inflammatory genes.
 Decrease production of inflammatory mediators as prostaglandins, leukotrienes,
histamine, PAF, bradykinin.
 Decrease production of cytokines IL-1, IL-2, interferon, TNF.
 Stabilize lysosomal membranes.
 Decrease generation of IgG, nitric oxide and histamine.
 Inhibit antigen processing by macrophages.
 Suppress T-cell helper function.
 decrease T lymphocyte proliferation.

31. Pharmacokinetics
Can be given orally or parenterally.
Pharmacodynamics
1. Suppression of response to infection
2. Anti-inflammatory and immunosuppressant.
3. Metabolic effects.

32. Indications
First-line therapy for solid organ allografts & hematopoietic stem
cell transplantation.
Autoimmune diseases such as refractory rheumatoid arthritis,
systemic lupus erythematosus (SLE), and asthma.
Acute or chronic rejection of solid organ allografts.

33. Adverse Effects
Adrenal suppression
Osteoporosis
Hypercholesterolemia
Hyperglycemia
Hypertension
Cataract
Infection

34. Cytotoxic drugs
Inhibitors of purine or pyrimidine synthesis
(Antimetabolites):
 Azathioprine
 Myclophenolate Mofetil
 Leflunomide
 Methotrexate
Alkylating agents
Cyclophosphamide

35. AZATHIOPRINE
CHEMISTRY:
Derivative of mercaptopurine.
Prodrug.
Cleaved to 6-mercaptopurine then to 6-mercaptopurine nucleotide,
thioinosinic acid (nucleotide analog).
Inhibits de novo synthesis of purines required for lymphocytes
proliferation.
Prevents clonal expansion of both B and T lymphocytes.

37. 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.

38. USES OF AZATHIOPRINE
 Acute glomerulonephritis
 Systemic lupus erythematosus
 Rheumatoid arthritis
 Crohn’ s disease.

39. Adverse Effects of Azathioprine
 Bone marrow depression: leukopenia,
Thrombocytopenia.
 Gastrointestinal toxicity.
 Hepatotoxicity.
 Increased risk of infections.

40. 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.

42. Pharmacokinetics:
Given orally, i.v. or i.m.
rapidly and completely absorbed after oral administration.
It undergoes first-pass metabolism to give the active moiety,
mycophenolic acid (MPA).
MPA is extensively bound to plasma protein.
metabolized in the liver by glucuronidation.
Excreted in urine as glucuronide conjugate
Dose : 2-3 g/d

43. CLINICAL USES
Solid organ transplants for refractory rejection.
Steroid-refractory hematopoietic stem cell transplant patients.
Combined with prednisone as an alternative to CSA or tacrolimus.
Rheumatoid arthritis, & dermatologic disorders.

44. ADVERSE EFFECTS MYCOPHENOLATE MOFETIL
GIT toxicity: Nausea, Vomiting, diarrhea, abdominal pain.
Leukopenia, neutropenia.
Lymphoma
Contraindicated during pregnancy

45. BIOLOGICAL AGENTS
 These are biotechnologically produced recombinant proteins or
polyclonal/monoclonal antibodies directed to cytokines or
lymphocyte surface antigens which play a key role in the immune
response.
 They are important recent additions,
 mostly as supplementary or reserve drugs for severe and
refractory cases of autoimmune diseases and graft versus host
reaction.

46. TNFa inhibitors
Etanercept infliximab • Adalimumab
• It is used mostly in combination
with Mtx in rheumatoid arthritis
patients who fail to respond
adequately to the latter alone
• Etanercept is also approved for
severe/refractory ankylosing
spondylitis, polyarticular
idiopathic juvenile arthritis, and
plaque psoriasis.
• Used by i.v. infusion every 4- 8
weeks along with Mtx and other
conventional therapy,
• it has proven useful in
refractory rheumatoid arthritis.
fistulating Crohn's disease,
ulcerative colitis, psoriasis and
ankylosing spondylitis
• It is fully human recombinant
anti-T Fa anti body indicated in
the same range of autoimmune
• Diseases such as infliximab. and
like the latter, docs not bind
TNF~. but is less an11genic. It
can be added to Mtx or other
conventional drugs for
additional benefit.

47. ll-1 receptor antagonist
Anakinra
 This recombinant human IL-I receptor antagonist prevents I L-1
binding to its receptor and has been approved for use in refractory
rheumatoid arthritis not controlled by conventional DMARDs.

48. ll-2 receptor antagonist
Basiliximab and Daclizumab
 Obtained by replacing murine amino acid sequences with human
ones.
 Basiliximab is a chimeric human-mouse IgG (25% murine, 75%
human protein).
 Daclizumab is a humanized IgG (90% human protein).
 Have less antigenicity & longer half lives than murine antibodies

49. Mechanism of action
 IL-2 receptor antagonists
 Are Anti-CD25
 Bind to CD25 (α-subunit chain of IL-2 receptor on activated
lymphocytes)
 Block IL-2 stimulated T cells replication & T-cell response
system
 Basiliximab is more potent than Daclizumab.
Basiliximab and Daclizumab

51. Pharmacokinetics
 Given I.V.
 Half life Basiliximab (7 days )
 Daclizumab (20 days)
 are well tolerated - only GIT disorders
USES
 Given with CsA and corticosteroids for Prophylaxis of acute rejection
in renal transplantation.

52. Anti-CD3 antibody Muromonab-CD3
 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.

53. Mechanism of action of Muromonab-CD3
 The drug binds to CD3 proteins on T-lymphocytes (antigen recognition
site) leading to transient activation and cytokine release followed by
disruption of T-lymphocyte function, their depletion and decreased
immune response.
 Prednisolone, diphenhydramine are given to reduce cytokine release
syndrome.

54. Uses Muromonab-CD3
 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.
 Fever
 CNS effects (seizures)
 Infection
 Cytokine release syndrome (Flu-like illness to shock like reaction).

55. Polyclonal antibodies
 Antithymocyte globulin (ATG) It is a polyclonal antibody purified from
horses or rabbit immunized with human thymic lymphocytes which
contain antibodies against many CD antigens as well as HLA antigens.
 It binds to T lymphocytes and depletes them.
 ATG is a potent immunosuppressant and has been used primarily to
suppress acute allograft rejection episodes, especially in steroid-resistant
cases.
 LYMPHOGLOBULIN (equine) 100 mg/vial inj.; 10 mg/kg/ day i.v.;
 THYMOGLOBULI N (rabbit) 25 mg/vial inj.; 1.5 mg/kg/day.
 ATG 100 mg inj; 200 mg i.v./day.

56. Rho (D) immune globulin
 Rho (D) is a concentrated solution of human IgG1 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

57. IMMUNOSUPPRESSION IN ORGAN
TRANSPLANTATION
 Induction regimen
 Maintenance regimen
 Antirejection regimen

58. I . Induction regimen
 This is given in the perioperative period: starting just before the
transplant to about 2-12 weeks after it.
 The most common regimens
 include triple therapy with cyclosporine/tacrolimus/sirolimus +
prednisolone + MMF/ azathioprine.
 newer biological agents are being increasingly used in induction
regimens.
 If no rejection develops, the doses are gradually reduced after 2 weeks
and this phase merges imperceptibly with the maintenance phase.

59. 2. Maintenance regimen
 This is given for prolonged periods and may be life-long.
 Triple drug regimen consisting of maintenance doses of any three of the following
choices-cyclosporine/ tacrolimus, sirolimus, prednisolone, azathioprine/ MMF are
generally favored because each component is needed in lower doses- reduces
toxicity and cost.
 Nephrotoxicity is often the limiting factor with cyclosporine/tacrolimus, while
long-term steroid therapy has its own problems. The component which produces
toxicity in a given patient is curtailed or dropped..
 ln case of intolerance to the first line drugs viz. cyclosporine, tacrolimus,
sirolimus, MMF, azathioprine, and prednisolone, the second line drugs like
cyclophosphamide, chlorambucil or daclizumab/basiliximab are substituted.

60. 3. Antirejection regimen
 This is given to suppress an episode of acute rejection.
 Steroid pulse therapy (methylprednisolone 0.5- 1 g i.v. daily for 3- 5
days) is effective in majority of cases.
 In case of no response, muromonab CD3/ATG is given as rescue
therapy or antibodies are combined with the steroid.
 Tacrolimus, sirolimus, MMF have also been used in rescue therapy of
steroid resistant rejection.

61. Adverse effects
 The two general untoward effects of immunosuppressant therapy are:
 (a) Increased risk of bacterial, fungal, viral (especially CMV) as well as opportunistic
 infections.
 (b) Development of lymphomas and related malignancies after a long latency due
to weakening of immunological surveillance against neoplasia

62. IMMUNOSTIMULANTS
 A number of disorders such as immunodeficiency sates (e.g., AIDS),
autoimmune disease, cancer and viral infections can be treated with
immunostimulant drugs.
 These agents are nonspecific and may affect innate as well as adaptive
immunity. These may work on the cellular or humoral immune system or
both.
 Because of their variable effects in different conditions and on different
components of immune system, these are more popularly known as
biological response modifiers or immunomodulators.

63.  Bacillus Calmette-Guerin (BCG)
 Levamisole
 Thalidomide and lenalidomide
 Recombinant cytokines
 Aldesleukin
 Recombinant interleukins-oprelvekin
 Colony stimulating factors-sargramostin, filgrastim,pegfilgrastim
 Recombinant interferons-interferon alfa, interferon beta 1a and beta1b, interferon gama