2. Contents:
Introduction
IMMUNOMODULATOR
Immune system
Diseases related to Immune system dysfunction
Immunosuppressants
Clinically used Immunosuppressants
Classification of drugs
Immunostimulants
Classification of drugs
References
3. IMMUNOMODULATION
Modulation of immune system
(Regulatory adjustment)
As part of immunotherapy : According to therapeutic goals
Immune responses are
Induced, Amplified, attenauted
,
Prevented,
Substances that helps to regulate the immune system Immunomodulators
4. Concept of immunomodulation
Nonspecific activation of the
Function and efficiency of
Macrophages, granulocytes, complement, Natural killer cells, Production of various
effector molecules
lymphocytes,
Protection against
bacteria Viruses fungi
Alternative to conventional chemotherapy
5. INTRODUCTION
The immune system evolved to discriminate self from nonself.
Innate, or natural, immunity is broadly reactive, does not require priming and is of relatively low affinity.
Adaptive, or learned, immunity is antigen-specific, depends upon antigen exposure or priming, and can be of very high
affinity.
The two arms of immunity work closely together, with the innate immune system being more active early in an immune
response and adaptive immunity becoming progressively dominant over time.
The major effectors of innate immunity are complement, granulocytes, monocytes/macrophages, natural killer cells, mast
cells, and basophils.
6. The major effectors of adaptive immunity are B and T lymphocytes. B lymphocytes make antibodies; T lymphocytes
function as helper, cytolytic, and regulatory (sup-pressor) cells.
These cells are important in the normal immune response to infection and tumors but also mediate transplant rejection and
autoimmunity
Immunoglobulins (antibodies) on the B lymphocyte surface are receptors for a large variety of specific structural
conformations.
In contrast, T lymphocytes recognize antigens as peptide fragments in the context of self major histocompatibility complex
(MHC) antigens [called human leukocyte antigens (HLA)] on the surface of antigen-presenting cells (APCs), such as
dendritic cells, macrophages, and other cell types expressing MHC class I and class II antigens.
7. Once activated by specific antigen recognition via their respective clonally restricted cell-surface receptors, both B and
T lymphocytes are triggered to differentiate and divide, leading to release of soluble mediators (cytokines,
lymphokines) that are effectors and regulators of the immune response
The impact of the immune system in human disease is enormous.
Immunological diseases (e.g., rheumatoid arthritis, type 1 diabetes mellitus, and asthma; solid tumors and hematologic
malignancies) growing at epidemic proportions that require aggressive and innovative approaches to develop new
treatments.
Immune system-mediated graft rejection remains a formidable obstacle to widespread use of organ transplantation.
8. Immune system
Innate immunity
Protection against
pathogens
Most rapidly acting
depends on
Neutrophils, macrophages, Dendritic cells, monocytes,
Adaptive immunity
Enhance the
protection
Involved in the release of nitric
oxide (NO) by inducible nitric oxide
synthase.
Leukocytes: perform phagocytic activities
chemotaxis Leukocytes
adhesion
Pathogen
engulfment
Intracellular killing to eliminate the pathogen
Presenting antigen to
CD4 T cells through
(MHC) class II antigen.
• Perform their functions
by Th-1,Th-2,Th-17 and
CD4 T cells
• Help B cells develop
into plasma cells.
• Activate T cells to
become activated
cytotoxic T cells.
T & B cells
9. Diseases related to Immune system dysfunction
Inflammatory diseases Autoimmunity Infectious diseases Atherosclerosis Hypersensitivity cancer
Inappropriate reaction to self antigen
Myasthenia gravis,
Type 1 diabetes,
Systemic lupus erythematosus,
Grave’s disease,
Celiac disease,
Pernicious anemia,
rheumatoid arthritis,
multiple sclerosis.
Overactive
Immune
response
The treatment of inflammatory and immune-related diseases due to defects or disorders of the
immune system necessitates modulation of the immune response
10.
11. Immunosupressants are used in the therapy of autoimmune diseases and to prevent or treat transplant
rejection .
Because they impair immune response they carry hazard of decreased response to infections
However the relationship between these adverse effects and potency in preventing graft rejection
varies with different drugs.
IMMUNO SUPPRESSIVE DRUGS
12. 1. To supress rejection of transplanted organ and tissues(heart, kidney, bone marrow &
liver )
2. To treat variety of conditions of auto immune disease like, Idiopathic
thrombocytopenic purpura, some forms of haemolytic anaemia, some form of
glomerulo nephritis, myasthenia gravis, SLE,
rheumatoid arthritis, psoriasis etc.
For transplantation of organ, cyclosporin is combined with glucocorticoids.
Uses
13. 1. GLUCOCORTICOIDS.
2. CALCINEURINE INHIBITORS
a) CYCLOSPORINE.
b) TACROLIMUS.
3. CYTOTOXIC DRUGS.
a) SIROLIMUS.
b) AZOTHIOPRINE.
c) MYCOPHENOLATE MOFETIL
IMMUNO SUPPRESSIVE DRUGS
14. 4. ANTIBODIES
a) ANTI THYMOCYTE GLOBULINE.
b) MONOCLONAL ANTIBODIES.
c) NEW GENERATION ANTI CD3 ANTIBODIES.
d) NEW GENERATION ANTI CD25 ANTIBODIES.
IMMUNO SUPPRESSIVE-(con.)
15. Cyclic poly peptide of 11 amino acid residue with potent immunosuppressive activity, but no effect on
the acute inflammatory reaction.
Lipophilic.
M.O.A.: Has numerous action on various cell types like, Potent inhibition of t -cell mediated immune
mechanism.
Suppresses some humoral activity also.
CALCINEURINE INHIBITORS
(CYCLOSPORINE)
16. CYCLOSPORINE
The main action is relatively selective inhibitory effects on IL-2 gene
transcription.
Interaction of antigen with T-helper cell receptor results in increased
intracellular Ca2+
Calcium stimulates a phosphatase called calcineurin, which further activates
various transcription factors, these inturn initiates the transcription of gene
for IL-2.
17. Cyclosporine binds with a cytosolic protein termed cyclophilin.
The drug-cyclophilin complex binds and inhibits calcineurin and thus interferes with activation of T-helper cells and
production of IL-2
CYCLOSPORINE
18. Oral, I.V.
Oral Administration- Peak Plasma Conc Is Attained Within 3-4hrs.
Plasma T1/2 Life= App.24hrs KI Metabolised In The Liver.
Exc: Faeces, Urine. Milk.
Uses:
1. Organ Transplantation
2. Rh.Arthritis,
3. Psoriasis,
PHARMACOKINETICS OF CYCLOSPORINE
19. A D R: Nephrotoxicity(most serious)
Hepatotoxicity
Hypertension,
Tremour
Hirsuitism
Paraesthasia
Gum Hypertrophy and
Gastro Intestinal Disturbances
CYCLOSPORINE
20. Macrolide antibiotic. Produced by strept.Sp.
M.O.A.: Similar to cyclosporin but considerably more potent
REDUCES T CELLACTIVATION BY INHIBITING
CALCINEURINE.
Intracelularly drug bind with a protein called FKBP(FK binding
protein. Because Tacrolimus was initially called FK506)
Tacrolimus-FKBP complex inhibits calcineurin with the effects
described about
TACROLIMUS
21. PH. KINETICS.
ORAL, iv .ORAL-INCOMPLETE ABSORBATION.
FOOD INTERFERS WITH ABSORBATION.
BINDS TO PLASMA PROTEIN 75 TO 99 PERCENT.
METABOLISM IN LIVER.
EXC: Faeces
T1/2 life= 7hrs
TACROLIMUS --- Cont.
22. USE: ALLOGRAFT REJECTION.
ADR: Similar to cyclosporin but more severe.
Incidence of nephrotoxicity and neurotoxicity is higher but that of
hirsuitism is lower,
G.I. upset,
Thrombocytopenia and hyperlipidaemia have been reported but are
TACROLIMUS --- Cont.
23. MOA:
• Immuno Suppressive.
• Anti Inflammatory Agent.
• Similar to cyclosporin Glucocorticoids restrain
the proloferation of T-helper cells by
inhibiting the action of transcription factors
such as AP-1 & NF-.B, thus decreasing the
transcription of the gene for IL-2
• However glucocorticoids also decreases the transcription of many other cytokine genes
• such as genes for TNF-¢ IFN-Y IL-1 and many other interleukins.
• Suppresses cellular immunity and Little action on humoral immunity.
GLUCOCORTICOIDS
24. USES.
TO PREVENT & TREAT ORGAN TRANSPLANT REJECTION.
AUTO IMMUNE DISORDERS- SLE & PSORIASIS, ASTHMA, INFLAMMATORY BOWEL DISEASE,
INFLAMMATORY OPHTHALMIC DISEASE.
HAEMATOLOGICAL DISORDERS, ULCERATIVE COLITIS TO SUPPRESS ALLERGIC REACTION.
GLUCOCORTICOIDS(CONT.)
25. GROWTH RETARDATION
HYPERGLYCEMIA,
HYPERTENSION
HIGH RISK OF INFECTION.
• PREPARATION: METHYL PREDNISOLONE SODIUM
SUCCINATE.
TOXICITY OF GLUCOCORTICOIDS
26. • It is an immunosuppressive drug used in organ
transplantation and autoimmune diseases and
• belongs to the chemical class of purine analogues
• Synthesized originally as a cancer drug and a prodrug
for mercaptopurine in 1957, it has been widely used
as an immunosuppressant for more than 50 years.
Azathioprine acts as a prodrug for mercaptopurine ,
inhibiting an enzyme required
for the synthesis of DNA . Thus, it most strongly affects
proliferating cells, such as the T cells and B cells
of the immune system
AZOTHIOPRINE
28. IMMUNOSTIMULANT DRUGS:
Those drugs that stimulate the immune system .
particularly important for the treatment of infectious
disease, tumors, immunodeficiencies and all the cases where
the immune system needs a boost.
30. Bacillus Calmette Guerin(bcg):
BCG is an live attenuated culture of BCG strain of
Mycobacterium bovis .
mechanism of action:
induction of a granulomatous reaction at the site of
administration it causes
activation of macrophages to make them more
effective killer cells.
31. Therapeutic uses:
Treatment and prophylaxis of carcinoma of
urinary bladder, prophylaxis of primary and
recurrent stage of papillary tumors after
transurethral resection.
ADVERSE EFFCTS :
hypersensitivity ,
shock ,
chills ,
fever ,
malaise, and
immune complex disease.
32. LEVAMISOLE
Levamisole/Ergamisol was synthesized originally as an
anthelmintic but appears to restore depressed immune
function of B lymphocytes ,T- lymphocytes ,monocytes
,and macrophages .
Therapeutic uses: adjuvant therapy with 5-
fluorouracil colon- cancer , agranulocytosis. Used to
treat immunodeficiency associated with Hodgkins
diseases..
Adverse effects: Flu-like symptoms ,allergics
manifestation ,nausea ,and muscle pain.
33. THALIDOMIDE
Thalidomide is best known for the severe
birth defects it caused when
administered to the pregnant women .
it is indicated for the treatment of
patient with erythema nodosum
leprosum.
and also is used in conditions such as
multiple myeloma its mechanism of
action is unclear.
Adverse effect: Teratogenicity
34. IMMUNIZATION:
Active immunization involves stimulation with an antigen to
develop immunologic defenses against a future exposure ,
while passive immunization involves administrations of
preformed antibodies to an individual who is already exposed or
is about to be exposed to an antigen .
vaccines active immunizations ,or vaccination involve
administrations of an antigen as a whole ,killed organism,
attenuated organism, or a specific protein or peptide
constituent of an organism .
Booster doses often are required specially when killed organism
are used as the immunogen .vaccination has sharply curtailed or
practically eliminated a variety of major infections including
polio, smallpox, diphtheria, measles, mumps, pertussis, rubella
,tetanus, Haemophilus influenzae type B, and pneumococcus.
35. Although most vaccines have targeted infectious
disease, a new generation of vaccines may
provide complete or limited protection from a
specific cancers or autoimmune diseases.
There is efficacy of DNA vaccines in models of
infectious diseases and cancer. The advantage of
DNA vaccinations over peptide immunization is
that it permit generations of entire proteins,
enabling determinant selections to occur in the
host without having to restrict immunization to
patient bearing specific HLA alleles.
one more approach is to generate Immune
response says against specific antigen consists of
infecting cells with recombinant viruses that
encode the protein antigen of interest.
36. IMMUNE GLOBULIN:
Passive immunization is indicated when an individual is deficient in
antibodies because of a congenital or acquired immunodeficiency, when an
individual with a high degree of risk is exposed to an agent and there is
inadequate time for active immunization (example -measles, rabies,
hepatitis B), or when a disease is already present but can be ameliorated by
passive antibodies( example- botulism ,diphtheria, tetanus).
immune globulin intravenous:
Cytomegalovirus immune globulin respiratory syncytial virus immune
globulin.
Hepatitis B immune globulin
Rabies immune globulin
Tetanus immune globulin
37. REFERENCES
1. Tara V Shanbhag , Pharmacology for Medical Graduate ,Elsevier Publication ,Fourth
edition, 2019,237-256.
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Patil U.S, Jaydeokar A.V, Bandawane D.D, immunomodulators: a pharmacological review,
international journal of pharmacy & pharmaceutical sciences, vol 4, suppl 1, 2012
Essentials of Medical Pharmacology: K.D. Tripathi, 7th edition
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