Immunomodulators

Dr. Kaushik Mukhopadhyay

Assistant Professor, Dept. Of Pharmacology
ESI-PGIMSR
 Immunomodulators

Immune
Immunosupression immunostimulation
Tolerance

a state of unresponsiveness of the immune

system to substances or tissue that have
the capacity to elicit an immune response.
1. Inhibition of gene expression
2. Selective attack on clonally expanding
lymphocytes
3. Inhibition of intracellular signalling
4. Neutralisation of Cytokines & receptors
required for T-cell stimulation
5. Selective depression of T-cells (or others)
6. Inhibition of co-stimulation by APC
7. Inhibition of Lymphocyte-target cell
interactions
8. Supression of innate immune cells &
complement activation (not shown here)
 Immunosupressants

Calcineurin Antiproliferative/ Biologicals

Glucocorticoids
Inhibitors Antimetabolites (Antibodies)
 Glucocorticoids have broad anti-inflammatory effects on multiple components of cellular
immunity.

 MOA –

To effect longer-term responses, steroids bind to receptors inside cells; either these
receptors, glucocorticoid-induced proteins, or interacting proteins regulate the
transcription of numerous other genes

 Glucocorticoids lyse and induce the redistribution of lymphocytes,

 Curtail activation of NF-КB, which increases apoptosis of activated cells, key pro-
inflammatory cytokines such as IL-1 and IL-6 are downregulated.

 T cells are inhibited from making IL-2 and proliferating.

 The activation of cytotoxic T lymphocytes is inhibited.

 Neutrophils and monocytes display poor chemotaxis and decreased lysosomal enzyme
release.
 combined with other immunosuppressive agents to prevent and treat
transplant rejection.
 graft-versus-host disease in bone-marrow transplantation.
 Glucocorticoids are routinely used to treat auto-immune disorders such
as
 RA
 SLE, psoriasis
 Asthma and other allergic disorders,
 inflammatory bowel disease
 acute exacerbations of MS (see "Multiple Sclerosis").
 to block first-dose cytokine storm caused by treatment with
muromonab-CD3 and to a lesser extent ATG
 Growth retardation in children,
 Avascular necrosis of bone, osteopenia
 Increased risk of infection
 Poor wound healing
 Cataracts
 Hyperglycemia
 Hypertension

The advent of combined glucocorticoid + calcineurin inhibitor regimens

has allowed reduced doses or rapid withdrawal of steroids, resulting in
lower steroid-induced morbidities.
 Tacrolimus Cyclosporine

 Perhaps the most effective immunosuppressive drugs

in routine use
 They target intracellular signalling pathways induced as
a consequence of T cell–receptor activation
 Tacrolimus (FK506) is a macrolide antibiotic produced by
Streptomyces tsukubaensis
 PK-
• Variable
• Trough level correlates better with clinical events
(100-200 ng/mL )
• The t 1/2 of tacrolimus is 12 hours
• CYP3A4
 USE –
• prophylaxis of solid-organ allograft rejection
• GVHD
 Nephrotoxicity,
 Neurotoxicity (e.g., tremor, headache, motor
disturbances, seizures),
 GI complaints,
 hypertension,
 hyperkalemia,
 Hyperglycemia and diabetes
 Cyclosporine, a cyclic polypeptide of 11 amino acids, is produced by
the fungus Beauveria nivea

 PK-
• 20-50% bioavailability
• CYP3A4
 USE –
• Clinical indications for cyclosporine are kidney, liver, heart,
and other organ transplantation
• Rheumatoid arthritis and psoriasis.
 Nephrotoxicity,
 GI complaints,
 hypertension,
 tremor,
 hirsutism,
 hyperlipidemia,
 and gum hyperplasia
 DDI - Sirolimus aggravates cyclosporine-induced renal dysfunction
 Sirolimus is a macrocyclic lactone produced by Streptomyces
hygroscopicus

 PK-
• Systemic availability is 15%
• A loading dose of three times the
maintenance dose will provide
nearly steady-state
• CYP3A4
 USE –
• Prophylaxis of organ transplant
rejection usually in combination
• At risk of calcineurin inhibitor–
associated nephrotoxicity MOA
 dose-dependent increase in serum cholesterol
 Lymphocele, a known surgical complication associated with renal
transplantation
 cyclosporine and sirolimus interact, and their administration
should be separated by time

Everolimus
chemically and clinically related to sirolimus but has distinct
pharmacokinetics.
The main difference is a shorter t1/2 and thus a shorter time to
achieve steady-state concentrations of the drug.
 It is an imidazolyl derivative of 6-mercaptopurine
 MOA –
cleaved to 6-mercaptopurine (via Glutathione),
A fraudulent nucleotide, 6-thio-IMP, is converted to 6-
thio-GMP and finally to 6-thio-GTP, which is
incorporated into DNA.
converted to additional metabolites that inhibit de
novo purine synthesis
Cell proliferation thereby is inhibited, impairing a
variety of lymphocyte functions.
 PK –
 Well absorbed orally
 T1/2 = 10 mins (active metabolites)
 USE-
 adjunct for prevention of organ transplant rejection
 Severe RA
 ADR –
 The major side effect of azathioprine is bone marrow suppression
 increased susceptibility to infections (HSV),
 hepatotoxicity, alopecia, GI toxicity, pancreatitis,
 It is an ester of mycophenolic acid (MPA).

 MOA –
 MMF is a prodrug that is rapidly
hydrolyzed to the active drug, MPA
 MPA - a selective, noncompetitive,
reversible inhibitor of inosine
monophosphate dehydrogenase (IMPDH),
 IMPDH is an enzyme @ de novo pathway
of guanine nucleotide synthesis
 B and T lymphocytes are highly
dependent on this pathway for cell
proliferation (others- salvage pathway)
 PK –
 The parent drug - within a few minutes. The t1/2 of MPA is 16 hours.
 T1/2 = 10 mins (active metabolites)
 USE-
 MMF is indicated for prophylaxis of transplant rejection, and it
typically is used in combination (Glucocorticoid/Calcineurin)
 off label - SLE
 ADR –
 Gut -
 Hematologic – PRCA, leucopenia
 Congenital anomaly
 Methotrexate
 Cyclophosphamide
 Chlorumbucil
 Origin Suffix =
Prefix Target
Subsystem mab

Inf Li Xi mab
Oma Li Zu mab Omalizumab

Ab ci xi mab Abciximab

Ri tu xi mab Rituximab

Ada Lim u mab Adalimumab

 Levamisole – colorectal CA
 BCG – intravesical therapy of superficial bladder cancer
 Cytokines – Interferrons,
 Filgramostim – chemotherapy induced
myelosupression
 Thalidomide – ENL, Multiple myeloma
 Imiquimod
Thank You