Immunomodulators

Dr. Kaushik Mukhopadhyay

Assistant Professor, Dept. Of Pharmacology

ESI-PGIMSR

Immunomodulators

ImmunosupressionImmune

Toleranceimmunostimulation

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

GlucocorticoidsCalcineurin

InhibitorsAntiproliferative/Antimetabolites

Biologicals(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.

Perhaps the most effective immunosuppressive drugs in routine use

They target intracellular signalling pathways induced as a consequence of T cell–receptor activation

Tacrolimus Cyclosporine

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

Tacrolimus (FK506) is a macrolide antibiotic produced by Streptomyces tsukubaensis

Nephrotoxicity,

Neurotoxicity (e.g., tremor, headache, motor disturbances, seizures),

GI complaints,

hypertension,

hyperkalemia,

Hyperglycemia and diabetes

PK-

• 20-50% bioavailability

• CYP3A4

USE –

• Clinical indications for cyclosporine are kidney, liver, heart, and other organ transplantation

• Rheumatoid arthritis and psoriasis.

Cyclosporine, a cyclic polypeptide of 11 amino acids, is produced by the fungus Beauveria nivea

Nephrotoxicity,

GI complaints,

hypertension,

tremor,

hirsutism,

hyperlipidemia,

and gum hyperplasia

DDI - Sirolimus aggravates cyclosporine-induced renal dysfunction

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

Sirolimus is a macrocyclic lactone produced by Streptomyces hygroscopicus

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 inosinemonophosphate 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

Inf Li Xi mab

Prefix TargetOrigin

Subsystem

Suffix =

mab

Oma Li Zu mab

Ab ci xi mab

Ri tu xi mab

Ada Lim u mab

Omalizumab

Abciximab

Rituximab

Adalimumab

Levamisole – colorectal CA

BCG – intravesical therapy of superficial bladder cancer

Cytokines – Interferrons,

Filgramostim – chemotherapy induced myelosupression

Thalidomide – ENL, Multiple myeloma

Imiquimod

Thank You