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Immunosuppressants, Mechanism of action, Anti-TNFα, Clinical pharmacology…
Immunosuppressants
Mechanism of action
Both cyclosporine and tacrolimus are chemically different and bind to different molecular targets
but yet they share a common mechanism in inhibiting normal T-cell signal transduction.
They bind to immunophilin i.e. cyclosporine to cyclophilin and tacrolimus to FKBP-12.
After binding to immunophilin they subsequently interact with calcineurin and block its phosphatase activity and cause immunosuppressant effect.
This is because the calcineurin-catalyzed phosphorylation is necessary for movement of a component of nuclear factor of activated T lymphocyte (NFAT) into the nucleus.
NFAT is required to induce various cytokine genes such as IL-2 (prototype cell growth and differentiation factor).
Ultimately, they inhibit the gene transcription of IL-2, IL-3 and IFN - gamma and other factors produced by antigen stimulated T-cells.
Anti-TNFα
Adalimumab (human mAb to TNFα)
Certolizumab (anti-TNFα, humanized Fab fragment)
Golimumab (human mAb to TNFα)
Infliximab (chimeric antibody to TNFα)
Etanercept (decoy receptor)
Clinical pharmacology and tips
• Broad effects on cellular immunity
• Affects transcription of many genes; ↓ nuclear factor-κB activation,
↓ proinflammatory cytokines IL-1 and IL-6
• ↓ T-cell proliferation, cytotoxic T-lymphocyte activation and neutrophil and
monocyte function
• Can cause ↑ blood glucose, hypertension, cushingoid habitus, ↑ weight, ↑ risk
of infection, osteoporosis, glaucoma, cataracts, depression, anxiety, psychosis
Long-term treatment → adrenal suppression; withdraw slowly on alternate days
Anti–IL-6
Sarilumab (antibody to IL-6R)
Satralizumab (antibody to IL-6R)
Tocilizumab (antibody to IL-6R)
Siltuximab (chimeric mAb to IL-6)
S1PR Modulators
Ponesimod (S1P1 R)
Siponimod (S1P1,5R)
Ozanimod (S1P1,5R)
Fingolimod (S1P1,3,4,5R)
mTOR inhibitor
It inhibits activation of T lymphocytes and reduces the number of IL-2 and other T-cell growth factor receptors.
Although they form a complex with FKBP-12 similar to tacrolimus but this complex doesn't inhibit the calcineurin.
It acts by blocking the cell cycle progression at G1→S phase by inhibiting a protein kinase called mammalian target of rapamycin (mTOR).
Anti–IL-5
Benralizumab (blocking antibody to IL-5Rα)
Mepolizumab (antibody to IL-5)
Reslizumab (antibody to IL-5)
Therapeutic uses
Moderate-to-severe plaque psoriasis, active psoriatic arthritis,
moderately to severely active Crohn’s disease,
and moderately to severely active ulcerative colitis
Anti–IL-17
Brodalumab (antibody to IL-17RA)
Ixekizumab (antibody to IL-17A antibody)
Secukinumab (antibody to IL-17A antibody
Anti–IL-23
Guselkumab
Risankizumab
Tildrakizumab
Mycophenolate mofetil
prodrug that is
rapidly hydrolyzed to the active drug MPA,
a selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase,
an enzyme in the de novo pathway of guanine nucleotide synthesis
(inhibits GMP synthesis → selective inhibition of DNA synthesis in B and T cells
Therapeutic uses
Prophylaxis of transplant rejection,
used off-label for systemic lupus erythematosus, MS, sarcoidosis
Therapeutic uses
• Rheumatoid arthritis
Deplete circulating mature B lymphocytes
Therapeutic uses
MS
Deplete circulating mature B lymphocytes
Anti–IL-2
Basiliximab (antibody to IL-2R α chain/CD25)
Daclizumab (antibody to IL-2R α chain)
JAK1/JAK2 inhibitors
Ruxolitinib
Baricitinib
JAK1 inhibitors
Upadacitinib
Abrocitinib
JAK2 inhibitors
Fedratinib
Pacritinib
Therapeutic uses
• Prevent and treat transplant rejection;
treat GVHD in bone marrow transplant,
autoimmune disease, rheumatoid arthritis,
ulcerative colitis, MS, systemic lupus erythematosus
Therapeutic uses
• Rheumatoid arthritis, uveitis, ulcerative colitis,
vasculitis, sarcoidosis, systemic lupus erythematosus
Therapeutic uses
• Systemic lupus erythematosus, MS
Therapeutic uses
• Rheumatoid arthritis, idiopathic
thrombocytopenic purpura
Therapeutic uses
• Transplant rejection prophylaxis, transplant rejection rescue therapy,
rheumatoid arthritis, psoriasis and other skin diseases, xerophthalmia
Clinical pharmacology and tips
• Use algorithms to delay dosing until renal function okay in kidney transplant patients
• Side effects: tremor, hallucinations, drowsiness, coma, nephrotoxicity, hypertension, hirsutism, hyperlipidemia, gum hyperplasia
• Metabolized by CYP3A → drug interactions
• Severe interactions with antiarrhythmics
• Monitor Cp to avoid side effects
Therapeutic uses
• Transplant rejection prophylaxis, transplant
rejection rescue therapy
Clinical pharmacology and tips
• GI absorption is incomplete and variable
• Side effects include nephrotoxicity, neurotoxicity, GI complaints, and hypertension
• Glucose intolerance and diabetes mellitus
• Metabolized by CYP3A → drug interactions
• Monitor blood levels to avoid nephrotoxicity
Therepeutic uses
• Lupus nephritis
Clinical pharmacology and tips
• Side effects include nephrotoxicity, high blood pressure, neurotoxicity
• Metabolized by CYP3A4 → drug interactions
• ↑ risk of skin cancers and lymphomas
• ↑ risk of infections
Azathioprine
inhibits purine
synthesis and DNA replication
Therapeutic uses
• Adjunct for prevention of organ transplant
rejection, rheumatoid arthritis
Clinical pharmacology and tips
• Side effects include bone marrow suppression (leukopenia > thrombocytopenia > anemia)
• Susceptibility to infections, hepatotoxicity, alopecia, GI toxicity
• Avoid allopurinol because of drug interactions
Therapeutic uses
• Prophylaxis of organ transplant rejection,
incorporated into stents to inhibit occlusion
Clinical pharmacology and tips
• Side effects include GI (diarrhea and vomiting) and hematological (leukopenia, pure red cell aplasia) problems
• Contraindicated in pregnancy
Clinical pharmacology and tips
• Monitor blood levels
• Hyperlipidemia
• Anemia, leukopenia, thrombocytopenia
• GI effects, mouth ulcers, hyperkalemia
• Anticancer effects
• Metabolized by CYP3A → possible drug interactions
Therapeutic uses
• Astrocytoma, breast cancer, kidney and liver transplant reception prophylaxis,
pancreatic neuroendocrine tumor, renal
angiomyolipoma, renal cell cancer
Clinical pharmacology and tips
• Pharmacokinetics distinct from sirolimus
• Toxicity similar to that of sirolimus
Therapeutic uses
• Advanced renal cell carcinoma
Clinical pharmacology and tips
• Weekly intravenous administration
• Pharmacokinetics distinct from sirolimus and everolimus
• Toxicity similar to that of sirolimus
Belatacept
(binds to CD80/CD86, blocking CD28 costimulation)
Therapeutic uses
• Prevention of renal transplant rejection
Clinical pharmacology and tips
• ↑ Risk of posttransplant lymphoproliferative disorder involving the CNS, PML,
and serious CNS infections → administration of higher or more frequent dosing than the recommended doses is not recommended
Therapeutic uses
• Prevention and treatment of organ
transplant rejection, aplastic anemia
Therapeutic uses
Chronic lymphocytic leukemia, MS,
prevention and treatment of transplant rejection
Therapeutic uses
• Psoriasis
Therapeutic uses
• Systemic lupus erythematosus, lupus
nephritis
Anakinra
Anakinra is an FDA-approved recombinant, nonglycosylated form of human IL-1RA for the management of joint disease in rheumatoid arthritis.
Anakinra is also approved for cryopyrin-associated periodic syndromes (CAPS), a group of rare inherited inflammatory diseases associated with overproduction of IL-1
that includes familial cold autoinflammatory and Muckle-Wells syndromes, and for treatment of neonatal-onset multisystem inflammatory disease.
Canakinumab
It is an IL-1β mAb that is FDA-approved for CAPS and
active systemic juvenile idiopathic arthritis.
Therapeutic uses
• Prophylaxis of acute organ transplant
rejection
Rilonacept
approved for CAPS
Anti–IL-4
Dupilumab (mAb to IL-4Rα)
Therapeutic uses
Moderate-to-severe atopic dermatitis,
maintenance treatment of moderate to-severe asthma with eosinophilic phenotype or glucocorticoid-dependent asthma,
maintenance treatment of chronic rhinosinusitis with nasal polyposis
Therapeutic uses
• Maintenance treatment of severe asthma (eosinophilic phenotype)
• Mepolizumab is also indicated for eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome
Tocilizumab and sarilumab:
approved for the treatment of rheumatoid arthritis in patients who do not adequately respond to one or more disease-modifying agents.
Tocilizumab:
also approved for the treatment of giant cell arteritis,
polyarticular juvenile idiopathic arthritis,
systemic juvenile idiopathic arthritis,
and cytokine release syndrome
Satralizumab:
approved for the treatment of neuromyelitis optica spectrum disorder in adult patients who are positive for anti– aquaporin-4 antibody
Siltuximab:
approved for treatment of multicentric Castleman disease if patient is negative for HIV and human herpesvirus-8
Therapeutic uses
Patients aged 6 years or older with moderate-to-severe plaque psoriasis who are are candidates for systemic therapy or phototherapy
• Adults with active psoriatic arthritis, active ankylosing spondylitis, or active nonradiographic axial spondyloarthritis with objective signs of inflammation
Therapeutic uses
• Moderate-to-severe plaque psoriasis
• Guselkumab is also approved for active psoriatic arthritis
Therapeutic uses
• Rheumatoid arthritis, Crohn’s disease,
ankylosing spondylitis, plaque psoriasis,
psoriatic arthritis, ulcerative colitis
GM-CSF
Sargramostim (recombinant GM-CSF)
Therapeutic uses
• Acceleration of myeloid reconstitution following autologous bone marrow or peripheral blood progenitor cell transplantation
• Promotion of neutrophil recovery following chemotherapy
• Mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis and autologous transplantation in adult patients
• Acute exposure to myelosuppressive doses of radiation
Therapeutic uses
• Rheumatoid arthritis, graft-versus-host
disease, myelofibrosis, polycythemia vera
Therapeutic uses
Rheumatoid arthritis, psoriatic arthritis,
atopic dermatitis
Therapeutic uses
• Myelofibrosis
Therapeutic uses
• Rheumatoid arthritis, psoriasis, ulcerative colitis, polyarticular course juvenile idiopathic arthritis
Pan-JAK inhibitor
Peficitinib (inhibits JAK1, JAK2, JAK3, and TYK2; modest selectivity for JAK3
Natalizumab
(targets α4, blocking both α4β1 and α4β7 integrin)
Therapeutic uses
• MS (relapsing forms of and active secondary progressive disease), Crohn’s disease (moderate-to-severe active disease that does not adequately respond to conventional therapies or anti-TNFα)
Therapeutic uses
Peficitinib (approved in Japan and Korea):
rheumatoid arthritis
Therapeutic uses
• Ulcerative colitis and Crohn’s disease
(moderate-to-severe active disease)
Therapeutic uses
• Relapsing-remitting MS (all), secondary progressive MS (siponimod, ponesimod),
ulcerative colitis (ozanimod)
Glucocorticoids
Prednisone (prednisone →
prednisolone in liver)
Prednisolone
Methylprednisolone
Dexamethasone
Calcineurin Inhibitors
Cyclosporine
Tacrolimus
Voclosporin
Antiproliferative and Antimetabolic Agents
Sirolimus (mTOR inhibitor)
Everolimus (mTOR inhibitor)
Temsirolimus (mTOR inhibitor)
T-Cell Costimulatory Blocker
Antibodies Against Cell Surface Molecules
Antilymphocyte globulin/antithymocyte globulin
Anti-CD52
Alemtuzumab
Anti-CD20
Rituximab
Anti-CD20
Ocrelizumab
Anti-CD2
Alefacept
Anti-BLyS
Belimumab
Biologicals Targeting Cytokines and Their Receptors
Anti–IL-1
Anti–IL-12/IL-23
Ustekinumab
Small-Molecule Inhibitors of Cytokine Receptor Signaling
JAK inhibitors
JAK1/JAK3 inhibitor
Tofacitinib
Biologicals Targeting Integrins
Vedolizumab (blocks α4β7 but
not α4β1 integrin)