Transcript 3. Antiproliferative and antimetabolic drugs

Drugs affecting
immune function
Immunopharmacology
Immunomodulating agents
- Classification • Immunosuppressive agents
(immunosuppressants)
• Immunopotentiating agents
(immunostimulants)
• Immunization (prophylaxis)
•
Vaccines; Immune globulin
Immunosuppressants
• 1. Glucocorticoids
•
(糖皮质激素类)：
prednisolone (泼尼松龙) , methylprednisolone (甲泼尼松龙)
• 2. Calcineurin inhibitors (钙调磷酸酶抑制剂) ：
•
cyclosporine (CsA, 环孢素), tacrolimus
(FK506, 他克莫司)
• 3. Antiproliferative and antimetabolic drugs (抗增殖/抗代谢类)：
•
rapamycin (雷帕霉素, sirolimus 西罗莫司), mycophenolate mofetil (MMF, 霉酚酸酯),
azathioprine (Aza, 硫唑嘌呤) , cyclophosphamide (CTX, 环磷酰胺)
• 4. Antibodies (抗体类)：
•
antithymocyte globulin (ATG, 抗胸腺细胞球蛋白)
• 5. Active TCM components (中药有效成分)：
•
tripterygium glycosides (雷公藤总苷)
Immunosuppressants
- application • 1. Organ transplantation therapy
•
•
Multi-tiered approaches to immunosuppressive drug therapy
Established rejection: blocking activated T lymphocytes, such as
high dose glucocorticoids, polyclonal antilymphocyte antibodies, or
muromonab-CD3 mAb
•
Maintenance immunotherapy: such as calcineurin inhibitors,
glucocorticoids and mycophenolate mofetil
•
Intensive induction and lower-dose maintenance
• 2. Autoimmune diseases
• Rhumatic arthritis, rheumatoid arthritis, osteoarthritis, systemic lupus
erythematosus, polyarthritis nodosa, nephritic syndrome, etc.
• 3. Others
hypersensitivity
Immunostimulants
• 1. Microbial products:
•
Bacillus Calmette-Guerin (BCG,卡介苗)
•
恶性黑色素瘤、白血病、肺癌
• 2. Immunological products from human or
animals:
•
•
interferons (干扰素), interleukin-2 (IL-2, 白介素-2)
IFN:毛状细胞白血病、恶性黑色素瘤、对肾细胞癌
• 3. Chemical drugs:
•
•
levamisole (左旋咪唑 )
降低免疫缺陷的感染发生率、慢性反复细菌感染
• 4. Others:
•
polysaccharides (多糖类), active TCM components
Immunostimulants
- application • 1. Immunodeficient diseases
• 2. Chronic refractory infections
• 3. Tumors
•
- Adjuvant therapy -
Immunosuppressants
Cell-mediated and humoral immune responses
Immune responses and the actions of immunomodulating agents
1. Glucocorticoid drugs
Prednisone
泼尼松
H
Prednisolone
泼尼松龙
1. Glucocorticoid drugs
 Effects on immune
 Suppressing immunological functions and allergy
 a) inhibiting all stages of immune responses
 b) inducing apoptosis of T and B lymphocytes
 c) inhibiting transcription factor － such as nuclear
factor B (NF-B) or activating protein-1 (AP-1)
activity
1. Glucocorticoid drugs
One of glucocorticoids’ actions:
Inhibition of gene transcription (AP-1 and NFB)
1. Glucocorticoid drugs
 Clinical uses
 (1) Autoimmune disorders: reumatic fever, reumatic
carditis,
rhumatic
arthritis,
rheumatoid
arthritis,
osteoarthritis, systemic lupus erythematosus, polyarthritis
nodosa, nephritic syndrome, etc.
 (2) Rejection of organ transplantation
 (3) Allergic diseases: urticaria, serum sicknss, contact
dermatitis, drug allergic reactions, chronic severe asthma,
status asthmaticus, angioneurotic edema, etc.
2. Calcineurin inhibitors
钙调磷酸酶
环孢素
他克莫司 (FK506)
2. Calcineurin inhibitors
• Cyclosporin (cyclosporin A, CsA)
• Pharmacological effects
• Suppressing T-cell-dependent immune mechanisms.
• Inhibiting antigen-triggered signal transduction in T-cells,
blunting expression of many cytokines including IL-2, and the expression
of antiapoptotic proteins.
•
Forming a complex with cyclophilin (环孢素受体) , which binds to calcineurin,
inhibiting Ca2+-stimulated dephosphorylation of the cytosolic component of NFAT.
This prevents NFAT dephosphorylation such that NFAT does not enter the nucleus,
gene transcription is not activated, and the T lymphocyte fails to respond to specific
antigenic stimulation.
• Increasing TGF-β expression, so inhibiting IL-2-stimulated T-cell
proliferation and generation of cytotoxic T lymphocytes.
2. Calcineurin inhibitors
• Clinical uses
• Organ transplantation
(kidney, liver, heart, and
other organs)
• Autoimmune disorders
(systemic lupus
erythematosus, rheumatoid arthritis, psoriasis (银屑病),
etc.)
2. Calcineurin inhibitors
• Adverse reactions
• Renal dysfunction: especially combined with other renal toxic
drugs
• Hepatic toxicity
• CNS toxicity: tremor, convulsion, coma, etc.
• Increased risk of neoplasia
• Increased susceptibility to infections
• Others: hirsutism, hypertension, hyperlipidemia, and gum
hyperplasia , etc.
2. Calcineurin inhibitors
• Tacrolimus (FK506)
• Binding to FKBP (FK506-binding protein)
• Used in organ transplantation
• CNS, renal, reproductive toxicities
3. Antiproliferative and
antimetabolic drugs
西罗莫司
霉酚酸酯
3. Antiproliferative and
antimetabolic drugs
• Rapamycin (Rapa, sirolimus)
• Pharmacological effects
• Inhibiting T-cell activation and proliferation
downstream of the IL-2 and other T-cell growth factor
receptors
•
It binds to and inhibits a protein kinase, designated
mammalian target of rapamycin (mTOR), which is a key enzyme in
cell-cycle progression
3. Antiproliferative and
antimetabolic drugs
• Clinical uses
• prophylaxis of organ transplant rejection in
combination with a calcineurin inhibitor and
glucocorticoids
3. Antiproliferative and
antimetabolic drugs
• Adverse reactions
• Gastrointestinal effects
• Other adverse effects: anemia, leukopenia,
thrombocytopenia, hypokalemia or
hyperkalemia, fever. Delayed wound healing
may occur with sirolimus use.
3. Antiproliferative and
antimetabolic drugs
• Mycophenolate mofetil (霉酚酸酯，MMF)
• A prodrug of mycophenolic acid (MPA)
• Pharmacological effects
• a selective, noncompetitive, and reversible inhibitor
of inosine monophosphate dehydrogenase (IMPDH,
次黄嘌呤单核苷磷酸脱氢酶) , which is an important enzyme in the
de novo pathway of guanine nucleotide (鸟嘌呤苷酸) synthesis
and B and T lymphocytes are highly dependent on this
pathway for cell proliferation
3. Antiproliferative and
antimetabolic drugs
• Clinical uses
• Prophylaxis of transplant rejection, and it
typically is used in combination with glucocorticoids
and a calcineurin inhibitor, but not with azathioprine
• Systemic lupus erythematosus, rheumatoid
arthritis, psoriasis (银屑病) , etc.
3. Antiproliferative and
antimetabolic drugs
• Adverse reactions
• Gastrointestinal and hematologic toxicities
including diarrhea, vomiting and leukopenia
3. Antiproliferative and
antimetabolic drugs
• Azathioprine (Aza)
3. Antiproliferative and
antimetabolic drugs
Phamacological effects
• Interfering purine nucleotide synthesis in
lymphocytes.
• Azathioprine appears to be a more potent
immunosuppressive agent than 6-mercaptopurine,
which may reflect differences in drug uptake or
pharmacokinetic differences in the resulting
metabolites.
3. Antiproliferative and
antimetabolic drugs
• Clinical uses
• Organ transplantation, systemic lupus
erythematosus, rheumatoid arthritis, etc.
3. Antiproliferative and
antimetabolic drugs
• Adverse reactions
• Bone marrow suppression, including leukopenia
(common), thrombocytopenia (less common), and/or
anemia (uncommon) bone marrow suppression,
including leukopenia (common), thrombocytopenia
(less common), and/or anemia (uncommon)
• Increased susceptibility to infections
(especially varicella and herpes simplex viruses),
• Hepatotoxicity, alopecia, GI toxicity,
pancreatitis, and increased risk of neoplasia
4. Antibodies
• Antithymocyte globulin (抗胸腺细胞球蛋白)
• Inducing immunosuppression: renal transplant patients
with delayed graft function to avoid early treatment with the
nephrotoxic calcineurin inhibitors and thereby aid in recovery
from ischemic reperfusion injury.
• Also used for acute rejection of other types of organ
transplants and for prophylaxis of rejection.
• Inducing allergic reactions, including fever and chills with
the potential for hypotension. including fever and chills with
the potential for hypotension.
4. Antibodies
• Muromonab-CD3 (OKT3, 莫罗单抗-CD3,
• anti-CD3 monoclonal antibodies )
• Binding to the εchain of CD3, a monomorphic
component of the T-cell receptor complex involved in
antigen recognition, cell signaling, and proliferation
• Acute organ transplant rejection
• “Cytokine release syndrome": high fever,
chills/rigor, headache, tremor, nausea/vomiting,
diarrhea, abdominal pain, malaise, myalgias,
arthralgias, and generalized weakness.