B.26

Question 1

Immunopharmacology I(cytotoxic agents)

Answer 1

1. Inhibitors of purine/pyrimidine synthesis (antimetabolites): Methotrexate, Leflunomide, Azathioprine, Mycophenolate-mofetil
2. Alkylating agent: Cyclophosphamide

Question 2

Cyclophosphamide

Answer 2

Chemistry: derived from mustard gas, the group called Bis(chlorethyl)amine;
MOA:
(1)prodrug,
(2)alkylates DNA on N7 of Guanosine, where it forms cross-links inside of DNA chain or between the 2 chains,
(3)inhibits both T and B cells;
IND: (immunosuppressive drug), SLE, Systemic sclerosis, vasculitis diseases, autoimmune glomerulonephritis, BM transplantation;
Dose: 2-10(12) mg/kg/T p.o OR as bolus treatment (750-1000mg monthly i.v.);
SEs: BM suppression, Oligospermia/ovarian dysfunction, GI disturbances, Hemorrhagic cystitis, Teratogenic (FDA category D), possibly mutagenic

Question 3

Methotrexate (MTX)

Answer 3

Antimetabolite;
MOA: Blocks DNA synthesis (inhibits DHF-reductase and causes depletion of folic acid), the polyglutamates of MTX persist longer in cells→ The anti-inflammatory mechanism is likely due to the inhibition of AICAR-transformylase by MTX-polyglutamate;
IND: Autoimmune diseases (Rheumatoid arthritis, Psoriasis, Chron’s disease, Multiple sclerosis), Oncologic diseases (breast-, head & neck-, Bladder-, Lung cancers, Osteosarcoma, Leukemias, Trophoblastic neoplasms);
Kinetics: p.o, i.v., intrathecally administration;
SEs: Liver enzyme elevation, Mucositis, Stomatitis, Diarrhea, Nephrotoxicity, Fibrotic pneumonitis, BM suppression(myelotoxicity, megaloblastic anemia), Teratogenic;
Reduce SEs: administration of Leucovorin (see MOA below)

Question 4

Leflunomide

Answer 4

MOA: Inhibits Dihydroorotate-dehydrogenase (DODH)→this blocks pyrimidine synthesis, Teriflunomide is the active metabolite of Leflunomide, they block T-cell proliferation and Ab production of B-cells;
IND: Rheumatoid arthritis, remitting-relapsing multiple sclerosis (teriflunomide);
SEs: Liver damage, Diarrhea, Skin exanthemas, Alopecia, HTN

Question 5

Azathioprine

Answer 5

MOA: it is transformed to 6-mercaptopurine (6-MP)→6-MP turns into 6-thio-IMP, which blocks AMP and GMP synthesis. It is more specific immunosuppressive agent than 6-MP (unknown why), mainly block cellular immunity;
Kinetics: Azathioprin is given p.o, thio-IMP is catabolized by xanthin-oxydase (has strong toxicity when given with allopurinol since allopurinol inhibits xanthine oxidase and thio-MP accumulates to toxic levels);
IND: Transplantations, IBDs, SLE, Vasculitis diseases, (Rheumatoid arthritis);
SEs: BM suppression, liver toxicity (rarely-hepatic vein occlusion syndrome=Budd Chiari)

Question 6

Mycophenolate-mofetil

Answer 6

Chemistry: isolated from Penicillium sp.;
MOA: blocks IMP-dehydrogenase→ blocks de novo GMP synthesis, lymphocytes can not use salvage-pathway for nucleotide uptake (they are extremely sensitive to de novo blockade);
IND: Solid organ transplantations (1st choice for heart, liver and kidney). GVH, SLE, Nephritis, Myasthenia, Psoriasis;
SEs: BM suppression, GI disorders, HTN

Question 7

Main groups of immunosuppressive drugs

Answer 7

1. Cytotoxic drugs
2. Inhibitors of cytokine (e.g. IL-2) production/action
3. Inhibitors of cytokine gene expression
4. Immunosuppressive antibodies
5. Other non-specific immunosuppressants
6. Interferon
7. Immunostimulants

Question 8

1. Cytotoxic drugs

Answer 8

→ Inhibitors of purine or pyrimidine synthesis (Antimetabolites):
- Methotrexate
- Leflunomide
- Azathioprine
- Myclophenolate-mofetil
→ Alkylating agents
- Cyclophosphamide

Question 9

2. Inhibitors of cytokine (e.g. IL-2) production/action

Answer 9

→ Calcineurin inhibitors:
- Cyclosporine A, Voclosporin
- Tacrolimus (FK506), Pimecrolimus
→ mTOR inhibitors:
- Sitrolimus (Rapamycin), Everolimus, Temsirolimus
→ Janus kinase inhibitors (JAKi):
- Tofactinib, Baricitinib, Ruxolitinib, Abrocitinib, Filgotinib, Upadacitinib, Peficitinib, Brepocitinib, Deuravacitinib

Question 10

3. Inhibitors of cytokine gene expression

Answer 10

→ Corticosteroids
→ Sulfasalazin

Question 11

4. Immunosuppressive antibodies

Answer 11

→ Blocking T-cell surface molecules involved in signaling of immunoglobulins:
- Anti-lymphocyte globulins (ALG)
- Anti-thymocyte globulins (ATG)
- Rho (D) immunoglobulin
→ Antibodies against T cells:
- Basiliximab
- Muromonab-CD3
→ Antibodies against B-cells:
- Rituximab
→ Antibodies against adhesion molecules/cytokines:
- Anti-TNFα: Infliximab, Adalimumab
- Anti-IL-1β: Canakinumab, Anakinra, Rilonacept
- Anti-IL-6R: Tocilizumab
- Anti-IL-17: Secukinumab
- Anti-IL-23: Ustekinumab
- Anti-α4-integrin: Natalizumab
- Anti-IL-13R: Dupilumab
- CTLA4 activator: Abatacept

Question 12

5. Other non-specific immunosuppressants

Answer 12

→Immunomodulants