Biomedical Engineering Reference
In-Depth Information
22.4 IMMUNOSUPPRESSIVE AGENTS
The proliferative nature of the immune response may be controlled with immunosuppressive drugs.
These drugs work by inhibiting the division of cells and, therefore, also suppress nonimmune cells
leading to side effects such as anemia, neurotxicity, hepatotoxicity, nephrotoxicity, and diabetes.
In addition the same immune system that we are suppressing in order to avoid graft rejection in
transplantation or reactivity against auto antigens in autoimmune diseases is responsible for patho-
gen infections and tumor surveillance; thus, the immunosupressed patient is liable to come down
with opportunistic infections and malignancies.
The most used immunosuppressive drugs are azathioprine, cyclosporine A, lel unomide, cyclo-
phosphamide, glucocorticoids, and methotrexate. The mechanism of action of these drugs on the
immune system is briel y described in the following.
Azathioprine is rapidly hydrolyzed in the blood to 6-mercaptopurine (Figure 22.5). In this form
(as a purine analog), it incorporates into the DNA, inhibiting nucleotide synthesis by causing
feedback inhibition in the early stages of purine metabolism. This ultimately prevents mitosis and
proliferation of rapidly dividing cells, such as activated B- and T-lymphocytes. Through this action,
Azathioprine is able to block most T cell functions and inhibit primary antibody synthesis.
Cyclosporine A is a small (11 amino acids) fungal (nonribosomal) cyclic peptide that is a
calcineurine inhibitor (Figure 22.6). Cyclosporine works by binding to a protein found in the
cytosol: cyclophilin. This complex inhibits calcineurin and ultimately leading to the inhibition
of IL-2 production and secretion. The interaction between IL-2 and the IL-2 receptor is crucial
in the activation and differentiation of B and T cells. Cyclosporine is therefore a highly effective
immunosuppressant. The clinical introduction of cyclosporine has signii cantly increased graft
survival and signii cantly reduced the occurrence of acute rejection in transplant patients.
Lel unomide (Figure 22.5) interferes with an enzyme called dihydroorotate dehydrogenase, an
enzyme involved in the de novo pyrimidine synthesis. Thus lel unomide inhibits the synthesis of
pyrimidines and thereby inhibits lymphocyte proliferation, and reduces adhesion molecules that
allow the immune cells to home in to the area of inl ammation. As a result the immune process is
slowed. The drug is developed for RA and is also used in combination with methotrexate.
Cyclophospham ide is an inactive cyclic phospham ide ester of mechloretham ine. It is transfor med
via hepatic and intracellular enzymes to active alkylating metabolites, 4-hydroxycyclophophosph-
amide, aldophosphamide, acrolein, and phosphoramide mustard (Figure 22.7). Cyclophosphamide
causes the prevention of cell division primarily by cross-linking DNA strands. It is therefore referred
NO
2
N
N
H
3
C
S
S
N
N
N
N
N
N
N
N
Azathioprine
6-Mercaptopurine
N
N
O
CH
3
O
F
3
C
Lelunomide
FIGURE 22.5
Azathioprine is an immunosuppressant and it is a prodrug, converted in the body to active
metabolites 6-mercaptopurine and 6-thioinosinic acid, which is a purine synthesis inhibitor. Lel unomide is
used in moderate to severe RA and psoriatic arthritis and is a pyrimidine synthesis inhibitor.
