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Cyclosporine
Introduction
Pharmacology
Fig A showing the cascade of molecular events that occurs when T cell receptor
gets the signal. In T cell cytoplasm, a series of tyrosine kinase are activated which
phosphorylated tyrosine residues on CD-3 and other tyrosine kinase which will
further initiate downstream signaling pathway. Several important pathways are
activated like Phospholipase C which hydrolyses phosho-inositol and releases IP3. IP3
binds to its receptor and causes release of calcium from Endoplasmic reticulum.
Increased concentration of calcium inside the cell causes the activation of
Calcineurin, which in turn dephosphorylates nuclear factor activated T cell proteins
(NFAT) which translocates to nucleus and binds to IL-2 promoter and causes
transcription of IL-2 genes.
Showing when T cell receptor gets signal in the presence of Cyclosporine. Normal
downstream signaling occurs. Cyclosporine inside the T cell binds to cyclophilin, this
complex then interacts with calcineurin and prevents its activation by calcium.
Thereby downstream process of dephosphorylation of NFAT is blocked and it NFAT
can no longer enter nucleus. Preventing the production of IL-2 mRNA.
Drug-drug interaction
Calcium channel antagonists like nifedipine, verampamil and diltiazepam
increases the CsA concentration in blood and CsA metabolities reach 5 times
higher concentration in plasma than without calcium channel antagonists.
So, concomitant use of other medicine should be done very carefully.
Phramacokinetic studies have shown that calcium channel antagonists like
diltiazem increase the terminal hal life of CsA by 2 hours.
Since CsA is extensively metabolized in liver by cytochrome P450 (drug
metabolizing enzymes) so drugs which are inducers of CYP enzymes can
reduce the concentration of CsA in plasma and can lead to increased
requirement of CsA and in unmonitored situation can lead to organ rejection.
On the other hand when CYP inducers are withdrawn without appropriate
reduction in dose can lead to elevated levels of CsA in the blood and causes
adverse drug reactions.
Inducers and inibitors of P450 like Rifampacin and Ketoconazole changes the
bioavailability of the CsA which could not be predicted even on considering
the phenomenon of induction and inhibition. This suggests that significant
amount of CsA being metabolized by intestines limiting the amount of CsA
reaching the systemic circulation.
So, it is evident that combination of CsA with other drugs that could interact
with CsA metabolism or with those drugs with whom CsA can compete can
result in serious adverse effects.
CsA has toxic effects on numerous organ systems that comprises of immune
system, renal, hepatic and nervous system. However CsA is still being used
extensively with therapeutic drug monitoring which involves adjustment of
dose or withdrawal of the drug.
Immunological complications
Transplant patients on CsA treatment have lower risk of getting bacterial and
fungal infections, this fact can be associated with lower requirement of
steroid. However, these patients have increased risk of getting viral
infections such as herpes simplex, cytomegalovirus etc.
Renal complications
Hepatic complications
Neurological complications
Hypertensive complications
OTK3 orthoclone:
Two types of side-effects may occur that are either the consequences of over
immunosuppression or activation of immune system, since ORT/OKT3
behaves as a foreign antigen.
Pharmacology:
Used in organ transplant prophylaxis, Orthoclone OKT3 (Ortho Biotech) or
OKT-3 binds specifically to the CD-3 complex, which is involved in antigen
recognition and cell stimulation, on the surface of T lymphocytes.
Immediately after administration CD-3-positive T lymphocytes are abruptly
removed from circulation. It has been effective in reversing corticosteroid-
resistant acute rejection in renal, liver, and cardiac transplant recipients.
Mechanism of action:
T cell recognizes a substance as foreign and produces a cytotoxic effect when it binds to MHC
different from host. T cell recognizes antigen as self or own by its recognition sites. If T cell
recognizes cell as non-self, it causes proliferation of T cells and produces cytotoxic response
towards antigen.
OKT3 is excessively powerful immunosuppressive drug which has wide array of adverse
reaction, discussed later.
Toxicity:
Under in vitro conditions, OKT3 has initially stimulating effect on the T cells
on binding to CD3 complex. It causes release of lymphokines such as TNF,
interleukin 2, γ-interferon due to activation of T cells. Since OKT3 is a murine
monoclonal antibody, host immune system gets immunized against antibody
and produces two types of anti-OKT3 CD3 antibody, anti-mouse isotype and
anti-idiotype. Anti-idiotypic antibody blocks the binding of OKT3 and nullifies
its effect. In some patients increase in the concentration of IgE is also
observed which causes anaphylactic reactions.
Patient with fluid overload develop sever pulmonary oedema upon treatment
with Muromonab, patients had developed cytokine release syndrome apart
from cardio toxicity.
Severe pulmonary oedema has also been reported, people suffering with this
involved increased pulmonary vascular permeability and reduced left
ventricle compliance.
OKT3 has been suspected to increase the coagulation and causes thrombosis
leading to organ rejection. Apart from being a potent immunosuppressive
agent OKT3 also posses a risk of post transplantation malignancy
Discussion:
On the other hand, CsA is small molecule which undergoes extensive hepatic
metabolism and not suitable for concomitant use with other drugs. As drugs
which modulates the activity of CYP enzymes affects the bioavailability of
CsA. It has a shorter half-life of 17-24 hours. Removing CsA in case of
overdose is comparatively easy by introducing an inducer of CYP enzyme
which will lower plasma concentration of CsA. When we compare the adverse
effects both drugs have on organ system, OKT3 is better than CsA as due to
several reasons. Major side effect of OKT3 is cytokine release syndrome
which could be overcome by injecting bolus dose of corticosteroid 1 hour
before OKT3 administration; fever could be controlled by administering
acetaminophen 1 hour before administering OKT3. Other severe side effects
could be controlled by administering anti-histamines I.V before starting
OKT3, OKT3 is given in slow infusion rather than bolus dose to control side
effects. Furosamide is used to control pulmonary edema. Whereas if we see
adverse effects of CsA, there exists no combination regime to control or to
reduce the wide spread toxic effect. But still CsA is used widely across the
globe because it is cheap and easy to administer.
But as the drug discovery has progressed, a new form of cyclosporine has
been developed, Cyclosporin G which has less nephrotoxicity than
conventionally used cyclosporine.