Calcineurin INHIBITORS | CYCLOSPORINE | TACROLIMUS PHARMACOLOGY.
Hello dear students welcome back to the second part of the immunosuppressant agents so just to glance through let us see how this immoral response and still mediated immune response will be mediated so quickly the macrophage which is called as antigen presenting cell which will be associated with the major histocompatibility complex which gets attached with the
Antigen and this complex will be attaching with the cd for helper t cells and the cd4 helper t cells will be activated by the interleukin 1 and following that with the help of interlock into the cd4 helper t cells will be activated on the other end the antigen which will be combining with the b cells leading to differentiation and proliferation of the b cells
To form the plasma cells so thereby the plasma cells will be releasing the anti bodies so to this process the cytokine which is at least from the activated cd4 t cells will also enhance the differentiation and proliferation of the b cells leading to the formation of plasma cells which in turn releases the antibody and this antibody will combine with the antigen
And there will be neutralization of the antigen on the other end the antigen which is presenting to the macrophages will be binding to the precursor cytotoxic lymphocytes and this precursor cytotoxic lymphocytes will be activated with the help of the interleukin-2 released from the activated cd4 helper t cells and also cd4 helper t cells directly helps in the
Maturation as well as the activation process of the cytotoxic lymphocytes and thereby there will be formation of the mature cytotoxic lymphocytes and this mature cytotoxic lymphocytes will be binding with the antigen which has been produced by the foreign cells leading to lysis of the foreign cells so now let us see which are all the targets where you can
Identify so that those targets can be used as the immunosuppressant agents so next you have first we have glucocorticoids glucocorticoids example was spread this alone so this glucocorticoids will going to inhibit the activity of the macrophages that is the antigen presenting cell activity will be hindered so thereby the macrophages fails to identify the antigen
And also it will going to inhibit the interlock in one activity as well as interleukin to activity so next we have a cytotoxic drug cytotoxic drugs are nothing but they are also called as the anti-proliferative drugs examples are azathioprine methotrexate cyclophosphamide chlorambusel mycophenolate morphetyl so this cytotoxic drug will going to mainly inhibit
The differentiation and proliferation of the beta cells along with it it will also inhibit the activity of the activated cd4 helper t cells so when next coming to the cyclosporin tacrolimus which is the calcium urine inhibitors and xerolimus is the hemptor inhibitors so these drug will going to mainly inhibit the cd4 helper t cells thereby cd4 helper t cells
Will not be activated and also it inhibits the interlock into activity so that the cd4 helper t cells will not be activated on the other hand we have got mural monap cd 3 and anti-thymocyte globulin so these drugs will mainly again inhibit the activity of the cd4 helper t cells so next coming to the major mechanism of action produced by calcineurin inhibitor
Hemtor inhibitors so as you can see here it is a macrophage which is also called as the antigen presenting cell which will be associated with the major histocompatibility complex class 2. it carries the antigen and this antigen will be binding with the t cell receptors located on the helper t cells so this is the helper t cells so following the attachment
Of antigen with the macrophage this antigen comes and bind with the t cell receptors so on the surface of the helper t cells you have got other two receptor sites that is cd4 as well as cd3 so once the antigen binds to the t cell receptors this will lead to activation of tyro kinase this tyrosine kinase will lead to phosphorylation of the phosphor lipase c so
There will be phosphor phosphorylation of the phospholiphc with the help of tyrosine kinase and following that there will be formation of the phosphatidyl enosin this phosphate and this phosphatidyl hynosine base phosphate will going to release diazel laser all where subsequently it will going to activate the protein kinase c which will mediate the other cell
Mediated responses and on the other hand there will be release of the inos acetyl triphosphate this ionocetal triphosphate will going to increase the intracellular calcium levels so along with the raised intracellular calcium levels this calcium will going to combine with the calmodillin so this calmodyline calcium complex will going to activate the calcium
So activated calcium urine will going to dephosphorylate the n-fat in fat stands for nuclear factor of activated t cells so there will be dephosphorylation to release in fat this end fat will be translocated into the nucleus in the nucleus there will be transcription of the cytokine interlocking two genes and there will be production of the specific mrna
Which is responsible for the release or production of the interleukin 2 so this interlock into which is produced will going to act on the interleukin 2 receptor which is located on the surface of the helper t cells leading to proliferation of the t cells so along with that there is a emptor that is mammalian target of rapamycin which will also enhance the
T cell proliferation so next let us see the target sites here so i got immunophilin you have got two immunoflin one is the cyclophilin and another is the one more iminoflin where the tackle lemurs will be binding to that site that is fk binding protein so now to this cyclophilin so this is the cyclophilin the drug which is binding to the cyclophyllin is the
Cyclosporine so this is the cyclosporine will be binding with the cyclophiline and this complex will going to inhibit the calcium urine activity on the other hand we have got one more immuno filling that is fk binding protein to this fk binding protein the tacrolimus which is again the calcium urine inhibitor this tacrolimus will be binding to fk binding protein
And this complex will going to inhibit the calcium urine activity on the other hand we have got mtar inhibitor that is serolimus so this is the serolima serolimas will going to inhibit the mtor activity before inhibiting it will combine with the fk binding protein similar to that of the tachrolimus and these complex will going to inhibit the emptor activity and
There is one more drug that is mural monap cd3 which will going to inhibit the cd3 activity which is present on the surface of the helper t cells so this is the major mechanism of action of the casino urine inhibitors as well as m to organizers so next coming to the other activity which is seen with respect to cyclosporine so cyclosporine in addition it will
Going to stimulate the transforming growth factor beta which in turn inhibits the interlock into activity and further leading to inhibition of the t cell function so following that there will be inhibition of the cytotoxic lymphocyte activity so basically the cyclosporine will going to inhibit the cell mediated immune response so this cyclosporin can be made
Utilized during graft rejections during renal transplant liver transplant heart transplant and bone marrow transplantation so usually this can be administered through oral route as well as intravenous route through orally it should be administered 12 hours prior to the surgery and if there is a any rejection which takes place during surgery you can go with the
Intravenous cyclosporine and please remember that cyclosporine has got dose dependent toxicity that is it can cause nephrotoxicity so nephrotoxicity is the most common dose limiting toxicity of the cyclosporine apart from that other side effects of cyclosporine are it will increase the blood pressure it will increase the potassium levels as well as urea levels
It can cause hyperkalemia and hyperuricemia it can cause aerosotism it can cause hypertrophy of the gum it can cause tremors it can cause seizure it can cause opportunistic infections so apart from their indication in preventing the graph rejection this cyclosporin is also indicated in autoimmune diseases like in case of rheumatoid arthritis bronchial asthma
Chronic uveitis dermatomyositis psoriasis inflammatory bowel disease and the hyplastic anemia and one should remember that whenever you are giving a cyclosporine you need to understand the microsomal enzyme inhibitor as well as microsomal enzyme inducer concept so here you can see that the phenytoin rifampicin and the phenobarbiton are the enzyme inducers
Where these group of drugs will going to metabolize the cyclosporine leading to decreased concentration of the cyclosporine thereby in turn they will going to decrease the efficacy of the cyclosporine so on the other hand you have got microsomal enzyme inhibitors that is erythromycin ketoconazole etc these microsomal enzyme inhibitors will go into decrease the
Metabolism of the cyclosporine thereby increasing the concentration of the cyclosporine which can lead to toxicity of cyclosporine so please remember that there are some drug interaction which can occur with cyclosporine as we discussed in the earlier slide cyclosporine those limiting toxicity is nephrotoxicity so cyclosporine should not be combined with the
Other group of drugs which has got nephrotoxicity the example can be remembered as van so this van drugs have got nephrotoxicity as a side effects so v stands for vancomycin a stands for glycoside a stands for amphotericin b and n stands for non-steroidal anti-inflammatory drugs so these are the group of drugs you should avoid in combination with cyclosporine
As this combination will going to increase the nephrotoxicity risk apart from that you should also avoid usage of the potassium supplementation as well as potassium spearing diuretics along with the cyclosporine as you already know that cyclosporine will increase the potassium levels so if you are giving a potassium supplementation and potassium sparing diuretics
It will going to increase the potassium levels so this was regarding the cyclosporin which is the calcium urine inhibitors so next we have a tacrolimus again tacrolimus is also a calci neuron inhibitor but compared with the calcium cyclosporin this stackroll ms has got 100 times more potent than the cyclosporine so that’s why the tacrolimus can be used in the
Acute rejection reactions so when compared to the cyclosporine tachrolimus can also be given through oral root as well as the injection but please remember that for absorption to takes place the cyclosporine was dependent on bile whereas tacrolimus to absorption to takes place it does not depends on the bile so that’s why it can be used effectively during liver
Transplantation so other indications of tacrolimus is it can be used in atopic dermatitis and chronic and crohn’s disease so again similar to that of the cyclosporine tacrolimus has got those limiting toxicity that is nephrotoxicity in addition to this this tacrolimus will also cause side effects such as dna that is it can predispose the patient to diabetes it
Can cause diarrhea it can lead to neurotoxicity it can lead to hello basia so this was about the class on calcium inhibitors you have learnt about cyclosporine and the tacrolimus how the inhibit calcineurin activity and their uses as well as the dose limiting toxicity that is nephrotoxicity so if you find this video useful please do subscribe to my channel i
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Transcribed from video
Immunosuppressants PART – 2 | Calcineurin INHIBITORS | CYCLOSPORINE | TACROLIMUS By ilovepharmacology