Immunosuppressive Drug Therapy

IMMUNOSUPPRESSIVE DRUG THERAPY BY Abhishek S. Sharma

Immune Response Immune response is a highly sophisticated defense mechanism of the body which is composed of Cell mediated and Humoral immunity (Nossel 1987) . Both of these response have a high level of specificity directed to antigenic epitopes expressed on molecular components of infectious agents , foreign (Grafts) or transformed (Malignants) , or even autologous cells (autoimmunity).

Cells participating in the immune response

General principles of Immunosuppression Immunosuppression:-Immunosuppression is a process of inhibiting the immune response at different steps . Principles governing Immunosuppression:Primary immune response can be more effectively suppressed then secondary response . If immunologic memory has been established immunosuppressive therapy will have modest effects. Immunosuppressive therapy is most effective before generation of immune response. But ironically autoimmune disease like Rheumatoid arthritis are treated after the response is generated

Sites of action of specific immunosuppressive drugs on various stages of immune response

Pharmacological Classification of Immunosuppressant 

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Glucocorticoids: Immunosuppressive mechanism Anti – inflammatory effects Cytostatics: Alkylating agents Antimetabolites Cytotoxic drugs

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Antibodies: Polyclonal antibodies Monoclonal antibodies Drugs acting of immunophilins Cyclosporine, Tacrolimus , Sirolimus Miscellaneous Interferons, Mycophenolate mofetil, TNF binding proteins

Mechanism of Immunosuppressants Glucocorticoids:- These drugs prevent the conversion of APCs to CD4 Helper cells by inhibiting the production of IL-1 Eg:-Prednisolone,Hydrocortisone, etc. Cytostatics:-These drugs inhibit the conversion of CD8 cells to Cytotoxic T cells and B cells to plasma cells and memory cells by inhibition of purine synthesis. Eg:- Azathioprine , Mercaptopurine

Antibodies:- They are used generally in cases where steroid resistence occurs , they act as antigens and suppress the cell mediated responses and are generally T cell directed Eg.:- OKT3,Anti Thymocyte Globulin(ATG) Drugs acting on Immunophilins:- They are also called calcineurin inhibitors as they inhibit calceneurin which is responsible for production of IL-2 . Eg.:- Cyclosporine , Tacrolimus , Sirolimus

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Cyclosporine

Description:Was discovered in 1972 Isolated from fungi Available as I.V , Caps , Tabs , Sol. Mechanism Of Action:1. Binds with cyclophilin of Tlymphocytes. 2. Inhibits calcineurin which induces the transcription of IL-2.

Adverse drug reactions:High blood pressure Unusual hair growth Nephrotoxicity Drug-drug interactions:Enzyme inducers: Carbamazepine,Phenobarbitone. Enzyme inhibitor: Acyclovir,antifungals. Drug-food interactions: Grape fruit juices should be avoided,vaccination should not be done.

Tacrolimus • •

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Description:Odourless and tasteless white crystalline powder. Isolated from cultures of Streptomyces tsukubaensis, strain no. 9993 MOA:Inhibits T – lymphocyte activation by forming complex with an intracellular protein FKBP 12 The complex formed inhibits calcineurin.

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ADR:Hyperglycaemia Myocardial Hypertrophy Hypomagnesia , Hyperkalemia

Drug-Drug interaction:Enzyme inducers: Anticonvulsants,Rifabutin , Rifampin Enzyme Inhibitors:Anti fungals , Macrolides

Azathioprine Description:Immunosuppressive metabolite MOA:Non enzymatically cleaved in mercaptopurine which acts as a purine analogue and inhibitor of DNA synthesis

Azathioprine ADR:Hematological and gastrointestinal problems

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Drug-Drug interactions:Usual dosage of azathioprine should be reduced when used in conjunction with allopurinol. Use with other leukocyte enhancer like cotrimoxazole may increase leukopenia in kidney transplant patients Use with ACE inhibitor may lead to leukopenia

Mycophenolate Mofetil 

Description:Newer variety of immunosuppressant derieved from penicillium culture. MOA:Mycophenolic acid inhibits lymphocyte purine synthesis by non competitive inhibition of enzyme Inosine Monophosphate Dehydrogenase.

ADR:Diarrhoea , nausea , vomiting , infections , anemia.

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Drug-Drug Interactions:Enzyme Inducer:Antacids with Mg and Al hydroxides Cholestyramine Enzyme Inhibitor:Acyclovir

Renal Transplant Operation

Drug Regime Post Kidney Transplant  Immunosuppressants  Antibiotics in order to prevent infection on surgical wounds & protection against nosocomial infections.  Corticosteroids are given to in order to increase the effect of antibiotics and as anti inflammatory  Inj. Erythropoetin is given for a couple of weaks in order to initiate the production of newer R.B.Cs

Role of the Transplant Pharmacist  Disease state management – – – – –

Hypertension Diabetes Mellitus Osteoporosis Hyperlipidemia Electrolyte abnormalities

 Patient understanding and adherence to the drug regimen  Pharmacokinetic drug level monitoring  Drug interactions (esp. with immunosuppressants)  Adverse drug reaction monitoring

Research Abstracts  Mcdonald J.W et.al. at Medicine LHSC – UC , A-LL132,339 Windermere Road, London,Ontario,Canada,N6A 5A5. [email protected] have proved “Cyclosporine for induction of remission in Crohn’s disease” in Cochrane Database Syst Rev. 2005 Apr 18;(2)CD000297(10)  J Grinyo et. Al. from dept. of nephrology and urology ,Hospital de Bellvitge , CSUB, University of Barcelona , C.Fexia Llarga,Barcelona,Spain. Have proved that “Primary immunosuppression with mycophenolate mofetil; and antithymocyte globulin for kidney transplant recipients of a suboptimalgraft.” In Nephrology Dialysis Transplantation , Vol 13 , issue 10 2601 – 2604 , copyright 1998 by Oxford university.(11)

Research Articles  Gabardi s et. al. from the Dept. of Pharmacy Services , Brigham and Women’s Hospital , Boston , MA 02115-6110 , USA . [email protected] have proved the significance of enteric Mycophenolate sodium tablet over Mycophenolate mofetil tablet in Ann Pharmacother 2003 nov ; 37 (11) : 1685 – 93(!2)  Quang Hieu De Tran, Elizabeth Guay et al have proved the use of “Tacrolimus ointment in dermatitis and pyoderma gangreonosm” in Journal of Cutaneous Medicine and Surgery : Incorporating Medical and Surgical Dermatology vol. 5 , number 4 /August 2001 pg no. 329 – 335 published by Springer New York(!3).

CONCLUSIONS 

The success rate of Renal Transplantation should be supported with best possible medical facilities to the nephrologists and best possible hospital facilities.

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Immunosuppressant drug therapy is a long term treatment for acceptance of grafts especially renal transplants.

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Post transplant care is to be monitored very keenly by the Pharmacist & Family for post operative case.

CONCLUSIONS  Renal Transplant patients are prone to secondary and nosocomial infections like Tuberculosis, URTI, LRTI, UTI, Meningitis etc. hence proper care for Food and Hygiene should be maintained by Nutritionist and Dietetics and Cleaning staff of the hospital.  Cost of combination therapy which includes immunosuppressants ,Broad spectrum antibiotics, Erythropoetin and related injections, multi vitamins etc. is very high and hence should be made feasible to underdeveloped countries.  DPCO(Drug Price Control) 1985 act for life saving drugs of this class should be taken into deep consideration.

BIBLIOGRAPHY       

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( Ref : - Goodman & Gilman’s The pharmacological basis of theraputics , 9th edition , by Hardman Joel . G , Limbird Lee E , published by McGraw Hill, int edition 1996 , pg no. 1291 – 1296) http://en.wikipedia.org/wiki/Immunosuppressant#immunosuppressive http://www.answers.com/topic/cyclosporine-1 http://www.emcure.co.in/html/vingraf.htm http://www.rxlist.com/cgi/generic/azathioprine_ad.htm 6)http://gsm.about.com/compact/showmono.asp?monotype=&cpnum=419&r=6078&match=F Reference:- Smith’s general urology, 13th edition , year of publication :-1992, b Tanagho Emil .A MD (University of California. San Francisco) McAninch Jack W MD (University of California….San Francisco)Pg no. 556-562 Book provided by Dr. Sunil Agrawal MS , Sanjeevani Hospital, Malad(E) http://www.aakp.org/aakp-library/Transplant-Drugs/ http://www.vesalius.com http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list _uids=15846602&query_hl=2&itool=pubmed_docsum http://ndt.oxfordjournals.org/cgi/content/abstract/13/10/2601?maxtoshow=&HITS=10 &hits=10&RESULTFORMAT=&fulltext=immuno+suppressants&searchid=1&FIRSTIN DEX=30&resourcetype=HWCIT http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list _uids=14565799&query_hl=6&itool=pubmed_docsum http://www.springerlink.com/content/rvg24my1hw80t9fx/