IMMUNOSUPPRESSIVE IMMUNOSUPPRESSIVE DRUG THERAPYDRUG THERAPY

BYBY

Abhishek S. SharmaAbhishek S. Sharma

Immune ResponseImmune Response

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

Cells participating in the immune Cells participating in the immune responseresponse

General principles of General principles of ImmunosuppressionImmunosuppression

ImmunosuppressionImmunosuppression:-Immunosuppression is a process of :-Immunosuppression is a process of inhibiting the immune response at different steps .inhibiting the immune response at different steps .

Principles governing Immunosuppression:-Principles governing Immunosuppression:-

• Primary immune response can be more effectively suppressed Primary immune response can be more effectively suppressed then secondary response .then secondary response .

• If immunologic memory has been established immunosuppressive If immunologic memory has been established immunosuppressive therapy will have modest effects.therapy will have modest effects.

• Immunosuppressive therapy is most effective before generation of Immunosuppressive therapy is most effective before generation of immune response.immune response.

• But ironically autoimmune disease like Rheumatoid arthritis are But ironically autoimmune disease like Rheumatoid arthritis are treated after the response is generatedtreated after the response is generated

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

of immune responseof immune response

Pharmacological Classification Pharmacological Classification of Immunosuppressantof Immunosuppressant

GlucocorticoidsGlucocorticoids:: Immunosuppressive mechanismImmunosuppressive mechanism Anti – inflammatory effectsAnti – inflammatory effects CytostaticsCytostatics:: Alkylating agentsAlkylating agents Antimetabolites Antimetabolites Cytotoxic drugsCytotoxic drugs

AntibodiesAntibodies:: Polyclonal antibodiesPolyclonal antibodies Monoclonal antibodiesMonoclonal antibodies Drugs acting of immunophilinsDrugs acting of immunophilins Cyclosporine, Tacrolimus , SirolimusCyclosporine, Tacrolimus , Sirolimus MiscellaneousMiscellaneous Interferons, Mycophenolate mofetil, Interferons, Mycophenolate mofetil,

TNF TNF binding proteins binding proteins

Mechanism of Mechanism of ImmunosuppressantsImmunosuppressants

GlucocorticoidsGlucocorticoids:- These drugs prevent the :- These drugs prevent the conversion of APCs to CD4 Helper cells by conversion of APCs to CD4 Helper cells by inhibiting the production of IL-1inhibiting the production of IL-1

Eg:-Prednisolone,Hydrocortisone, etc.Eg:-Prednisolone,Hydrocortisone, etc.

CytostaticsCytostatics:-These drugs inhibit the conversion of :-These drugs inhibit the conversion of CD8 cells to Cytotoxic T cells CD8 cells to Cytotoxic T cells

and B cells to plasma cells and memory cells by and B cells to plasma cells and memory cells by inhibition of purine synthesis.inhibition of purine synthesis.

Eg:- Azathioprine , MercaptopurineEg:- Azathioprine , Mercaptopurine

Antibodies:Antibodies:- They are used generally in cases - They are used generally in cases where steroid resistence occurs , they act as where steroid resistence occurs , they act as antigens and suppress the cell mediated antigens and suppress the cell mediated responses and are generally T cell directedresponses and are generally T cell directed

Eg.:- OKT3,Anti Thymocyte Globulin(ATG)Eg.:- OKT3,Anti Thymocyte Globulin(ATG)

Drugs acting on Immunophilins:- They are also Drugs acting on Immunophilins:- They are also called calcineurin inhibitors as they inhibit called calcineurin inhibitors as they inhibit calceneurin which is responsible for production of calceneurin which is responsible for production of IL-2 .IL-2 .

Eg.:- Cyclosporine , Tacrolimus , SirolimusEg.:- Cyclosporine , Tacrolimus , Sirolimus

CyclosporineCyclosporine

DescriptionDescription:-:-Was discovered in 1972Was discovered in 1972Isolated from fungiIsolated from fungiAvailable as I.V , Caps , Tabs , Available as I.V , Caps , Tabs ,

Sol.Sol.

Mechanism Of Action:- Mechanism Of Action:- 1. Binds with cyclophilin of T-1. Binds with cyclophilin of T-

lymphocytes.lymphocytes.2. Inhibits calcineurin which 2. Inhibits calcineurin which induces the transcription of induces the transcription of

IL-2.IL-2.

Adverse drug reactions:-Adverse drug reactions:-High blood pressureHigh blood pressureUnusual hair growthUnusual hair growthNephrotoxicityNephrotoxicity

Drug-drug interactions:-Drug-drug interactions:- Enzyme inducers: Enzyme inducers:

Carbamazepine,Phenobarbitone.Carbamazepine,Phenobarbitone. Enzyme inhibitor:Enzyme inhibitor: Acyclovir,antifungals.Acyclovir,antifungals.Drug-foodDrug-food interactionsinteractions: Grape fruit juices should : Grape fruit juices should

be avoided,vaccination should not be done.be avoided,vaccination should not be done.

TacrolimusTacrolimus

Description:-Description:-Odourless and tasteless Odourless and tasteless white crystalline powder.white crystalline powder.Isolated from cultures of Isolated from cultures of Streptomyces Streptomyces tsukubaensis, strain no. tsukubaensis, strain no. 99939993

MOAMOA:-:-• Inhibits T – lymphocyte Inhibits T – lymphocyte

activation by forming activation by forming complex with an complex with an intracellular protein FKBP - intracellular protein FKBP - 1212

• The complex formed The complex formed inhibits calcineurin.inhibits calcineurin.

ADRADR:-:- HyperglycaemiaHyperglycaemia Myocardial HypertrophyMyocardial Hypertrophy Hypomagnesia , HyperkalemiaHypomagnesia , Hyperkalemia

Drug-Drug interaction:-Drug-Drug interaction:- Enzyme inducers: Anticonvulsants,Rifabutin , Enzyme inducers: Anticonvulsants,Rifabutin ,

RifampinRifampin Enzyme Inhibitors:-Enzyme Inhibitors:- Anti fungals , MacrolidesAnti fungals , Macrolides

AzathioprineAzathioprine

Description:-Description:-

Immunosuppressive Immunosuppressive metabolitemetabolite

MOA:-MOA:-

Non enzymatically Non enzymatically cleaved in cleaved in mercaptopurine which mercaptopurine which acts as a purine acts as a purine analogue and inhibitor analogue and inhibitor of DNA synthesisof DNA synthesis

AzathioprineAzathioprine ADR:-ADR:- Hematological and gastrointestinal problemsHematological and gastrointestinal problems Drug-Drug interactions:-Drug-Drug interactions:-

Usual dosage of azathioprine should be reduced Usual dosage of azathioprine should be reduced when used in conjunction with allopurinol.when used in conjunction with allopurinol.Use with other leukocyte enhancer like Use with other leukocyte enhancer like cotrimoxazole may increase leukopenia in kidney cotrimoxazole may increase leukopenia in kidney transplant patientstransplant patientsUse with ACE inhibitor may lead to leukopeniaUse with ACE inhibitor may lead to leukopenia

Mycophenolate MofetilMycophenolate Mofetil

Description:-Description:- Newer variety of Newer variety of

immunosuppressant immunosuppressant derieved from penicillium derieved from penicillium culture.culture.

MOA:- MOA:- Mycophenolic acid inhibits Mycophenolic acid inhibits

lymphocyte purine lymphocyte purine synthesis by non synthesis by non competitive inhibition of competitive inhibition of enzyme Inosine enzyme Inosine Monophosphate Monophosphate Dehydrogenase. Dehydrogenase.

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

Drug-Drug Interactions:-Drug-Drug Interactions:-Enzyme Inducer:-Enzyme Inducer:-

Antacids with Mg and Al hydroxidesAntacids with Mg and Al hydroxidesCholestyramineCholestyramine

Enzyme Inhibitor:-Enzyme Inhibitor:-AcyclovirAcyclovir

Renal Transplant OperationRenal Transplant Operation

Drug Regime Post Kidney Drug Regime Post Kidney TransplantTransplant

ImmunosuppressantsImmunosuppressants

AntibioticsAntibiotics in order to prevent infection on in order to prevent infection on surgical wounds & protection against nosocomial surgical wounds & protection against nosocomial infections.infections.

CorticosteroidsCorticosteroids are given to in order to increase are given to in order to increase the effect of antibiotics and as anti inflammatorythe effect of antibiotics and as anti inflammatory

InjInj. . ErythropoetinErythropoetin is given for a couple of weaks is given for a couple of weaks in order to initiate the production of newer R.B.Csin order to initiate the production of newer R.B.Cs

Role of the Transplant PharmacistRole of the Transplant Pharmacist

Disease state managementDisease state management– HypertensionHypertension– Diabetes MellitusDiabetes Mellitus– OsteoporosisOsteoporosis– HyperlipidemiaHyperlipidemia– Electrolyte abnormalitiesElectrolyte abnormalities

Patient understanding and adherence to the drug Patient understanding and adherence to the drug regimenregimen

Pharmacokinetic drug level monitoringPharmacokinetic drug level monitoring Drug interactions (esp. with immunosuppressants)Drug interactions (esp. with immunosuppressants) Adverse drug reaction monitoringAdverse drug reaction monitoring

Research AbstractsResearch Abstracts Mcdonald J.W et.al. at Medicine LHSC – UC , A-LL132,339 Mcdonald J.W et.al. at Medicine LHSC – UC , A-LL132,339

Windermere Road, London,Ontario,Canada,N6A 5A5. Windermere Road, London,Ontario,Canada,N6A 5A5. john.mcdonald@lhsc.on.cajohn.mcdonald@lhsc.on.ca have proved “ have proved “Cyclosporine for induction Cyclosporine for induction of remission in Crohn’s disease”of remission in Crohn’s disease” in Cochrane Database Syst Rev. in Cochrane Database Syst Rev. 2005 Apr 18;(2)CD000297(10)2005 Apr 18;(2)CD000297(10)

J Grinyo et. Al. from dept. of nephrology and urology ,Hospital de J Grinyo et. Al. from dept. of nephrology and urology ,Hospital de Bellvitge , CSUB, University of Barcelona , C.Fexia Bellvitge , CSUB, University of Barcelona , C.Fexia Llarga,Barcelona,Spain. Have proved that “Llarga,Barcelona,Spain. Have proved that “Primary Primary immunosuppression with mycophenolate mofetil; and immunosuppression with mycophenolate mofetil; and antithymocyte globulin for kidney transplant recipients of a antithymocyte globulin for kidney transplant recipients of a suboptimalgraft.suboptimalgraft.” In Nephrology Dialysis Transplantation , Vol 13 , ” In Nephrology Dialysis Transplantation , Vol 13 , issue 10 2601 – 2604 , copyright 1998 by Oxford university.(11)issue 10 2601 – 2604 , copyright 1998 by Oxford university.(11)

Research ArticlesResearch Articles

Gabardi s et. al. from the Dept. of Pharmacy Services , Gabardi s et. al. from the Dept. of Pharmacy Services , Brigham and Women’s Hospital , Boston , MA 02115-6110 , Brigham and Women’s Hospital , Boston , MA 02115-6110 , USA . USA . sgabardi@partners.orgsgabardi@partners.org have proved the have proved the significance of enteric Mycophenolate sodium tablet significance of enteric Mycophenolate sodium tablet over Mycophenolate mofetil tabletover Mycophenolate mofetil tablet in Ann Pharmacother in Ann Pharmacother 2003 nov ; 37 (11) : 1685 – 93(!2)2003 nov ; 37 (11) : 1685 – 93(!2)

Quang Hieu De Tran, Elizabeth Guay et al have proved the Quang Hieu De Tran, Elizabeth Guay et al have proved the use of “use of “Tacrolimus ointment in dermatitis and Tacrolimus ointment in dermatitis and pyoderma gangreonosm”pyoderma gangreonosm” in Journal of Cutaneous in Journal of Cutaneous Medicine and Surgery : Incorporating Medical and Surgical Medicine and Surgery : Incorporating Medical and Surgical Dermatology vol. 5 , number 4 /August 2001 pg no. 329 – Dermatology vol. 5 , number 4 /August 2001 pg no. 329 – 335 published by Springer New York(!3).335 published by Springer New York(!3).

CONCLUSIONSCONCLUSIONS

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

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

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

CONCLUSIONSCONCLUSIONS Renal Transplant patients are prone to secondary and nosocomial Renal Transplant patients are prone to secondary and nosocomial

infections like Tuberculosis, URTI, LRTI, UTI, Meningitis etc. infections like Tuberculosis, URTI, LRTI, UTI, Meningitis etc. hence proper care for Food and Hygiene should be maintained by hence proper care for Food and Hygiene should be maintained by Nutritionist and Dietetics and Cleaning staff of the hospital.Nutritionist and Dietetics and Cleaning staff of the hospital.

Cost of combination therapy which includes Cost of combination therapy which includes immunosuppressants ,Broad spectrum antibiotics, Erythropoetin immunosuppressants ,Broad spectrum antibiotics, Erythropoetin and related injections, multi vitamins etc. is very high and hence and related injections, multi vitamins etc. is very high and hence should be made feasible to underdeveloped countries.should be made feasible to underdeveloped countries.

DPCO(Drug Price Control) 1985 act for life saving drugs of this DPCO(Drug Price Control) 1985 act for life saving drugs of this class should be taken into deep consideration.class should be taken into deep consideration.

BIBLIOGRAPHYBIBLIOGRAPHY ( Ref : - Goodman & Gilman’s The pharmacological basis of theraputics , 9th edition , by Hardman ( 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)Joel . G , Limbird Lee E , published by McGraw Hill, int edition 1996 , pg no. 1291 – 1296) http://en.wikipedia.org/wiki/Immunosuppressant#immunosuppressivehttp://en.wikipedia.org/wiki/Immunosuppressant#immunosuppressive http://www.answers.com/topic/cyclosporine-1http://www.answers.com/topic/cyclosporine-1 http://www.emcure.co.in/html/vingraf.htmhttp://www.emcure.co.in/html/vingraf.htm http://www.rxlist.com/cgi/generic/azathioprine_ad.htmhttp://www.rxlist.com/cgi/generic/azathioprine_ad.htm 6)http://gsm.about.com/compact/showmono.asp?monotype=&cpnum=419&r=6078&match=F6)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 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 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 California….San Francisco)Pg no. 556-562 Book provided by Dr. Sunil Agrawal MS , Sanjeevani Hospital, Malad(E)Hospital, Malad(E)

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