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 . Both of these response have a high level of specificity directed to antigenic epitopes infectious

expressed agents

,

on

molecular

foreign

(Grafts)

components or

of

transformed

(Malignants) , or even autologous cells (autoimmunity).

Derivation and Relationships of 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 generation of immune response.

most

effective

before

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 



Glucocorticoids: 1. Immunosuppressive mechanism 2. Anti – inflammatory effects Cytostatics: 1.Alkylating agents 2.Antimetabolites 3.Cytotoxic drugs



Antibodies: 1. Polyclonal antibodies 2. Monoclonal antibodies i. T-cell receptor directed antibodies

ii. IL-2 receptor directed antibodies 



Drugs acting of immunophilins 1. Cyclosporine 2. Tacrolimus 3. Sirolimus Miscellaneous 1. Interferons 2. Mycophenolate mofetil 3. 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

Mechanism of Immunosuppressants 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

CYCLOSPORINE Description: Was discovered in 1972Isolated from fungi Available as I.V , Caps , Tabs , Sol. Mechanism Of Action: 1. Binds with cyclophilin of T-lymphocytes. 2. Inhibits calcineurin which induces the transcription of IL-2. 3. Also inhibits lymphokine production and interleukin release, leading to a reduced function of effector T-cells.

CYCLOSPORINE Adverse drug reactions: High blood pressure Unusual hair growth Nephrotoxicity Drug-drug interactions: Enzyme inducers: Carbamazepine,Phenobarbitone. Enzyme inhibitor: Acyclovir, Antifungals- Azoles Drug-food interactions: Grape fruit juices should be avoided,vaccination should not be done. Use: To prevent the rejection of organ transplant and kidney grafts

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

TACROLIMUS Adverse drug reactions: • Hyperglycaemia • Myocardial Hypertrophy • Hypomagnesia , Hyperkalemia Drug-Drug interactions: Enzyme inducers: Anticonvulsants,Rifabutin , Rifampin Enzyme Inhibitors: Anti fungals , Macrolides Use: To prevent rejection after organ transplant

AZATHIOPRINE Description: Immunosuppressive metabolite Mechanism Of Action: 1. Non enzymatically cleaved to Mercaptopurine which acts as a purine analogue and inhibitor of DNA synthesis 2. By preventing the clonal expansion of lymphocytes in the induction phase of the immune response, it affects both the cell and the humoral immunity. It is also efficient in the treatment of autoimmune diseases

AZATHIOPRINE Adverse drug reactions: Hematological and gastrointestinal problems 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

AZATHIOPRINE Azathioprine is used in  Homograft Survival Immuno-inflammatory  Response Renal Homotransplantation Rheumatoid Arthritis  Renal Dysfunction

MYCOPHENOLATE MOFETIL

Description: Newer variety of immunosuppressant derived from Penicillium culture. Mechanism of Action: Mycophenolic acid inhibits lymphocyte purine synthesis by non competitive inhibition of enzyme Inosine Monophosphate dehydrogenase.

MYCOPHENOLATE MOFETIL Adverse Drug Reaction: Diarrhoea , nausea , vomiting , infections , anaemia. Drug-Drug Interactions: Enzyme Inducer: Antacids with Mg and Al hydroxides Cholestyramine Enzyme Inhibitor: •

Acyclovir

Use: In organ transplant and grafts to prevent rejection.

Need to Study Renal Transplant Kidney—47 % Liver—13% Pancreas Transplantable—2% Intestine—7% Pancreas after kidney—19% Heart—7% Lung—4% Skin—1%

Organ Donation Scenario--WHO

RENAL TRANSPLANTATION SURGERY

Historic FIRST Kidney Transplant

RENAL TRANSPLANTATION SURGERY Selection & Preparation of Recipients: Primarily in End stage renal disease. The most common diseases treated by renal transplantation chronic glomerulonephritis (54%), chronic pyelonephritis (12%) polycystic kidney disease (5%) , and malignant nephrosclerosis (6%) . Other diseases, including hereditary nephritis, account for 23% of cases.

Selection & Preparation of Recipients: Exclusions: Accepted-- Patients with systemic diseases Rejected--Patients with active infections & ESRD due to primary Oxalosis

Preliminary Nephrectomy: 2. Patients with active infections 3. Severe hypertension uncontrolled by medications or dialysis 4. Severe hypertension uncontrolled by medications or dialysis

DONOR SELECTION Living Related Donor: Donor – Recipient matching- Histocompatiblity is assessed by determination of human leukocyte antigens ( HA) to establish the inheritance pattern in a family group. Donor – specific blood transfusions (DST)Three donor-specific blood transfusions from the potential kidney donor are administered to the recipient. The transplant is performed no earlier than 4 weeks only if the recipient does not become sensitized to the donor after the third transfusion

Cadaver Donor: Unacceptable cadaver donors Age- New born and persons over 60 years Disease- Abdominal sepsis, Hypertension, Diabetes, Lupus erythematous or malignant neoplastic disease ORGAN PRESERVATION Hypothermic Storage

Pulsatile Perfusion The perfusate for continuous pulsatile perfusion is currently a 10% Pentastarch-based solution

Donor Nephrectomy 3. Technique of Donor Nephrectomy 2. Management of Multiple Vessels 3. Treatment of Living Related Donor 4. Treatment of The Cadaver Donor

Technique of renal Transplantation 1.The renal artery of the kidney, previously branching from the abdominal aorta in the donor, is often connected to the external iliac artery in the recipient. 2. The renal vein of the new kidney, previously draining to the inferior vena cava in the donor, is often connected to the external iliac vein in the recipient.

Immediate Post Transplant Care Foley catheter drainage is maintained for 5 days because of the impaired wound healing associated with immunosuppressive therapy Rejection of kidney graft Acute rejection during the first several months after transplantation Treatment -increasing the dosage corticosteroids, but the use of antithymocyte globulin or monoclonal antibodies has also proved very effective in reversing rejection Chronic rejection is a late cause of renal deterioration

Kidney dialysis 4. Haemo-dialysis

2.Peritoneal dialysis

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  i. v. Erythropoetin is given for a couple of weaks in order to initiate the production of newer R.B.Cs

Role of the Pharmacist in Transplant Patient  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. have reported “Cyclosporine for induction of remission in Crohn’s disease” from Windermere Road, London,Ontario,Canada,N6A 5A5. [email protected]  J Grinyo et. Al. Have reported “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.



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



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

term renal

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 

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

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http://www.emcure.co.in/html/vingraf.htm

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http://www.rxlist.com/cgi/generic/azathioprine_ad.htm

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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 By DR. SUNIL AGRAWAL MS , Sanjeevani Hospital, Malad(E)

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