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 expressed on molecular components

of infectious agents , foreign (Grafts) or 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 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

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. 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

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

Mechanism of Immunosuppressants

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 pressureUnusual hair growthNephrotoxicity

Drug-drug interactions: Enzyme inducers:

Carbamazepine,Phenobarbitone. Enzyme inhibitor: Acyclovir, Antifungals- AzolesDrug-food interactions: Grape fruit juices should be

avoided,vaccination should not be done.Use: To prevent the rejection of organ transplant and

kidney grafts

CYCLOSPORINE

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.

Adverse drug reactions: Hyperglycaemia Myocardial Hypertrophy Hypomagnesia , Hyperkalemia

Drug-Drug interactions: Enzyme inducers: Anticonvulsants,Rifabutin , Rifampin Enzyme Inhibitors: Anti fungals , MacrolidesUse: To prevent rejection after organ transplant

TACROLIMUS

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 patientsUse with ACE inhibitor may lead to leukopenia

Azathioprine is used in Homograft Survival Immuno-

inflammatory Response Renal Homotransplantation

Rheumatoid Arthritis Renal Dysfunction

AZATHIOPRINE

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.

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.

MYCOPHENOLATE MOFETIL

Need to Study Renal Transplant 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--WHOOrgan 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.

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

Preliminary Nephrectomy: 1. Patients with active infections

2. Severe hypertension uncontrolled by medications or dialysis

3. Severe hypertension uncontrolled by medications or dialysis

Selection & Preparation of Recipients:

DONOR SELECTION

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

Living Related Donor:

Cadaver Donor:

Unacceptable cadaver donorsAge- New born and persons over 60 yearsDisease- 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

1. 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.

Foley catheter drainage is maintained for 5 days because of the impaired wound healing associated with immunosuppressive therapy

Immediate Post Transplant Care

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

1.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. john.mcdonald@lhsc.on.ca

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 . sgabardi@partners.org 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

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

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

3. Post transplant care is to be monitored very keenly

by the Pharmacist & Family for post operative case.

CONCLUSIONS4. 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.

5. 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.

6. DPCO(Drug Price Control) 1985 act for life saving drugs

of this class should be taken into deep consideration.

BIBLIOGRAPHY

1. 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)

2. http://en.wikipedia.org/wiki/Immunosuppressant#immunosuppressive

3. http://www.answers.com/topic/cyclosporine-1

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

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

6. 6)http://gsm.about.com/compact/showmono.asp?

monotype=&cpnum=419&r=6078&match=F

7. 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)

8. http://www.aakp.org/aakp-library/Transplant-Drugs/

9. http://www.vesalius.com

10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15

846602&query_hl=2&itool=pubmed_docsum

11. http://ndt.oxfordjournals.org/cgi/content/abstract/13/10/2601?

maxtoshow=&HITS=10

&hits=10&RESULTFORMAT=&fulltext=immuno+suppressan

ts&searchid=1&FIRSTIN DEX=30&resourcetype=HWCIT

12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?

db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=14

565799&query_hl=6&itool=pubmed_docsum

13. http://www.springerlink.com/content/rvg24my1hw80t9fx

THANK YOUTHANK YOU