Immunosuppressive Drug Therapy
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Transcript of 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 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. [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
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
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7. SMITH’S GENERAL UROLOGY, 13th edition , year of publication :-
1992, b Tanagho Emil .A MD (University of
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By DR. SUNIL AGRAWAL MS , Sanjeevani Hospital, Malad(E)
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