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. 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. 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

 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 term

treatment for acceptance of grafts especially renal
transplants.

 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
 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
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California….San Francisco)Pg no. 556-562
By DR. SUNIL AGRAWAL MS , Sanjeevani Hospital, Malad(E)
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THANK YOU