Introduction Classifications & Mechanism of action of immunosuppressant Clinical applications (uses) Precautions of uses

1. By
Ahmed Noaman Elsayed
Assist. Lecturer of Internal Medicine & Clinical Immunology
Traditional Immunosuppressant

2. Objectives
 Introduction
 Classifications & Mechanism of action
of immunosuppressant
 Clinical applications (uses)
 Precautions of uses

3. Introduction
 Immunomodulation
Is modulation (regulatory adjustment) of the immune
system . It has natural and human-induced forms.
Homeostasi
s
Immunomodulation as
part of immunotherapy
Immune responses are induced,
amplified, attenuated, or prevented
according to therapeutic goals
Using regulatory T
cells, cell signaling
molecules, and so
forth)
Immunosuppressi

4. Introduction cont.
Immunosuppression
Is a reduction of the activation or efficacy of
the immune system.
Divided into
Deliberately induced Non
deliberately
Medications (immunosuppressant)
surgery (splenectomy)
Plasmapheresis or radiation
Ataxia-telangiectasia,
Complement
deficiencies
Many types of cancer
Certain chronic
infections such

5. Introduction cont.
 History
 The ability to prolong life by transplanting organs had
long been a dream of medical practitioners
 Skin and eyes were among the first successful
transplants.
 The kidney was the first complex organ to be
successfully transplanted.
 Initial attempts at immunosuppression were with total
body radiation, but all the patients died.
 Steroids alone were then used, also without success.

6. Rathee et al.,

7. Introduction cont.

8. Introduction cont.

9. Classification
of
Immunosuppressants

11. Clin J Am Soc Nephrol , 2015. doi:

12. Clin J Am Soc Nephrol , 2015. doi:
10.2215/CJN.08570814

13. Traditional Immunosuppressant
Classification
 Glucocorticoids
 Cytostatics
 Drugs acting on Immunophilins
 Antibodies
 Other drugs

14. GLUCOCORTICOIDS
Shimobayashi et al., Nat Rev Mol Cell Biol 15:
155–162, 2014

15. I.GLUCOCORTICOIDS
 They act by inhibiting genes that code for the cytokines IL-1, IL-2,
IL3, IL-4, IL-5, IL-6, IL-8 and TNF-γ.
 Expression of smaller amounts of IL-2 and of IL-2 receptors.
 Reduction of the T cell proliferation.
 Suppression of the humoral immunity.
 Diminishe both B cell clone expansion and antibody synthesis.

16. GLUCOCORTICOIDS cont.
Side effects
The common early adverse effects, such as :-
sweatiness, hoarse voice, loss of diurnal sleep patterns, and
appetite stimulation.
Rarely, more serious acute psychiatric disturbances are
seen such as agitation, aggression or psychosis.
The Longterm, and less reversible adverse effects, such
as:-
Cushingoid appearance, proximal myopathy,
hypertension,hyperlipidaemia, diabetes, cataract formation,
peptic ulceration, osteopenia and aseptic necrosis of bone.

17. II.CYTOSTATICS
They inhibit cell division
 In immunotherapy, they are used in smaller doses
than in the treatment of malignant diseases.
 They affect the proliferation of both T cells and B
cells.
 They includes the following:
 Alkylating agents
 Antimetabolites
 Cytotoxic antibiotics.

18. II.CYTOSTATICS cont.
 Alkylating agents
(Cyclophosphamide) eg. Endoxan
Cyclophosphamide is probably the most potent immunosuppressive
compound.
Primary toxicities, such as bladder toxicity, gonadal toxicity, and later
malignancy, have led to attempts to minimize exposure.
It’s used as an immunosuppressant in life-threatening or severe
rheumatologic and renal diseases, including ANCA-related vasculitis,
lupus nephritis, and other systemic vasculidites.
(<250–300 mg/kg cumulative dose to avoid gonadal and <360 mg/kg cumulative
dose to minimize the risk of malignancy)

19. II.CYTOSTATICS cont.
 Antimetabolites
(Inhibition of DNA Synthesis)
Azathioprine
AZA is an analog of 6
mercaptopurine; the
metabolites of these agents
act as both purine analogs
(interfering with de novo
purine synthesis and thus,
DNA and RNA synthesis)
and immunomodulatory
Mycophenolat
e
It is an inhibitor of IMPDH,
the rate-limiting enzyme of
guanine nucleotide
synthesis critical for de
novo purine synthesis and
thus, DNA synthesis.
LeflunomideMethotrexate

20. II.CYTOSTATICS cont.
 Antimetabolites cont.
(Inhibition of DNA Synthesis)
Side effects
Primary side effects are bone marrow suppression
and gastrointestinal intolerance (primarily upper
gastrointestinal symptomatology).
The Efficacy of Mycophenolate in the prevention of
rejection compared with AZA together with better
tolerability than mTOR inhibitors have led to its use
as the primary antimetabolite in transplantation,
despite a lack of definitive long-term data showing
improved graft outcomes.

21. III.DRUGS ACTING ON
IMMUNOPHILINS
Keymeulen et al., N Engl J Med
2005

22. III.DRUGS ACTING ON
IMMUNOPHILINS cont.
 Side effects
 Cyclosporine (peptide antibiotic) eg.Neoral
Nephrotoxicity, hypertension, hyperglycemia, liver
dysfunction, hirsutism and little bone marrow toxicity.

23. III.DRUGS ACTING ON
IMMUNOPHILINS cont.
 Tacrolimus FK 506 (macrolide antibiotic) eg.
Prograf
Like CAS nephrotoxicity, neurotoxicity, hypertension,
hyperkalemia, and gastrointestinal complaints but no
hirsutism and more hyperglycemia effect.
 Sirolimus & EverolimusThrombocytopenia, hepatotoxicity,
diarrhea, hypertriglyceridemia,
pneumonitis, and headache.

24. IV- IMMUNOSUPPRESSVE
ANTIODIES
 Polyclonal antibodies
Intravenous Ig
(IVIG)
Polyclonal Antithymocyte
Globulin
The primary mechanism of
action of ATGs is
lymphocyte depletion,
predominantly by
complement-dependent lysis
and T cell activation–
induced apoptosis.
Monoclonal antibodies
Due to their high immunogenicity
almost all patients have an acute
reaction to the treatment. As (fever,
and even anaphylaxis).

25. V. OTHER DRUGS
 Interferons
IFN-β suppresses the production of Th1 cytokines and
the activation of monocytes. It is used to slow down the
progression of multiple sclerosis. IFN-γ is able to trigger
lymphocytic apoptosis.
 Opioids
Decrease in proliferation as well as immune function has
been observed in macrophages as well as
lymphocytes. It is thought that these effects are
mediated by opioid receptors expressed on the surface
of these immune cells.

26. Clinical uses
 Arteritis
 Autoimmune diseases
 Behcet's Disease
 CIDP
 Polyneuropathy
 Collagenous Colitis
 Crohn's disease
 Dermatomyositis
 Glomerulonephritis
 Goodpasture syndrom
 Lupus
 Myasthenia Gravis
 Polyarteritis nodosa
 Reiter’s syndrome
 Rheumatoid arthritis
 Sjogren's Syndrome
 Temporal arteritis
Organ
Transplants

27. Aspects of uses

28. Aspects of uses cont.
Increased risk of
infections
Taking such
antibiotics as co-
trimoxazole prevents
some of these
infections.
Increased risk of
cancer
Minor side effects include
loss of appetite, nausea or
vomiting, increased hair
growth, and trembling or
shaking of the hands.
Skin cancer

29. Aspects of uses cont.
Post Transplantation
DM
According to the International Consensus Guidelines 2013, the diagnosis of
PTDM can be made using any of the following American Diabetes
Association/World Health Organization criteria for the diagnosis of diabetes .
Once the transplant recipient has been discharged from the hospital and
tapered to their maintenance immunosuppression.
1) Fasting glucose >126 mg/dL (7 mmol/L) on more than one
occasion.
2) Random glucose >200 mg/dL (11.1 mmol/L) with symptoms.
3) Two-hour glucose after a 75-g OGTT of >200 mg/dL (11.1 mmol/L).
4) HbA1c >6.5%.
Transplantation Journal. 96(4):333–360, AUG
2013

30. Post Transplantation
DM

31. Post Transplantation DM

32. Aspects of uses cont.
The effects of one or both
drugs may change.
Or
The risk of side effects
may be greater.
Other drugs may also
have an adverse effect on
immunosuppressant
therapy.

33. Example
s :
The effects of azathioprine may be greater in
people who take allopurinol, a medicine
used to treat gout.

34.  Examples
:
A number of drugs, including female hormones
(estrogens), male hormones (androgens), the
antifungal drug ketoconazole (Nizoral), the ulcer
drug cimetidine (Tagamet) and the
erythromycins (used to treat infections), may
increase the effects of cyclosporine.

35.  Examples
:
When Sirolimus is taken at the same time as
Cyclosporin, the blood levels of sirolimus may be
increased to a level where there are severe side effects.
Although these two drugs are usually used together, the
sirolimus should be taken four hours after the dose of
cyclosporin.

36.  Examples
:
Tacrolimus is eliminated through the kidneys. When
the drug is used with other drugs that may harm the
kidneys, such as antibiotics gentamicin and
amikacin, or the antifungal drug amphotericin B,
blood levels of tacrolimus may be increased. Careful
kidney monitoring is essential when tacrolimus is
given with any drug that might cause kidney
damage.

37. Take Home Message
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