IMMUNOSUPPRESSANT

DRUGS
Setyawati SK
 Suppression of cellular functions in the clinical
practice  Immunosuppression
Groups of immunosuppressive drugs:

I. Inhibitor of cytokine gene expression  Corticosteroids

II. Inhibitors of cytokine (IL-2) production or action

(Non-cytostatic immunsuppressive agents) 
Cyclosporine A, Tacrolimus and Rapamycin

III.Cytostatic drugs
Alkylating agents, folic acid antagonists, purine/pyrimidin
inhibitors

IV. Immunosuppressive antibodies

I. Inhibitors of cytokine gene expression

Corticosteroids
Prednisone

 Prednisolone
 Methylprednisolone
 Dexamethasone

They have both anti-inflammatory action and

immunosuppressant effects.
 Corticosteroid
Mechanism of action
 Bind to glucocorticoid receptors and the complex interacts with

DNA to inhibit gene transcription of inflammatory genes.

 Decrease production of inflammatory mediators as

prostaglandins, leukotrienes, histamine, PAF, bradykinin.

 Decrease production of cytokines IL-1, IL-2, interferon, TNF.
 Stabilize lysosomal membranes.
 Decrease generation of IgG, nitric oxide and histamine.
 Inhibit antigen processing by macrophages.
 Suppress T-cell helper function
Corticosteroids are Gene-Active
Very important anti-inflammatory mechanisms of corticosteroids are the
inhibition of phospholipase A2 directly and indirectly (by synthesizing
lipocortin-1; a PA2 inhibitor) and, the inhibition of cyclooxygenases (like
NSAIDs).

Inhibition of the arachidonic acid pathway  decreases the pro-

inflammation mediators prostaglandins (PGE2 for example) and
leukotrienes (LTs).
In addition as does endogenous cortisol:
↓ proliferation and differentiation of mast cells
↓ platelet activating factor
↓ NO production
↓ number of circulating T cells
↓ interleukin production
↓ IFN-γ production
Anti-inflammatory actions of corticosteroids
Corticosteroid inhibitory effect
Hypothalamopituitary adrenal (HPA) axis: Negative Feedback
Immune
Stress system:
Circadian Hypothalamus altered
rhythm Muscle:
CRH Net loss of amino
Posterior Acids (glucose)
Anterior Liver:
Pituitary Gland Pituitary Gland Deamination of
(-) ACTH
proteins into amino
acids,
Glucocorticoids, gluconeogenesis
Adrenals (glucose)
Catecholamines, etc..
Fat Cells:
Kidney Free fatty
acid
mobilization
Heart rate:
Increased
HPA AXIS
Pharmacological Actions
 Direct (Intended) Actions
Anti-inflammatory
Anti-allergy
Anti-immunity
 Permissive Actions

Lipolytic effects

Effect on blood pressure

Effect on bronchial muscles

 (e.g.,sympathomimetic amine)
 Immunosuppressive and anti-allergic actions
 Suppresses all types of hypersensitivity and allergic
phenomenon
 At High dose: Interfere with all steps of immunological
response
 Causes greater suppression of Cell-mediated immunity
(graft rejection and delayed hypersensitivity)
 Transplant rejection: antigen expression from grafted
tissues, delay revascularization, sensitisation of T
lymphocytes etc.
 Anti inflammatory actions
 Recruitment of WBC and monocyte- macrophage into
affected area & elaboration of chemotactic substances
 Lipocortin
 ELAM1 and ICAM-1 in endothelial cells
 TNF from phagocytic cells
 IL1 from monocyte-macrophage
 Formation of Plasminogen Activator
 Action of MIF and fibroblastic activity
 Expression of COX II
 Other Pharmacological Actions

1. Carbohydrate 8. Stomach
2. Protein 9. Blood
3. Lipid
10. Respiratory system
4. Electrolyte and H2O
11. Growth and Cell Division
5. CVS
12. Calcium metabolism
6. Skeletal Muscle
7. CNS
Actions: Carbohydrate and protein metabolism
Negative nitrogen balance and hyperglycemia

 Gluconeogenesis
 Peripheral actions (mobilize aas and glucose and glycogen)
 Hepatic actions

 Peripheral utilization of glucose

 Glycogen deposition in liver

(activation of hepatic glycogen synthase)
Actions: Lipid metabolism
 Redistribution of Fat
 Buffalo
hump
 Moon face

 Promote adipokinetic agents activity

(glucagon, growth hormone, adrenaline, thyroxine)
Actions: Skeletal Muscles

Addison's disease: weakness and fatigue is due to

inadequacy of circulatory system
Prolonged use: Steroid myopathy

Needed for maintaining the normal function of Skeletal

muscle
 Actions: CNS

 Direct:
 Mood
 Behaviour
 Brain excitability
 Indirect:
 maintain glucose, circulation and electrolyte balance
Actions: Stomach

Aggravate peptic ulcer. May be due to:

 Acid and pepsin secretion
 immune response to H.Pylori

Actions: Blood
RBC: Hb and RBC content
(erythrophagocytosis )

WBC: Lymphocytes, eosinophils, monocytes, basophils

Polymorphonucleocytes
 Actions: Growth and Cell division
 Inhibit cell division or synthesis of DNA
 Delay the process of healing
 Retard the growth of children

Actions: Calcium metabolism

Intestinal absorption decrease
Renal excretion increase
Excessive loss of calcium from spongy bones (e.g., vertebrae, ribs, etc)
 Actions: Respiratory system
 Not bronchodilators
 Most potent and most effective anti-inflammatory
 Effects not seen immediately (delay 6 or more hrs)
 Inhaled corticosteroids are used for long term control
 IMMUNOSUPPRESSIVE DRUGS
CORTICOSTEROIDS

Prednisolone
Methylprednisolone

Budesonide
Triamcinolone
betamethasone
 Preparations
Drug Anti-inflam. Salt retaining Topical
Cortisol 1 1.0 1
Cortisone 0.8 0.8 0
Prednisone 4 0.8 0
Prednisolone 5 0.3 4
Methylpredni- solone 5 0 5
Intermediate acting
Triamcinolone 5 0 5
Paramethasone 10 0 -
Fluprednisolone 15 0 7
 Preparations
Drug Anti-inflam. Salt retaining Topical
Long acting
Betamethasone 25-40 0 10
Dexamethasone 30 0 10
Mineralocorticoids
Fludrocortisone 10 250 10
DOCA 0 20 0
Glucocorticoid Analogues
Clinical Uses
 For most clinical purposes, synthetic glucocorticoids are
used because they have a higher affinity for the receptor,
are less activated and have little or no salt-retaining
properties.
 Hydrocortisone used for: orally for replacement therapy,
i.v. for shock and asthma, topically for eczema
(ointment) and enemas (ulcerative colitis).
 Prednisolone the most widely used drug given orally in
inflammation and allergic diseases.
Clinical Uses
 Betamethasone and dexamethasone: very potent,
w/o salt-retaining properties; thus, very useful for
high-dose therapies (e.g., cerebral edemas).
 Beclometasone, diproprionate, budesonide: pass
membranes poorly; more active when applied
topically (severe eczema for local anti-inflammatory
effects) than orally; used in asthma, (aerosol).
 Triamcinolone: used for severe asthma and for local
joint inflammation (intra-articular inj.).
SIDE EFFECTS
II. Inhibitors of cytokine (IL-2) production or action

 Inhibitor of cytokines (IL-2) production

Calcineurin inhibitors :
- Cyclosporine
- Tacrolimus (FK506)
 Inhibitors of cytokines (IL-2) action

- Sirolimus (Rapamycin)
CYCLOSPORINE
Mechanism of Action:
 Acts by blocking activation of T cells by inhibiting interleukin-2
production (IL-2).
 Cyclosporine- immunophilin complex inhibits calcineurin, a
phosphatase necessary for dephosphorylation of transcription
factor (NFATc) required for interleukins synthesis (IL-2).
 Decreases proliferation and differentiation of T cells.
 Suppress cell mediated immunity
 CYCLOSPORINE (cont)
Pharmacokinetics :
 Can be given orally or i.v. infusion
orally (25 or 100 mg) soft gelatin capsules, microemulsion.
 Orally, it is slowly and incompletely absorbed.
 Peak levels is reached after 1– 4 hours, elimination half life 24 h.
 Oral absorption is delayed by fatty meal (gelatin capsule formulation)
 Microemulsion ( has higher bioavailability-is not affected by food).
 50 – 60% of cyclosporine accumulates in blood (erythrocytes – lymphocytes).
 Metabolized by CYT-P450 system (CYP3A4).

 CYCLOSPORINE (cont)

Therapeutic Uses:

 Organ transplantation (kidney, liver, heart) either alone or with

other immunosuppressive agents (Corticosteroids).
 Autoimmune disorders (low dose 7.5 mg/kg/d). e.g. endogenous
uveitis, rheumatoid arthritis, active Crohn’s disease, psoriasis,
psoriasis, nephrotic syndrome, severe corticosteroid-dependent
asthma, early type I diabetes.
 Graft-versus-host disease after stem cell transplants
CYCLOSPORINE (cont)

Adverse Effects (Dose-dependent)

Therapeutic monitoring is essential
 Nephrotoxicity
(increased by NSAIDs and aminoglycosides).
 Liver dysfunction.
 Hypertension, hyperkalemia.(K-sparing diuretics should not be used).
 Hyperglycemia.
 Viral infections (Herpes - cytomegalovirus)
 Lymphoma (Predispose recipients to cancer).
 Hirsutism
 Neurotoxicity (tremor).
 Gum hyperplasia.
 Anaphylaxis after I.V.
CYCLOSPORINE (cont)

Drug Interactions

 Clearance of cyclosporine is enhanced by co-administration of CYT p

450 inducers (Phenobarbitone, Phenytoin & Rifampin )  rejection
of transplant.

 Clearance of cyclosporine is decreased when it is co-administered

with erythromycin or Ketoconazole, Grapefruit juice  cyclosporine
toxicity.
TACROLIMUS (FK506)

 a fungal macrolide antibiotic.

 Chemically not related to cyclosporine
 both drugs have similar mechanism of action.
 The internal receptor for tacrolimus is
immunophilin ( FK-binding protein).
 Tacrolimus-FKBP complex inhibits calcineurin.
TACROLIMUS (FK506)

PHARMACOKINETICS
 Given orally or i.v or topically (ointment).

 Oral absorption is variable and incomplete, reduced by fat and

carbohydrate meals.
 Half-life after I.V. form is 9-12 hours.

 Highly bound with serum proteins and concentrated in erythrocytes.

 metabolized by P450 in liver.

 Excreted mainly in bile and minimally in urine.

TACROLIMUS (FK506)

Therapeutical Uses as cyclosporine

 Organ and stem cell transplantation

 Prevention of rejection of liver and kidney
transplants (with glucocorticoids).
 Atopic dermatitis and psoriasis (topically).
TACROLIMUS (FK506)

Toxic effects
 Nephrotoxicity (more than CsA)
 Neurotoxicity (more than CsA)

 Hyperglycemia ( require insulin).

 GIT disturbances

 Hperkalemia

 Hypertension

 Anaphylaxis

NO hirsutism or gum hyperplasia

 Drug interactions as cyclosporine.

Sirolimus (Rapamycin)

 SRL is macrolide antibiotic.

 SRL is derived from fungus origin.
 It binds to FKBP and the formed complex binds to mTOR (mammalian Target
Of Rapamycin).
 mTOR is serine-threonine kinase essential for cell cycle progression, DNA
repairs, protein translation.
 SRL blocks the progression of activated T cells from G1 to S phase of cell
cycle (Antiproliferative action).
 It Does not block the IL-2 production but blocks T cell response to cytokines.
 Inhibits B cell proliferation & immunoglobulin production.
Sirolimus (Rapamycin) cont

Pharmacodynamics
 Immunosuppressive effects

 Anti- proliferative action.

 Equipotent to CsA.

Pharmakinetics
 Given orally and topically, reduced by fat meal.

 Extensively bound to plasma proteins

 metabolized by CYP3A4 in liver.

 Excreted in feces.
Sirolimus (Rapamycin) cont

USES
 Solid organ allograft
 Renal transplantation alone or combined with (CSA,
tacrolimus, steroids, mycophenolate).
 Heart allografts
 In halting graft vascular disease.
 Hematopoietic stem cell transplant recipients.
 Topically with cyclosporine in uveoretinitis.
 Synergistic action with CsA
Sirolimus (Rapamycin) cont

Toxic effects
 Hyperlipidaemia (cholesterol, triglycerides).
 Thrombocytopenia
 Leukopenia
 Hepatotoxicity
 Hypertension
 GIT dysfunction
 III. Cytotoxic Drugs
 Inhibitors of purine or pyrimidine synthesis
(Antimetabolites):
 Azathioprine

 Myclophenolate Mofetil

 Leflunomide

 Methotrexate

 Alkylating agents
 Cyclophosphamide
 IV. Immunosuppressive Antibodies

Block T cell surface molecules involved in signaling

immunoglobulins
 Antilymphocyte globulins (ALG).
 Antithymocyte globulins (ATG).
 Rho (D) immunoglobulin.
 Basiliximab
 Daclizumab
 Infliximab
 Monoclonal antibodies Basiliximab and Daclizumab

 Basiliximab is a chimeric human-mouse IgG (25% murine, 75%

human protein).
 Daclizumab is a humanized IgG (90% human protein).
 Have less antigenicity & longer half lives than murine antibodies

Mechanism of action
 IL-2 receptor antagonists, Anti-CD25
 Bind to CD25 (α-subunit chain of IL-2 receptor on activated

lymphocytes)
 Block IL-2 stimulated T cells replication & T-cell response system

 Basiliximab is more potent than Daclizumab

Monoclonal antibodies 

Infliximab
 A chimeric human-mouse IgG
 Directed against TNF-α
 Is approved for ulcerative colitis, Crohn’s disease &rheumatoid arhritis
Omalizumab
 A humanized monoclonal IgE
 Directed against Fc receptor on mast &basophils
 Is approved for asthma in steroid-refractory patient

USES
 Given with CsA and corticosteroids for Prophylaxis of acute
rejection in renal transplantation.