September 2014

Introduction
Immunosuppression
An act to reduce the activation or efficacy of the
immune system, leading to a reduced ability to fight
infections and other diseases, such as cancer.
An integral part of the immune system that some
portions of the system itself have immunosuppressive
effects on the other parts of the system
A result of
Treatment (such as radiotherapy or cancer
chemotherapy)
Medical conditions (such as AIDS or lymphoma)
A deliberate use of drugs to achieve an
immunosuppressive state for a therapeutic
purpose, e.g., autoimmune diseases

DMARDs & Immunosuppresants

System Pharmacology II
HAS4916
By Philip Mok

Clinical uses of
Immunosuppressants

Immunosuppresants
Drugs with immunosuppressive effects
An agent that decreases the bodys immune
responses by inhibiting cell-mediated & antibodymediated response, thus reducing the bodys ability to
fight infections and other diseases, such as cancer

Antiinflammatory agents
Suppression of the functions of nonspecific
inflammatory cells

Potentials for prevention of permanent structural

damage & functional impairment
Systemic lupus erythromatosus (SLE), Rheumatoid
arthritis, Juvenile arthritis, Spondyloarthropathies,
Psoriasis, Inflammatory bowel diseases (Crohns
disease and Ulcerative colitis)

Treatment of non-autoimmune inflammatory

diseases

Distinction between immunosuppressants &

antiinflammatory drugs

Allergy and Asthma

Not always clear

3

Brief descriptions of Selected

Autoimmune diseases

Prevention & treatment of transplant rejection

and graft-versus-host diseases

Brief descriptions of Selected

Autoimmune diseases
Sjgren syndrome ()

Systemic lupus erythematosus (SLE)

A chronic systemic inflammatory disease with
a clinical course of alternating exacerbations
& remissions
Major immunologic features

A chronic inflammatory disease characterized

by diminished lacrimal & salivary gland
secretion Keratoconjunctivitis &
xerostomia (dryness in eyes, mouth, nose,
trachea, bronchi, vagina, & skin)
Major immunologic features

Autoantibodies
serum complement levels during flares
Immunoglobulins & complement deposit in the
kidney & epidermal-dermal junction

Infiltration of salivary & lacrimal glands by CD4 T

cells & B cells
Autoantibodies
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System Pharmacology II - DMARDs &

Immunosuppresants/MOK

Treatment of autoimmune diseases or diseases

with a likely autoimmune origin

September 2014

Brief descriptions of Selected

Autoimmune diseases

Immunosuppressant Classes
Corticosteroids

Spondyloarthropathies

Immunosuppressants with antiinflammatory effects

Ankylosing spondylitis ()

Cytotoxic drugs

A chronic progressive inflammatory disorder

involving the sacroiliac joints, spine, & large
peripheral joints

Drugs with the capacity to kill cells for the treatment of

malignancies and in low doses as immunosuppressants

Antibodies

Reiters syndrome
A triad consisting of arthritis, urethritis / cervicitis, &
conjunctivitis / uveitis

Monoclonal antibodies against well defined targets with MANY

applications

Drugs acting on Immunophilins

Drugs interfering the signaling pathways during T-cell activation

Psoriatic arthritis

Cytokine inhibitors

A chronic, recurrent, asymmetrical, erosive

polyarthritis that occurs in ~25% of psoriasis

Drugs targeting specific proinflammatory cytokines, such as

TNF, IL-1, IL-6, etc.

Arthritis of inflammatory bowel disease

Others

Rheumatoid arthritis
Disease-modifying
antirheumatic drugs (DMARDs)
Drugs traditionally named for those drugs with
ability to modify the underlining pathology of
RA, preventing long-term joint damage & loss
of functions, but their use has been extended
to many other autoimmune diseases

Inflammation of the synovium in many

diarthrodial joints
Excessive amounts of pro-inflammatory cytokines
Tumor necrosis factor- (TNF)
Drugs targeting
Interleukin-1 (IL-1)
these cytokines
Interleukin-6 (IL-6)
Infiltration of lymphocytes & other inflammatory cells
Swelling, pain, a decrease in movement range (loss
of function)

10

Drugs for Rheumatoid arthritis

DMARDs
Potentials for

Drugs for Symptomatic relief

Reduction or prevention of joint damage

Preservation of joint integrity and function

NSAIDs & other analgesic drugs

Corticosteroid

Characteristics of the group

Disease-modifying antirheumatic drugs

(DMARDs)

Slow onset of action

Weeks to months after initiation of therapy

Traditional DMARDs
Biological agents from recombinant DNA
technology

Some DMARDs
Also for other autoimmune diseases, such
as psoriasis, inflammatory bowel disease, etc.
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Immunosuppresants/MOK

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September 2014

Non-biological DMARDs --

Biological DMARDs

More common

Etanercept, Infliximab, Adalimumab, Golimumab,

Certolizumab pegol

Methotrexate
The most commonly used in this group
A cytotoxic agent in low-dose as
immunosuppressant
Others: Azathioprine, Cyclophosphamide

Anti-TNF agents

Abatacept
T lymphocyte co-stimulation modulator

Rituximab
Depletion of CD-20 positive B lymphocytes

Tocilizumab

Leflunomide

Inhibitor of IL-6 receptor

A pyrimidine inhibitor

Canakinumab
Anti-IL-1 agent

Hydroxychloroquine and chloroquine

Anakinra

Antimalarial agents

Sulfasalazine (sulphasalazine)

IL-1 receptor antagonist

13

Other DMARDs -- Less commonly

14

Methotrexate (MTX)

used / no longer used

The DMARD of first choice

An anti-folate with cytotoxic &
immunosuppressant activities

Cyclosporine
An immunosuppressant

Auranofin, Aurothiomalate sodium

High dose for cancer chemotherapy

Much lower dose in RA or other autoimmune
disorders

Organic gold salts

D-Penicillamine

Mechanism of action

A chelating agent

In chemotherapeutic section

A teratogenic agent

Minocycline

Use of effective contraceptives is absolutely essential

A tetracycline
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Azathioprine (Imuran)

Methotrexate (MTX)
Adverse effects

The pro-drug of mercaptopurine

Usually well tolerated

Post-dose reactions

Mercaptopurine, a purine analog that is

classified as an anti-metabolite cytotoxic drug

Mechanism of action

Malaise, fatigue, arthralgia, myalgia

Stomatitis, anorexia, nausea, abdominal

cramps, increased liver function tests
Skin rash, rheumatoid skin nodules, alopecia
Bone marrow suppression (myelosuppression)
Pulmonary toxicity

Cytotoxic action (in chemotherapeutic section)

Unclear mechanisms leading to
immunosuppression

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System Pharmacology II - DMARDs &

Immunosuppresants/MOK

Lymphopenia of both T cells and B cells

Inhibition of both cell-mediated & antibodymediated immune response

September 2014

Leflunomide (Arava)

Azathioprine

An immunomodulating drug

Adverse effects
Bone marrow suppression (myelosuppression)
GI disturbances (nausea, vomiting)
Risk of infections & lymphomas

Uses as an immunosuppressant
RA
Other autoimmune diseases
Prevention of renal allograft rejection

Orally bioavailable

Mechanism of action
A competitive inhibition of Dihydro-orotate
dehydrogenase (an enzyme important for de novo
synthesis of pyrimidines) Decrease synthesis
of ribonucleotides
Selective inhibitory effects on activated
lymphocytes
T cells rely on the de novo pathway as a major
source of pyrimidine

19

Leflunomide (Arava)

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Chloroquine & Hydroxychloroquine

Adverse effects

Antimalarial drugs also as DMARDs

Diarrhea (frequent; can be serious)

Alopecia (reversible), Bone marrow
suppression
Skin rash, increased blood pressure, liver
toxicity (can be serious)
Carcinogenic & teratogenic

Unknown mechanism of action as DMARD

Adverse effects
GI -- Nausea, vomiting, anorexia
Hematological
Hemolytic anemia (in patients with G-6-PD deficiency)

Eye toxicity

Pregnancy -- Contraindication

Uses

Clinical use

Mild RA
Systemic lupus erythematosus & Sjgrens syndrome

Rheumatoid arthritis
Efficacy similar to methotrexate as a DMARD

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Sulfasalazine (sulphasalazine)

Sulfasalazine
Adverse effects

Mechanism of action

GI -- Nausea, vomiting, anorexia

Skin -- Rash, urticaria
Hematological -- Hemolytic anemia (in
patients with G-6-PD deficiency), neutropenia,
thrombocytopenia

Unclear mechanism leading to immunosuppression

Conversion to sulfapyridine & 5-aminosalicylic

acid (5-ASA) by enteric bacteria in the intestine
Sulfapyridine
The active product as a DMARD

5-aminosalicylic acid

Uses

Not absorbed and for the treatment of inflammatory bowel

disease

Mild RA
Juvenile chronic arthritis
Ankylosing spondylitis & associated uveitis

+
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Immunosuppresants/MOK

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September 2014

TNF antagonists

TNF antagonists

TNF is a central pro-inflammatory cytokine in

RA

Etanercept (Enbrel; 1998) -- SC injection

A soluble fusion protein consisting 2 p75 TNF receptors linked to
a Fc fragment of human IgG

TNF affects cell functions by activation of specific

TNF receptors on the cell surfaces & in soluble
forms

Infliximab (Remicade; 1998) -- IV injection

A chimeric anti-TNF IgG mAb

TNFR1 (= p55) -- a 55 kDa receptor

TNFR2 (= p75) a 75 kDa receptor

Adalimumab (Humira; 2002) -- SC injection

A humanized anti-TNF IgG mAb

Mechanism of action

(Chimera)

Certolizumab pegol (Cimzia; 2008) -- SC Injection

Preventing the activities of TNF by binding with

soluble TNF

A recombinant, humanized antibody Fab fragment conjugated to

an ~ 40kDa PEG (absence of Fc fragment No complement
fixation & Antibody-dependent cell-mediated cytotoxicity in vitro)

Clinical effects for RA

Golimumab (Simponi; 2009) -- SC injection

Rapid response
Symptom relief
Reduction of inflammation and damage of joint

A humanized anti-TNF IgG mAb

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TNF antagonists

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TNF antagonists
Adverse effects

Adverse effects
Injection site reactions (skin reactions a
localized rash with burning or itching; may last
up to a week) & IV infusion reactions
(Infliximab)
Hypersensitivity (including anaphylaxis)
Headache, dizziness
Cytopenia

Increased risk of infections

Tuberculosis (TB) and others
Avoid combination of 2 TNF antagonists / other
biological DMARD
Increased risk of malignancies
Lymphoma & skin cancer

Newly onset or Worsening of existing heart failure

Not to use

Reduced effectiveness of vaccination

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Approved
Indications

Etanercept

Infliximab

Adalimumab

Certolizumab
pegol

Golimumab

Rheumatoid
Arthritis

Juvenile
idiopathetic
arthritis

Psoriatic
arthritis

Ankylosing
spondylitis

Crohns
disease

Ulcerative
colitis
Plaque
psoriasis

Inflammatory
bowel disease

(+ MTX)

(including
Pediatric)

(including
pediatric)

System Pharmacology II - DMARDs &

Immunosuppresants/MOK

(+ MTX)

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IL-6 inhibitor
Tocilizumab (Acetemra; 2010)
A recombinant humanized IL-6 receptor antagonizing
IgG mAb

Mechanism of action
IL-6 is a pro-inflammatory cytokine produced by a
variety of cells, including T cells, B cells, monocytes,
and fibroblasts as well as synovial & endothelial cells
in joints affected by inflammatory processes
Activities of IL-6: T-cell activation, induction of Ig secretion,
initiation of hepatic acute phase protein synthesis, &
stimulation of hematopoietic precursor cell proliferation &
differentiation

Tocilizumab binds to both soluble and membranebound IL-6 receptors, thus inhibiting IL-6 mediated
signaling through these receptors
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September 2014

Tocilizumab

Tocilizumab

Adverse effects

Clinical use

Infusion-related reactions (such as fever and

chills)
Increased risk of infections
Headache, and diarrhea
Elevated cholesterol levels
Increased liver enzymes
Decreased white blood cell count and
platelets
Bowel perforation (rare)

Adult RA: For moderately to severely active

RA that the patients with inadequate response
to one or more DMARDs
MTX or other non-biological drugs
NOT with another biologic response modifier
Monthly (q4w) IV infusion; Onset: 6 12 weeks

Juvenile idiopathic arthritis (JIA)

Children 2 years of age and over
Polyarticular: Q4Wk
Systemic: Q2Wk
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Canakinumab (Ilaris)

IL-1 inhibitors
IL-1

A human anti-IL-1 IgG mAb

Plasma IL-1 level increases in patients with active

inflammation
Pathologic implications: RA, Juvenile idopathic
arthritis (JIA), Cryopyrin-associated periodic
syndromes (CAPS; a rare autosomal dominant genetic

FDA approval in 2009

Mechanism of action
Canakinumab binds to IL-1 and neutralizes its
activity by blocking its interaction with IL-1
receptors

disorder, in which the gene encode for cryopyrin is mutated.

Cryopyrin regulates protease caspase-1 and controls the
activation of IL-1), Acute gout

IL-1 inhibition
IL-1 blocker
Canakinumab
IL-1 receptor antagonist
Anakinra (2001 FDA approval; No longer available
33
in HK)

T lymphocyte costimulation
modulator

Canakinumab
Adverse effects

Abatacept (Orencia; 2005 FDA approval)

Injection site reactions

Upper respiratory infections
Headache, nausea, abdominal pain, diarrhea
Increased risk of serious infections

A soluble fusion protein of the extracellular domain of

human cytotoxic T-lymphocyte-associated antigen 4
(CTLA-4) linked to a Fc fragment of IgG

Mechanism of action
Abatacept binds to CD80 and CD86 on the
antigen-presenting cell & prevents these
receptors from binding to CD28 receptors on
T cells

Use
Systemic juvenile idiopathic arthritis
SC Q4Wk

Cryopyrin-associated periodic syndrome

SC Q8Wk

Being evaluated (in clinical study):

Chronic obstructive pulmonary disease (COPD)
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System Pharmacology II - DMARDs &

Immunosuppresants/MOK

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Decreasing inflammation by blocking the activation

of T lymphocytes

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September 2014

Dendritic cell
(APC)

T helper cell

Antigen
signal
Antigen-MHC
complex

TCR

CD80/CD86

CD28

Abatacept

T cell activation

Adverse effects

Co-stimulatory
signal

Antigen
signal
Antigen-MHC
complex

TCR
CTLA-4

CD80/CD86

NO
T cell activation

Most common ( 10%): Headache, upper respiratory

tract infections, nausea
Injection site reactions
Hypersensitivity (including anaphylaxis)
Increased risk of serious infections & lymphoma
Not to be combined with a TNF antagonist (serious
infections)

Inhibitory
signal

Approved indications
Antigen-MHC
complex

TCR

CD80/CD86

CTLA-4

Hindrance of
T cell activation

Abatacept
(CTLA-4 + Fc fragment)

Adult rheumatoid arthritis (SC / IV infusion)

Juvenile idiopathic arthritis (IV infusion)

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Targeted B lymphocyte therapy

Rituximab
Adverse effects

Rituximab (Mabthera; 1997)

Infusion reactions

A chimeric anti-CD20 IgG mAb targeting CD20

Urticaria, hypotension, angioedema, hypoxia, bronchospasm,

pulmonary infiltrates, acute respiratory distress syndrome,
myocardial infarction, ventricular fibrillation, cardiogenic
shock, anaphylactoid reactions, death

Mechanism of action
CD20 is a protein on the cell surface of pre-B cells
and mature B cells (not on hematopoietic stem cells,
pro-B cells, normal plasma cells, or other tissues)
Rituximab selectively binds to CD20 on B cells
Lysis of B cells (possibly by complement-dependent
cytotoxicity and antibody-dependent cell mediated
cytotoxicity), leading to depletion of peripheral B cells &
decrease in serum immunoglobulin levels
In RA: Also reduction of certain biologic markers of
inflammation, such as IL-6, anti-citrullinated peptide (antiCCP), etc.

Severe mucocutaneous reactions

Including Steven Johnson syndrome (SJS) & toxic epidermal
necrolysis (TEN)

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Rituximab

40

B-lymphocyte inhibitors
Belimumab (Benlysta; 2011)

Uses
By IV infusion
RA

A human monoclonal antibody targeting soluble Blymphocyte stimulator (BLyS)

In combination with MTX for patients with moderate to severe

RA who have inadequate response to one or more TNF
antagonist therapies

Hematologic cancers
Non-Hodgkins lymphoma (NHL; )
Chronic lymphocytic leukemia (CLL;
)
Granulomatosis with polyangiitis (;
Wegeners granulomatosis) & Microscropic
polyangiitis ()
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System Pharmacology II - DMARDs &

Immunosuppresants/MOK

Increased risk of infections

Hepatitis B virus reactivation & hepatitis
Bowel obstruction and perforation
Cytopenia
Tumor lysis syndrome (In treatment of lymphoid
malignancies)

Mechanism of action
BLyS (a cytokine; also known as B-cell activating
factor, BAFF) is a B-cell survival factor, which is a B
cell activator and plays an important role in the
proliferation & differentiation of B cells
Belimumab binds to soluble BLyS, inhibiting the
survival of B cells (including autoreactive B cells) and
reduces differentiation of B cells into immunoglobulinproducing plasma cells
Reducing B cells and IgG in the blood circulation
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September 2014

Belimumab
Adverse effects

Calcineurin inhibitors,
mTOR inhibitors &
Other immunosuppressants

Nausea, diarrhea, fever, upper respiratory infections,

insomnia, pain in extremity, migraine
Increased risk of serious infections
Hypersensitivity (including anaphylaxis)
Depression & suicidality

Use
Systemic lupus erythromatosus
Adult patients with active, autoantibody-positive and
receiving standard therapy
IV infusion Q2Wk for the first 3 doses & Q4Wk thereafter
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Other cells (B cells,

T cytotoxic cells, etc.)

Ag-presenting cell

Introduction

IL-2R
CD80 /
CD86

Immunophilins

Ag
As paracrine

TCR
Protein tyrosine
Kinases (Scr, Ick, etc.)

T helper cell
(enlarged)

Isomerases that catalyze cis-trans isomerization of peptide

bonds of the amino acid proline in target proteins
Protein folding, signal transduction, trafficking, assembly and
cell cycle regulation

IL-2

[Ca++]

IL-2R
mTOR

Calcineurin
NFAT PO4

Proteins in the cells that act as peptidyl-prolyl cistrans isomerases

Examples of immunophilins
As autocrine

NFATc
Proliferation
Expression of
IL-2 gene & other
cytokine genes

Cyclophilins
FK-binding proteins (FKBP), such as FK506-binding
protein and FKBP-12 (macrophilin-12)

Targets of immunosuppressants, such as

cyclosporin, tacrolimus

IL-2

Other cytokines
(ILs, IFN, etc.)
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Introduction

Introduction

Calmodulin (calcium-modulated protein)

IL-2

A Ca-binding messenger protein as a multi-purpose

intracellular Ca receptor, governing many Caregulated processes
Activated Ca/Calmodulin binds to its target proteins
(such as enzymes, membrane transport proteins)

A 133- amino acid glycoprotein produced by activated T cells

and NK cells

IL-2 receptor
Responsiveness depends on the expression of IL-2 receptors by
target cells

Calcineurin
A calcium-dependent protein phosphatase (enzyme that
dephosphorylates a target protein) that activates nuclear
factor of activated T cell, cytoplasmic (NFATc)

Activated NFATc
An activated transcription factor that translocates into
the nucleus, where it up-regulated the expression of
IL-2 (and other cytokines, such as IFN)

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System Pharmacology II - DMARDs &

Immunosuppresants/MOK

Resting T cells & nearly all types of tumor cells lack receptor
expression & are unresponsive to IL-2

3 components: an chain (CD25) for IL-2 binding, a chain for

intracellular signaling, & a chain that is a component of many
cytokine receptors (IL-2, IL-4, IL-7, IL-9, IL-15, & IL-21)
Activities
Stimulation of the proliferation of activated T cells and secretion of
cytokines from NK cells & monocytes
Stimulation of cytotoxic killing by NK cells and T cells
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September 2014

Other cells (B cells,

T cytotoxic cells, etc.)

Ag-presenting cell

Calcineurin inhibitors
IL-2R
CD80 /
CD86

Cyclosporin, Tacrolimus, & Pimecrolimus

Mechanism of action

Ag
As paracrine

TCR

Binding to an immunophilin and forming a complex,

which inhibits calcineurin

Protein tyrosine
Kinases (Scr, Ick, etc.)

T helper cell
(enlarged)

Cyclophilin: Cyclosporin
FKBP-12: Tacrolimus & Pimecrolimus

IL-2

[Ca++]

Without the dephosphorylation of NFATc

Expression of IL-2 gene and subsequent
activation of T cells
Inhibition on the early stages of T cell activation
Addition activity for Tacrolimus & Pimecrolimus

IL-2R
mTOR

Calcineurin
NFAT PO4

As autocrine

NFATc
Proliferation

Prevention of release of inflammatory cytokines & mediators

from mast cells & basophils

Expression of
IL-2 gene & other
cytokine genes

IL-2

Other cytokines
(ILs, IFN, etc.)

49

Cyclosporin (Cyclosporin A)

Cyclosporin (Cyclosporin A)

Ciclosporin (INN), Cyclosporine (USAN),

Cyclosporin (former BAN)

Pharmacokinetics
Sandimmun Conc. solution for IV infusion; Neoral
Cap/Solution

A cyclic immunosuppressant consisting of 11

amino acids produced by the fungus
Tolypocladium inflatum (Beauveria nivea)

Neoral is an oral formulation that forms a microemulsion in

an aqueous environment

Other brands for oral capsules & solution

Incomplete & erratic oral absorption

Clinical uses
Prophylaxis of organ allograft rejection

Microemulsion formulation improves oral bioavailability

Kidney, liver, heart

Eye drop (in emulsion form)

Metabolized by CYP3A

RA
Psoriasis
51

Cyclosporin (Cyclosporin A)
Adverse effects
Nephrotoxicity
Hypertension
Tremor, headache, hirsutism (hair growth),
acne, gum hyperplasia (reduced by brushing &
flossing), GI distress (nausea, vomiting, abdominal
pain), muscle cramps, numbness & tingling of
the hands & feet (extremities)
Increased risk of infections & skin cancers
Hepatotoxicity
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Immunosuppresants/MOK

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Many drug-drug interactions

Grapefruit inhibits its metabolism

52

Tacrolimus
Formerly known as FK506
A macrolid antibiotic produced by Streptomyces
tsukubaensis
Use
Prophylaxis of allograft rejection
Liver, kidney, heart transplants
Advagraf prolonged-release Cap
Prograf Cap; Prograf conc. solution for Infusion

Moderate to severe atopic dermatitis refractory to

other treatments
Short-term and non-continuous chronic treatment
Protopic ointment / Remus ointment
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September 2014

Pimecrolimus (Elidel)

Tacrolimus

A derivative of ascomycin

Adverse effects
Increased risk of infections and malignancies (skin
cancers & lymphoma)
New onset diabetes
Nephrotoxicity
Hyperkalemia
Hypertension
Myocardial hypertrophy
Hyperlipidemia
GI distress, tremor, headache, insomnia, paresthesia
Anemia, leukopenia

Ascomycin is produced by Streptomyces

hygroscropicus and is a methyl analog of tacrolimus

Adverse effects
Local reactions (burning sensation, stinging, soreness,
or pruritus)
A possible increased risk of skin cancer & lymphoma

Use
A second-line agent for short-term and noncontinuous chronic treatment of mild-to-moderate
atopic dermatitis
Topical use: BID to affected areas
Non-immunocompromised adults & children 2 years of age &
older, who fail to respond adequately other topical treatments

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mTOR

mTOR inhibitors
Sirolimus, everolimus, Temsirolimus
Mechanism of action

Mammalian target of rapamycin (=

sirolimus)

Sirolimus forms a complex with FKBP-12 that binds to

and inhibits mTOR, leading to decreased expression
of mRNAs necessary for cell cycle progression
Arresting cells in G1 phase
Selected results
Inhibition of T cell activation & clonal proliferation
(second phase of T cell activation)
Inhibition of antibody production
Inhibition of the expression of vascular endothelial
cell growth factor (VEGF) and hypoxia-inducible
factors (HIFs) Inhibition of tumor angiogenesis

A serine/threonine kinase which is part of the

PI3K/AKT/mTOR signal pathway
A key regulatory kinase

The signal pathway responds to a number of

signals from different growth factors (e.g.,
insulin, interleukins (such as IL-2), and EGF,
etc.)
Affecting cell growth, cell proliferation, protein
synthesis), cell metabolism, and apoptosis
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Other cells (B cells,

T cytotoxic cells, etc.)

Ag-presenting cell

58

Sirolimus (Rapamune)

IL-2R
CD80 /
CD86

Ag
As paracrine

TCR
Protein tyrosine
Kinases (Scr, Ick, etc.)

T helper cell
(enlarged)

IL-2

[Ca++]

IL-2R
mTOR

Calcineurin
NFAT PO4

As autocrine

Proliferation

Prophylaxis of allograft rejection

Kidney

IL-2

Prevention of re-stenosis

Other cytokines
(ILs, IFN, etc.)

Sirolimus-eluting coronary stent for angioplasty

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Immunosuppresants/MOK

First discovered from a soil sample in Easter Island in

1970s
Found to stop fungal activity at the G1 phase of cell
cycle and block G1 to S phase transition in the T cells
of rats

Uses

NFATc
Expression of
IL-2 gene & other
cytokine genes

Previous known as rapamycin

A macrolide antibiotic produced by
Streptomyces hygroscopicus

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September 2014

Temsirolimus (Torisel)

Everolimus
A derivative of sirolimus
Use

A sirolimus analog
IV infusion

Prophylaxis of allograft rejection

Kidney (0.75 mg BID as soon as possible after
transplantation), liver (1 mg BID starting 30 days after
transplantation)
Certican 0.25 mg, 0.5 mg, 0.75 mg, 1 mg Tab; 0.1 mg, 0.25
mg Dispersible Tablets

Adverse effects
Hypersensitivity / Infusion reactions
Pre-treatment with an antihistamine for
hypersensitivity reactions

Use

Cancer chemotherapies
Afinitor 2.5 mg, 5 mg, 10 mg Tablets

Advanced renal cell carcinoma

Prevention of re-stenosis
Everolimus-eluting coronary stent for angioplasty
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Sirolimus & derivatives

62

Other selected immunosuppressant

Adverse effects

Mycophenolate mofetil

Peripheral edema
Hyperlipidemia (triglycerides & cholesterol)
Hypertension
Impaired renal function
GI distress
Headache, arthralgia
Anemia, thrombocytopenia
Increased risk of infections and malignancies

A prodrug of mycophenolic acid

For better oral bioavailability
Tablets, Gastro-resistant Tablets, Capsules,
Powder for IV infusion

A semi-synthetic derivative from a fungal

antibiotic (from Penicillium stoloniferum)
An inosine monophosphate dehydrogenase
inhibitor
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Mycophenolate mofetil

Mycophenolate mofetil

Mechanism of action

Adverse effects

Inosine monophosphate dehydrogenase (IMPDH)

An important enzyme in the de novo pathway of guanine
nucleotide synthesis
T cells and B cells critically depend on this synthetic pathway
for cell proliferation

Mycophenolic acid is a selective, noncompetitive,

reversible inhibitor of IMPDH
Suppression of proliferation of both T cells and B
cells (a cytostatic effect) in response to mitogens /
graft
Additional activities: Interfering leukocyte adhesion to
endothelial cells (for migration to site of inflammation)
and suppression of antibody formation
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Immunosuppresants/MOK

GI distress (reduced by taking with food)

Headache, dizziness, insomnia, tremor, and rash
Increased risk of infections & malignancies

Uses
Prophylaxis of organ rejection
Kidney, heart, liver

Non-FDA approved indications

Autoimmune disorders: RA, SLE (especially involving the
kidneys), vasculitis, inflammatory bowel disease (such as
Crohns disease), inflammatory eye disease (such as uveitis
and scleritis), some kidney or skin disorders
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September 2014

Basiliximab

Anti-IL-2 receptor (Anti-CD25) mAb

Adverse effects

Basiliximab (Simulect; 1998 FDA Approval)

Acute hypersensitivity (including anaphylaxis)

Increased risk of infections

A chimeric IgG mAb as an IL-2R antagonist

Mechanism of action
IL-2 is an important cytokine in immune response
IL-2R (also known as CD25) is selectively
expressed on the surface of activated T cells
Basiliximab binds to IL-2R, thus inhibiting IL-2
binding and preventing IL-2 mediated activation of
lymphocytes (which is important in cellular immune
response involved in allograft rejection)

Use
Prophylaxis of organ transplantation
Part of an immunosuppressive regimen that
includes cyclosporin & corticosteroid
By IV infusion
1st dose: 2 hours before surgery
2nd dose: 4 days after transplantation
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System Pharmacology II - DMARDs &

Immunosuppresants/MOK

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