Download Immunomodulating dru..

Naglaa F.El-Orabi,
Ph D, MSc, B Pharm Sc
Assistant professor
Department of Pharmacology &Toxicology
College of Pharmacy, Girls section
King Saud University,
Riyadh, KSA
Immune system :
The importance of the immune system is to protect the
body against harmful foreign molecules (living and nonliving pathogens) and defend against diseases.
Components of immune system:
1- Lymphoid organs and tissues
2- Leukocytes (WBCs)
3- Soluble proteins:
Immune system (cont’d)
1- Lymphoid organs and tissues
Immune system (cont’d)
2- Leukocytes
lymphocytes
granulocytes
Monocytes (Phagocytes)
Immune system (cont’d)
3- Soluble proteins:
- Complement system.
- Acute phase proteins.
- Antibodies.
- Cytokines.(are soluble , signaling proteins that produced by
various population of immune cells and other cells to interact
with cell surface receptors on a variety of affecter cells and
they play many roles as pro-inflammatory, anti-nflammatory,
growth regulation and others).

Cytokines include
◦ Interleukins (ILs)
◦ Interferons (IFNs),
◦ Tumor Necrosis Factors (TNFs),
◦ Transforming Growth Factors (TGFs)
◦ Colony-stimulating factors (CSFs).
Innate immunity
Acquired immunity
Passive immunity
Innate immunity
 Non First
 No
specific, constitutive.
line of defense. Present from birth.
immunologic memory.
Innate Immunity
 Includes physical, chemical and biochemical barriers.
Innate Immunity
 Includes physical, chemical and biochemical barriers.
•Microbes.
•Microbial products.
•Tissue damage.
Inflammation
 It is secondary to the innate response.
 Adaptive and specific.
 Recognition ( self/ non-self or pathogenic discrimination).
Essential to the development of specific immunity is the recognition of antigen.
 Immunological memory (long lasting).

Two types of specific immune response:
- Cell-mediated immunity (CMI):
All immunologic activities in which cellular elements play a
direct role e.g. activation of antigen-specific T-lymphocytes.
Abnormal cell e.g
cancer cell, infected cell
Killer T-cell
recognises antigen
Antigen
Clones of killer T-cell
attach to antigen
Killer T-cells release
perforin pores
Normal cell
Helper T-cell stimulates
correct killer T-cell to
multiply
Destruction of abnormal
cell
- Humoral immunity (HI):
It is directly dependent on the production of antigen –specific
antibody by B lymphocytes and involve the coordinated
interaction of antigen-presenting cells, T lymphocytes and Blymphocytes.

Function of T helper cells:
Acquired Immunity
Antigen presenting cells (APCs) present antigen on their Class II MHC
molecules (MHC2). Helper T cells recognize these, with the help of their
expression of CD4 co-receptors (CD4+, CD3+,……). The activation of a
resting helper T cell causes it to release cytokines and other stimulatory
signals (green arrows) that stimulate the activity of macrophages, killer T
cells and B cells, the latter producing antibodies. The stimulation of B cells
and macrophages succeeds a proliferation of T helper cells.
 It is a form of induced immunity.
 Antibodies are borrowed from another sources.
 It usually gives short-term resistance (2 weeks – 6 months).
Two types are recognized:
Natural Passive
e.g. Baby in uterus (placenta)
and Breast-fed babies (milk)
Artificial Passive
e.g. Gamma globulin injection
Extremely fast, but short
lived (e.g. snake venom)


In some instances, the response of immune system can result in
serious problems. For example, the introduction of an allograft
(that is, the graft of an organ or tissue from one individual to
another who is not genetically identical) can elicit a damaging
immune response, causing rejection of the transplanted tissue.
Transplantation of organs and tissues (for example, kidney,
heart, or bone marrow) has become routine due to improved
surgical techniques and better tissue typing.
Another immune-related problem is the problem associated
with autoimmune diseases (e.g. SLE, RA, MS, autoimmune
hemolytic anemia, acute glomerulonephritis), when the
immune system fail to recognize the self antigen and attack it.


Immunosuppressant drug are now utilized to inhibit
rejection of transplanted tissues and to treat the
autoimmune diseases.
Because of their severe toxicities when used as
monotherapy, a combination of immunosuppressive
agents (2-4 agents with different mechanisms of
action), usually at lower doses, is generally
employed.
I.
Immunophilin-binding drugs (act as inhibitors of
cytokine production or function):
1Calcineurin inhibitors
•Cyclosporine
•Tacrolimus (FK506)
2) Antiproliferative drugs
• Sirolimus (Rapamycin).
•Everolimus, Biolimus A9
Novolimus,and Zotarolimus
(umirolimus),
Myolimus,
II. Corticosteroides (mainly act by alteration of gene
expression of many immune-regulating proteins like
cytokines and others)
◦ Corticosteroids
(Prednisone,
Prednisolone,
Methylprednisolone, Dexamethasone)
III. Cytotoxic/Cytostatic drugs
• Inhibitors of purine or pyrimidine synthesis
(Antimetabolites):
◦
Azathioprine
◦
Myclophenolate Mofetil
◦
Leflunomide
◦
Methotrexate
• Alkylating agents:
Cyclophosphamide
IV. Immunosuppressive antibodies
that block T cell surface molecules involved in
signaling immunoglobulins
◦ antilymphocyte globulins (ALG).
◦ antithymocyte globulins (ATG).
◦ Rho (D) immunoglobulin.
◦ Basiliximab
◦ Daclizumab
◦ Muromonab-CD3
V. Miscellanous: e.g. Interferons, opoids, Fingolimod,
….
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Immunophilins are abundant endogenous cytosolic proteins that
catalyze the cis‐trans isomerization of proline residues within proteins,
generally to aid in protein folding. Immunophillins (e.g. FKBP-12, and
cyclophillin)
are the intracellular binding proteins of several
immunosuppressive drugs.
Immunophilin-binding drugs act mainly as inhibitors of cytokine gene
expression or cytokine function. Cytokines are soluble, antigennonspecific, signaling proteins that bind to cell surface receptors on a
variety of cells.
Of particular interest when discussing immunosuppressive drugs is IL-2
cytokine, a growth factor that stimulates the proliferation of antigenprimed (helper) T cells, which subsequently produce more IL-2, IFNɣ,
and TNFα. These cytokines collectively activate natural killer cells,
macrophages, and cytotoxic T lymphocytes.
Drugs that interfere with the production of IL-2, such as cyclosporine,
and Tacrolimus (FK506) are also known as calcineurin inhibitors .
Example of drugs that inhibit IL-2 action is sirolimus (rapamycin)
Cyclosporin
Cyclosporin (Sandimmune)

Cyclosporine (CsA) is a lipophillic cyclic
polypeptide composed of 11 amino acids that is
extracted from a soil fungus (Tolypocladium inflatum).
Cyclosporin (cont’d)
Mechanism of action:



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Cyclosporine preferentially suppresses cell-mediated immune
reactions, whereas humoral immunity is affected to a far lesser
extent.
It acts by blocking activation of T cells by inhibiting interleukin-2
production (IL-2).
It also decreases proliferation and differentiation of T cells.
After diffusing into the T cell, CsA binds to cytosolic protein known
as cyclophilin (immunophilin) that acts as CsA intracellular
receptors. Cyclosporine-immunophilin complex inhibits calcineurin,
a phosphatase necessary for dephosphorylation of transcription
factor NFATc (cytosolic Nuclear Factor of Activated T cells).
required for interleukins synthesis (IL-2). Inhibition of NFATc
dephosphorylation suppresses cell-mediated immunity.
Cyclosporin (cont’d)
Pharmacokinetics:
⁻ Can be given orally or I.V. infusion. It is slowly and incompletely
absorbed from GIT.
⁻ Peak levels is reached after 2– 4 hours, elimination half life is 24 h.
⁻ Oral absorption is delayed by fatty meal. CsA is usually available in
soft gelatin capsules, microemulsion that has higher bioavailabilityis not affected by food.
⁻ 50 – 60% of cyclosporine accumulates in blood (erythrocytes &
lymphocytes).
⁻ CsA is extensively metabolized by liver CYP-450, primarily by
hepatic CYP3A4.
⁻ Excreted mainly through the biliary route, and about 6% is
excreted in urine.
Cyclosporin (cont’d)
Therapeutic Uses:



CsA is used to prevent rejection of kidney, liver, and cardiac
allogeneic transplants.
CsA is most effective in preventing acute rejection of
transplanted organs when combined in a double-drug or
triple-drug regimen with corticosteroids and an
antimetabolite such as mycophenolate mofetil.
CsA is used for the treatment autoimmune disorders like
severe, active rheumatoid arthritis, and recalcitrant psoriasis
that does not respond to other therapies.
Cyclosporin (cont’d)
Adverse Effects:
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Many of the adverse effects caused by CsA are dose dependent;
therefore, it is important to monitor blood levels of the drug
Nephrotoxicity; critical to monitor kidney function. Reduction of
the CsA dosage can result in reversal of nephrotoxicity in most
cases, although nephrotoxicity may be irreversible in 15% of
patients. Symptoms of nephrotoxicity is enhanced by coadministeration with NSAIDs and aminoglycosides antibiotics.
Liver dysfunction.
Hypertension, hyperkalemia.(K-sparing diuretics should not be
used).
Hyperglycemia.
Multiple infections especially viral infections (Herpes cytomegalovirus).
Cyclosporin (cont’d)
Adverse Effects (cont’d):
◦
◦
◦
◦
◦
Lymphoma (Predispose recipients to cancer).
Hirsutism
Neurotoxicity (tremor).
Gum hyperplasia.
Anaphylaxis may experienced after I.V.
Drug Interactions



Clearance of cyclosporine is enhanced by co-administration of
CYP450 inducers (Phenobarbitone, Phenytoin & Rifampin ) 
rejection of transplant.
Clearance of cyclosporine is decreased when it is co-administered
with cimetidine, erythromycin or Ketoconazole, Grapefruit juice 
cyclosporine toxicity.
Additive nephrotoxicity: NSAIDs, aminoglycosides.
Tacrolimus (FK506)
Tacrolimus (Prograft, Protopic)

Tacrolimus (TAC, originally called FK506) is a macrolide
antibiotic that is isolated from a soil actinobacteria
(Streptomyces tsukubaensis)
Tacrolimus (cont’d)
Mechanism of action:

TAC exerts its immunosuppressive effect in the same
mechanism as CsA, except that it binds to a different
immunophilin protein , FKBP-12 (FK506-binding
protein-12) creating a new complex (tacrolimusFKBP12 complex) that inhibits calcineurin.
Tacrolimus (cont’d)
Pharmacokinetics:
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TAC may be administered orally , I.V., or some topical
preperations (ointment).
GI absorptin of TAC is incomplete and variable, reduced by fat
and carbohydrate meals.
TAC is from 10- to 100-fold more potent than CsA.
It has half-life after I.V. adminsteration is 9-12 hours.
It is highly bound to plasma proteins and is also concentrated in
erythrocytes.
It is undergoes hepatic metabolism by the CYP3A4 isozyme;
thus, the same drug interactions with CsA occur.
At least one metabolite of TAC has been shown to have
immunosuppressive activity.
Excreted mainly in bile and minimally in urine.
Tacrolimus (cont’d)
Therapeutic Uses:
as cyclosporine
 Organ and stem cell transplantation
 Prevention of rejection of liver and kidney transplants
(given with a corticosteroids and/or an antimetabolite).
 TCA is also used in treatment of dermal symptoms
associated with some autoimmune disorders (e.g.
dermatitis and psoriasis).
Tacrolimus (cont’d)
Adverse Effects:

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
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Nephrotoxicity (more than CsA)
Neurotoxicity; tremor, seizures, and hallucinations,
(more than CsA)
insulin-dependent diabetes mellitus
GIT disturbances
Hperkalemia
Mild hypertension
Anaphylaxis
NO hirsutism or gum hyperplasia
Drug interactions: as CsA
Tacrolimus (cont’d)
What are the differences between CsA and TAC ?
TAC is more favorable than CsA due to:
 TAC is 10 – 100 times more potent than CsA in
immunosupression capacity.
 TAC has decreased episodes of rejection.
 TAC is combined with lower doses of glucocorticoids.
 TAC has also been found to have a lower incidence of
cardiovascular toxicities such as hypertension and
hyperlipidemia, both of which are common disease states found
in kidney transplant recipients.
But,
TAC is more nephrotoxic and neurotoxic.
Sirolimus (rapamycin)
Sirolimus (Rapamune)

Sirolimus (SRL) is macrolide antibiotic

It was first discovered as a product of the bacterium
(Streptomyces hygroscopicus ) in a soil sample from a pacific
island known as Rapa Nui, hence it was initially marketed
under the name Rapamycin
Sirolimus (cont’d)
Mechanism of action:



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Sirolimus is to bind the cytosolic protein FKBP12 (in a manner
similar to tacrolimus), but instead of inhibition of calcineurin,
Sirolimus-FKBP12 complex inhibits the mammalian target of
rapamycin1 (mTOR).
mTOR is a serine-threonine kinase that is essential for many
cellular functions, such as cell-cycle progression, DNA repair,
and regulation of protein translation
Binding of Sirolimus-FKBP12 complex to mTOR blocks the
activated T -cells proliferation, B cell proliferation &
immunoglobulin production.
Unlike CsA and TAC, SRL does not owe its effect to lowering
IL-2 production but, rather, to inhibiting the cellular
responses to IL-2.
Sirolimus (cont’d)
Pharmacokinetics:
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The drug is available only as oral preparations.
It is readily absorbed from GIT (rate is decreased by high-fat
meals)
A loading dose is required at the time of initiation of therapy.
SRL is extensively bound to plasma proteins (~ 92%) and has a
long half-life (57-63 hours) compared to those of CsA and TAC.
SRL is metabolized by the CYP3A4 isozyme and has the same
drug-drug interactions as CsA and TAC.
Due to competition in protein binding sites, SRL increases the
drug concentrations of CsA, and careful blood level monitoring
of both agents must be employed to avoid harmful drug toxicities
uppon combined therapy.
SRL and its metabolites are predominantly eliminated in the
feces.
Sirolimus (cont’d)
Therapeutic Uses:
SRL has both anti-proliferative and immunosuppressive effects
(equipotent to CsA).
 In renal transplantation(used mainly combined
with CsA and
corticosteroids)
 To limit the long-term side effects of the calcineurin inhibitor, SRL
is often utilized in calcineurin inhibitor withdrawal protocols in
patients who remain rejection free during the first 3 months
posttransplant.
 Heart allografts
 In halting graft vascular disease (SRL-coated stents inserted into the
cardiac vasculature inhibit neointimal vascular hyperplasia and
restenosis of the blood vessels by reducing proliferation of the
endothelial cells).
 Hematopoietic stem cell transplant recipients.
Sirolimus (cont’d)
Adverse Effects:




Hyperlipidemia (elevated cholesterol and triglycerides),
The combination of CsA and SRL or TAC and SRL are more
nephrotoxic than CsA or TAC alone
headache, nausea and diarrhea, leukopenia, and
thrombocytopenia.
Impaired wound healing especially in obese and diabetic
patients which may represents a problem immediately
following the transplant surgery.
II. Corticosteroids

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The corticosteroids were the first pharmacologic agents to be
used as immunosuppressives both in transplantation and in
various autoimmune disorders.
They
have
both
anti-inflammatory
action
and
immunosuppressant effects.
They are still one of the mainstays for attenuating rejection
episodes. The most common agents are Prednisone,
prednisolone,
methylprednisolone,
and
betamethasone
dexamethasone
Pridinsone
Pridinsolone
Dexamethasone
Corticosteroids
Mechanism of action:


On entering cells, they bind to the glucocorticoid receptor (GR). The
glucocorticoid-GR complex translocates into the nucleus and interacts
with DNA to regulates the gene transcription of .
Among the genes affected are those involved in inflammatory
responses.
◦ Decrease production of inflammatory mediators as prostaglandins,
leukotrienes, histamine, PAF, bradykinin mainly by their stimulatory
action on annexin-1 (a phoshplipase A inhibitor).
◦ Decrease production of a wide array of proinflammatory cytokines
like IL-1, IL-2,IL-3,…, TNF-, GM-CSF.
◦ Stabilize lysosomal membranes.
◦ Decrease generation of IgG, and nitric oxide.
◦ Inhibit antigen processing by macrophages.
◦ Suppress T-cell helper function
◦ Decrease T-lymphocyte proliferation.
Corticosteroids (cont’d)
Pharmacokinetics:
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Corticosteroids may be administered by a variety of routes. Most are
active when given orally, and parentrally . In addition topical
preparations, eye/ear/ nasal drops and aerosoles are also available.
Corticosteroids (~90%) bind to corticosteroid-binding globulin (CBG)
and to albumin with variable tendencies.
Plasma half-life 2-8 hours, with variable durations depending on
preparation ;(8-12 hrs for SAGCs e.g. Cortisol, 18-36 hrs for IAGCs e.g.
Predinsolne, and 36-54 hrs for LAGCs e.g. Dexamethasone,
Betamethasone).
Generally GCs are metabolized in the liver by both microsomal (mainly
CYP3A4 & CYP2D6) and non-microsomal enzymes, where they are
reduced and conjugated (glucourinate and sulfate), forming inactive
water-soluble metabolites that are excreted by the kidney (~75%) in
addition to ~25% are execreted in feces.
Some GCs are bioactivated after adminstration like Prednisone that is
converted in vivo to active metabolite prednisolone.
Corticosteroids (cont’d)
Therapeutic Uses:
Corticosteroids are first line therapy for solid organ
allografts & haematopoietic stem cell transplantation to
attenuating rejection episodes.
Acute or chronic rejection of solid organ allografts (given
with TAC/CsA and/or an antimetabolite).
Autoimmune diseases as refractory rheumatoid arthritis,
systemic lupus erythematosus, temporal arthritis, and
asthma.
Corticosteroids (cont’d)
Adverse Effects:

The use of these agents is associated with numerous
adverse effects. For example,
◦ Hypercholesterolemia
◦ Hyperglycemia
◦ Hypertension
◦ Cataract
◦ Osteoporosis
◦ Increase liability to infection
◦ Adrenal suppression
III. Cytotoxic agents
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Alkylating agents
e.g. Cyclophosphamide
Inhibitors of purine or pyrimidine synthesis
(Antimetabolites):
Azathioprine
Mycophenolate Mofetil
Leflunomide
Methotrexate
Cyclophosphamide
Cyclophosphamide (Cytoxan)


Cyclophosphamide is a cytotoxic agent acts by alkaylation of the
DNA. Cyclophosphamide is a prodrug that is undergo some
modification by the effect of multiple liver CYP450 to form the active
compounds, phosphoramide mustard and acrolein.
Reaction of the phosphoramide mustard with DNA is considered to
be the cytotoxic step especialy to those rapidly deviding cells like
neoplastic cells, proliferating lymphoid cells and germ cells.
Cyclophosphamide (cont’d)
• It is administered orally& intravenously
• Cyclophosphamide is converted by
mixed-function
oxidase
enzymes
(cytochrome P450 system) in the liver
to active metabolites. The main active
metabolite
is
4hydroxycyclophosphamide,
and
aldophosphamide. Most of the
aldophosphamide is oxidised by the
enzyme aldehyde dehydrogenase
(ALDH) to make carboxyphosphamide.
A small proportion of aldophosphamide
freely diffuses into cells, it is
decomposed into two compounds,
phosphoramide mustard and acrolein.
• The execretion occurs equally between
renal and biliary routs.
Cyclophosphamide (cont’d)
Therapeutic Uses:


It is widely utilized in treatment of a wide variety of neoplastic diseases
(anticancer), such as lymphoma and breast cancer.
Immunosupressant in autoimmune disorders such as rheumatoid arthritis ,
systemic lupus erythrematosus, Autoimmune hemolytic anemia
Adverse effects:
◦ Alopecia and GIT disorders (Nausea -vomiting-diarrhea)
◦ Bone marrow suppression
◦ Hemorraghic cystitis , which can lead to fibrosis of the bladder. The latter
toxicity has been attributed to acrolein which is toxic to the bladder
epithelium. This can be prevented through the use of aggressive hydration
and/or MESNA (sodium 2-mercaptoethane sulfonate), which neutralizes
the toxic metabolites, minimizes this problem.
◦ Sterility (testicular atrophy and aspermia in male& amenorrhea in females)
◦ Veno-occlusive disease of the liver
Antimetabolites
1- Azathioprine
Azathioprine (Imuran)
• It is a purine analogue immunosuppressive drug that
was the first agent to achieve widespread use in organ
transplantation.
• It is a prodrug that is converted first to 6mercaptopurine (6-MP) and then to the corresponding
nucleotide, thioinosinic acid.
Azathioprine (cont’d)
Mechanism of action:
• The immunosuppressive effects of azathioprine are due
to this nucleotide analog; thioinosinic acid.
• Because of their rapid proliferation in the immune
response, lymphocytes (B &T) are predominantly
affected by the cytotoxic effects of azathioprine.
• Azathioprine Inhibits de novo synthesis of purines
required for lymphocytes proliferation.
Pharmacokinetics:
◦ It is administered orally or intravenously.
◦ Widely distributed but does not cross BBB.
◦ Metabolized in the liver to 6-mercaptopurine or to
thiouric acid (inactive metabolite) by xanthine oxidase.
◦ Excreted primarily in urine.
Azathioprine (cont’d)
Therapeutic Uses:


It is used to prevent organ rejection following organ
transplantation
To treat a vast array of autoimmune diseases, including
rheumatoid arthritis, systemic lupus erythematosus
inflammatory bowel diseases (such as Crohn's disease and
ulcerative Colitis), multiple scleroses, autoimmune hepatitis,
atopic
dermatitis,
myasthenia
gravis,
acute
glomerulonephritis, and others.
Azathioprine (cont’d)
Adverse effects:
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
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Bone marrow suppression (leukopenia &
thrombocytopenia).
Nausea , vomiting and diarrhea
Hepatotoxicity.
Increased risk of infections and mutagencity (Lymphoma)
Drug Interactions:


Concomitant use with ACE inhibitors in renal transplant
patients can lead to an exaggerated leukopenic response.
Allopurinol, an inhibitor of xanthine oxidase that is used to
treat gout, significantly inhibits the metabolism of
azatihioprine; therefore, the dose of azathioprine must be
reduced by 60 to 75 %.
2- Mycophenolate Mofetil
Mycophenolate Mofetil (Mycept)
•
It is a semisynthetic derivative of mycophenolic acid from fungus
source.
• Prodrug; it is rapidly hydrolyzed in the gastrointestinal tract to
mycophenolic acid (MPA)
Mechanism of action:
◦ Inhibits de novo synthesis of purines.
◦ mycophenolic acid is a potent inhibitor of inosine
monophosphate dehydrogenase (IMP), crucial for purine
synthesis deprivation of proliferating T and B cells of nucleic
acids.
Mycophenolate Mofetil (cont’d)
Pharmacokinetics:
◦ It is given orally, I.V or I.M. Dose 2-3 g/day.
◦ Rapidly and completely absorbed after oral
administration.
◦ It undergoes first-pass metabolism to give the active
moiety, mycophenolic acid (MPA).
◦ MPA is extensively bound to plasma protein.
◦ metabolized in the liver by glucuronidation.
◦ Excreted in urine as glucuronide conjugate
Mycophenolate Mofetil (cont’d)
Therapeutic uses:
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Solid organ transplants (heart, kidney, and liver transplants).
Steroid-refractory hematopoietic stem cell transplant patients.
Combined with prednisone as alternative to CSA or tacrolimus.
Rheumatoid arthritis & dermatologic disorders.
Adverse effects & drug interaction:
◦
◦
◦
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GIT toxicity: Nausea, Vomiting, diarrhea, abdominal pain.
Leukopenia, neutropenia & anemea
Higher risk of CMV infection.
It is CI to be administered during pregnancy
Concomitant administration with antacids containing Mg2+ or
Al 3+, or with cholestyramine, can decrease absorption of the
drug.
3- Leflunamide
Leflunamide (Arava)
•
•
•
Leflunomide is a synthetic disease-modifying antirheumatic
group of drugs- antimetabolite immunosupressant
(DMARD).
It acts by inhibiting dihydroorotate dehydrogenase (an
enzyme involved in de novo pyrimidine synthesis)
It is a prodrug ,following oral administration, leflunomide is
metabolized to teriflunomide, which is responsible for all of
the drug's activity in vivo.
Luflunamide (cont’d)
Pharmacokinetics:
• The drug is given orally. It is rapidly metabolized to its
pharmacologically- active metabolite teriflunomide.
• Teriflunomide is metabolized in the liver and excreted as well renally
and biliary.
• After oral administration, peak plasma levels of teriflunomide
occurred between 6 and 12 hours after dosing. Due to its very long
half-life (approximately 2 weeks), a loading dose of 100 mg for 3 days
is required to reach steady-state levels quickly.
Therapeutic uses:
-
Leflunomide has both immunosuppressant and anti-inflammatory
effects. Leflunomide has been approved for the treatment of
rheumatoid arthritis or psoriatic arthritis. It slows the progression of
the disease and relief the associated symptoms such as joint
tenderness and decreased joint and general mobility in human
patients.
Luflunamide (cont’d)
Adverse effects:
• Elevation of liver enzymes
• Renal impairment
• Teratogenicity (Women or men should not have babies
before 2 years after termination of therapy have elapsed
or undergo a rapid wash-out procedure like an eleven-day
scheme with oral cholestyramine or the use of activated
charcoal is indicated and will soon decrease plasma levels
below the critical limit of 0.02 mg/l ).
• Cardiovascular effects (tachycardia).
• Leflunomide
has
the
potential
to
promote
myeloid/lymphatic malignancies or solid cancers
4- Methotrexate
Methteraxate
◦ Methotrexate (MTX) is synthetic antimetabolite used
mainly in treatment of cancer, and autoimmune diseases
◦ It acts by inhibiting the metabolism of folic acid. It Inhibits
DHFR enzyme required for folic acid activation
(tetrahydrofolic) and as a result Inhibition of DNA, RNA &
protein synthesis occur.
◦
Methotrexate (cont’d)
Pharmacokinetics:
◦ It can be taken orally or administered by injection (I.M., I.V., S.C., or
I.T.). Methotrexate is metabolized by intestinal bacteria to the
inactive metabolite 4-amino-4-deoxy-N-methylpteroic acid (DAMPA),
which accounts for less than 5% loss of the oral dose
◦ Oral doses are taken weekly.
◦ It is excreted in urine.
Therapeutic uses:

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
Cancer Chemotherapy: In the treatment of a number of cancers including:
breast, head and neck, leukemia, lymphoma, lung, osteosarcoma, and
bladder.
Autoimmune disorders: It is used as a treatment for some autoimmune
diseases including: psoriasis and psoriatic arthritis, Crohn's disease, and
rheumatoid arthritis.
Pregnancy termination: Methotrexate is commonly used (generally in
combination with misoprostol) to terminate pregnancies during the early
stages (i.e., as an abortifacient). It is also used to treat ectopic
pregnancies.
Methotrexate (cont’d)
Adverse effects & drug interaction:
◦ Nausea, vomiting, diarrhea, abdominal pain, ulcerative
stomatitis.
◦ Fatigue, fever, and dizziness
◦ Alopecia
◦ Bone marrow depression (leukocytopenia)
◦ Predisposition to multiple infection
◦ Pulmonary fibrosis
◦ Renal & hepatic disorders
◦ Methotrexate is a highly teratogenic drug and
contrindicated during pregnancy.