Side Effects

Download Report

Transcript Side Effects

Immunosuppressants
Prof. Alhaider, 1431 H
I.
II.
Definition
Clinical Uses (Organ transplants & Autoimmune
diseases)
Pre-requisite to understand immunosuppressive
drugs (Basic immunology).
Review of immune system (see Table 56-1)
III.
IV.
I.
II.
III.
IV.
Cell mediated vs humoral immunity
Importance of cytokines
Immunophilins
Calcineurin
Classification of Immunosuppressant (Based on
Mechanism of Action)
• A) Antiprolifirative Agents
1) Drugs Acting on Immunophilins:
a) Selective Inhibitors of Cytokine production )
(Calcineurin Inhibitors) (e.g: Cyclosporine; Tacrolimus)
b) Inhibitor of cytokine function (e.g. Sirolimus).
3) Antimetabolites (Azathioprine; Mycophenolate Mofetil)
4) Alkylating Agents (Cyclophosphamide)
B) Lymphocyte Depletion Agents
1) Corticosteroids
2. Immunosuppressive Antibodies
a) Polyclonal Antibodies (Antilymphocyte Globulin)
b) Monoclonal Antibodies (Selective inhibitors of IL2 (Basiliximab;
Daclizumab)
Immunosuppressant Classes
Non-selective
• Corticosteroids
 Prednisone (PO) &
Methylprednisolone (IV)
• Antimetabolite (DNA
synthesis inhibitors)
 Azathioprine &
Myclophenolate mofetil
 Immunoglobulins
 Anti-lymphocyte antibodies
Selective
•


•
Calcineurin Inhibitors
Cyclosporine
Tacrolimus (Rapamycin)
Selective IL-2 Receptor
antagonists
 Basiliximab, Daclizumab &
Infliximab
 Mamalian target of
Rapamycin (mTOR)
inhibitors
 Sirolimus
Selective Inhibitors of Cytokine Production
(Drugs Acting on Immunophilins)
• 1) Cyclosporine (Cyclic peptide from Soil
Fungus (1971)
– MOA: (See Figure 40.4)
• CsA binds to cyclophillin forming a comlex
Bind to
Calcineurin
dephosphorylation NFATc
Synthesis
of IL 2
proliferation of T cells
• Thus, decreases the level of IL-2, the primary chemical
stimulus for increasing the number of T lymphocytes
• Note: Suppress only cell immunity with no effect on humoral immunity.
– PK
• CsA available as oral (capsule) or parental (i.v)
• Oral bioavailability (20-50%), it undergoes
extensive hepatic metabolism by CytP450
(CYP3A4) (Affected by some drugs EXAMPLES)
and mainly excreted in the bile.
– Clinical Uses of Cyclosporine:
• 1) Drug of choice for preventing organ transplant rejection in combination
with steroids and other immunosuppressants.
• 2) Severe active rheumatoid arthritis, as alternative for methotrexate
• 3) Lower doses (7.5 mg/kg/d) for autoimmune diseases (Uveitis; RA; early
Rx of DM 1)
• 3) Psoriasis and asthma ?.
– Side Effects (remember most immunosuppressant are very toxic)
• Dose-dependent nephrotoxicity ( Risk of Rejection); enhanced of given
with other nephrotoxic drugs (Aminoglycosides; NSADs)
• Hepatotoxicity
• Neurotoxicity as tremor and hallucination
• Infection How?
• Lymphoma and cancer How?
• Hypertension; hyperlipedemia; Hyperkalemia; D.M; Osteoporosis
Hirsutism and gum hyperplacia (So What)
• 2. Tacrolimus (FK 506):
– More potent than Cyclosporine
– MOA: Similar to Cyclosporine (Calcineurin Antagonist)
but it bind to different immunophilin (FKBP) Figure 40.6.
– PK: Almost Similar to Cyclosporine
– Side Effects: differ from Cyclosporine, that it ((Tac) has no
hirsutism or gum hyperplasia but may show more
hyperglycemia than cyclosporine.
– Note: It is like cyclosporine, could lead to nephrotoxicity
and hyperglycemia (more hyperglycemia than
cyclosporine) , and hyperlipedemia.
• Clinical uses of Tacrolimus:
Preferred over CsA because:
 of more potency (50-100 times more
potent than cyclosporine).
lower rejection episodes,
 and lower doses of glucocorticoids are
used with lower side effects
Better first choice for woman?
Severe refractory atopic dermatitis,
local application of an ointment
An ointment for psoriasis.
• 3. Sirolimus (Rapamycin Maclolides)
– MOA:
• 1) Binds to the same immunophilin as Tacrolimus, but
does not form a complex with calcineurin, instead, it
binds to mTOR (Mammalian Target of Rapamycin)
which is essential for many cellular functions (See
Figure 40.6)
• 2) Sirolimus does not affect IL-2 production, unlike
CsA & TAc, rather inhibits T-cell response to it
(Blocks cytokine-stimulated cell proliferation)
• 3) Potent inhibitor of B-cell proliferation and
immunoglobulin production (humor immunity)
• Uses of Sirolimus:
– 1) can be used together with cyclosporine (to
increases the activity of cyclosporine for organ
transplanted patients.
– 2) As replacement of cyclosporine if transplanted
patient developed cancer of skin or lips.
– 3) used in cardiac catheter stint to prevent
stenosis??
– 4) as an ointment for atopic dermatitis and
psoriasis
• Side Effects:
– 1) Pneumonitis
– 2) hyperlipedemia (more then calcineurinantagonist)
• Antiproliferatives (Continue…)
• 2. Antimetabolites (Cytotoxic Drugs)
– 1) Azathioprine: is a prodrug of mercaptopurine.
• Cytotoxic, rarely used as chemotherapeutic drug, but
commonly used for immunosuppression.
• It is a pro-drug converted in the body to the active
metabolite, 6-mercaptopurine and thioinosinic acid.
• MOA: (see Figure)
– Simply, it inhibits purine synthesis (antimetabolite), thus
interfering with nucleic acid metabolism and lead to
inhibition of the proliferation of leukocytes and
lymphocytes.
– Why it is considered as cytotoxic agent?
– Because the purine analog of Azathioprine can destroy
lymphoids cells.
– Why it is very important to know the structure of
azathioprine?.
Metabolic pathway for azathioprine
6-thiouracil
(-)
Xanthine
Oxidase
Alloburinol
Nonenzymatic
AZA
HPRT
6-MP
TPMT
6-MMP
thioiosinic acid
(TIMP)
TPMT
6-MMP
ribonucleides
6-thioguanine
( 6-TG)
• Cliniclal Uses of Azathioprine (ImuranR)
– 1) maintenance of renal allograft and other transplantations
together with steroids and cyclosporine.
– 2) Can be used for glomerulonephtitis and SLE; RA;
Crohn’s disease and multiple sclerosis.
• Side Effects
– 1) it is like cyclosporine, not teratogenic (Unlike TAC or
Siro) but carcinogenic if given together with alkylating
agents. (here higher doses are used as compared to
autoimmune diseases.
– 2) strong bone marrow suppression (Leucopenia; anemia;
thrombocytopenia How?
– 3) Hepatic dysfunction as increase AP and mild jaundice.
– 4) Hypersensitivity reactions (as rashes, fever, diarrhea)
Why?.
Adverse Effects: bone marrow
suppression (leukopenia,
thrombocytopenia, anemia),
hepatotoxicity,
Combination with ACEIs or cotrimoxazole
can cause severe leukopenia in renal
transplants
It can be given both orally and by IV
• 2) Mycophenolate Mofetil (CellceptR)
– The most important discovery among the
immunosuppressant agents.
– MOA: (See Figure)
• Mycophenolic acid acts as non-competitive, selective 7
reversible inhibitor of inosine monophosphate dehydrogenase
• Decreases GMP, which is a key enzyme in the de novo pathway
of purine synthesis. This leads to suppression of both B and T
lymphocyte activation.
• PK: Good oral absorption;
– Side Effects
• Less than azathioprine, Bone marrow suppresion (leukopenia
and anemia); NV and diarrhea (decresed by Enteric-coated
form).
• Unlike azathiorine it is teratogenic.
– Clinical Uses
• 1) As a replacement for the more cytotoxic drug, azathioprine
in renal allograft patients as well as liver, heart et act. Why?
• As replacement of azathioprine or cyclophosphamide for
autoimmune diseases (RA, SLE (especialy before lupus
nephritis); Glomerulonephritis
• Has good oral bioavailability
• Note:
in renal or liver transplant, patients may take
the followings:
• Corticosteriods as prednisolone (Low dose) +
cyclosporine or Tac + Mycophenolate Mofetil
– 3. Lefunomide:
- A Pro-drug of an inhibitor ofn PYRIMIDINE synthesis rather than
purine like azathioprine and mycophenolate.
– Orally active used only for RA
– Side effects: Alopecia; increase LFT, nephrotoxicity, teratogenicity.
•
3. Alkylating Agents (e.g. Cyclophosphamide)
– The most potent immunosuppressant
– Destroys proliferating lymphoid cells (cytotoxic agent) also alkylate
some resting cells (Thus, it is very toxic)
– Clinical Uses:
• Before the discovery of Mycophenolate, cyclophosphamide was the drug
of choice for treatment of many autoimmune diseases like SLE;
autoimmune hemolytic diseases and RA.
– Side Effects
•
•
•
•
Pancytopenia
Hemorrhagic cystitis
Infertility
Teratogenic
B) Lymphocyte Depletion Agents
• 1. Corticosteroids
• The most commonly used immunosuppressant
• MOA:
– At biochemical level: act on gene expression, which
lead to decrease synthesis of PGs; LKTs; cytokines
and other signaling molecules that participate in
immune response.
– At the cellular level: they inhibit the proliferation of T
lymphocytes (cell mediated) and slightly dampen
humoral immunity (by increasing the catabolism of
immunoglobulins).
– At immunosuppressive doses, Corticosteroids are
cytotoxic and continuous uses lowers IgG.
• Uses:
– In combination with other
immunossppressants for transplanted patients
(To prepare the patients as well as
maintenance).
– To Rx acute rejection episodes (high doses)
– To Rx undesirable immunoreactions (to drugs
or asthma).
– To autoimmune diseases (ITP; IBD; RA; SLE;
GN)
– Side Effects:
Adverse effects: (revise endocrine system)
 Increased blood pressure How?
 hyperglycemia due to increased gluconeogenesis, insulin resistance,
and impaired glucose tolerance ("steroid diabetes");
 Osteoporosis
 Visceral and truncal fat deposition (central obesity) and appetite
stimulation
 Weight gain (water & salt retention) How?
 Muscle breakdown (proteolysis), weakness; reduced muscle mass
and repair
 Increased skin fragility, easy bruising
 Cataracts
 Adrenal cortex suppression (NO ABRUPT WITHDRAWAL)
 Increase tendency to infections How?
2. Immunosuppressive Antibodies
a) Polyclonal Antibodies (Antilymphocyte
Globulins)
Definition: Thymocytes are considered as T-cell precursors.
What are the differences between polyclonal and monoclonal antibodies?
1) Antithymocyte (Antilymphocyte) Globulins (ALG): this antisera can be
obtained by immunization of large animals (e.g.rabbits) with human lymphoid cells.
MOA: Antibodies bind to the surface of circulating T lymphocytes
forming a comlex. This complex will be phagocytosed in liver or
spleen and leading to destruction or inactivation of T cells.
ALG mainly affects the cellular immunity with no effect on
humoral, resulting in antibodies against these foreign proteins.
PK: Administered by IM or slow IV infusion with long half-life of 3-9 days
Side Effects:
1) Mainly result from the introduction of foreign proteins obtained from
heterogeneous serum (Anaphylactic and serum sickness reactions;
Local pain and erythema at site of injection).
2) Chills & fever and Leukopenia & thrombocytopenia
3) Viral infections and skin rashes
4) Lymphoma and cancer
Polyclonal Antibodies (continue…)
Clinical Uses of ALG :
1) Rx of hyperacute phase of allograft rejection
2) To prepare the bone marrow transplanted patient
(Large doses of ALG for 7 days)
2) Immune globulin Intravenous (IGIV):
- Prepared from a pool of thousands of healthy
donors.
Uses:
1) Refractory ITP
Advantages: Has no antigenicity
B) Monoclonal Antibodies (Muromonab;
Basiliximab; Abciximab; Daclizumab.
1) Muromonab-CD3 (IL-2-antagonist):
From its name, it is murine monoclonal antibody that
prepared by hypridoma technology and directed against
the glycoprotien CD3 antigen of human T cells. Used
mainly for cases of acute allograft rejections of kidney,
heart and liver.
it is also used to deplete T cells from donor bone marrow
before transplantation.
Advantage over ALG: More specific and T lymphocytes
return to normal within 24 hr.
Side Effects:
1) Cytokine release syndrome (Anaphylactoid reactions)
Why; and seizure (contraindication)
Therefore it is not used.
Side Effect of Muromonab
• Its use has been declined much because of multiple side
effects and the emergence of newer and more selective
antibodies therapy
Anaphylaxis may occur
Cytokine release syndrome, flu-like to
dangerous shock-like reactions can occur, &
high fever
CNS: Seizures, encephalopathy, cerebral
edema & headache
Infection like CMV
Contraindicated with pregnancy, breast
feeding, history of seizures, uncompensated
heart failure
• 2) Modified Types of monoclonal antibodies
(e.g: Selective Inhibitors of IL2):
• Note: Monoclonal Antibodies are not limited for
immunosuppression but could be utilized for
other purposes (See Table 56-3)
• By using the genetic engineering, most murine
amino acids of Muromonab have been replaced
by human ones; producing monoclonal antibody
designated humanized (e.g. Daclizumab;
Transtuzumab). While the chimeric (Mixed)
antibodies contain XI in their name (e.g.
Abciximab; Infliximab; Rutuximab).
• Clinical Uses: See Table 56-3
• Advantages over polyclonal antibodies
B- Selective IL-2 Receptor Antagonists
Basiliximab & Daclizumab
• Basiliximab is a chimeric antibody
composed of 25% murine & 75% human
protein. Block IL
• Daclizumab is humanized antibody
composed of 90% human protein
• Therapeutic Use:
Prophylaxis against acute rejection of
kidney transplantation
Used in combination with steroids or CsA
Selective IL-2 Receptor Antagonists
Basiliximab & Daclizumab (Continue…)
• Mechanism of action:
They are anti-CD25 antibodies
They bind to the -chain of the IL-2R (CD25
or TAC subunit) on the activated T-cells
Then, IL-2 binding to IL-2R is prohibited & Tcell activation and proliferation are
suppressed
VI- Selective IL-2 Receptor Antagonists
Basiliximab & Daclizumab (Continue...)
• Pharmacokinetics: Given by IV route
Daclizumab has serum half-life of 20 days
& receptor blockade for 120 days
 Administered in 5 doses; the first 24 hours
before transplantation and next 4 doses at
14-days intervals
Basiliximab has serum half-life of 7 days
 Administered in two doses; the first at 2hours before transplantation & the second at
4 days after surgery
Selective IL-2 Receptor Antagonists
Basiliximab & Daclizumab )Contiue..)
• Adverse Effects:
Both are well-tolerated
Gastrointestinal toxicity is the major one
NO antibodies, of clinical relevance, to the
drugs are produced
Infection & malignancy are not reported
• Alemtuzumab:
• Humanized monoclonal antibody directed
against CD-52, and produce profound
depletion of T cells.
• Used for refractory B- cell chronic
lymphocytic leukemia. However, it is
currently in use for organ transplant.
3- RhoD Immunoglobulin
• Rho(D) Immune Globulin (Rhogam)
Rhogam is an immunoglobulin that
recognizes the Rho(D) antigen
Prepared from pooled sera from Rhonegative volunteers immunized with D+
erythrocytes
It prevents erythroblastosis fetalis or
hemolytic disease of the newborn
When a Rho(D)-negative mother carries a
Rho(D)-positive fetus, mother becomes
sensitized
RhoD Immunoglobulin
• It is usually given to the mother within 72
hours after the birth of Rh-positive baby
• This would prevent hemolytic anemia that
may occur in subsequent pregnancies
• Adverse Effects:
Chills
Fever
Anaphylaxis (rare)
Rho(D) Immune Globulin: •
– Used to prevent Rh hemolytic disease in
newborn.
– Thus, Rho(D) Immune Globulin antibodies are
given to the mother within 72 Hrs after birth of
Rh positive baby.
– Uses:
• Erythroblastosis Faetalis
• Miscarriages