Transcript Drugs for Immune System Modulation

Drugs for Immune System
M ARIS WIDODO
PPD UNISMA
Immune System
“a biochemical complex that protects the body
against pathogenic organisms and other
foreign bodies. The system incorporates the
humoral immune response, which produces
antibodies to react with specific antigens, and
the cell mediated response, which uses T-cells
to mobilize tissue macrophages in the
presence of a foreign body.”
Mosby’s Pocket Dictionary, p. 530
Lines of Protection/Defense
• Compare and contrast the body’s protection
against pathogens.
– First line (non-specific)
– Second line (specific)
Immune System
• Defends the body against invading pathogens,
foreign antigens, and its own cells that
become cancerous
• Can also sometimes attack itself, causing
“autoimmune diseases” or immune-mediated
diseases
• Participates in analphylaxis & tissue/organ
rejection
Immune Response
• Compare and contrast the divisions of the
immune response.
– Humoral
– Cell mediated
Vaccines
• Prototype: Hepatitis B Vaccine, p. 460
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Cytokines
• Hormone-like substance that:
– Regulate the intensity and duration of response
– Mediate cell-to-cell communication
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Immunosuppressants
• Agents that decrease or prevent an immune
response, thus suppressing the immune
system
• Used to prevent or treat rejection of
transplanted organs
Immunosuppressants (cont’d)
• All suppress certain T-lymphocyte cells lines,
preventing their involvement in the immune
response
• Result: a pharmacologically
immunocompromised state
• Mechanisms of action vary according to agent
Immunosuppressants (cont’d)
– Corticosteroids
– azathioprine
– muromonab-CD3
– daclizumab
– sirolimus
– cyclophosphamide
– cyclosporine
– tacrolimus
– basiliximab
– glatiramer acetate
Immunosuppressants (cont’d)
• Indications vary from agent to agent
• Primarily indicated for the prevention of organ
rejection
• Some also used for immunological diseases
such as rheumatoid arthritis and multiple
sclerosis
Immunosuppressants (cont’d)
• azathioprine
– Used as an adjunct medication to prevent
rejection of kidney transplants
– Also used in the treatment of rheumatoid arthritis
Immunosuppressants (cont’d)
• cyclosporine
– Primary agent used in the prevention of kidney,
liver, heart, and bone marrow transplant rejection
– May be used for other autoimmune disorders
• tacrolimus
– Used for the prevention of liver and kidney
transplant rejection
Immunosuppressants (cont’d)
• glatiramer acetate
– The only immunosuppressant agent used for the
treatment of multiple sclerosis (MS)
– Used to reduce the frequency of MS relapses
(exacerbations) in relapsing-remitting multiple
sclerosis (RRMS)
Immunosuppressants (cont’d)
• Side effects vary according to agents, and may
be devastating
**All immunosuppressed clients have a
heightened susceptibility to opportunistic
infections**
Immunizing Biologicals
• Biological antimicrobial agents
– Also called biologicals
– Antitoxins
– Serum
– Toxoids
– Vaccines
– Used to prevent, treat, or cure infectious diseases
Toxoids
• Antigenic (foreign) preparations or bacterial
exotoxins
• Detoxified with chemicals or heat
• Cannot revert back to a toxic form
• Stimulate one’s immune system to produce a specific
antibody
• The production of these antibodies protect against
future exposures to the antigen
• Ex. Tetanus
Vaccines
• Suspensions of live, attenuated (weakened) or
killed (inactivated) micro-organisms
• The weakened form prevents the person from
contracting the disease
Vaccines (cont’d)
• Also stimulate the production of antigens
against a specific antibody
• Vaccinations with live bacteria or virus provide
lifelong immunity
• Vaccinations with killed bacteria or virus
provide partial immunity, and booster shots
are needed periodically
Active Immunization
• The body is exposed to a relatively harmless
form of an antigen
• The immune system is stimulated, and
“remembers” this antigen if subsequent
exposures occur
• The immunizations do not cause a full-blown
infection
Examples of
Active Immunizing Agents
• BCG vaccine (tuberculosis)
• Diphtheria,tetanus, and pertussis toxoids, several
forms
• Cholera vaccine
• Haemophilus influenzae type b conjugate vaccine
• Hepatitis A and B virus vaccines
• Measles, mumps, and rubella virus vaccine, live—
several forms
• Poliovirus vaccine, several forms
Examples of Active Immunizing
Agents (cont’d)
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Rabies virus vaccine
Smallpox virus vaccine
Tetanus toxoid
Varicella virus vaccine (chicken pox)
Yellow fever virus vaccine
Indications
• Active immunization
– Prevents infection caused by bacterial toxins or
viruses
– Provides long-lasting or permanent immunity
– “Herd immunity”
Passive Immunization
• Serum or concentrated immune globulins from
humans or animals are injected into a person
• The substances needed to fight off invading microorganisms are given directly to a person
• The immune system is bypassed
• Short-lived compared with active immunization, but
works faster
Passive Immunization (cont’d)
• Naturally acquired passive immunity
– From mother to fetus through the placenta
– From mother to infant through breast milk
• Artificially acquired passive immunity
– Acquired from an external source, such as
injection of antibodies or immunoglobulins
Examples of
Passive Immunizing Agents
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Antivenins
Diphtheria antitoxin
Hepatitis B immune globulin
Immune globulin, various forms
Rabies immune globulin (human)
Rh0(D) immune globulin (RhoGAM)
Tetanus immune globulin
Varicella zoster immune globulin (chicken
pox/shingles)
Indications (cont’d)
• Passive immunization
– Antitoxins, antivenins, immune globulins
– Minimizes effects of poisoning by the venoms of
spiders and certain snakes
– Provides quick immunity before a person’s own
immune system has a chance to make antibodies
(such as in cases of exposure to hepatitis B or
rabies viruses)
Indications (cont’d)
• National Advisory Committee on
Immunization recommendations for adult and
pediatric immunizations (Canada)
– Provide specific dosages and intervals for
immunizations
Mechanism of action:vaccines
Anitgens: foreign substances
Anitbodies: immunoglobulins
Once the vaccine is administered the body produces
immunoglobulins: IgG, IgA, IgE, IgD, IgM to attack
and kill the foreign invader
Anitbody titre: the amount of immunoglobulin in the
body that must be present to protect the body
against the pathogen
Booster shot: given when antibody titre reveals low
levels
Side Effects
• Range from mild and transient to very serious
or life threatening
• Minor effects
– Fever, minor rash, soreness at injection site,
itching
• Severe effects
– Fever >38° C, encephalitis, convulsions,
anaphylactic reaction, dyspnea, others
IMMUNOMODULATING AGENTS
– Agents that act as stimulators of immune
responses.
– Have important therapeutic uses, including
the treatment of immune deficiency
diseases, chronic infectious diseases, and
cancer.
IMMUNOMODULATING AGENTS
• Aldesleukin:
Aldesleukin is in a class of drugs known as cytokines,
Aldesleukin increases the body ability to fight cancer.
• Interferons:
Interferons are a group of proteins produced by white
blood cells, fibroblasts, or T-cells as part of an
immune response to a viral infection or other
immune trigger.
IMMUNOMODULATING AGENTS
• BCG (Bacille Calmette-Guérin):
BCG is an effective immunization against
tuberculosis.
• Thymosin:
Is a hormone secreted from the thymus. Its
primary function is to stimulate the
production of T cells, which are an important
part of the immune system.
IMMUNOSUPPRISSIVE
DRUGS
WHAT IS IMMUNOSUPPRISSIVE DRUGS?
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Any of a variety of substances used to prevent production
of antibodies.
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They are commonly used to prevent rejection by a
recipient's body of an organ transplanted from a donor.
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Immunosuppressive drug has one meaning:
a drug that lowers the body's normal immune response.
CLASSIFICATION OF
IMMUNOSUPRISSIVE DRUGS
DRUGS ACTING ON IMMUNOPHILINS:
Cyclosporine, Tacrolimus.
ADRINOCORTICOIDS:
Methylprednisolone, Prednisolone, Prednisone.
ANTIBODIES:
Lymphocyte Immune Globulin, Rh0 (D) Immune
Globulin, Monoclonal antibodies.
IMMUNOSUPPRISSIVE ANTIMETABOLITES:
Azathioprine, mycophenolate mofetil.
CYCLOSPORINE
Clinical uses:
• Cyclosporine was discovered in the 1970s,
but was not approved for use until 1983.
• Cyclosporine used in solid organ transplantation
and in graft-versus-host syndrome in bone
marrow transplants.
CYCLOSPORINE
Adverse effect:
• Nephrotoxicity is the most common and important adverse
effect of cyclosporine.
• Infections in patient taking Cyclosporine are common and may
be life-threatening.
• Viral infections due to herpes group.
• Lymphoma may occur, presumable due to
immunosuppression.
• Other toxicities include hypertension, hyperkalemia, tremor,
hirsutism, glucose intolerance, and gum hyperplasia.
CYCLOSPORINE
Monitoring Parameters:
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Cyclosporine trough levels.
Serum electrolytes.
Renal function.
Hepatic function.
Blood pressure.
serum cholesterol.
TACROLIMUS
Clinical uses:
It was first approved by the Food and Drug
Administration (FDA) in 1994 for use in liver
transplantation, this has been extended to
include kidney, heart, small bowel, pancreas,
lung, trachea, skin, cornea, bone marrow,
and limb transplants.
TACROLIMUS
Doses:
• Cardiac transplant rejection; Prophylaxis: initial,
0.075 mg/kg/day ORALLY in 2 divided doses (given
every 12 h).
• Liver transplant rejection; Prophylaxis: initial,
0.1 to 0.15 mg/kg/day ORALLY in 2 divided doses
(given every 12 h).
• Renal transplant rejection; Prophylaxis: initial, 0.2
mg/kg/day ORALLY in 2 divided daily doses (given
every 12 h).
TACROLIMUS
Adverse effect:
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Nephrotoxicity.
Hyperglycemia.
Hyperkalemia.
Hypomagnesaemia.
Tremor.
Headache.
Diarrhea.
Hypertension.
CORTICOSTEROIDS
PREDNISOLONE
Clinical uses:
• Prednisolone is used alone or in combination
with other agents in a wide variety of
medical conditions involving an undesirable
immunologic reaction.
• Used to suppress immunologic reactions in
patients who undergo organ transplantation.
PREDNISOLONE
DOSES:
0.1-2 mg/kg/day
PREDNISOLONE
Adverse effect:
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Insomnia, Nervousness.
Increased appetite, indigestion.
Diabetes mellitus.
Glaucoma.
Epistaxis.
PREDNISOLONE
Monitoring parameters:
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Clinical improvement.
Blood pressure.
Electrolyte.
Blood glucose.
Mental status.
Ophthalmic exam (with prolonged therapy).
Signs and symptoms of infection.
TACROLIMUS
Monitoring parameters:
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Blood pressure.
Echocardiography.
Hepatic and renal function.
Electrolyte (especially magnesium and potassium).
Fasting glucose.
CBC.
signs and symptoms of rejection, serum tacrolimus
levels.
CYCLOSPORINE
Doses:
Adults, children, P.O:
• Initial:
14-18 mg/kg/day, beginning 4-12 hr prior to organ
transplantation.
• Maintenance:
5-10 mg/kg/day divided every 12-24 hrs;
maintenance dose is usually tapered to 3-10
mg/kg/day.
PREDNISOLONE
Clinical uses:
• Prednisolone is used alone or in combination
with other agents in a wide variety of
medical conditions involving an undesirable
immunologic reaction.
• Used to suppress immunologic reactions in
patients who undergo organ transplantation.
PREDNISOLONE
Adverse effect:
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Insomnia, Nervousness.
Increased appetite, indigestion.
Diabetes mellitus.
Glaucoma.
Epistaxis.
PREDNISOLONE
Monitoring parameters:
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Clinical improvement.
Blood pressure.
Electrolyte.
Blood glucose.
Mental status.
Ophthalmic exam (with prolonged therapy).
Signs and symptoms of infection.
ANTIMETABOLITES
AZATHIOPRINE
Clinical use:
• Azathioprine is used in autoimmune diseases
(e.g., systemic lupus erythematosus,
rheumatoid arthritis).
• As immunosuppression in renal homografts.
AZATHIOPRINE
DOSES:
• I.V. dose is equivalent to oral dose.
• Dose should be based on ideal body weight.
• Children and adults:
-Starting dose: 2-5 mg/kg/day.
-Maintenance dose:1-2 mg/kg/day.
AZATHIOPRINE
Adverse effect:
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Fever.
Nausea.
Bone marrow suppression.
Thrombocytopenia.
Leucopenia.
Anemia.
Hepatotoxicity.
AZATHIOPRINE
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Monitoring parameters:
CBC, platelets counts.
Total bilirubin.
Alkaline Phosphatase.
liver function.
MYCOPHENOLATE
Clinical uses:
• The drug has been used successfully as a sole
agent in Kidney, Liver, and heart transplants.
• In renal transplants, it’s used with low-dose
cyclosporine has reduced cyclosporineinduced nephrotoxicity.
MYCOPHENOLATE
DOSES:
• Cardiac transplant: 1.5 g IV/ORAL twice daily.
• Liver transplant: 1 g IV twice daily or 1.5 g
ORALLY twice daily.
• Renal transplant: 1 g IV/ORAL twice daily.
MYCOPHENOLATE
Adverse effect:
1% to 10% Thrombophlebitis and thrombosis,
4% with I.V administration.
MYCOPHENOLATE
Monitoring parameters:
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Signs and symptoms of rejection.
CBC.
Renal function.
Blood pressure.
Heart rate.
Electrolytes.
Hepatic function.
Cardiac and pulmonary function.
Signs and symptoms of lymphoma.
Signs and symptoms of infections.
ANTIBODIES AS
IMMUNOSUPPRESSANT
ANTIBODIES AS IMMUNOSUPPRISSANT
Antibodies are used as a quick and potent
immunosuppression method to prevent the
acute rejection reaction.
Lymphocyte Immune Globulin
Clinical use:
• Used prior to bone marrow transplantation
to prevent the graft-versus-host (GVH)
reaction.
• It is also used in combination with
cyclosporine or cytotoxic drugs (or both) for
maintenance following bone marrow, heart,
and renal transplantation.
Lymphocyte Immune Globulin
Adverse effect:
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Chills or fever in most patients.
May cause hypersensitivity reactions.
Pain and erythema occur at injection sites.
Lymphoma has been noted as late
complication.
• Risk of developing an infection.
• Risk of bleeding.
Rh (D) Immune Globulin
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Clinical use:
Rho (D) immune globulin is used for prevention
of Rho hemolytic disease of the newborn. In
women treated with Rho (D) immune globulin,
maternal antibodies to Rh-positive cells are
not produced in subsequent pregnancies, and
hemolytic disease of the neonate is averted.
Monoclonal Antibodies
Examples:
• Muromonab-CD3
• Daclizumab.
Muromonab-CD3
Clinical use:
• Is used to manage a renal homograft
rejection crisis.
Muromonab-CD3
DOSES:
• Cardiac transplant rejection, Steroid-resistant: 5
mg IV bolus once daily for 10 to 14 days; begin
after corticosteroid therapy has failed.
• Renal transplant rejection: 5 mg IV bolus once daily
for 10 to 14 days.
• Renal transplant rejection; Prophylaxis: 5 mg IV
once daily for 5 to 14 days.
Muromonab-CD3
Adverse effect:
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Diarrhea, Nausea, Vomiting.
Anaphylaxis, Neoplastic disease.
Encephalopathy.
Blindness AND/OR vision impairment level,
Irreversible.
• Pulmonary edema.
• Infectious disease.
• Inflammatory disorder.
Muromonab-CD3
Monitoring parameters:
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Signs and symptoms of rejection.
Blood pressure.
Fluid status.
Neurologic symptoms.
CBC.
Renal and hepatic function.
Muromonab-CD3 plasma levels.
DACLIZUMAB
Clinical use:
• These saturate the receptors and prevent T
cell activation and thus prevent formation of
antibodies against the transplant.
• Daclizumab is not used for acute rejection
episodes.
DACLIZUMAB
DOSES:
Renal transplant rejection, With regimen
including cyclosporine and corticosteroids:
1 mg/kg IV beginning within 24 h prior to
transplant, then 1 mg/kg IV every 14 days for a
total of 5 doses.
DACLIZUMAB
Adverse effect:
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Edema.
Hypertension.
Hypotension.
Tachyarrhythmia.
Bleeding.
Blood coagulation disorder.
Dyspnea.
Fever.
Infectious disease.
DACLIZUMAB
Monitoring parameters:
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Signs/symptoms of rejection.
CBC .
Renal function.
Acute hypersensitivity reactions (including
anaphylaxis).
• Signs and symptoms of infection.