Drugs for Immune System

M ARIS WIDODOPPD 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

• .

Cytokines

• Hormone-like substance that:– Regulate the intensity and duration of response– Mediate cell-to-cell communication

.

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)

• 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 micro-organisms 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

• 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 substancesAnitbodies: immunoglobulinsOnce 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?

• Any of a variety of substances used to prevent production of antibodies.

• They are commonly used to prevent rejection by a recipient's body of an organ transplanted from a donor.

• 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:

• 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:• 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:• Insomnia, Nervousness.• Increased appetite, indigestion.• Diabetes mellitus.• Glaucoma.• Epistaxis.

PREDNISOLONE

Monitoring parameters:• Clinical improvement.• Blood pressure.• Electrolyte. • Blood glucose.• Mental status. • Ophthalmic exam (with prolonged therapy). • Signs and symptoms of infection.

TACROLIMUS

Monitoring parameters:• 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:• Insomnia, Nervousness.• Increased appetite, indigestion.• Diabetes mellitus.• Glaucoma.• Epistaxis.

PREDNISOLONE

Monitoring parameters:• 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:• Fever.• Nausea.• Bone marrow suppression.• Thrombocytopenia.• Leucopenia.• Anemia.• Hepatotoxicity.

AZATHIOPRINE

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 cyclosporine-induced 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:• 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:• 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.

RhO (D) Immune Globulin

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:• Diarrhea, Nausea, Vomiting. • Anaphylaxis, Neoplastic disease. • Encephalopathy. • Blindness AND/OR vision impairment level,

Irreversible. • Pulmonary edema. • Infectious disease.• Inflammatory disorder.

Muromonab-CD3

Monitoring parameters:• 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:• Edema. • Hypertension.• Hypotension.• Tachyarrhythmia. • Bleeding.• Blood coagulation disorder. • Dyspnea. • Fever.• Infectious disease.

DACLIZUMAB

Monitoring parameters:• Signs/symptoms of rejection. • CBC .• Renal function. • Acute hypersensitivity reactions (including

anaphylaxis). • Signs and symptoms of infection.