DRUGS ACTING ON THE

IMMUNE SYSTEM
INTRODUCTION TO THE IMMUNE
RESPONSE AND INFLAMMATION
The body has many defense systems in place to keep it intact and to protect from
external stressors:
1. Bacteria
2. Viruses
3. Other foreign pathogens
4. Trauma
5. Exposure to extreme environment conditions
INTRODUCTION TO THE IMMUNE
RESPONSE AND INFLAMMATION
The same defense systems that protect the body also help to repair it after cellular
trauma or damage

Understanding the basic mechanisms involved in these defense systems helps to

explain the actions of drugs that affect the immune system and inflammation
Body Defenses
• The body’s defenses include barrier defenses, cellular defenses, the inflammatory
response, and the immune response. Each of these defenses plays a major role
in maintaining homeostasis and preventing disease.
1. Barrier Defenses
2. Cellular Defenses
3. Inflammatory Defenses
4. Immune Response
Barrier Defenses
• Certain anatomical barriers exist to prevent the entry of foreign
pathogens and to serve as important lines of defense in protecting
the body. These barriers include the skin and mucous membranes,
gastric acid, and the major histocompatibility complex (MHC).
Barrier Defenses
• Skin
• The skin is the first line of defense.
• The skin acts as a physical barrier to protect the internal tissues
and organs of the body.
• Glands in the skin secrete chemicals that destroy or repel many
pathogens.
• Sebum contains chemicals that are toxic to bacteria
• The top layer of the skin falls off daily, which makes it difficult for
any pathogen to colonize on the skin.
• In addition, the normal bacterial flora of the skin help to destroy
many disease-causing pathogens.
Barrier Defenses
• Mucous Membranes
• Mucous membranes line the areas of the body that are exposed to
external influences but do not have the benefit of skin protection.
• These body areas include the respiratory tract, which is exposed to air;
the gastrointestinal (GI) tract, which is exposed to anything ingested by
mouth; and the genitourinary (GU) tract, which is exposed to many
pathogens from the perineal and rectal area. Like the skin, the mucous
membrane acts as a physical barrier to invasion.
• It also secretes a sticky mucus capable of trapping invaders and
inactivating them for later destruction and removal by the body. In the
conducting airways of the respiratory tract, the mucous membrane is
lined with tiny, hair-like processes called cilia.
Barrier Defenses
• Mucous Membranes
• The cilia sweep any captured pathogens or foreign materials upward toward
the mouth, where they will be swallowed. The cilia also can move the
captured material to an area causing irritation, which leads to removal by
coughing or sneezing.
• In the GI tract, the mucous membrane serves as a protective coating,
preventing erosion of GI cells by the acidic environment of the stomach, the
digestive enzymes of the small intestine, and the waste products that
accumulate in the large intestine.
• The mucous membrane also secretes mucus that serves as a lubricant
throughout the GI tract to facilitate movement of the food bolus and of waste
products.
• The mucous membrane acts as a thick barrier to prevent foreign pathogens
from penetrating the GI tract and
entering the body. In the GU tract, the mucous membrane provides direct
protection against injury and trauma and traps any pathogens in the area for
destruction by the body.
Barrier Defenses
• Gastric Acid
• The stomach secretes acid in response to many stimuli. The
acidity of the stomach not only aids digestion but also destroys
many would-be pathogens that are either ingested or swallowed
after removal from the respiratory tract. Normal flora that live in
this acidic environment also help to destroy many of these
ingested pathogens.
Barrier Defenses
• Major Histocompatibility Complex
• The body’s last barrier of defense is the ability to distinguish between
selfcells and foreign cells. All of the cells and tissues of each person
are marked for identification as part of that individual’s genetic code.
No two people have exactly the same code. In humans, the genetic
identification code is carried on a chromosome and is called the major
histocompatibility complex. The MHC produces several proteins called
histocompatibility antigens, or human leukocyte antigens (HLAs).
These antigens (proteins) are located on the cell membrane and allow
the body to recognize cells as being self-cells. Cells that do not have
these proteins are identified as foreign and are targeted for destruction
by the body.
Cellular Defenses
• Any foreign pathogen that manages to get past the barrier defenses
will encounter the human inflammatory and immune systems, or the
mononuclear phagocyte system (MPS).
• Previously called the reticuloendothelial system the MPS is
composed primarily of leukocytes, lymphocytes, lymphoid tissues,
and numerous chemical mediators.
Cellular Defenses
• Leukocyte
• White blood cells
• Two types:
• Lymphocyte
• Key component of the immune system and consists of T cells, be cells and
natural killer cells
• Myelocyte
• Different cell types those are important in both the basic inflammatory response and
the immune response. Myelocytes include: neutrophils, basophils, eosinophils, and
monocytes or macrophages
Myelocyte
• Neutrophils
• Neutrophils are polymorphonuclear leukocytes that are capable of moving
outside of the bloodstream (diapedesis) and engulfing and digesting foreign
material (phagocytosis).
• When the body is injured or invaded by a pathogen, neutrophils are rapidly
produced and moved to the site of the insult to attack the foreign material
• Able to identify nonself-cells by use of MHC
• Basophils
• Basophils are myelocytic leukocytes that are not capable of phagocytosis.
• They contain chemical substances or mediators that are important for
initiating and maintaining an immune or inflammatory response. These
substances include histamine, heparin, and other chemicals used in the
inflammatory response.
Myelocyte
• Eosinophils
• Eosinophils are circulating myelocytic leukocytes.
• They are often found at the site of allergic reactions and may be
responsible for removing the proteins and active components of the
immune reaction from the site of an allergic response.
• Monocytes/Macrophages
• Monocytes or mononuclear phagocytes are also called macrophages.
• They are mature leukocytes that are capable of phagocytizing an
antigen.
• Macrophages help to remove foreign material from the body, including
pathogens, debris from dead cells, and necrotic tissue from injury
sites, so that the body can heal. They also can process antigens and
present them to active lymphocytes for destruction.
Myelocyte

• Mast Cell
• Fixed basophils that do not circulate

• Can be found in respiratory and GI tracts and in

the skin
Lymphoid Tissues

• Lymphoid tissues that play an important part in the cellular

defense system include the lymph nodes, spleen, thymus
gland (a bipolar gland located in the middle of the chest,
which becomes smaller with age), bone marrow, and
lymphoid tissue throughout the respiratory and GI tracts.
The bone marrow and the thymus gland are important for
creation of the cellular components of the MPS.
Inflammatory Response

• The inflammatory response is the local reaction of the

body to invasion or injury
• Any insult to he body that injures cells or tissues
• Cell injuries causes the activation of a chemical in the
plasma called Factor XII or Hageman Fcator
Inflammatory Response
• Hageman factor is responsible for activation of the “kinin”
system
• Hageman factor activates kallikrein, a substance found in local
tissues
• Kallikrein causes the precursor substance kininogen to be converted
to bradykinin
• Bradykinin causes vasodilation to bring more blood to the injures
area
• Allow white blood cells to escape into the tissues, increase
permeability
Inflammatory Response

• Bradykinin also causes the release of arachidonic acid

from the cell membrane
• Arachidonic acid causes the release of autochoids.
Autochoids act like local hormones release from cell
and cause an effect on the immediate area
Inflammatory Response
• Prostaglandins- augments the inflammatory reaction
and stimulates nerve endings which causes pain
• Leukotrienes- causes vasodilation and increased
capillary permeability and has the property called
chemotaxis, which is the ability to attract neutrophils
and to stimulate them and other macrophages in the
area to be very aggressive
• Thromboxanes – causes local vasoconstriction and
facilitates aggregation and blood coagulation
Inflammatory Response

• Injury to cells membranes causes the release of

histamine which causes vasodilation and brings more
blood components to the area.
• Histamine also increases the permeability of the
capillary, making it easier for neutrophils and blood
chemicals to leave the blood stream and enter the
injure area
Inflammatory Response
• Clinical Presentation
• Calor (heat)
• Occurs because of the increased blood flow to the area
• Tumor (swelling)
• Occurs because of the fluid that leaks into the tissues as a result of the
change in capillary permeability
• Rubor (redness)
• Related to the increase blood flow caused by the vasolidtion
• Dolor (pain)
• Comes from the activation of pain fibers by histamine and the kinin
system
IMMUNE RESPONSE

• The body’s action plan devised to combat invading organisms or

substances by leukocyte and antibody activity
• Antigen 4
• is any foreign substance capable of stimulating an immune response
• Immunity
• the ability to destroy like antigens
• Immunogen
• an antigen is one that can be readily destroyed by an immune response and
immunity results
IMMUNE RESPONSE

• Allergen
• mediating substances that are released that cause tissue injury and allergic
symptoms
• They may be ingested (foods such as eggs or wheat), inhaled (pollen, dust, or
mold spores), injected (drugs), or absorbed across the skin or mucous
membranes (poison ivy)
IMMUNE SYSTEM ORGANS AND CELLS

• B-Lymphocytes
• Originating in the bone marrow
• Develop into plasma cells and memory cells when exposed to antigens
• Plasma cells
• Secrete large quantities of immunoglobulins or antibodies,
which bind to and destroy specific antigens (humoral
immunity)
• Memory cells
• Responsible for retaining the formula or ability to produce
specific immunoglobulins
• Immunoglobulins are classified as IgG, IgA, IgM, IgD, and IgE
IMMUNE SYSTEM ORGANS AND CELLS

• T lymphocytes
• Account for 70% to 80% of blood lymphocytes and are responsible for cell-
mediated immunity
• Produced by the bone marrow but mature under the influence of the thymus
gland
• They react specifically to viruses, fungi, and parasites but have an effect on all
antigens
IMMUNE SYSTEM ORGANS AND CELLS

• T lymphocytes Types:
• Cytotoxic (killer) T cells are T lymphocytes that have the specific feature of
binding to the surface of antigens and directly destroying the cell membrane and
therefore the cell (phagocytes)
• Helper T cells(CD4 cells), stimulate B lymphocytes to divide and mature into
plasma cells and begin secreting immunoglobulins
• Suppressor T cells, are T cells that reduce the production of immunoglobulins
against a specific antigen and prevent their overproduction
TYPES OF IMMUNITY

• Humoral immunity
• refers to immunity created by antibody production or B-lymphocyte
involvement
• Cell-mediated immunity
• is the type of immune response caused by T-lymphocyte activity.
TYPES OF IMMUNITY

• Humoral immunity
• refers to immunity created by antibody production or B-lymphocyte
involvement
• begins when helper T cells recognize an antigen and cause activation of B
lymphocytes
• The specific B lymphocytes differentiate into plasma cells and begin creation of
specific immunoglobulins that mark the antigen for destruction
TYPES OF IMMUNITY

• Cell-mediated immunity
• is the type of immune response caused by T-lymphocyte activity.
• Cytotoxic T cells attack and directly destroy invading antigens through the
release of chemical compounds on the antigen membrane, injection of a toxin
directly into the antigen, or secretion of lymphokines
Other Mediators
• Interferons
• Are chemicals that are secreted by cells that have been invaded by viruses and
possibly by other stimuli
• Prevents viral replication and also suppress malignant cell replication and tumor
growth
• Interleukins
• Chemicals secreted by active leukocytes to influence other leukocytes
• Interleukin 1 (IL-1) stimulates T and B cells to initiate an immune response.
• IL-2 is released from active T cells to stimulate the production of more T cells and to
increase the activity of B cells, cytotoxic cells, and natural killer cells.
• Interleukins also cause fever, arthralgia, myalgia, and slow-wave sleep induction—
all things that help the body to conserve energy for use in fighting off the invader.
Other Mediators

• Tumor necrosis factor (TNF)

• a cytokine, is a chemical released by macrophages, which

inhibits tumor growth and can actually cause tumor

regression.
Anti-inflammatory, Antiarthritis and
Related Agents
• The inflammatory response is designed to protect the body from injury and
pathogens. It employs a variety of potent chemical mediators to produce the
reaction that helps to destroy pathogens and promote healing. As the body reacts
to these chemicals, it produces signs and symptoms of disease, such as swelling,
fever, aches, and pains. Occasionally, the inflammatory response becomes a
chronic condition and can result in damage to the body, leading to increased
inflammatory reactions.
• Anti-inflammatory agents generally block or alter the chemical reactions
associated with the inflammatory response to stop one or more of the signs and
symptoms of inflammation.
SALICYLATES
• Block inflammatory response, antipyretic (fever-blocking, and analgesic (pain-
blocking properties
• They were extracted from willow bark, poplar trees, and other plants by ancient
people to treat fever, pain, and what we now call inflammation.
• They are generally available without prescription and are relatively non toxic when
used as directed
• Aspirin
• Most widely used

• Balsalazide, choline magnesium trisalicylate, diflunisal, mesalamine, olsalazine,

salsalate, sodium thiosalicylate
SALICYLATES
• Therapeutic Actions and Indications:
• inhibit the synthesis of prostaglandin, an important mediator of the inflammatory
reaction
• The antipyretic effect of salicylates may be related to blocking of a prostaglandin
mediator of pyrogens (chemicals that cause an increase in body temperature and that
are released by active white blood cells) at the thermoregulatory center of the
hypothalamus.
• At low levels, aspirin also affects platelet aggregation by inhibiting the synthesis of
thromboxane A2, a potent vasoconstrictor that normally increases platelet aggregation
and blood clot formation.
• At higher levels, aspirin inhibits the synthesis of prostacyclin, a vasodilator that inhibits
platelet aggregation.
SALICYLATES
• Pharmacokinetics
• Absorbed directly from the stomach
• Contraindications and Cautions
• contraindicated in the presence of known allergy to salicylates, other nonsteroidal
antiinflammatory drugs (NSAIDs) (more common with a history of nasal polyps, asthma, or
chronic urticaria),
• tartrazine (a dye that has a cross-sensitivity with aspirin) because of the risk of allergic
reaction;
• bleeding abnormalities because of the changes in platelet aggregation associated with
these drugs;
• impaired renal function because the drug is excreted in the urine;
• chickenpox or influenza because of the risk of Reye syndrome in children and teenagers;
• surgery or other invasive procedures scheduled within 1 week because of the risk of
increased bleeding;
• pregnancy or lactation because of the potential adverse effects on the neonate or mother.
SALICYLATES
• Adverse Effects
• Gi:
• Nausea, dyspepsia, heartburn, epigastric discomfort
• Clotting system
• Blood loss, bleeding abnormalities
• Salicylism can occur with high levels of aspirin; dizziness, ringing in the ears, difficulty
hearing, nausea, vomiting, diarrhea, mental confusion, and lassitude can occur.
• Signs of salicylate toxicity include hyperpnea, tachypnea, hemorrhage, excitement,
confusion, pulmonary edema, convulsions, tetany, metabolic acidosis, fever, coma,
and cardiovascular (CV), renal, and respiratory collapse.
NON STEROIDAL ANTIINFLAMMATORY
AND RELATED AGENTS
• provide strong antiinflammatory and analgesic effects without the adverse
effects associated with the corticosteroids
• This group of drugs includes propionic acids, acetic acids, fenamates, oxicam
derivatives, and cyclooxygenase-2 (COX-2) inhibitors.
NON STEROIDAL ANTIINFLAMMATORY
AND RELATED AGENTS
• Therapeutic Action and Indication
• The antiinflammatory, analgesic, and antipyretic effects of the NSAIDs are largely
related to inhibition of prostaglandin synthesis
• The NSAIDs are indicated for relief of the signs and symptoms of rheumatoid
arthritis and osteoarthritis, for relief of mild to moderate pain, for treatment of
primary dysmenorrhea, and for fever reduction.
NON STEROIDAL ANTIINFLAMMATORY
AND RELATED AGENTS
• Pharmacokinetics
• The NSAIDs are rapidly absorbed from the GI tract, reaching peak levels in 1 to 3 hours.
They are metabolized in the liver and excreted in the urine.
• NSAIDs cross the placenta and cross into breast milk. Therefore, they are not
recommended during pregnancy and lactation because of the potential adverse effects
on the fetus or neonate.
• Contraindication and Caution
• Allergy to salicylates and celecoxib is contraindicated to those allergic to sulfonamides
• CV dysfunction or hypertension because of the varying effects of the prostaglandins;
• Peptic ulcer or known GI bleeding because of the potential to exacerbate the GI
bleeding;
• pregnancy or lactation because of potential adverse effects on the neonate or mother
• Caution should be used with renal or hepatic dysfunction, which could alter the
metabolism and excretion of these drugs, and with any other known allergies, which
indicate increased sensitivity.
NON STEROIDAL ANTIINFLAMMATORY
AND RELATED AGENTS
• Adverse Effects
• nausea, dyspepsia, GI pain, constipation, diarrhea, or flatulence
• Headache, dizziness, somnolence, and fatigue also occur frequently
and could be related to prostaglandin activity in the CNS
• Bleeding, platelet inhibition, hypertension, and even bone marrow
depression have been reported with chronic use and probably are
related to the blocking of prostaglandin activity.
• Rash and mouth sores may occur, and anaphylactoid reactions
ranging up to fatal anaphylactic shock have been reported in cases of
severe hypersensitivity.
ACETAMINOPHEN
• Acetaminophen (Tylenol, Ofirmev) is used to treat moderate to mild pain and
fever and often is used in place of the NSAIDs or salicylates.
• It has been the most frequently used drug for managing pain and fever in
children.
• It is widely available OTC and is found in many combination products.
• It can be extremely toxic. It causes severe liver toxicity that can lead to death
when taken in high doses.
ACETAMINOPHEN
• Therapeutic Actions and Indications
• acts directly on the thermoregulatory cells in the hypothalamus to cause
sweating and vasodilation; this in turn causes the release of heat and lowers
fever.
• indicated for the treatment of pain and fever associated with a variety of
conditions, including influenza; for the prophylaxis of children receiving
diphtheria–pertussis–tetanus immunizations and for the relief of
musculoskeletal pain associated with arthritis
ACETAMINOPHEN
• Pharmacokinetics
• Acetaminophen is rapidly absorbed from the GI tract, reaching peak levels in 0.5 to
2 hours.
• It is extensively metabolized in the liver and excreted in the urine, with a half-life of
about 2 hours.
• It is also available for IV use in adults and children 2 and over if oral use of the drug
is not possible.
• Contraindications and Cautions:
• contraindicated in the presence of allergy to acetaminophen because of the risk of
hypersensitivity reactions.
• It should be used cautiously in pregnancy or lactation because of the potential for
adverse effects on the fetus or baby and in hepatic dysfunction or chronic
alcoholism because of associated toxic effects on the liver.
ACETAMINOPHEN
• Adverse Effects:
• headache, hemolytic anemia, renal dysfunction, skin rash, and fever.
• Hepatotoxicity is a potentially fatal adverse effect that is usually associated with
chronic use and overdose and is related to direct toxic effects on the liver.
• acetylcysteine can be used as an antidote
ANTIARTHRITIS AGENT
• Arthritis is a potentially debilitating inflammatory process in
the joints that causes pain and bone deformities.
• Antiarthritis drugs include one gold compound, which is used
to prevent and suppress arthritis in selected patients with
rheumatoid arthritis.
• The other antiarthritis drugs are specifically used to block the
inflammation and tissue damage of rheumatoid arthritis
ANTIARTHRITIS AGENT
• Gold Compound
• treatment with gold salts, also known as chrysotherapy, in
which gold is taken up by macrophages, which then inhibit
phagocytosis;
• it is reserved for use in patients who are unresponsive to
conventional therapy and can be very toxic.
• The gold salt available for use is auranofin (Ridaura).
ANTIARTHRITIS AGENT
• Gold Compound
• Chrysotherapy results in inhibition of phagocytosis
• Because phagocytosis is blocked the release of lysosomal
enzymes is inhibited and tissue destruction is decreased. This
action allows gold salts to suppress and prevent some arthritis
and synovitis.
• Gold salts are indicated to treat selected cases of rheumatoid
and juvenile rheumatoid arthritis in patients whose disease has
been unresponsive to standard therapy
• This drug does not repair damage; it may prevent further
damage and so is most effective if used early in the disease.
ANTIARTHRITIS AGENT
• Gold Compound
• Gold salts can be quite toxic and are contraindicated in the
presence of any known allergy to gold, severe diabetes,
congestive heart failure, severe debilitation, renal or hepatic
impairment, hypertension, blood dyscrasias, recent radiation
treatment, history of toxic levels of heavy metals, and
pregnancy or lactation.
• Adverse Effects: Stomatitis, glossitis, gingivitis, pharyngitis,
laryngitis, colitis, diarrhea, and other GI inflammation; gold
bronchitis and interstitial pneumonitis; bone marrow
depression; vaginitis and nephrotic syndrome; dermatitis,
pruritus, and exfoliative dermatitis; and allergic reactions
ranging from flushing, fainting, and dizziness to anaphylactic
shock.
ANTIARTHRITIS AGENT (TUMOR
NECROSIS FACTOR BLOCKERS)
• TNF blockers are often the first class used with progressing arthritis.
• These drugs include adalimumab (Humira), certolizumab (Cimzia), etanercept
(Enbrel), golimumab (Simponi), and infliximab (Remicade).
• TNF blockers act to decrease the local effects of TNF, a locally released cytokine
that can cause the death of tumor cells and stimulate a wide range of
proinflammatory activities. The actions of this cytokine when inflammation
occurs within a joint capsule can lead to the destruction of bone and the
malformation of joints that is associated with arthritis. Drugs that block that
action of TNF slow the inflammatory response and the joint damage associated
with it.
ANTIARTHRITIS AGENT (TUMOR
NECROSIS FACTOR BLOCKERS)
• TNF blockers act to decrease the local effects of TNF, a locally
released cytokine that can cause the death of tumor cells and
stimulate a wide range of proinflammatory activities. The
actions of this cytokine when inflammation occurs within a
joint capsule can lead to the destruction of bone and the
malformation of joints that is associated with arthritis. Drugs
that block that action of TNF slow the inflammatory response
and the joint damage associated with it.
ANTIARTHRITIS AGENT (TUMOR
NECROSIS FACTOR BLOCKERS)
• Pharmacokinetics
• TNF blockers must be given subcutaneously, with the exception
of infliximab, which is given IV.
• They have a slow onset, usually peaking in 48 to 72 hours.
• They are primarily excreted in the tissues and have very long
half-lives ranging from 115 hours to 2 weeks.
• They cross the placenta and may enter breast milk, so use in
pregnancy and breastfeeding should be discouraged.
ANTIARTHRITIS AGENT (TUMOR
NECROSIS FACTOR BLOCKERS)
• Adverse Effects:
• come with black box warnings about the risk of serious
to fatal infections and the development of lymphomas
and other cancers.
• Demyelinating disorders have occurred, including
multiple sclerosis and various neuritis conditions.
• Myocardial infarction (MI), heart failure, and
hypotension are also reported with the use of these
drugs.
• Irritation at the injection site can also occur.
Other Disease-Modifying Antirheumatic
Drugs (DMARDS)