Drugs Acting on the Immune System

Drugs Acting on the Immune System

I. 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. These
stressors can include:
o Bacteria
o Viruses
o Other foreign pathogens
o Trauma
o Exposure to extremes of environmental conditions
- 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
• Inflammatory response
• Immune response
A. 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.
o 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.
• The acid pH of skin secretions inhibits bacterial growth.
• Glands in the skin secrete chemicals that destroy or repel many pathogens. Ex. Sebum contains chemicals that
are toxic to bacteria.
• The skin sloughs off daily, making it difficult for any pathogen to colonize on the skin.
• An array of normal flora bacteria lives on the skin and destroys many disease causing pathogens.
o Mucous membrane
♣ Mucous membranes line the areas of the body that are exposed to external influences but do not have the
benefit of skin protection.
• Respiratory tract
o The mucous membrane is lined with tiny, hair-like processes called cilia. The cilia sweep any captured pathogens
or foreign materials upward toward the mouth, either to be swallowed or to cause irritation to the area and be
removed by a cough or a sneeze.
• Gastrointestinal tract
o 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 intestines, and the waste products that accumulate in the large
intestine.
o The stomach mucosa secretes hydrochloric acid and protein digesting enzymes. Both kill pathogens.
o 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.

B. Cellular Defenses
- Any foreign pathogen that manages to get past the barrier defenses will encounter the human immune system, or
mononuclear phagocyte system (MPS) composed of:
o Thymus gland
o Lymphatic tissue
o Leukocytes
o Lymphocytes chemical mediators

a. Leukocyte
♣ White blood cells
♣ Two types of WBC
• Lymphocytes- key components of the immune system and consist of T cells, B cells and natural killer cells
• Myelocytes- different cell types those are important in both the basic inflammatory response and the immune
response. Myelocytes include neuthrophils, basophils, eosinophils and monocytes or macrophages.
1. Neuthrophils
o Polymorphonuclear lukocytes that are capable of diapedesis and phagocytosis.
♣ Diapedesis- moving outside of the bloodstream.
♣ Phagocytosis-engulfing and digesting foreign material
o When the body is injured or invaded by a pathogen, neuthrophils are rapidly produced and moved to the site of
the insult to attack the foreign material.
o Able to identify nonself-cells by use of MHC.
2. Basophils
o Myelocytic leukocytes that are not capable of phagocytosis.
o Full of chemical substances that are important for intiating and maitaining an immune or inflammatory response.
Ex histamine and heparin

3. Eosinophils
o Circulating myelocytic leukocytes.
o Often found at the site of allergic reaction and responsible for removing proteins and active componets of the
immune reaction from the site of an allergic response.

4. Monocytes
o Monuclear phagocytes also called macrophages
o Mature leukocytes that are capable of phagocytizing an antigen.
♣ Antigen- an substance capable of exciting our immunne system and provoking an immune response. As far as our
immune system is concern, they are foreign intruders in the body
o A major role of macrophages is to engulf foreign particles and present fragments of these antigens, like signal
flags, on their own surfaces, where theyczn be recognized by immunocompetent T cells.

5. Mast cells
o Fixed basophils that do not circulate
o Can be found in the respiratory and GI tracts and in the skin.

C. The Inflammatory Response

o The inflammatory response is the local reaction of the body to invasion or injury.
o Any insult to the body that injures cells or tissues sets into action a sereis of events and chemicals reactions.
o Cell injuries causes the activation of a chemical in the plasma called factor XII or Hageman Factor.
♣ Hageman Factor-responsible for activating the Kinin System:
• Clottting cascade- which starts blood clotting
•+
♣ Hageman factor activates kallikrein, a bustance found in the local tissues.
♣ Kallikrein causes the precursor substance kininogen to be converted to bradykinin.
♣ Bradykinin
• Causes local vasodilation to bring more blood to the injured area
• Allow white blood cells to ecape into the tissues. Increase permeability.
• Stimulates nerve ending to cause pain,which alerts the body to the injury.
♣ Bradykinin also causes the release of arachidonic acid from the cell memebrane.
♣ Arachidonic acid causes the release of autochoids. Autochoids act like local hormes release from the cell and
cause an eefect in the immediate area:
• Protaglandins- augments the inflamatory reaction and stimulates nerve ending which causes pain.
• Leukotrines- causes vasodilation and increased capillary permeability. Leukotrines has a property called
chemotaxis, which is the ability to attarct neuthrophils and to stimulate them and other macrophages in the area to
be very aggressive.
• Thromboxanes- cause local vasoconstriction and facilitates aggregation and blood coagulation.
♣ Injury to the cell membrane causes the release of Histamine.
♣ Histamine causes vasodilation, which bring more blood and blood components to the area. Histamine also
increases the permeability of the capillary, making it easier for neuthrphils and blood chemicals to leave the blood
sream and enter the injured area.

D. The Immune Response

- More specific invasion can stimulate a more specific response through the immune system.
- A major component of the immune response are the lymphocytes
o 2 major types of lymphocytes:
a. T cells
♣ T cells are programmed in the thymus gland
♣ It provides to what is called a cell mediated immunity
♣ Cell mediated immunity is an immune response that does not involve antibodies but rather involves the
activation of macrophages and antigen specific cytotoxic T cells, and the release of various cytokines in response to
an antigen.
♣ T cells develop into at least 3 different cell types
1. Effector or cytotoxic T cells
• Are found throughout the body
• Aggressive against non-self cells
• Releases cytokines, or chemicals that can either directly destroy a foreighn cell or mark it for aggressive
destruction.
• Attacks body’s own cells that have been invaded by a virus, neoplastic cancer, or transplant foreign cells.
2. Helper T cells
• Stimulates other lymphocytes to be more aggressive and responsive.
3. Suppresor T cells
• Responds to the rising levels of chemicals associated w/ an immune response to suppress or slow reaction.

- The balance of the helper and suppresor T cells allow for rapid response to body injury or invasion. And slowing
allows the body to conserve energy and the component of the immune and inflammatory reaction.

b. B cells
♣ Are programmed to identifay specific protein, or antigens. They provide what is called humoral immunity.
♣ Humoral immunity is the aspect of immunity that is mediated by secreted antibodies.
♣ Antibodies also known as immunoglobulins, are used by the immune system to identify and neutralize foreign
objects or microorganms.
♣ When B cells reacts w/ its specific antigen, it changes to become a plasma cell.
♣ Plasma cells produce antibodies, w/c circulate in the body and react w/ this specific antigen when it is
encounterd.
♣ Reaction between an antigen ang antibodies will form a Ag-Ab complex will cause an activation of complement.
♣ Complement is a biochemical cascade of the innate immune system that helps clear pathogens fron an organism.

Anti-inflammatory Agents

- The inflammatory response is designed to protect the body from and pathogens. It employs a variety of potent
chemical mediators to produce reactions that helps to destroy pathogens and promote healing.
- As the body reacts to these chemicals, it produces some signs and symptoms of disease:
o Swelling
o Pain
o Redness
o Heat/fever
- Anti iiflammatory agenys generally block or alter the chemical reactions associated with the inflammatory
response to stop one or more of the signs and symptoms of inflammation.

Several diffrent types of drugs are used as anti-inflammatory agents:

1. Corticosteroids- are used sytemically to block the inflammatory and immune systems. Blocking these important
protective processes may produce many adverse effects, including decreased resistance to infection and neoplasm.
2. Antihistamines- are use to block the release of histamine in the initiation of the inflammatory response.
3. Salicylates- are popular anti-inflammatory agebts, not only because of their ability to block the inflammatory
response but also because of their antipyretic and analgesic properties. They are generally available without
prescription and are relatively nontoxic when used as directed.
4. Nonsteroidal anti-inflammatory drugs (NSAIDS)- are some of the most widely used drugs. They provide strong
anti-inflammatory and analgesic effects yet do not have the adverse effects that are associated with the
corticosteroids.
5. Acetaminophen- also is widely used agent. It has antipyretic and analgesic properties but does not have the anti-
inflammatory effects of salicylates or the NSAIDs.

- Because many anti-inflammatory drugs are available over the counter, there is the potential for abuse and
overdosing.
- Patients may take these drugs and block the signs and symptoms of a present illness, thus potentially causing the
misdiagnosis of a problem.
- Patients also may combine these drugs and unknowingly induce toxicity.

SALICYLATES
- Are some of the oldest anti-inflammatory drugs used.
- Ancient peoples extract salicylates from willow bark and poplar trees, used to treat fever, pain and inflammation.
- Nowadays synthetic salicylates are commonly used.
- Synthetic salicylates includes the following drugs:
o Aspirin- one of the most widely used drugs for treating inflammatory conditions, it is available OTC.
o Balsalazide- a new type of anti-inflammatory drug that is delivered intact to the colon, where it delivers a local
anti-inflammatory effect for patients with ulcerative colitis.
o Choline magnesium trisalicylate- is used to treat mild pain and fevers, as well as arthritis.
o Choline salicylate- is used to treat mild pain and fevers, as well as arthritis, it is available only as an OTC.
o Mesalanine- is a unique compound that release aspirin in the large intestine for a direct anti-inflammatory effect
in ulcerative colitis or other condition involving inflammation of the large intestine.
o Olsalazine- is a drug that is converted to mesalamine in the colon and has the same direct anti-inflammatory
effects.
o Salsalate- is used treat pain, fever, and inflammation.
o Sodium thiosalicylate- is used mainly for episodes of acute gout and muscular pain, and to treat rheumatic fever.

Therapeutic Actions
o Salicylates inhibit the synthesis of prostaglandin
o The antipyretic effect of salicylates maybe related to blocking of a prostaglandin mediator of pyrogen.
♣ Pyrogen are chemicals that can cause an increase in body temperature and that are released by active WBC,
they act at the thermoregulatory of the hypothalamus.
o 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 clotting.
o At high levels, aspirin inhibits the synthesis of prostacyclin , a vasodilator that inhibits platelet aggregation.

Indications
Salicylates are indicated for the treatment of:
• Mild to moderate pain
• Fever
• Numerous inflammatory conditions:
o Rheumatoid arthritis
o Ostheoarthritis
• Low doses indicated for the prevention of transient ischemic attack
• Stroke in adults with a history of emboli
• Reduce the risk of death and myocardial infarction in patients with history of MI or unstable angina.

Pharmacokinetics
• Salicylates are readily absorbed in the stomach
• Metabolized in the liver
• Excreted in the urine
• Crosses the placenta barrier and enter breast milk
• Not indicated for use during pregnancy and lactation because of the potential adverse effect on the neonates

Contraindications
• Allergy to salicylates
• Bleeding abnormalities

Adverse Reactions
• Stomach (gastric irritant)
o Nausea
o Dyspepsia
o Heartburn
o Epigastric discomfort
• Clotting systems
o Blood loss
o Bleeding abnormalities
• Salicylism (high levels of salicylates)
o Dizziness
o Ringing in the ears
o Difficulty hearing
o Nausea vomiting
o Diarrhea
o Mental confusion
o Lassitude
• Acute salicylate toxicity (occurs at doses of 20-40g in adults, 4 g in children)
o Hyperpnea (increase depth in breathing)
o Tachypnea
o Hemorrhage
o Excitement
o Confusion
o Pulmonary edema
o Convulsions
o Tetany (spasms due to decrease calcium)
o Metabolic acidosis
o Fever
o Coma
o Cardiovascular collapse
o Renal failure
o Respiratory collapse
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

The NSAIDs are a drug class that has become one of the most commonly used types. This group of drugs includes
the following agents:

Propionic Acid
1. Fenopropen- is used to treat pain and manage arthritis.
2. Flurbipropen- is used for the long-term management of arthritis and as atopical preparations for managig pain
after eye surgery.
3. Ibufrofen- is used as an OTC pain medication and for long-term management of arthritis pain and dysmenorrhea;
it is the most widely used of the NSAIDs.
4. Ketoprofen- is available for short-term management of pain and as atopical agent to relieve ocular itching caused
by seasonal rhinitis.
5. Naproxen- is available for OTC pain relief and to treat arthritis and dysmenorrhea.
6. Oxaprozin- is very successfully used to manage arthritis.

Acetic Acids
1. Diclofenac- is used to treat acute and long term pain associated with inflammatory conditions.
2. Etodolac- is widely used for arthris pain.
3. Indomethacin- is available in oral, topical, and rectal preparations for the relief of moderate to severe pain
associated with inflammatory conditions and in intravenous form to promote closure of the patent ductus arteriosus
in premature infants.
4. Ketorolac- is used for short-term management of pain and topically to relieve ocular itching.
5. Nabumetone- is used treat acute and chronic arthritis pain.
6. Sulindac- is used for long-and short term treatment of the signs and symptoms of various inflammatory
conditions.
7. Tolmetin- is used to treat acute attacks of rheumatoid arthritis and juvenile arthritis.

Fenamates
1. Mefenamic acid- is used only for short-term tratment of pain.
2. Piroxicam- is used to treat acute and chronic arthritis.
3. Diflunisal- is used for moderate pain and for the treatment of arthritis

Oxicam Derivative
1. Meloxicam- is used for the relief of juvenile arthritis, osteoarthritis, and rheumatoid arthristis.

Cyclooxygenase-2 Inhibitor
1. Celcoxib- is used for the acute and long term treatment of arthritis, particularly in patients who cannot tolerte the
GI effects of other NSAIDs.

Therapeutic Actions
• The anti-inflammatory, analgesic and antipyretic effects of NSAIDs are largely related to the inhibition of
prostaglandin.
• The NSAIDs block 2 enzymes:
o Cyclooxygenase-1 (COX-1)- involves in many body functions including:
♣ Blood clotting
♣ Protecting the stomach lining
♣ Maintaining sodium and water balance
♣ COX-1 turns arachidonic acid into prostaglandins as needed in a variety of tissues.
o Cyclooxygenase-2 (COX-2)
♣ Is active at sites of trauma or injury when more prostaglandins are needed, but it does not seem to be involved in
the other tissue function, unlike COX-2.
o The adverse effects associated with most NSAIDs are related to blocking of both of these enzymes and changes in
the functions that they influence:
♣ Changes in bleeding time
♣ GI effects
♣ Water retention

Indications
• 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.

Pharmacokinetics
• Rapidly absorbed from the GI tract
• Metabolized in the liver
• Excreted in the urine
• NSAIDs cross the placenta and cross into breast milk
• Not recommended during pregnancy and lactation because of the potential adverse effects on the fetus or
neonate.

Contraindications
• Allergy to any NSAIDs or salicylates.
• Celecoxib is also contraindicated in the presence of allergy to sulphonamides.
• Cardiovascular dysfunction
• Hypertension
• Peptic ulcer or known GI bleeding
• Renal or hepatic dysfunction

Adverse Effects
• Nausea
• Dyspepsia
• GI pain
• Constipation
• Diarrhea
• Flatulence
• Potential for GI bleeding
• Headache
• Dizziness
• Fatigue
• Bleeding
• Platelet inhibition
• Bone marrow depression
• Rash and mouth sores
• Anaphylactic shock in cases of severe hypersensitivity.