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 o o o o Bacteria Viruses Other foreign pathogens Trauma 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 bodys 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.

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. The stomach mucosa secretes hydrochloric acid and protein digesting enzymes. Both kill pathogens. 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 o o o Thymus gland Lymphatic tissue Leukocytes 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. o Diapedesis- moving outside of the bloodstream. Phagocytosis-engulfing and digesting foreign material

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. Able to identify nonself-cells by use of MHC.

2. Basophils o Myelocytic leukocytes that are not capable of phagocytosis.

Full of chemical substances that are important for intiating and maitaining an immune or inflammatory response. Ex histamine and heparin

3. Eosinophils o o Circulating myelocytic leukocytes. 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 o Monuclear phagocytes also called macrophages 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

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 o Fixed basophils that do not circulate 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. Any insult to the body that injures cells or tissues sets into action a sereis of events and chemicals reactions.

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 bodys 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 o o o -

Swelling Pain Redness 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. 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. Choline magnesium trisalicylate- is used to treat mild pain and fevers, as well as arthritis. Choline salicylate- is used to treat mild pain and fevers, as well as arthritis, it is available only as an OTC. 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. Olsalazine- is a drug that is converted to mesalamine in the colon and has the same direct anti-inflammatory effects. Salsalate- is used treat pain, fever, and inflammation. Sodium thiosalicylate- is used mainly for episodes of acute gout and muscular pain, and to treat rheumatic fever.

o o

Therapeutic Actions o o Salicylates inhibit the synthesis of prostaglandin 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.

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. 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 o Rheumatoid arthritis 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 o o o Nausea Dyspepsia Heartburn Epigastric discomfort

Clotting systems o o Blood loss Bleeding abnormalities

Salicylism (high levels of salicylates) o o o o o o o Dizziness Ringing in the ears Difficulty hearing Nausea vomiting Diarrhea Mental confusion Lassitude

Acute salicylate toxicity (occurs at doses of 20-40g in adults, 4 g in children) o o o o o Hyperpnea (increase depth in breathing) Tachypnea Hemorrhage Excitement Confusion

o o o o o o o o o

Pulmonary edema Convulsions Tetany (spasms due to decrease calcium) Metabolic acidosis Fever Coma Cardiovascular collapse Renal failure 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.

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.

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.