Lecture Drugs 6. Anti-inflammatory INFLAMMATION Inflammation is a defense reaction caused by tissue damage or injury Can be elicited by numerous stimuli including: infectious agents antigen-antibody interaction ischemia thermal and physical injury Noxious chemicals Inflammatory responses occur in three distinct phases: 1. An acute transient phase, characterized by: local vasodilation and its resulting increased blood flow causes the redness (rubor) and increased heat (calor) Increased permeability of the blood vessels results in an exudation (leakage) of plasma proteins and fluid into the tissue (edema), which manifests itself as swelling (tumor). 2. A delayed phase, most prominently characterized by: Infiltration of leukocytes and phagocytic cells to the injured /inflamed tissue 3. A chronic proliferative phase, in which tissue: Degeneration and fibrosis occur Signs of inflammation Redness due to vasodilation of capillaries to increase blood flow. Heat - due to local vessel dilatation. Swelling due to Increased vascular permeability and influx of plasma proteins and phagocytic cells into the tissue spaces Pain due to -Hyperalgesia, sensitization of nociceptors -local release of enzymes and -increased tissue pressure Mediators of the inflammatory response i) Complement system: The complement system is a biochemical cascade that helps, or the ability of antibodies to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime. i) Histamine Secreted from mast cell: Increases gap junction space causes tissue congestion & swelling causes bronchoconstriction causes sneezing, watery eyes, itching causes pressure & pain iii). Serotonin- is a vasoactive mediator like histamine found in mast cells and platelets in the GI tract and CNS. Serotonin also increases vascular permeability, dilates capillaries, and causes contraction of nonvascular smooth muscle. iv). Bradykinin - major contributors to symptoms of inflammation. A vasoactive protein which is able to induce vasodilation, increase vascular permeability, cause smooth muscle contraction, and induce pain v). leukotrienes - increase vascular permeability and leakiness - increase mobilization of endogenous mediators of inflammation vi). Prostaglandins PGE2 promote Vasodilation, Bronchodilation leukocyte infiltration, Directly Cause Pain and Induces Fever PGI2 - increase vascular permeability, enhance pain producing properties of bradykinin vii) Thromboxane A2 (TXA2)- Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. Cause platelets vasoconstriction to aggregate causes smooth causes muscle contraction enhances function of inflammatory cells Anti-inflammatory Drugs Steroidal - Cortisone - Hydrocortisone Non-steroidal - Acetaminophen - Aspirin Anti - inflammatory Drugs (NSAIDs) NON STEROIDAL ANTI INFLAMMATORY DRUGS NSAID The NSAIDs are a group of chemically dissimilar agents that differ in their antipyretic, analgesic, and anti-inflammatory activities. They act primarily by inhibiting the cyclooxygenase enzymes that catalyze the first step in prostanoid biosynthesis. This leads to decreased prostaglandin synthesis with both beneficial and unwanted effects. Mechanism of action of NSAIDs 1. Antiinflammatory effect due to the inhibition of the enzymes cyclooxygenase, or COX, which converts arachidonic acid to prostaglandins, and to TXA2 and prostacyclin. Aspirin irreversibly inactivates COX-1 and COX-2 by acetylation of a specific serine residue. This distinguishes it from other NSAIDs, which reversibly inhibit COX-1 and COX-2. 2. Analgesic effect A. The analgesic effect of NSAIDs is thought to be related to: the peripheral inhibition of prostaglandin production may also be due to the inhibition of pain stimuli at a subcortical site. B. NSAIDs inhibits bradykinin from stimulating pain receptors 3. Antipyretic effect The antipyretic effect of NSAIDs is believed to be related to: inhibition of production of prostaglandins induced by cytokines such as interleukin-1 (IL-1) and interleukin6 (IL-6) in the hypothalamus the resetting of the thermoregulatory system, leading to vasodilatation and increased heat loss. **Mechanism of action 1- Analgesia ( treatment of pain and headache) Through block the undesirable effects of prostaglandins, which cause headache and pain. 2- Antipyretic ( reduce fever) Through inhibit prostaglandin E2 within the thermal regulatory center in brain. 3- Anti-inflammatory (relief of inflammation) Through inhibit the leukotriene or prostaglandin pathway, or both NSAIDs **Six structurally related groups: Acetic acids Carboxylic acids Propionic acids Enolic acids Fenamic acids Non- acidic compounds Acetic Acid derivatives -Diclofenac sodium ( Voltaren ) - diclofenac potassium ( Cataflam ) - indomethacin ( Indocin ) All have anti-inflammatory, analgesic, and antipyretic activity. They act by reversibly inhibiting cyclooxygenase. Carboxylic Acids - salicylic acid (aspirin ) - sodium salicylate - magnesium salicylate Propionic Acids - ibuprofen (profinal) - ketoprofen (Orudis) Enolic acids - phenyl butazone Fenamic acids - me fenamic acid - meclo fenamic acid Therapeutic Use NSAIDs are first-line drugs used to arrest inflammation and the accompanying pain of rheumatic and nonrheumatic diseases. The salicylic acid derivatives are used in the treatment of gout, rheumatic fever, osteoarthritis, and RA, juvenile arthritis,psoriatic arthritis, ankylosing spondylitis, Reiter syndrome. Commonly treated conditions requiring analgesia include headache, arthralgia, and myalgia, dysmenorrhea. Pain and inflammation of bursitis and tendonitis also respond to NSAIDs. NSAIDs: do not significantly reverse the progress of rheumatic disease they slow destruction of cartilage and bone allow patients increased mobility and use of their joints. Treatment of chronic inflammation requires use of these agents at doses well above those used for analgesia and antipyresis the incidence of adverse drug effects is increased. Drug selection is generally dictated by the patient's ability to tolerate the adverse effects, and the cost of the drugs. Antiinflammatory effects may develop only after several weeks of treatment. Adverse effects i)Gastrointestinal: The most common GI effects of the salicylates are epigastric distress, nausea, and vomiting. Microscopic GI bleeding is almost universal in patients treated with salicylates. [Note: Aspirin is an acid. At stomach pH, aspirin is uncharged; consequently, it readily crosses into mucosal cells, where it ionizes (becomes negatively charged) and becomes trapped, thus potentially causing direct damage to the cells. Aspirin should be taken with food and large volumes of fluids to diminish dyspepsia. Additionally, misoprostol or a PPI may be taken concurrently.] ii) Blood: The irreversible acetylation of platelet cyclooxygenase reduces the level of platelet TXA2, resulting in inhibition of platelet aggregation and a prolonged bleeding time. For this reason, aspirin should not be taken for at least 1 week prior to surgery. When salicylates are administered, anticoagulants may have to be given in reduced dosage, and careful monitoring and counseling of patients are necessary. iii)Respiration: In toxic doses, salicylates cause respiratory depression and a combination of uncompensated respiratory and metabolic acidosis. iv)Metabolic processes: Large doses of salicylates uncouple oxidative phosphorylation.4 The energy normally used for the production of adenosine triphosphate is dissipated as heat, which explains the hyperthermia caused by salicylates when taken in toxic quantities. v) Reye's syndrome: Aspirin and other salicylates given during viral infections has been associated with an increased incidence of Reye's syndrome, which is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar (hypoglycemia). The classic features are a rash, vomiting, and liver damage. The exact cause is unknown and, while it has been associated with aspirin consumption by children with viral illness, it also occurs in the absence of aspirin use. -The disease causes fatty liver with minimal inflammation and severe encephalopathy (with swelling of the brain). -The liver may become slightly enlarged and firm, and there is a change in the appearance of the kidneys. Jaundice is not usually present -This is especially encountered in children, who therefore should be given acetaminophen instead of aspirin when such medication is required to reduce fever. Ibuprofen is also appropriate. vi)Drug interactions: Concomitant administration of salicylates with many classes of drugs may produce undesirable side effects. Because aspirin is found in many over-the-counter agents, patients should be counseled to read labels to verify aspirin content to avoid overdose. Salicylate is 90 to 95 percent protein bound and can be displaced from its protein-binding sites, resulting in increased concentration of free salicylate; alternatively, aspirin could displace other highly protein-bound drugs, such as warfarin, phenytoin, or valproic acid, resulting in higher free concentrations of the other agent . Chronic aspirin use should be avoided in patients receiving probenecid or sulfinpyrazone, because these agents cause increased renal excretion of uric acid whereas aspirin (<2 g/day) cause reduced clearance of uric acid. Concomitant use of ketorolac and aspirin is contraindicated because of increased risk of GI bleeding and platelet aggregation inhibition. Children who have received live varicella virus vaccine should avoid aspirin for at least 6 weeks after vaccination to prevent Reye's syndrome. vii)In pregnancy: Aspirin is classified as FDA pregnancy category C risk during Trimesters 1 and 2 and category D during Trimester 3. Because salicylates are excreted in breast milk, aspirin should be avoided during pregnancy and while breastfeeding. B- Steroids anti- inflammatory drugs (SAIDs) - Containing steroid in their structure. - Commonly referred to as steroids, corticosteroids are a type of anti-inflammatory drug. They are typically used to treat rheumatologic diseases, like rheumatoid arthritis, lupus or vasculitis (inflammation of the blood vessels). Glucocorticoids (GC) Cortisone Glucocorticoids are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. Glucocorticoids are part of the feedback mechanism in the immune system, which reduces certain aspects of immune function, such as inflammation. They are therefore used in medicine to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases, and sepsis. **Types of Glucocorticoids ( SAIDs): 1- Natural - Cortisone - Hydrocortisone 2- Synthetic - Beta methasone - Dexa methasone - Predinsone Mechanism of Action : They act by indirect inhibition of the enzyme phospholipase A2 which activate synthesis of arachidonic acid with subsequent formation of prostaglandins. - This occur by induce synthesis of a protein lipocortin-1 which has the inhibitory effect on phospholipase A2. **Side Effects Immunosuppression Hyperglycemia Osteoporosis (reduced bone density) , higher fracture risk, slower fracture repair Muscle breakdown (proteolysis), weakness , reduced muscle mass and repair Anovulation and irregularity of menstrual cycle Growth failure , pubertal delay Redistribution of body fat : moon face, buffalo hump and truncal obesity. Glaucoma due to increased cranial pressure Adrenal insufficiency Moon face buffalo hump
