Budlao Block 262 (CCC) Inflammation - is a response to tissue injury and infection. - When the inflammatory process occurs, a vascular reaction takes place in which fluid, elements of blood, leukocytes, and chemical mediators accumulate at the injured tissue or infection site. - is a protective mechanism in which the body attempts to neutralize and destroy harmful agents at the site of injury and to establish conditions for tissue repair.
Infection - is caused by microorganisms and results in inflammation, but not all inflammations are caused by infections. - Injury can cause inflammation
PATHOPHYSIOLOGY Phases of inflammation 1. Vascular phase - occurs 10 to 15 minutes after an injury; is associated with vasodilation and increased capillary permeability during which blood substances and fluid leave the plasma and go to the injured site. 2. Delayed phase - phase occurs when leukocytes infiltrate the inflamed tissue.
Cardinal signs of inflammation
1. Redness (erythema) - occurs in the first phase of inflammation. Blood accumulates in the area of tissue injury because of the release of the body’s chemical mediators (such as kinins, prostaglandins, and histamine) 2. Swelling (edema) - is the second phase of inflammation. Plasma leaks into the interstitial tissue at the injury site. 3. Heat - caused by increased blood accumulation and may result from pyrogens (substances that produce fever) that interfere with the temperature-regulating center in the hypothalamus. 4. Pain - is caused by tissue swelling and the release of chemical mediators. 5. Loss of function - loss because of the accumulation of fluid at the tissue injury site and because of pain, which decreases mobility in the affected area.
Prostaglandins - Biosynthesis of prostaglandins is significantly increased in inflamed tissue and they contribute to the development of the cardinal signs of acute inflammation. - Prostaglandins (PGs) are arachidonic acid metabolites produced by the action of the enzyme cyclooxygenase (COX).
Cyclooxygenase (COX) is the enzyme responsible for converting arachidonic acid into prostaglandins and their products. This synthesis of prostaglandins causes inflammation and pain at a tissue injury site. - COX-1 - protects the stomach lining and regulates blood platelets - COX-2 - triggers inflammation and pain Christine Marie U. Budlao Block 262 (CCC)
ANTIINFLAMMATORY AGENTS Prostaglandins Inhibitors - a.k.a. Antiinflammatory agents. It inhibits the biosynthesis of prostaglandins; a Common example is Aspirin. - These are also: - Analgesic - relieve pain - Antipyretic - reduce elevated body temperature - Anticoagulant - inhibit platelet aggregation
Aspirin - Oldest anti-inflammatory drug, and was first used for its analgesic and antipyretic properties
Nonsteroidal Antiinflammatory Drugs
(NSAIDs) - used to decrease inflammation and pain for patients who have some arthritic condition. - Are aspirin and aspirin-like drugs that inhibit the enzyme COX, which is needed for the biosynthesis of prostaglandins. - Also called prostaglandin inhibitors - their antipyretic effect is less than their antiinflammatory effect, thus are not suggested for use in alleviating mild headaches and mildly elevated temperature - NSAIDs are more appropriate for reducing swelling, pain, and stiffness in joints. Christine Marie U. Budlao Block 262 (CCC) - Other than aspirin, the only NSAIDs that can be purchased over-the-counter (OTC) are ibuprofen (Motrin, Advil) and naproxen (Aleve) - All other NSAIDs require a prescription.
Seven groups of NSAIDs:
1. Salicylates 2. Para-chlorobenzoic acid derivatives, or indoles 3. Phenylacetic acids 4. Propionic acid derivatives 5. Fenamates 6. Oxicams 7. Selective COX-2 inhibitors - also called. second-generation NSAIDs Christine Marie U. Budlao Block 262 (CCC)
I. Salicylates - Derived from salicylic acid. - Aspirin comes from this family and is also called acetylsalicylic acid (ASA). - was developed in 1899 by Adolph Bayer, making it the oldest anti-inflammatory agent. - As a prostaglandin inhibitor, it decreases the inflammatory process. Aspirin decreases platelet aggregation, and thus blood clotting is decreased. Christine Marie U. Budlao Block 262 (CCC) - Because high doses of aspirin are usually needed to relieve inflammation, gastric distress is a common problem. Enteric-coated (EC) tablets may be used. - Aspirin must not be taken with other NSAIDs because it decreases the blood level and effectiveness of NSAIDs. - Inhibition of COX-1 produces the desired effect of decreasing platelet aggregation, but the undesirable effect of decreasing the protection of the stomach lining. - Thus New NSAIDs called COX-2 Inhibitors, block only COX-2 and not COX-1. These drugs can cause no gastric bleeding and ulcers while delivering relief for pain and inflammation. Such drugs are celecoxib (Celebrex), meloxicam (Mobic), and nabumetone (Relafen). ASPIRIN Pharmacokinetics: - Aspirin is well absorbed from the GI tract. - It can cause GI upset, so it should be taken with water, milk, or food. - The EC or buffered form can cause decreased gastric distress. - Aspirin has a short half-life. It should not be taken during the last trimester of pregnancy, because it could cause premature closure of ductus arteriosus in the fetus. - Aspirin should not be taken by children with flu symptoms, because it may cause the potentially fatal Reye syndrome (swelling in the liver and brain).
Pharmacodynamics: - Aspirin inhibits prostaglandin synthesis by inhibiting COX-1 and COX-2 - the onset of aspirin is within 30 mins - Its peak is in 1-2 hours - the duration of action is an average of 4-5 hours Christine Marie U. Budlao Block 262 (CCC) Christine Marie U. Budlao Block 262 (CCC) Hypersensitivity to Salicylate products: Tinnitus (ringing in the ears), vertigo (dizziness), and bronchospasm - especially in asthmatic patients - are symptoms of aspirin overdose.
II. Para-chlorobenzoic acid, or indoles
- indomethacin (indocin); is used for rheumatoid arthritis, gouty arthritis, and osteoarthritis, and it is a potent prostaglandin inhibitor. - It is highly protein bound (90%) and displaces other protein-bound drugs, resulting in potential toxicity. - It has a moderate half-life (4.5 hours). - Indomethacin is very irritating to the stomach and should be taken with food. - This group of NSAIDs may cause sodium and water retention and increased blood pressure.
III. Phenylacetic acids
- Diclofenac sodium (Voltaren-XR), a phenylacetic acid derivative, has a plasma half-life of 1.2 to 2 hours. - Its analgesic and anti-inflammatory effects are similar to those of aspirin, but it has minimal to no antipyretic effects. - Ketorolac (Toradol), another phenylacetic acid derivative, is the first injectable NSAID. It inhibits prostaglandin synthesis, but it has greater analgesic properties than other anti-inflammatory agents. Ketorolac is recommended for short-term management of pain, and for postsurgical pain. It is administered intramuscularly in doses of 30 to 650 mg every 6 hours for adults. It is also available in PO, IV, and intranasal preparations. Christine Marie U. Budlao Block 262 (CCC) IV. Propionic acid derivatives - Aspirin-like, but have stronger effects and create less GI irritation. - Ibuprofen (Motrin) is the most widely used propionic acid NSAID, and it may be purchased OTC in lower doses (200 mg).
IBUPROFEN Pharmacokinetics: - well absorbed from the GI tract. - These drugs have a short half-life but are highly protein-bound. - If ibuprofen is taken with another highly protein-bound drug, severe side effects may occur. - The drug is metabolized in the liver to inactive metabolites and is excreted as inactive metabolites in the urine. Pharmacodynamics: - inhibit prostaglandin synthesis and are therefore effective in alleviating inflammation and pain. - short onset of action, peak concentration time, and duration of action. - It may take several days for the antiinflammatory effect to be evident. - Hypoglycemia may result when ibuprofen is taken with insulin or an oral hypoglycemic drug. - There is a high risk of toxicity when ibuprofen is taken concurrently with calcium channel blockers. Christine Marie U. Budlao Block 262 (CCC) V. Fenamates - This group includes potent NSAIDs used for acute and chronic arthritic conditions. - Gastric irritation is a common side effect of fenamates. Other side effects include edema, dizziness, tinnitus, and pruritus. - Patients with a history of peptic ulcer should avoid taking this group of drugs.
VI. Oxicams - Piroxicam (Feldene), an oxicam, is indicated for long-term arthritic conditions such as rheumatoid arthritis and osteoarthritis. - Can cause gastric problems such as ulceration and epigastric distress, but the incidence is lower than for some other NSAIDs. - It is well tolerated, and its major advantage over other NSAIDs is its long half-life, which allows it to be taken only once daily. - Full clinical response to piroxicam may take 1-2 weeks. - This drug is highly protein-bound and may interact with another highly protein-bound drug if taken together. Piroxicam should not be taken with aspirin or other NSAIDs.
General side effects and Adverse Reactions for First-Generation NSAIDs:
- Most NSAIDs tend to have fewer side effects than aspirin when taken at antiinflammatory doses, but gastric irritation is still a common problem when NSAIDs are taken without food. - Sodium and water retention may occur. - Alcoholic beverages consumed with NSAIDs may increase gastric irritation and should be avoided. Christine Marie U. Budlao Block 262 (CCC)
VII. Selective COX-2 inhibitors (a.k.a. Second Generation NSAIDs)
- COX-2 inhibitors became available in the last several years to decrease inflammation and pain. - Most NSAIDs are nonselective inhibitors that inhibit COX-1 and COX-2. - By inhibiting COX-1, protection of the stomach lining is decreased and clotting time is also decreased, which may benefit the patient with cardiovascular or coronary artery disease (CAD). - Selective COX-2 inhibitors are drugs of choice for patients with severe arthritic conditions who need high doses of an anti-inflammatory drug, because large doses of NSAIDs may cause peptic ulcer and gastric bleeding. - Currently, there is one drug classified as a COX-2 inhibitor: celecoxib (Celebrex). Christine Marie U. Budlao Block 262 (CCC)
Corticosteroids - This group of drugs controls inflammation by suppressing or preventing many components of the inflammatory process at the injured site. - The half-life of a corticosteroid is long (greater than 24 hours), and it is administered once a day in a large prescribed dose. When discontinuing steroid therapy, the dosage should be tapered over a period of 5-10 days.
Disease -Modifying Antirheumatic Drugs
(DMARDs) - When NSAIDs do not control immune-mediated arthritic disease sufficiently, other drugs, although more toxic, can be prescribed to alter the disease process. - DMARDs include immunosuppressive agents, immunomodulators, and antimalarials. - Immunosuppressive Agents - Used to treat refractory rheumatoid arthritis (arthritis that does not respond to anti-inflammatory drugs). - In low doses, selected immunosuppressive agents have been effective in the treatment of rheumatoid arthritis. - Drugs such as azathioprine (Imuran), cyclophosphamide (Cytoxan), and methotrexate (Mexate), are primarily used to suppress cancer growth and proliferation and might be used to suppress the inflammatory process of rheumatoid arthritis when other treatments fail. Christine Marie U. Budlao Block 262 (CCC) - Immunomodulators - Treat moderate to severe rheumatoid arthritis by disrupting the inflammatory process and delaying disease progression. - Interleukin (IL-1) receptor antagonists and tumor necrosis factor (TNF) blockers are two groups of drugs classified as immunomodulators. 1. Anakinra (Kineret), an IL-1 receptor antagonist, blocks the activity of IL-1 by inhibiting it from the binding to interleukin receptors located in cartilage and bone. IL-1 (Interleukin)is a proinflammatory cytokine that contributes to synovial inflammation and joint destruction, causing arthritis. Anakinra is administered subcutaneously. The peak is 3 to 7 hours, and the half-life is 6 hours. 2. Etanercept (Enbrel) was the first TNF (tumor necrosis factor) blocker developed and administered subcutaneously. The peak half-life is 115 hours. TNF blockers bind to TNF and block it from attaching to TNF receptors on synovial cell surfaces. By neutralizing TNF, a contributor to synovitis, the inflammatory disease process is delayed. Signs and symptoms of rheumatoid arthritis are suppressed rapidly with etanercept therapy but reappear if the drug is discontinued. Other TNF blockers include infliximab (Remicade), adalimumab (Humira), and leflunomide (Arava). Infliximab is administered intravenously (IV) over at least 2 hours, adalimumab is administered subcutaneously, and leflunomide is administered orally. - Both IL-1 receptor antagonists and TNF blockers predispose the patient to severe infections; they are contraindicated in active infection and should be discontinued when an infection occurs. Immunomodulators are usually very expensive Christine Marie U. Budlao Block 262 (CCC)
- Antimalarials - Antimalarial drugs may be used to treat rheumatoid arthritis when other methods of treatment fail. The mechanism of action of antimalarials in suppressing rheumatoid arthritis is unclear. Christine Marie U. Budlao Block 262 (CCC) - The effect may take 4 to 12 weeks to become apparent, and antimalarials are usually used in combination with NSAIDs in patients whose arthritis is not under control.
Antigout Drugs - Gout is an inflammatory condition that attacks joints, tendons, and other tissues. It may be called gouty arthritis. The most common site of acute gouty inflammation is at the joint of the big toe. - Gout is characterized by a uric acid metabolism disorder and a defect in purine (products of certain proteins) metabolism, which results in an increase in urates (uric acid salts) and an accumulation of uric acid (hyperuricemia) or an ineffective clearance of uric acid by the kidneys. - Gout may appear as bumps, or tophi, in the subcutaneous tissue of earlobes, elbows, hands, and the base of the large toe. - The complications of untreated or prolonged periods of gout include gouty arthritis, urinary calculi (kidney stones), and gouty nephropathy (acid or urate crystals deposited in parenchyma and tubule lumens and can cause injury to the kidney over time, eventuating in renal failure.). - Fluid intake should be increased while taking antigout drugs to promote uric acid excretion and prevent renal calculi. Christine Marie U. Budlao Block 262 (CCC) - Foods high in purine (e.g., organ meats, sardines, salmon, gravy, herring, liver, and meat soups) and alcohol (especially beer) should be avoided. Alcohol causes both an overproduction and underexcretion of uric acid. - Acetaminophen should be taken for discomfort instead of aspirin (salicylic acid) to reduce acidity.
- Colchicine - The first drug used to treat gout was introduced in 1936. - This anti-inflammatory gout drug inhibits the migration of leukocytes to the inflamed site. It is effective in alleviating acute symptoms of gout, but it is not effective in decreasing inflammation occurring in other inflammatory disorders. - It should not be used if the patient has a severe renal, cardiac, or GI problem. - Gastric irritation is a common problem, so colchicine should be taken with food. - Colchicine is well absorbed in the GI tract, and its peak concentration time is within 2 hours. Most of the drug is excreted in the feces, but 10% to 20% is excreted in the urine. - Uric Acid Inhibitor - Allopurinol (Zyloprim) first marketed in 1963, is not an anti-inflammatory drug; instead, it inhibits the final steps of uric acid biosynthesis and therefore lowers serum uric acid levels, preventing the precipitation of an attack. - This drug is frequently used as a prophylactic to prevent gout. It is a drug of choice for patients with chronic tophaceous gout. - Allopurinol is also indicated for gout patients with renal impairment. - It is useful for patients who have renal obstructions caused by uric acid stones and for patients with blood disorders such as leukemia and polycythemia vera. Allopurinol Pharmacokinetics: - Eighty percent of allopurinol is absorbed from the GI tract. - Biosynthesis of uric acid occurs in the liver in pure form and active metabolites. - The half-life of the drug itself is 2 to 3 hours and 20 to 24 hours for its active metabolites. - The protein-binding percentage is unknown - Approximately 80% to 100% of allopurinol and its metabolites are excreted in the urine.
Pharmacodynamics: - Allopurinol inhibits the production of uric acid by inhibiting the enzyme xanthine oxidase, which is needed in the synthesis of uric acid. - Allopurinol also improves the solubility of uric acid. - Its onset of action occurs within 30 to 60 minutes; - its peak time averages 2 to 4 hours. - Allopurinol has a long duration of action. Alcohol, caffeine, and thiazide diuretics increase the uric acid level. - Use of ampicillin or amoxicillin with allopurinol increases the risk of rash formation. Allopurinol can increase the effect of warfarin (Coumadin) and oral hypoglycemic drugs. Christine Marie U. Budlao Block 262 (CCC)
- Uricosurics - Uricosurics Increase the rate of uric acid excretion by inhibiting its reabsorption. These drugs are effective in alleviating chronic gout, but they should not be used during acute attacks. 1. Probenecid (Benemid) is a uricosuric that has been available since 1945. It blocks the reabsorption of uric acid and promotes its excretion. Probenecid can be taken with colchicine. - To begin initial therapy for relieving symptoms of gout and inhibiting uric acid reabsorption, small doses of colchicine should be given before adding probenecid. If gastric irritation occurs, probenecid should be taken with meals. - It has an average half-life of 8 to 10 hours and is 85% - 95% protein-bound. - Another uricosuric is sulfinpyrazone (Anturane). This drug is a metabolite of phenylbutazone and is more potent than probenecid. - Sulfinpyrazone should be taken with meals or with antacids to prevent gastric irritation. Christine Marie U. Budlao Block 262 (CCC)
Side effects and adverse reactions for antigout drugs:
flushed skin, sore gums, and headache. Kidney stones result from uric acid. Blood dyscrasias occur rarely. - could be prevented by increasing water intake and maintaining a urine pH above 6. - Aspirin use should be avoided because it causes uric acid retention. Christine Marie U. Budlao Block 262 (CCC)
