Anti-inflammatory & pain management agents Inflammation a reaction to tissue injury caused by the release of chemical mediators that

t trigger a vascular response and the migration of fluid and cells (leukocytes or WBC) to the injured site May not be the result of infection but might be cause by trauma, surgical interventions, extreme heat or cold and caustic chemical agents Chemical mediators HISTAMINE First mediator in the inflammatory process, causes dilation of the arterioles and increases capillary permeability Allows fluid to leave the capillaries and flow into the injured area KININS Also increase permeability and sensation of pain E.g. bradykinin PROSTAGLANDINS Causes an increase in vasodilation, capillary permeability, pain and fever Anti-inflammatory drugs i.e. non-steroidal anti-inflammatory drugs (NSAIDs) and steroids (cortisone) inhibit chemical mediators, decreasing inflammatory response

Tissue Injury

Vasoconstricction (momentary)

Release of chemical mediators (eg. Prostaglandins)

Dilated arterioles (vasodilation)

Increased capillary permeability

Pain

Fever

Redness: erythema (blood congestion)

Swelling: edema

Pain

Heat (vasodilation)

Loss of function

Pathophysiology 5 characteristics of inflammation(cardinal signs of inflammation) 1. Erythema (Redness) Blood accumulates in the area of tissue injury because of the release of the chemical mediators 2. Edema (Swelling) Plasma leaks into the interstitial tissue at the injury site Kinins dilate the arterioles increasing capillary permeability 3. Heat Caused by increased blood accumulation and may result from pyrogens (substances that produces fever) that interferes with thermo- regulating center in the hypothalamus 4. Pain Caused by tissue swelling and the release of chemical mediators 5. Loss of function Function is loss because of accumulation of fluid at the tissue site and pain which decreases mobility at the affected area Phases of inflammation Vascular phase Occurs 10-15 minutes after an injury Associated with vasodilation and increased capillary permeability Delayed phase Occurs when leukocytes infiltrate the inflamed tissue Cyclooxygenase (COX) Is an enzyme responsible for converting arachidonic acid into prostaglandins Causes inflammation and pain at the site of tissue injury 2 enzyme forms

COX-1 protects the stomach lining and regulates blood platelets, promoting blood clotting COX-2 triggers inflammation and pain at the injured site Anti-inflammatory agents Aka. Prostaglandin inhibitors Inhibit the biosynthesis of prostaglandin and affects the inflammatory process Uses: Relieves pain (analgesic) Reduces elevated body temperature (antipyretic) Inhibit platelet aggregation (anticoagulant) ASPIRIN is the oldest antiinflammatory drugs, the first to used as analgesic and antipyretic properties A. Nonsteroidal antiinflammatory drugs (NSAIDs) Primarily used as antiinflammatory agents to relieve inflammation and pain NSAIDs are more appropriate for reducing swelling, pain, and stiffness in joints Mode of action inhibits enzyme COX, needed for the biosynthesis of prostaglandins drug of choice for headaches and fever are aspirin, acetaminophen, and ibuprofen 8 groups of NSAIDs: 1. Salicylates 2. Para-chlorabenzoic acid derivatives 3. Phenylacetic derivatives 4. Propionic acid derivatives 5. Fenamates 6. Oxicams 7. Selective COX2 inhibitors The first six are now known as the first generation NSAIDs, and the COX2 inhibitors are called second generation NSAIDs a. Salicylates Aspirin as common family Aka. acetylsalicylic acid (ASA) Uses: It is an antiplatelet drug for clients with cardiac or cerebrovascular disorders (decrease platelet aggregation thus blood clotting is decreased) Prostaglandin inhibitor that decreases the inflammatory process Relief of mild to moderate pain Used to treat osteoarthritis and rheumatoid arthritis Rheumatoid arthritis (RA)

Osteoarthritis (OA)

Mode of action Inhibits the enzyme COX Inhibits COX-1 a. produces a desirable effect of decreasing platelet aggregation b. decreases protection to the stomach lining (stomach bleeding/ulcers) Inhibits COX-2 a. reduces pain, fever b. suppresses inflammation 2 enzyme forms of COX (Cyclooxygenase) COX-1 protects the stomach lining and regulates blood platelets, promoting blood clotting COX-2 triggers inflammation and pain at the injured site Pharmacokinetics well absorbed in the GI tract. can cause GI upset; therefore, it must be taken with water, milk, or food. should not be taken during the last trimester of pregnancy because it can cause premature closure of ductus arteriosus in the fetus Pharmacodynamics Aspirin inhibits prostaglandin synthesis by inhibiting COX-1 and COX-2, thus decreasing inflammation and pain Hypersensitivity/overdose to aspirin might cause: a. Tinnitus ringing in the ears b. vertigo (dizziness) c. bronchospasm

d. bleeding Medipren) Nursing considerations Monitor serum salicylate (aspirin) level when taking high doses normal therapeutic range is 12 to 50 mg/dl Observe client for signs of bleeding a. dark (tarry) stools b. bleeding gums c. petechiae (round red spots) d. ecchymosis (excessive bruising) Aspirin should not be taken with other NSAIDs decreases effect of other NSAIDs Must be taken with food to prevent GI discomfort

1. ibuprofen (Motrin, Advil, Nuprin, 2. naproxen (Naprosyn) 3. oxaprozin (Daypro) Pharmacokinetics Well absorbed from the GI tract Pharmacodynamics Inhibits prostaglandin synthesis alleviates inflammation and pain Adverse effects GI bleeding

b. Para-Chlorobenzoic Acid potent prostaglandin inhibitor used for rheumatoid arthritis, gouty arthritis, and osteoarthritis It is very irritating in the stomach and thus should be taken with food Prototype: 1. Indomethacin (Indocin) causes GI upset/ulceration 2. Sulindac (Clinoril) 3. tolmetin (Tolectin) produce less severe reactions than Indomethacin

E. Fenamates used for acute and chronic arthritic conditions Side effects: GI irritation - is a common side effect Edema Dizziness Pruritus Prototype: 1. Meclofenamate (Meclomen) 2. Mefanamic acid (Ponstel)

c. Phenylacetic acid Derivatives Has analgesic and antiinflammatory effect but no antipyretic effect Indicated for rheumatoid arthritis, osteoarthritis Prototype: 1. diclofenac sodium (Voltaren) - PO 2. ketorolac (Toradol) first injectable(IM/IV) NSAID, used for short term pain management (5 days or less) and for post-surgical pain

f. Oxicams Indicated for long term arthritic conditions such as rheumatoid arthritis and osteoarthritis Can cause gastric problems like ulceration and epigastric distress has long half-life which allows it to be taken only once daily, full clinical response may take 1 to 2 weeks Prototype: 1. Piroxicam (Feldene) 2. Meloxicam (Mobic) has some COX-2 selectivity

d. Propionic Acid Derivatives New group of NSAIDs Has aspirin-like but have stronger effects and creates less GI irritation Mode of action: Inhibits prostaglandin synthesis alleviates inflammation and pain Ibuprofen (Motrin) is the most widely used propionic acid NSAID Uses: 1. for mild to moderate pain 2. acute and chronic arthritis 3. reduces fever Prototype:

g. Selective COX2 Inhibitors Decrease inflammation and pain Does not cause GI distress Mode of action: Inhibits COX-2 but does not inhibit COX-1 Uses: Drug of choice for clients with severe arthritic conditions who need high doses of an antiinflammatory drug Relieves dysmenorrhea Prototype: Celecoxib (Celebrex) COX-2 inhibitor Nursing consideration (NSAIDs) Observe client for bleeding gums, petechiae, ecchymosis, black tarry tools Report GI discomfort

 Administer NSAIDs at mealtime or with food to prevent GI discomfort

1. azathioprine (Imuran) 2. cyclophosphamide (Cytoxan) 3. methotrexate (Mexate)

B. Corticosteroids Frequently used as antiinflammatory agents Control inflammation by suppressing or preventing many components of the inflammatory process at the injured site Not DOC for arthritis because of numerous SE Examples: prednisone, prednisolone, and dexamethasone

C. Antigout drugs GOUT - is an inflammatory condition that attacks joints, tendons, and other tissues Aka. gouty arthritis Characterized by accumulation of uric acid (hyperuricemia) and ineffective clearance of uric acid in the kidneys The most common site of tophi deposits is in joint of the big toe, hands and earlobes. 1. Colchicine First antiinflammatory drug drug used to treat gout Effective is alleviating symptoms of acute gout It should not be taken for patients with a severe renal, cardiac, or GI problem gastric irritation is a common problem (taken with food) Mode of action: Inhibits the migration of leukocytes to the inflamed site It does not inhibit uric acid synthesis and does not promote urid acid excretion 2. Uric Acid Inhibitor DOC for chronic gout Mode of action Inhibits the production of uric acid by inhibiting the enzyme (xanthine oxidase), needed in the synthesis of uric acid Lowers uric acid levels Prototype: Allopurinol (Elavil) 3. Uricosurics Effective in alleviating chronic gout, but should be used during acute attacks Treatment of hyperuricemia It should be taken with meals or antacids to prevent GI irritation Mode of action Increase the rate of uric acid excretion by inhibiting its reabsorption Prototype: 1. Probenecid (Benemid) 2. Sulfinpyrazone (Anturane) Nursing considerations (anti-gout) Fluid intake should be increased while taking anti-gout to promote uric acid secretion and renal calculi

C. Disease-Modifying Anti-rheumatic Drugs (DMARDs) DMRDs include gold drug therapy, immunosuppressive agents, and antimalarials It is more toxic than NSAIDs 1. Gold Aka. chrysotherapy or heavy metal therapy Prescribed to relieve inflammation and pain from Rheumatoid arthritis (RA) when NSAIDs and other measures are not effective Mode of action: depresses migration of leukocytes and suppresses prostaglandin activity Uses: Used to arrest rapid progression of RA and prevent deformities Used for palliative not curative effects for arthritis With injectable gold, results may take up to 2 months; oral dosages could take 3-6 months for clinical response Side effects: 25 to 45% of clients receiving gold therapy experience SE Dermatitis, urticaria, erythema, alopecia, stomatitis, pharyngitis, gastritis, blood dyscrasia Prototype: 1. auranofin (Ridaura) oral gold preparation 2. aurothioglucose (Solganal) - IM 3. gold sodium thiomalate (Myochrysine)- IM

2. Immunosuppressive Agents used to treat refractory rheumatoid arthritis primarily used to suppress cancer growth & proliferation might be used to suppress the inflammatory process of rheumatoid arthritis Prototype:

 Foods rich in purine e.g. organ meats, sardines, salted fish, alcohol (beer) must be avoided Taken with food to prevent GI distress Report GI symptoms such as gastric pain, N/V or diarrhea

Type of Pain

Definition

Drug Treatment

Cancer

Nonopioid & opioid analgesics Introduction Pain an unpleasant sensory and emotional experience related to tissue injury Pain threshold reflects the level if stimulus needed to create a painful sensation Pain tolerance amount of pain a person can endure without having interference with normal functioning Acute pain can be mild, moderate, severe with sudden onset and of short duration Chronic pain onset with a prolong duration Analgesics are prescribed for the relief of pain; the choice depends on the severity of pain. Mild to moderate pain of the skeletal muscles and joints nonopioid (aka. nonnarcotic) analgesics Moderate to severe pain in the smooth muscles, organs, and bones opioid (aka. Narcotic) analgesic Pathophysiology (PAIN)

Pain from pressure on nerves and organs, blockage to blood supply or metastasis to bone

NSAIDs and opioid drugs administered PO, transdermal, IM, IV

Somatic

Pain of skeletal muscle, ligaments and joints

Nonopioids: NSAIDs (aspirin, Motrin, Advil); also act as antiinflammatories and muscle relaxants Mild pain: nonopioid Moderate pain: combination of opioid and nonopioid analgesic

Superficial

Pain from surface areas such as skin and mucous membranes

Type of Pain

Definition

Drug Treatment

Vascular

Pain from vascular or perivascular tissues contributing to headaches or migraines Pain from smooth muscle and organs

Non-narcotic drugs

Type of Pain

Definition

Drug Treatment

Visceral

Narcotic

Acute

Pain occurs suddenly and responds to treatment.

Mild: Non-narcotic (acetaminophen, NSAIDs- aspirin, Motrin, Advil q6h) Moderate: Combination of nonnarcotic and narcotic (oxycodone 5mg & acetaminophen 325mg q4h) Severe: Narcotic (morphine 15mg q4h) Nonopioid drugs are suggested

A. Nonopioid (nonnarcotic) Analgesics Less potent than opioid analgesics Used for mild to moderate pain have antipyretic properties, antiinflammatory and antiplatelet effects Therapeutic use: dull, throbbing pain of headaches dysmenorrhea, Inflammation minor abrasions muscular aches and pain, mild to moderate arthritis. Prototype: 1. aspirin 2. Acetaminophen

Chronic

Pain persists for greater than 6 months and is difficult to treat or control

3. Ibuprofen 4. naproxen a. Nonsteroidal antiinflammatory drugs (NSAids) All NSAIDs have an analgesic, antipyretic, and antiinflammatory action Mode of action Inhibits biosynthesis of prostaglandin by cyclooxygenase (COX) enzyme COX1 and COX2 Inhibition of COX1 decreases protection to the stomach lining (stomach ulcer/bleeding) Inhibition of COX2 decreases inflammation and pain Example: Aspirin DOC for alleviating pain and inflammation in arthritic conditions ibuprofens (Advil, Midol IB, Motrin) naproxen(aleve) naproxen sodium (flanax) Adverse/Side effects: Aspirin is contraindicated to children younger than 12 years of age because of the danger of Reyes syndrome (neurologic problem associated with viral infections and the use of ASA) Gastric irritation common side effect Tinnitus, bronchospasm and rashes (aspirin) COX-2 inhibitors Developed to eliminate the GI side effects with aspirin and other NSAIDs do not cause gastric ulceration and have no effect on platelet function Allows stomach protection Example 1. Celecoxib (Celebrix) Another COX2 inhibitor, but not a true COX2 inhibitor: 1. meloxicam (Mobic) 2. nabumetone (Relafen) b. Acetaminophen a non-narcotic analgesic but is not an NSAID doesnt have the anti inflammatory effects of ASA or NSAIDs Mode of action: Inhibit (weaken) prostaglandin synthesis Inhibition of hypothalamic heat-regualiting center Therapeutic use: A popular nonprescription drug for the relief of pain, discomfort and fever in infants, children, adults and older adults Prototype:

Acetaminophen (Tylenol, Panadol, Tempra) - a safe, effective, analgesic and antipyretic drug used for muscular aches and pains. Pharmacokinetics well absorbed in the GI tract It has a short half-life so it could be administered q4H Large doses can be toxic to the liver Pharmacodynamics Acetaminophens weakly inhibits the prostaglandin synthesis, which decreases pain sensation Its onset of action is rapid, and the duration of action is 5 hours or less. Side effects Anorexia Nausea Vomiting Rash Adverse effects: Hypoglycemia Oliguria Rashes Blood dyscrasia life threatening hepatotoxicity

B. Opioid (Narcotic) Analgesics Aka. opioid agonists prescribed for moderate and severe pain Opium was used as early as 350 BC to relieve pain In 1803 a German pharmacist isolated morphine from opium. Codeine is another drug obtained from opium Opioid analgesics act mostly in the CNS, whereas non-opioid analgesics act on the PNS opioids not only suppress pain impulses but also suppress respiration and cough centers in the medulla of the brainstem. Most opioids have an antitussive (cough suppression) effect. a. Morphine a potent narcotic analgesic Mode of action: Depression of CNS Depression of pain impulses by binding with opiate receptors in the CNS Therapeutic use: It is effective against acute/severe pain from acute myocardial infarction and cancer Adverse reaction:

 respiratory depression - life threatening orthostatic hypotension Side effects: Nausea/vomiting Constipation (decreased peristalsis) Drowsiness Dizziness Sedation Cough suppression urinary retention Antidote: Naloxone (Narcan) opioid antagonist given for opioid overdose Pharmacokinetics Morphine may be taken orally. For severe pain, it is given through IV It has a short half-life. Morphine crosses the placenta and is present in a mothers breast milk Pharmacodynamics Morphine binds with the opiate receptor in the CNS. Rapid onset of action in IV. Slower in SC and IM Duration of action is 3-5 hours Nursing responsibilities Monitor VS to detect respiratory changes. Respiration of <10/mi indicate respiratory distress Record urine output because urinary retention is a SE (UO must be 600 ml/day) Check bowel sounds for decreased peristalsis (constipation) Nalaxone (Narcan) as an antidote to reverse respiratory depression Not to take alcohol or CNS depressant with morphine respiratory depression b. Mepiridine (Demerol) one of the first synthetic narcotics given for moderate to severe pain does not have the antitussive property of opium preparations Given as preoperative sedation, GI procedures Pharmacokinetics Given Orally, IM and IV It has a moderate half-life, therefore it can be administered several times a day at specified intervals. It is usually given IM especially for postoperative pain Pharmacodynamics

has a shorter duration of action than morphine It should not be taken with alcohol or sedative-hypnotics because the combination of these drugs causes an additive CNS depression. A major side effect is a decrease in BP Causes less constipation and urinary retention c. Codeine (sulfate, phosphate) Effective for mild to moderate pain Can be used with a nonopioid (acetaminophen) for pain relief Has antitussive effect Given orally, SC and IM C. Narcotic Agonist-Antagonists Medication in which an opioid antagonist (e.g. naloxone (Narcan)) is added to an opioid agonist to decreasing opioid abuse Given for moderate to severe pain Mode of action: Inhibition of pain impulses transmitted in the CNS by binding with opiate receptor and increasing pain threshold Adverse effect: Respiratory depression life threatening Hypotension tachyardia Prototype: Pentazocine (Talwin), butorphanol tartrate (Stadol) buprenorphine (Buprenex) nalbuphine HCl (Nubain) D. Narcotic Antagonists antidotes for overdoses of opioid analgesics have a higher affinity to the opiate receptor sites than the opioid being taken Mode of action: blocks the receptor site and displaces any opioid that would normally be at the receptor, thus inhibiting the opioid action Prototype: Naloxone (Narcan) - administered IM or IV Naltrexone HCl (ReVia) - administered orally by tablet or liquid. Nalmefene (Revex) Note: 1. Long quiz from anticholinergics to antiinflammatory agents, nextweek Wednesday at 4pm 2. Make up class nextweek Wednesday at 4pm