NURS 220: Anti-inflammatory RX Review

Inflammation Overview

• Inflammation occurs with any type of cell injury, serving to destroy, dilute, or wall off (sequester) both the injurious agent and the injured tissue.

• It is mediated by endogenous compounds, including:

  • Proteins of the complement system

  • Histamine

  • Serotonin

  • Bradykinin

  • Leukotrienes

  • Prostaglandins

Arachidonic Acid Pathway

• Arachidonic acid is oxygenated and transformed into various products that mediate or modulate inflammatory reactions via two primary pathways:

  • Leukotriene pathway (Lipoxygenase):

    • Leads to vasoconstriction and increased vascular permeability, contributing to inflammation.

  • Prostaglandin pathway (Cyclooxygenase, COX-1 & COX-2):

    • COX-1: maintains gi mucosam as well as inflamatory repsonse

    • COX-2 Primary role is inflamation repsonse

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

• Definition: A large and chemically diverse group of drugs.

• Mechanisms of Action:

  • Inhibition of the leukotriene pathway, prostaglandin pathway, or both.

  • Blocking the chemical activity of the cyclooxygenase (COX) enzyme.

• Types of NSAIDs (by COX Selectivity):

  • Non-selective COX Inhibitors: Inhibit both COX-1 and COX-2 enzymes. They offer anti-inflammatory, analgesic, and antipyretic effects but also carry GI and renal side effects due to COX-1 inhibition. Examples include Ibuprofen, Naproxen, and traditional aspirin doses.

  • COX-2 Selective Inhibitors: Primarily inhibit COX-2, minimizing GI side effects by largely sparing COX-1. While effective for inflammation and pain, they are associated with an increased risk of cardiovascular thrombotic events due to an imbalance between PGI2 TXA2. Celecoxib is a prime example.

• Therapeutic Effects:

  • Analgesic (pain relief)

  • nti-inflammatory

  • Antipyretic (fever reduction)

  • Platelet inhibition

NSAID Side Effects and Underlying Mechanisms

• NSAIDs exert side effects primarily through COX inhibition, impacting various physiological systems:

  • Gastrointestinal (GI) Effects (linked to COX-1 inhibition):

    • COX-1 is responsible for producing $PGE_2$ (prostaglandin E2) which promotes gastric protection by increasing mucus secretion, bicarbonate production, and mucosal blood flow.

    • Inhibition of COX-1 by NSAIDs reduces these protective factors, leading to:

      • Peptic ulcers

      • GI bleeding

  • Renal Effects (linked to COX-1 and COX-2 inhibition):

    • $PGE<em>2$ and $PGI</em>2$ (prostacyclin) cause afferent arteriolar vasodilation, maintaining glomerular filtration rate (GFR).

    • These prostaglandins also promote sodium and water excretion.

    • COX inhibition by NSAIDs leads to:

      • Sodium and water retention

      • Hypertension

      • Hemodynamic acute kidney injury (e.g., reductions in creatinine clearance, acute tubular necrosis).

  • Cardiovascular Effects (linked to COX-1 and COX-2 inhibition):

    • Vascular (COX-2: $PGI_2$) promotes vasodilation and inhibits platelet aggregation.

    • Platelet (COX-1: $TXA_2$ - thromboxane) promotes vasoconstriction and platelet aggregation.

    • Differential inhibition can lead to imbalances:

      • COX-2 selective inhibitors might reduce $PGI<em>2$ without affecting $TXA</em>2$, potentially increasing risk of thrombotic events.

      • COX-1 inhibition (like with aspirin) inhibits $TXA_2$, preventing platelet aggregation.

    • Overall, NSAID use (except aspirin) has a Black Box Warning for increased risk of adverse cardiovascular thrombotic events, including fatal myocardial infarction (MI) and stroke.

    • NSAIDs may counteract the cardioprotective effects of aspirin.

Chemical Categories of NSAIDs

• Salicylates: Aspirin, Arthropan

• Acetic acid derivatives: Indocin (Indomethacin), Voltaren (Diclofenac), Toradol (Ketorolac)

• Cyclooxygenase-2 (COX-2) inhibitors: Celebrex (Celecoxib)

• Propionic acid derivatives: Ibuprofen (Motrin, Advil), Naproxen (Aleve)

• Enolic acid derivatives: Relafen (Nabumetone), Mobic (Meloxicam), Feldene (Piroxicam)

Specific NSAIDs and Related Information

Salicylates: Aspirin (ASA)

• Most common salicylate.

• Actions:

  • Inhibits synthesis of prostaglandin, reducing pain and fever.

  • Inhibitor of COX-1 receptors within platelets, inhibiting platelet aggregation (antithrombotic effect).

• Pharmacokinetics:

  • Metabolized in the liver, excreted in the urine.

  • Peak effect in $5-30$ minutes.

• Formulations: Oral (PO), Topical, Per Rectal (PR) suppositories.

• Dosing:

  • Maximum: $4000$ mg/day.

  • Pain/fever: $650$ mg every $4-6$ hours.

  • Antithrombotic: Varies (e.g., $325$ mg PO chewed at the first sign of MI).

• Antithrombotic Use:

  • Used in the treatment of MI and other thromboembolic disorders.

  • Shown to reduce cardiac death after MI.

  • Should be administered at the first sign of MI.

  • If not given pre-hospital, it's one of the first drugs in the ED if no contraindications.

• Contraindications:

  • Known allergy.

  • Bleeding abnormalities.

  • Impaired renal or hepatic function.

  • Avoid use in children and teenagers due to the risk of Reye’s Syndrome.

Salicylate Toxicity (Salicism)

• Symptoms:

  • Increased heart rate.

  • Tinnitus, hearing loss, dimness of vision.

  • Headache, dizziness, mental confusion, drowsiness.

  • Nausea, vomiting, diarrhea.

  • Sweating, thirst.

  • Hyperventilation.

  • Hypo- or hyperglycemia.

• Reye's Syndrome:

  • A serious and potentially fatal condition characterized by encephalopathy and liver damage.

  • High risk with aspirin use in children and teens, especially if recovering from viral illnesses (e.g., flu, chickenpox).

Acetic Acid Derivatives

• Indomethacin (Indocin):

  • Analgesic, anti-inflammatory, antirheumatic, and antipyretic properties.

  • Uses: Rheumatoid arthritis (RA), osteoarthritis (OA), acute bursitis or tendonitis, ankylosing spondylitis, acute gouty arthritis, patent ductus arteriosus (PDA), and treatment of preterm labor.

  • Available in oral, rectal, and intravenous forms.

• Ketorolac (Toradol):

  • Possesses some anti-inflammatory activity.

  • Used primarily for its powerful analgesic effects, comparable to narcotic drugs like morphine.

  • Indication: Short-term use (up to $5$ days) for moderate to severe acute pain.

  • Adverse effects: Renal impairment, edema, GI pain, dyspepsia, nausea.

COX-2 Inhibitors

• Celecoxib (Celebrex):

  • Currently the first and only remaining COX-2 inhibitor.

  • Indications: OA, RA, acute pain symptoms, ankylosing spondylitis, and primary dysmenorrhea.

  • Adverse effects: Headache, sinus irritation, diarrhea, fatigue, dizziness, lower extremity edema, and hypertension.

  • Has little effect on platelet function.

  • Contraindication: Not to be used in patients with known sulfa allergy.

Propionic Acid Derivatives

• Ibuprofen (Motrin, Advil):

  • Most commonly used NSAID.

  • Uses: Analgesic effects in the management of RA, OA, primary dysmenorrhea, gout, dental pain, musculoskeletal disorders, and antipyretic actions.

• Naproxen (Aleve):

  • Second most commonly used NSAID.

  • Generally has a better adverse effect profile than ibuprofen.

  • Fewer drug interactions with ACE inhibitors (used for hypertension).

Enolic Acid Derivatives

• Used to treat mild to moderate OA, RA, and gouty arthritis.

• Examples: Piroxicam (Feldene), Meloxicam (Mobic), Nabumetone (Relafen).

• Nabumetone is generally better tolerated gastrointestinally than some other NSAIDs.

General NSAID Contraindications and Black Box Warnings

• Black Box Warning: All NSAIDs (except aspirin) carry a black box warning regarding an increased risk of adverse cardiovascular thrombotic events, including fatal MI and stroke.

  • NSAIDs may counteract the cardioprotective effects of aspirin.

• Known drug allergy.

  • Patients with documented aspirin allergy must not receive NSAIDs.

• Conditions that place the patient at risk for bleeding:

  • Vitamin K deficiency.

  • Peptic ulcer disease.

  • Liver dysfunction.

• Pregnancy: Misoprostol (Cytotec), a synthetic prostaglandin used to reduce stomach ulcers caused by NSAIDs, is contraindicated in pregnancy as it may cause abortion, premature birth, or birth defects.

Other NSAID Adverse Effects (General)

• GI: Dyspepsia, heartburn, epigastric distress, nausea, GI bleeding, mucosal lesions (erosions or ulcerations).

  • Management: Misoprostol (Cytotec) may be prescribed to high-risk patients to reduce these dangerous effects.

• Renal: Reductions in creatinine clearance, acute tubular necrosis with renal failure.

• Cardiovascular: Noncardiogenic pulmonary edema (swelling).

• Other Systems: Altered hemostasis, hepatotoxicity, skin eruption, sensitivity reaction, tinnitus, hearing loss.

Nursing Implications for NSAIDs

• Do not give salicylates to children and teenagers due to the risk of Reye’s syndrome.

• NSAIDs generally cause GI distress; they are often better tolerated if taken with food, milk, or an antacid to avoid irritation.

• Inform patients that therapeutic effects may not be seen for $3$ to $4$ weeks.

• Educate patients about adverse effects and instruct them to notify prescribers if effects become severe or if bleeding or GI pain occurs.

• Advise patients to watch closely for any unusual bleeding, such as in the stool.

• Enteric-coated tablets should not be crushed or chewed.

• Monitor for therapeutic effects, which vary depending on the condition being treated (e.g., decrease in swelling, pain, stiffness, and tenderness of a joint or muscle area).

NSAID Interactions

• Serious interactions can occur when given with:

  • Anticoagulants (increased bleeding risk).

  • Aspirin (NSAIDs may reduce cardioprotective effects of aspirin).

  • Corticosteroids and other ulcerogenic drugs (increased GI ulceration/bleeding risk).

  • Protein-bound drugs (competition for binding sites, altered drug levels).

  • Diuretics and ACE inhibitors (reduced effectiveness of these drugs, increased risk of renal toxicity).

Norco vs. Vicodin and Acetaminophen

• Both Norco and Vicodin are combination drugs containing hydrocodone and acetaminophen (APAP).

• Vicodin: $5$mg hydrocodone / $500$mg APAP.

• Norco: $10$mg hydrocodone / $325$mg APAP.

• Norco has a higher proportion of hydrocodone to acetaminophen than Vicodin.

• Acetaminophen:

  • Does not reduce inflammation.

  • Has no effect on platelets.

  • Provides only analgesic (pain relief) effects.

  • Mechanism of action is unknown; metabolized in the liver.