Inflammation and Pain Management

• The following notes cover anti-inflammatory, antipyretic, and analgesic agents.

Objectives

• Describe normal and abnormal inflammatory pathways.
• Understand the utility of Disease-Modifying Anti-Rheumatic Drugs (DMARDs) in treating autoimmune disease.
• Describe the cyclooxygenase pathway and the physiologic role of prostaglandins in fever, pain, and inflammation.
• Discuss the mechanisms of action, adverse effects, and pertinent drug-drug interactions for methotrexate, NSAIDs, COX-2 inhibitors, salicylates (including aspirin), acetaminophen, and their respective toxicities.

What is Inflammation?

• A normal body response that occurs in response to infection (viral/bacterial/fungal), physical trauma/injury, and noxious chemicals.
• The goal of inflammation is to prevent damage from invading organisms, set the stage for tissue repair, and remove toxins.
• Bacteria and pathogens enter the wound when infected.
• Platelets from blood release blood clotting proteins near the wound site.
• Mast cells secrete factors that promote vasodilation and vascular constriction
• Increased delivery of blood, plasma, and cells to the injured area occurs.
• Neutrophils secrete factors that kill and degrade pathogens.
• Neutrophils and macrophages remove pathogens by phagocytosis.
• Macrophages secrete hormones called cytokines that attract immune cells to the site for activation involved in tissue repair.
• The inflammatory response continues until the foreign material is eliminated and the wound is repaired.

Inflammatory Response Complexities

• Involves the immune system and agents like prostaglandins, bradykinin, histamine, and chemotactic factors.
• The inflammatory process subsides once healing is complete.

Prostaglandin Synthesis

• Prostaglandins are produced by almost all cells in the body.
• Prostaglandins are derived from unsaturated fatty acids present in cell membranes.
• Functions as "local hormones"
• Prostaglandins work locally
• Endocrine glands produce "traditional hormones," which, although produced locally can act at distant sites.
• Prostaglandins are derived from arachidonic acid (in the phospholipid bilayer) and are components of the cell membrane phospholipid.
• Prostaglandins are proinflammatory.
• In response to inflammatory stimuli, phospholipase A2 separates arachidonic acid from plasma phospholipids.
• Phospholipase A2 is inhibited by steroids "anti-inflammatories"

Arachidonic Acid Pathways

• Arachidonic acid is pro-inflammatory.
• Once freed from the cell membrane can follow one of two pathways to cause pain and inflammation with swelling.
• Lipoxygenase: involves allergies, mast cells & immune responses.
• Leukotrienes form from this pathway.
• Cyclooxygenase.
• Prostaglandins, thromboxanes (procoagulant), and prostacyclines (anticoagulant) form from this pathway.

Cyclooxygenase Enzyme Isoforms

• Two isoforms of cyclooxygenase enzyme exist.
• Cyclooxygenase 1 (COX-1) relates to gastric and platelet function.
• Cyclooxygenase 2 (COX-2) relates to pain inflammation and swelling.
• COX-1 provides gastric protection and is present in platelets.
• Different binding sites present in COX 1 and COX 2 allow for selective targeting.

Cyclooxygenase 1 (COX-1) Function

• Produces gastric secretion and mucous.
• Provides gastrointestinal protection.
• Functions in platelet activity.
• Maintains vascular homeostasis.
• Involved in reproductive and kidney function.
• Causes pain, fever, and inflammation.

Cyclooxygenase 2 (COX-2) Function

• Causes pain and fever.
• Involved in inflammation and bone formation.

Vascular Homeostasis: Cyclooxygenase 1 (COX-1)

• Affects Thromboxane A2.
• Responsible for the production of prostacyclin (PGI2, a prostaglandin) and vascular endothelium.
• Prostacyclin is an anticoagulant since it keeps platelets inactive.

Thromboxane A2 (TX A2)

• Thromboxane A2 is platelet-produced
• Thromboxane A2 is a procoagulant, which turns on platelets.

Prostacyclin

• Keeps platelets inactive
• Prevents platelet aggregation
• Promotes vasodilation

Thromboxane A2

• Activates platelets.
• Recruits platelets to the site of injury.
• Promotes vasoconstriction

Gastric Protection

• Prostacyclin (PGI2) inhibits gastric acid secretion.
• PG2 and PGF2a stimulate the production of protective mucus in the small intestine and stomach.

Cyclooxygenase 2 (COX-2)

• Responsible for Prostaglandin E2 production.
• Prostaglandin E2 is responsible for temperature regulation, pain, inflammation, bone healing, and vasodilation.

Combined COX 1 and COX 2 Impact

• Both impact pain, fever, and inflammation.

Only Cyclooxygenase 1 (COX-1) Impact

• Gastrointestinal tract protection, platelet function, and vascular homeostasis.

Prostaglandins and Arachidonic Metabolism

• In inflammatory stimuli, arachidonic acid is esterified in the membrane phospholipid and uses phospholipase A₂.
• Corticosteroids regulate them.
• Aspirin is mainly used for stroke patients to prevent strokes or heart attacks.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

• NSAIDs are named as such to distinguish them as anti-inflammatories that are not steroids.
• Steroids like prednisone exert powerful anti-inflammatory actions.
• NSAIDs have weaker anti-inflammatory actions, are more suitable for long-term therapy, and have fewer toxic effects

NSAIDs Mechanism of Action

• Competitive cyclooxygenase inhibitors with the exception of aspirin.
• Blocks the hydrophobic channel by which the substrate, arachidonic acid, accesses the active enzyme site.
• NSAIDs cause anti-inflammatory, analgesia, and anti-pyrexia reactions.

NSAIDs Properties: Anti-Inflammatory

• COX inhibition decreases the formation of prostaglandins.
• NSAIDs act as first-line drugs for inflammation and pain for rheumatic and non-rheumatic diseases.
• NSAIDs alone do not significantly reverse the progress of rheumatic diseases.
• Treatment of chronic inflammation requires higher dosages.
• Increasing the dose means more adverse events are likely.

NSAIDs Properties: Analgesia

• COX-2 inhibition thought to be responsible for analgesia and release of pain.
• PGE2 sensitizes nerve endings to actions of chemomediators (bradykinin, histamine, etc.) released by the inflammatory process.
• PGE2 and PGI2 are the most important prostaglandins involved in pain.
• NSAIDs can inhibit production of PGE2 and PGI2
• NSAIDs have comparable efficacy.
• NSAIDs work best for pain of muscular, bone, and vascular origin.
• NSAIDs are not helpful with visceral pain.

NSAIDs Properties: Fever (Antipyrexia)

• PGE2 synthesis leads to an elevated set point of the anterior hypothalamus thermoregulatory center.
• NSAIDs inhibit PGE2 synthesis and release.
• Increased heat dissipation as a result of peripheral vasodilation and sweating also occurs.
• NSAIDs "reset" the thermostat in the thermoregulatory system.
• NSAIDs have little effect on normal body temperature.

NSAIDs Classification

• Salicylates: Aspirin
• Propionic acids: Ibuprofen (Motrin, Advil), Ketoprofen (Orudis), Naproxen (Aleve, Naprosyn), Oxaprozin (Daypro)
• Enolic acids (oxicam class): Meloxicam (Mobic), Piroxicam (Feldene)
• Acetic acids: Diclofenac (Voltaren, Cataflam), Etodolac (Lodine), Indomethacin (Indocin), Ketorolac (Toradol), Nabumetone (Relafen), Sulindac (Clinoril)
• Fenamic acids: Mefenamic acid (Ponstel)

NSAIDs Pharmacokinetics

• Nearly complete gastrointestinal absorption.
• Absorbed fairly rapidly after administration.
• Food reduces rate but not extent of absorption.
• Extensive protein binding happens.
• Most NSAIDs are metabolized by the liver.
• Excreted renally

NSAIDs Pharmacokinetics Continued

• Variable half lives occur.
• Short (< 6 hours) include diclofenac, ketoprofen, ibuprofen, and indomethacin
• Long (> 10 hours) include naproxen, sulindac, nabumetone, and piroxicam

NSAIDs Adverse Effects

• Can cause nausea, vomiting, gastrointestinal distress, peptic ulceration, and bleeding in nature.
• Concomitant use of H2 receptor blockers or PPIs may help to prevent NSAID effects.
• Take with food or milk to make symptoms more tolerable.
• Can cause headache, dizziness, and drowsiness.
• Elevated liver function tests are a risk
• Affects platelet aggregation, leading to increased bleeding risk and stops platelets from sticking together.

NSAIDs Adverse Effects Continued

• Inhibition of vasodilation prostaglandins can cause nephrotoxicity, decreased renal blood flow, and GFR.
• May cause tissue injury leads to retention of sodium and water causing edema, high blood pressure, increased creatinine, and hyperkalemia
• Can cause hypersensitivity reactions (rash, bronchospasm); especially with asthmatics.

COX-2 Inhibitors

• Are unique in their selectivity and only target COX-2 .
• Inhibit COX 2 while saving COX 1 unaffected.
• Cause less gastrointestinal bleeding and dyspepsia.
• Have no effect on platelet function.
• May increase the risk of cardiovascular thrombotic events including MI and stroke, even though it does affect platelets.
• Pose a risk with all agents with higher COX-2 selectivity.
• Celecoxib (Celebrex) is contraindicated in patients with sulfa allergies

COX-2 Agents

• Agents include celecoxib (Celebrex) and meloxicam (Mobic).
• Rofecoxib (Vioxx) and valdecoxib (Bextra) have been removed from the market.
• Those drugs doubled the incidence of MI and CVA in patients using them.
• Commonly indicated for rheumatoid arthritis, osteoarthritis, and acute or musculokeletal pain.

Aspirin

• Aspirin lacks a significant COX-2 effect.
• It works better as an antiplatelet than as an analgesic or anti-inflammatory.

Aspirin (Acetylsalicylic Acid; ASA)

• Irreversibly inhibits cyclooxygenase (COX-1) at low doses.
• Decreases thromboxane A2 production.
• Suppression lasts the life of the platelet.
• Effect is related to the dose.
• Anti-inflammatory only at high doses.

Aspirin: Adverse Effects

• Has a higher relative specificity for COX-1, raising the risk of Gl events.
• Gastrointestinal adverse effects are most common.
• Aspirin decreases mucus secretion; effects worsen especially in high doses.
• Can cause nausea, heartburn, dose-related GI bleeding, and ulcer bleeding/gastric perforation.
• Can co-administer ASA with a proton pump inhibitor to reduce GI complications.
  • Example medicines are omeprazole (Prilosec), esomeprazole (Nexium), and lansoprazole (Prevacid).
• Enteric-coated ASA decreased the effect on Gl tract however, this may impact its function as an antiplatelet.

Aspirin: Adverse Effects Continued

• Inhibits platelet aggregation and clot formation, causing prolonged bleeding time and bleeding risk.
• Instruct patients to hold it one week prior to surgery.
• The effect is irreversible for life of the platelet.
• Exercise caution if combining ASA with NSAIDs.
• NSAIDs have a greater affinity for COX-1; aspirin's protective effects may be antagonized.

Aspirin: Hypersensitivity Effects

• Bronchospasm or hypersensitivity are uncommon overall but more common in patients with asthma, nasal polyps, and recurrent rhinitis.
• Patients can develop rash, bronchospasm, rhinitis, edema, and even anaphylaxis with shock.

Aspirin: Reye's Syndrome

• Aspirin is contraindicated in children (<19 years old) with viral syndromes due to the increased risk of Reye's syndrome.
• Reye's Syndrome is rapidly progressive.
• Liver failure, cerebral edema, and death occur.
• There is a 35% mortality rate.

Aspirin: Clinical Application as Anti-Platelet Agent

• Prevents clots.
• Prevents them from occurring again, acting in secondary and primary prevention.
• Low doses (75-160mg/day) reduce the risk of repeat myocardial infarction (MI), repeat cerebrovascular accidents (CVA, ischemic stroke), or stent thrombosis.
• High doses (160-325 mg/day) are used in patients with acute Ml to limit the extent of heart muscle damage.
• Primary prevention Adults 40-59 years with greater than 10% ASCVD risk.
• Adults older than 60 years of age are no longer recommended it.

Salicylate Toxicity

• "Salicylism" describes relatively mild toxicity.
• It is a dose dependent constellation of symptoms.
• May occur in some patients with the chronic use of large doses of aspirin and salicylates.
• Earliest signs include nausea, tinnitus (ringing in the ears), vomiting, diaphoresis, and sensorineural hearing loss
• Possible effects include vertigo, hyperventilation, tachycardia, and hyperactivity"

Salicylate Poisoning

• Can cause tinnitus, nausea, vomiting, lethargy, and excitability.
• Hyperventilation leads to respiratory alkalosis.
• Severe toxicity leads to metabolic acidosis and seizures.
• Toxic levels of salicylates include: 12 adult aspirin or 48 baby aspirin for a child.

Acute Salicylate Poisoning

• With therapeutic dosing, metabolism follows first-order kinetics.
• At increasing doses, metabolism is saturated, and elimination follows follows zero-order kinetics .
  • Half-life rises to 30 hours.
  • Greater-than-expected increases in serum and tissue concentrations take form.
• Salicylic acid (HS) exists in charged (deprotonated, sal-) and uncharged forms.
• Uncharged molecules (HS) can move easily across cellular barriers.
  • Metabolic acidosis drives the equilibrium towards the right, increasing plasma concentration of HS.
• diffusion across the blood-brain barrier causes CNS effects.

Signs and Symptoms

• Hallmarks of acute salicylate overdose include:
  • Hyperpnea (increased depth of breathing)
  • Tachypnea
  • Metabolic acidosis
  • Tachycardia
• Greater intoxication may cause mental changes, a coma, and death.
• Hyperthermia can be a sign severe toxicity.

Management

• Goals of treatment include correcting fluid and electrolyte imbalances and helping the patient enhance excretion.
• Increase systemic pH (alkalinization) by administering sodium bicarbonate.
  • Alkalinization "traps" salicylate anions in the blood and within renal tubule and facilitates excretion and limits diffusion into the CNS

N-Acetyl-P-Aminophenol (APAP) or Acetaminophen (Tylenol

• Acetaminophen treats both pain and fever, but it falls short in treating inflammation.
• Considered a weak inhibitor of prostaglandin synthesis both centrally and peripherally.
• Inhibits prostaglandin synthesis in the CNS.
• Analgesia can be achieved by blocking pain impulse generation and promoting antipyresis-Inhibition of hypothalamic heat-regulation.
• No anti-inflammatory or antiplatelet effects are present
• Less effect on COX in periphery due to inactivation leading to weak anti-inflammatory effects.

Acetaminophen Pharmacokinetics

• Can be given orally or via IV.
• Has an effect on analgesia in 5 - 10 minutes.
• Has an antipyretic effect within 30 minutes.
• Rectal formulations exist.
• Duration of effect is 4-6 hours.

Acetaminophen Pharmacokinetics continued

• Is primarily absorbed in the small intestine.
• Possesses many different formulations all with their own onset of action.
• Primarily goes through hepatic metabolism and is predominantly excreted in urine as a conjugated metabolite.
• Most acetaminophen is conjugated in the liver to create inactive glucuronidated or sulfated metabolites.
• Small portion is hydroxylated and forms N-Acetyl-p-benzoquinoneimine (NAPQI).

Reactive Metabolite

• Able to be handled at normal doses but no at high doses.
• NAPQI normally reacts with glutathione produced by the liver making it inactive.
• At high doses, glutathione is unable to keep up.
• NAPQI reacts with sulfhydryl groups leading to liver damage.

Maximum Dosage

• Maximum dose: one gram every 4 hours and no more than 4 grams every 24 hours for adults.
• Some medical experts recommend closer to 3 grams.

Acetaminophen Overdose

• One of the most common causes of OTC drug poisoning in the US.
• Causes about 300 deaths per year.
• 50/50 accidental versus intentional overdose.
• Many OTC drugs have acetaminophen in them.
• Leading cause of drug-induced liver failure in the US.

Acetaminophen Overdose: Symptoms of Toxicity

• Phase 1 occurs 0-24 hours after consumption: symptoms include nausea, vomiting, and general malaise or are asymptomatic.
• Phase 2 occurs 24-72 hours after consumption: symptoms include Right upper quadrant pain, elevated liver enzymes, and prolonged PT.
• Phase 3 occurs 72-96 hours after consumption: symptoms include Hepatic necrosis, encephalopathy, coagulopathy, renal failure.
• Phase 4 occurs 4 days-2 weeks after consumption: symptoms include irreversible damage or a complete hepatic dysfunction resolution

Acute Acetaminophen Overdose Nomogram

• Is used to measure acetaminophen plasma concentration and time after acetaminophen ingestion.
• Estimating probability of hepatotoxicity and whether acetylcysteine therapy should be administered are determined.

Acute Acetaminophen Overdose Treatment

• Uses N-Acetylcysteine*(NAC).
• Reduces extent of liver injury following acetaminophen overdose.

NAC Mechanism

• Maintains or restores glutathione levels.
• Acts as an substrate for conjugation of NAPQI.
• Is most effective when given early, within 8 hours of the ingestion.

What is Inflammation: Chronic

• Not all inflammation is temporary.
• Not all causes of chronic inflammation are the same.
• Can be triggered from allergic reactions, chemical irritants, infection, trauma, or burns.
• Can result in cardiovascular disease, neurological disease, autoimmune disease, Rheumatoid Arthritis, Cancer Lupus, Fibromyalgia, or Chronic Fatigue Syndrome

Chronic Inflammation

• Sometimes the immune system can be triggered even when there is no injury or insult.
• Autoimmune diseases are a collection of disorders where the body is being damaged by its own immune system.
• Autoimmune disorders require a combination of anti-inflammatory AND immunosuppressive agents.
• Reduces inflammation, or halts/slows progression.

Autoimmune Diseases Breakdown

• Affects Bone, Blood, Brain GI Tract, Lungs, Muscles Nerves, Skin or Thyroids
• There exist over 100 different types of autoimmune disorders.
• Disease-modifying anti-rheumatic drugs (DMARDs) combat autoimmune diseases.
• Medications used used in combination with anti-inflammatory medications
• Slow disease progression.
• Prevents further tissue damage.
• Induce remission.
• Includes both traditional and biological forms.

Traditional DMARDs

• Includes Methotrexate, Hydroxychloroquine, Leflunomide, Sulfasalazine, and Glucocorticoids.

Bioligic DMARDs

• adalimumab (humira), etanercept (Enbrel, rituximab, certolizumab (cimzia), golimumab (simponi aria), infliximab (remicade), abatacept (orencia)

Methotrexate for Autoimmune Diseases

• Folate acid antagonist that inhibits cytokine production and purine nucleotide biosynthesis, rendering it immunosuppressive and anti-inflammatory.
• It is a Mainstay of treatment in Rheumatoid arthritis and other autoimmune diseases and be combined with other agents.
• Possible side effects are mucosal ulceration, nausea, cytopenia (low white blood cell counts), and liver function test elevations.
• Is contraindicated in pregnancy because pregnancy needs folic acid for the neural tube development.