N333: Inflammation, Anti-Inflammatories, and Antipyretics

Inflammation

• Definition: The body’s protective response to injury, infection, or harmful stimuli that serves to remove harmful agents and begin the healing process

  • Essential for healing but can cause damage if prolonged or excessive

  • Intensity of the inflammatory response is proportional to the extent of tissue injury

Key Features of Inflammation

Redness, heat, swelling, pain, loss of function (cardinal signs)

Goals of Inflammation

• Wall off the area of injury

• Prevent the spread of the injurious agent

• Bring the body’s defenses to the region under attack

Acute Inflammation

• Onset: Rapid (minutes to hours)

• Duration: Short (hours to days)

• Key Mediators: Neutrophils (early responders), histamine, prostaglandins

• Response: Redness (rubor), heat, swelling and pain due to vasodilation and increased vascular permeability

• Examples: Trauma, infections, burns

Chronic Inflammation

• Onset: Slow

• Duration: Long (months to years)

• Key Mediators: Lymphocytes, macrophages, cytokines, growth factors

• Response: Persistent tissue damage and fibrosis, leading to scar tissue formation

• Examples: Rheumatoid arthritis, inflammatory bowel disease

Vasodilation (Vascular Phase)

Histamine and bradykinin cause blood vessels to widen, increasing blood flow to the injury site. This delivers more oxygen and nutrients for healing

Vascular Permeability (Vascular Phase)

Endothelial cells in the blood vessels contract, allowing fluids, WBCs (including neutrophils, macrophages, and lymphocytes), platelets, and proteins to exit the bloodstream and enter the injured tissue

Edema Formation (Vascular Phase)

Fluid leaks out, causing swelling

Phagocytosis (Vascular Phase)

Fluid with macrophages engulf and remove debris and pathogens

Exudate (Vascular Phase)

Fluid containing WBCs and debris (purulent) or clear fluid (transudate)

Cellular Phase of Acute Inflammation

• Recruitment of Immune Cells

  • Chemotaxis: Chemical signals attract WBCs (neutrophils, macrophages) to the site

  • Margination: WBCs line up along blood vessel walls at the injury site

• Cytokines: Inflammatory mediates (e.g., TNF-alpha, lLs) amplify or dampen the response

• Acute Phase Proteins: Cytokine-stimulated proteins (e.g., fibrinogen, CRP) modulate inflammation

Cytokines

Signaling proteins, such as interleukins (e.g., IL-1, IL-6) and tumor necrosis factor-alpha (TNFa), that mediate and regulate immune and inflammatory responses

Histamine

Released by mast cells (and basophils to a lesser extent); causes vasodilation, increased vascular permeability, and smooth muscle contraction, leading to redness and swelling

Bradykinin

Peptide that induces vasodilation, increases vascular permeability, and causes pain

Prostaglandins

Produced from arachidonic acid by COX enzymes, contribute to vasodilation, fever, pain, and overall inflammation

Leukotrienes

Derived from arachidonic acid, promote inflammation, especially in allergic reactions and asthma

Platelet-Activating Factor (PAF)

Causes platelet aggregation, vasodilation, and increased vascular permeability

C-Reactive Protein (CRP)

A key marker of active inflammation; Elevated levels indicate ongoing inflammation (systemic marker)

Erythrocyte Sedimentation Rate (ESR)

Measures the rate at which red blood cells (RBCs) precipitate out of plasma. While useful, it is less specific than CRP

Leukocytosis

An increase in white blood cells (WBCs) released from the bone marrow, often a response to infection or inflammation

Thrombocytosis

An increase in platelets released from bone marrow, in response to inflammation

Neutrophils

• Also known as polymorphonuclear (PMN) cells

• Immature cells (bands, stabs, or segs) are typically elevated in bacterial infections

Lymphocytes

B cells, T cells, and natural killer (NK) cells; typically elevated in viral infections

Eosinophils

Increased levels are commonly seen in allergic reactions and asthma responses

Basophils

• Elevate during immune responses, releasing histamine and serotonin

• Help prevent blood clotting

Monocytes (Macrophages)

Activated 24-48 hours after injury; These cells utilize phagocytosis to eliminate foreign material and debris

Systemic Response to Acute Inflammation

• Classic Signs: Fever, Pain, Lethargy

• Associated Symptoms:

  • Malaise: General feeling of unwellness

  • Lymphadenopathy: Swollen lymph nodes due to immune activation

  • Anorexia: Loss of appetite from inflammatory cytokines

  • Sleepiness: Increased need for rest to support immune function

  • Anemia: Decreased red blood cells due to chronic inflammation

  • Weight Loss: Result of increased metabolism and loss of appetite

Febrile Response

• Fever in Inflammation: The body’s systemic response to inflammation, primarily to inhibit pathogen replication

• Fever Mechanism: Induced by pyrogens (e.g., IL-1, TNF-alpha) that stimulate the hypothalamus to increase the body temperature

• Clinical Manifestation: Temperature > 102°, tachycardia (HR > 90 bpm), tachypnea (RR > 20/min)

• Lab Findings: Increased WBC count (>12,000/mm³), acute-phase reactants (C-reactive protein and Erythrocyte Sedimentation Rate)

• In older adults, even a lower fever can be indicative of infection

Reye’s Syndrome

• Causes liver failure and encephalopathy

• Associated with salicylate use (e.g., aspirin) in child/adolescent infections (<18 years)

• Found in OTC products such as Pepto-Bismol and Kaopectate

  • Contraindicated under age 3

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• A class of medications used to reduce inflammation, pain, and fever

• Inhibit the cyclooxygenase (COX) enzymes, which are involved in the production of prostaglandins — lipid compounds that mediate inflammation, pain, and fever

Types of NSAIDs

• Nonselective NSAIDs

  • Salicylates — e.g., aspirin

  • Ibuprofen-like drugs — e.g., ibuprofen, naproxen

• Selective NSAIDs

  • Selective COX 2 inhibitors — e.g., celecoxib

COX-1

• Function: Produces prostaglandins that:

  • Protect the stomach lining by stimulating mucus production

  • Regulate renal blood flow

  • Promote platelet aggregation (important for blood clotting)

• Inhibition by NSAIDs:

  • Leads to GI side effects such as ulcers and bleeding

  • Inhibits platelet function, which can increase bleeding risk

COX-2

• Function: Produces prostaglandins that cause:

  • Pain and Fever

  • Increased vascular permeability during inflammation

  • Decreased platelet aggregation

• Inhibition by NSAIDs:

  • Reduces inflammation, pain, and fever with less GI toxicity compared to COX-1 inhibition

  • COX-2 selective inhibitors: Reduce inflammation with fewer GI side effects but have an increased cardiovascular risk

  • Causes blood clots

NSAID Indications

• Pain Relief: Headaches, muscle aches, dental pain, and minor injuries

• Inflammatory Conditions: Arthritis (osteoarthritis, rheumatoid arthritis), bursitis, tendonitis

• Fever Reduction: Fevers related to infection or inflammation

• Dysmenorrhea: Menstrual pain

• Cardiovascular Protection (Aspirin): Low-dose aspirin used for prevention of cardiovascular events (e.g., heart attack, stroke)

NSAID Adverse Effects

• GI irritation: Nausea, dyspepsia, GI bleeding (COX-1 inhibition)

• Kidney toxicity: From reduced renal blood flow

• Cardiovascular risk: Increased risk of heart attack and stroke (especially for COX-2 inhibitors)

• Hepatic Dysfunction: Elevated liver enzymes from long-term use

• Allergic Reactions

• Increase salt retention — don’t use with hypertension

Corticosteroids (Steroidal Anti-Inflammatory Drugs)

Powerful anti-inflammatory drugs that mimic adrenal hormones, used to treat inflammatory conditions by suppressing the immune system

• Mechanism of Action: Inhibit phospholipase A2, which leads to a decrease in the production of arachidonic acid and subsequent reduction of prostaglandins and leukotrienes

Steroid Indications

• Autoimmune disorders (e.g., lupus, rheumatoid arthritis)

• Allergic reactions (e.g., asthma, allergic rhinitis)

• Inflammatory conditions (e.g., inflammatory bowel disease, dermatitis)

• Acute conditions (e.g., anaphylaxis, shock)

• Post-surgical inflammation

Antipyretics

Medications that reduce fever by lowering the body’s set point temperature in the hypothalamus

• Inhibit prostaglandin synthesis in the brain

• Include acetaminophen, ibuprofen, naproxen, and aspirin