Chapter 41:  Anti-inflammatory Agents

Nonsteroidal Anti-Inflammatory Drugs; Disease-Modifying Antirheumatic Drugs; Nonopioid Analgesics; Drugs Used in Gout

• Inflammation: Three Phases --

  •  Acute inflammation

    • initial response to injury

    • mediators: autacoids release

      • histamine

      • serotonin

      • bradykinin

      • prostaglandins

      • leukotrienes

    • precedes immune response development

•  Immune response

  • activation of immune cells and responds to antigenic substances/ organisms

  • acute or chronic inflammatory responses

  • Inflammation may be beneficial or harmful (chronic)

•  Chronic inflammation

  • Mediators of chronic inflammation

    •  IL-1, IL-2, IL-3 (interleukins)

    •  GM-CSF (Granulocyte-Macrophage Colony Stimulating Factor)

    •  TNF-a (tumor necrosis factor alpha)

    •  Interferons

    •  PDGF (platelet-derived growth factor)

  • Example: clinical condition involving chronic inflammation:

    • Rheumatoid arthritis --

      • Clinical Characteristics:rheumatoid arthritis

        •  Pain

        •  Bone/cartilage destruction

        •  Significant disability

        •  Reduced lifespan

  • Cellular Damage associated with inflammation:

    1.  leukocytes release → lysosomal enzymes

    2.  precursors release →  arachidonic acid

    3.  eicosanoid synthesis  

  • Released Active Compounds:

    •  kinins, neuropeptides, histamine

    •  complement components, cytokines

    •  neutrophil membrane produces free radicals:

      • superoxide anion (from reduction of molecular oxygen) →  hydrogen peroxide; hydroxyl radicals

    •  agents interacting with arachidonic acid→  chemotactic factors→  inflammatory response continuation

  • Prostaglandin Effects:

    •  Varied: actions on blood vessels; nerve endings; cells involved in the inflammatory response

    •  cyclooxygenase isozyme (COX-II): catalyzes prostaglandin synthesis by cells involved in inflammation.

      • COX-II selective inhibition: advantageous in management of inflammation

        • Celecoxib (Celebrex) is an example of a nonsteroidal antiinflammatory drug that works as a result of prostaglandin synthesis inhibition (inhibition COX-II)

      • another cyclooxygenase isozyme (COX-I): catalyzes prostaglandin synthesis by other cells.

  • Leukotrienes Effects:

    •  Chemotactic:

      • eosinophils

      • neutrophils

      • macrophages

    •    Vascular permeability changes

    •  Bronchoconstriction

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• Goals:

  • Pain Relief

    • nonsteroidal antiinflammatory drugs: important role

    • most nonopioids (aspirin) -- anti-inflammatory effects

    • appropriate for chronic/acute management of inflammation

  • Reducing on-going tissue damage

• Drug Categories: Introduction

  • Nonsteroidal antiinflammatory drugs

  • Nonopioid analgesics (aspirin)

  • Glucocorticoids

    •  powerful anti-inflammatory action

    •   toxicities prevent use for chronic anti-inflammatory management

      • useful for control of acute exacerbations

  • Slow-acting antirheumatic drugs (SAARDs)

  • Disease-modifying antirheumatic drugs (DMARDs)

• Aspirin & Other Salicylates

  •  Shared Properties:

    • weak organic acids

    • inhibit prostaglandin biosynthesis

    • may decrease free radicals production

    • may decrease superoxide production

    • may alter cellular cAMP concentration

    • probably do not affect the disease course

• Chemistry/Pharmacokinetics--aspirin/salicylates

  • Salicylic acid; acetylsalicyclic acid

    • salicylic acid:simple organic acid; pKa 3.0

    • aspirin (acetylsalicyclic acid); pKa 3.5

    • equally effective: anti-inflammatory action

    •  analgesic: aspirin -- maybe more effective

    •  rapidly absorbed: stomach and upper small intestine

    • peak plasma salicylates level: 1-2 hours

    •  at stomach pH: salicylates --mainly nonionized, favoring absorption

    •  at higher gastric pH (3.5 or higher by buffering): less gastric irritation

  • Aspirin:

    • rapidly hydrolyzed →  acetic acid + salicylate, catalyzed by tissue/blood esterases

    •  Excretion:

      • most converted to water-soluble conjugates; renally cleared

      • saturated pathway: small increase in aspirin dose; significant ­ plasma levels

      • urine alkalinization ­ excretion of free salicylate

      • Lower dose aspirin (< 600 mg): first order elimination kinetics; half-life: 3--5 hours

      • Higher dose aspirin: zero-order (capacity-limited) and first-order mixture

      • Anti-inflammatory doses (> 4 grams per day), probably capacity-limited; half-life: > 12 hours

• Pharmacodynamics:

  • Mechanism of Action:aspirin

    •  inhibition of cyclooxygenase {prostaglandin synthase}

      • Prostaglandin synthase: catalyzes arachidonic acid →  endoperoxide compounds

    •  action of salicylate (cyclooxygenase inhibitor; oxygen radical scavenger)

    •  Aspirin (in certain doses):

      1. reduces prostaglandin formation

      2. reduces thromboxane A₂ formation

      3. does not affect leukotriene synthesis

      4. not a selective COX-II inhibitor

  • Anti-inflammatory Effects:aspirin

    •  reduced synthesis: eicosanoid mediators

    •  interference: kallikrein system mediators

      • inhibits granulocyte adherence to damaged vasculature

      • stabilizes lysosomes

      • inhibits polymorphonuclear leukocyte/macrophage migration to inflammation sites

  • Analgesic Effects:aspirin

    •  Effective for management of mild to moderate pain

    •  Pain may arise from:

      • musculature

      • dental work

      • vascular

      • postpartum conditions

      • arthritis

      • bursitis

    •  Sites of action:

      1. peripherally -- sites of inflammation

      2. subcortical sites

  • Antipyretic  Effects:aspirin

    •  "normal" temperature: slightly affected

    •  "elevated" temperature: reduced

    •  Mechanisms of Antipyretic Action:

      • vasodilation (superficial vessels): ­ heat dissipation

    • Fever associated with infection: mechanism

      1. Prostaglandin production in the CNS: induced by bacterial pyrogens

      2. Interleukin 1: produces a hypothalamic effect which increases temperature

         • Interleukin 1: produced by macrophages; released during inflammation; activates lymphocytes

         • Aspirin blocks:

           • pyrogen-induced prostaglandin production

           • CNS response to interleukin 1

  • Effects on Platelets:aspirin

    •  Reduced hemostasis;

    •  Mechanism of Action:

      • Inhibition of platelet aggregation because of thromboxane synthesis inhibition

    •  Aspirin: -- longer antiplatelet duration of effect compared to:

      • ticlopidine

      • dipyridamole

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•  Analgesia/Anti-inflammatory Effects

  • Commonly used for management of mild to moderate pain

  • Often sold in combination with other agents (combination agents -- not shown more effective or less toxic than aspirin monotherapy)

  •  Management of poisonings (overdosage) involving combinations: more difficult

  • Particular issues:

    • Phenacetin-aspirin combinations:

      • Phenacetin may cause interstitial nephritis (renal impairment)

    •  Aspirin -- Not Effective for :

      • management of severe visceral pain, e.g. -- acute abdomen, pericarditis, myocardial infarction (antiplatelet action may be useful), renal colic.

    •  Aspirin in combination with opioid analgesics: effective management of some cancer pain.

      • anti-inflammatory effects of aspirin act to enhance opioid analgesia

    •  High-dose Salicylates have significant anti-inflammatory properties making them useful in treatment of:

      • rheumatic fever

      • rheumatoid arthritis

      • other inflammatory joint diseases

• Other Clinical Uses:

  • Antipyretic Activity:

    •  Elevated Body Temperature: generally not a useful defense mechanism (exceptions: neurosyphilis, chronic brucellosis)

    •  Aspirin -- best drug for reducing fever if needed; and without contraindications present

  • Antiplatelet:

    •  reduce incidence of transient ischemic attacks (prophylaxis)

    •  reduce incidence of unstable angina in males (prophylaxis)

    •  may reduce frequency of coronary artery bypass graft thrombosis

    •  may reduce incidents of coronary artery thrombosis

•  Gastrointestinal Side Effects

  •  Gastric upset causes:

    1. gastric mucosal irritation (undissolved tablet)

    2. stomach absorption of nonionized salicylate

    3. inhibition of protective prostaglandins

       1. reduced/absent prostaglandin may make gastric mucosa more likely to be damaged

       2. misoprostol: decreased frequency to peptic ulceration recurrence in patients taking large NSAIDs dosages

  •  Gastric Bleeding:

    • Upper GI bleeding associated with aspirin: erosive gastritis

    • fecal blood loss: slightly increased with aspirin (normal one ml→  four mls)

    • Management:

      • appropriate buffering (food; antacids)

•   Central Nervous System Effects:

  • High doses: "Salicylism"

    • tinnitus

    • decreased hearing

    • vertigo

  • Higher doses: hyperpnea (increaset respiration rate)-- medullary effect

  • low toxic salicylate levels: initial respiratory alkalosis (due to increased ventilation)

    • accumulation of salicylic acid derivatives + respiratory depression →  acidosis

•   Other Adverse Effects:

  1. aspirin doses < 2 grams/day: ­ increase serum uric acid levels

  2. aspirin doses > 4 grams/day: ¯ decrease urate levels < 2.5 mg/dL

  3. mild, typically asymptomatic hepatitis--typically in patients with:

     • systemic lupus erythematosus

     • juvenile & adult rheumatoid arthritis

  4. reversible decrease in glomerular filtration rates (patients usually have underlying renal dysfunction)

  5.  Large doses: vascular dilation; depression of cardiac function

  6.  Hypersensitivity reactions: -- leukotriene-mediated

     • asthma patients

     • patients with nasal polyps

     • associated: bronchoconstrictions/shock

  7. Contraindications: hemophilia

  8. Not typically recommended: in pregnant women

  9.  Aspirin in children during/immediately after viral infection: associated with increased risk of Reye's syndrome: use acetaminophen

•  Aspirin Overdosage Toxicity

  •  gastric lavage

  •  if patient hyperthermic: alcohol sponges/ice packs

  •  manage acid-based abnormality

  •  insure high urine volume

  •  urine alkalinization (sodium bicarbonate infusion) promotes salicylate excretion

• Drug-Drug Interactions

  • Promote salicylate intoxication when ingested concurrently:

    • acetazolamide

    • ammonium chloride

  • increased bleeding: alcohol

  • Aspirin displaces drugs from protein binding sites:

    • tolbutamide

    • chlorpropamide

    • nonsteroidal antiinflammatory drugs

    • methotrexate

    • phenytoin

    • probenecid

  • aspirin reduces: spironolactone pharmacologic action

  • aspirin --penicillin G competition for tubular secretion

  • aspirin: inhibits uricosuric effect of:

    • probenecid

    • sulfinpyrazone