Medical Pharmacology 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

• 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 and 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

      • Eental 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

• Clinical Uses 

  • 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

• Adverse Effects: aspirin

  •  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

      • Recal 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 and 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

  • Ensure 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

Primary Reference: Katzung, B. G. and Furst, D. E. Nonsteroidal Anti-Inflammatory Drugs; Disease-Modifying Antirheumatic Drugs; Nonopioid Analgesics; Drugs Used in Gout, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 578-602.

Lipsky, P.E. Rheumatoid Arthritis, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1880-1888.Agudelo, C.A.

Gout in Medicine for the Practicing Physician, Fourth edition, (Hurst, J. Willis, editor in chief) Appleton and Lange, 1996, pp 223-226.