Inflammation Page 1

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Inflammation: Overview Three Phases Acute Inflammation Immune Response Chronic Inflammation Mediators Rheumatoid Arthritis Clinical Characteristics Cellular Damage Released Active Compounds Prostaglandins cyclooxygenase isozyme COXII Celecoxib (Celebrex) Leukotrienes Effects Chemotactic Vascular Pulmonary Therapeutic Approaches Goals Pain Relief Drug Categories Nonsteroidal Antiinflammatory Drugs Aspirin and other Salicylates Shared Properties Chemistry/Pharmacokinetics--aspirin/salicylates Salicylic acid; acetylsalicyclic acid Aspirin Excretion Pharmacodynamics Mechanism of Action Antiinflammatory Effects Analgesic Effects Antipyretic Effects Fever associated with infection Effect on Platelets Clinical Uses Analgesia/Antiinflammatory Effects Other Clinical Uses Adverse Effects Gastrointestinal Side Effects GI Upset Gastric Bleeding Central Nervous System Other Adverse Effects Aspirin Overdosage Drug-Drug Interactions	Nonacetylated Salicylates Drug List Properties Diflusnisal Properties Clinical Uses Other Nonsteroidal Antiinflammatory Drugs Overview Chemistry Drug Classes: Examples Pharmacodynamics: NSAIDS Mechanism of Inflammation Reduction:NSAIDs Properties: NSAIDS Pharmacokinetics: NSAIDS Ibuprofen Properties Contraindications Side-Effects Naproxen & Fenoprofen Properties Naproxin Fenoprofen Adverse Effects Flubiprofen Properties Clinical Use Ketoprofen Properties Clinical Use Oxaprozin Properties Diclofenac Properties Clinical Use Sulindac Properties Clinical Use Tolmetin Properties Etodolac Properties Nabumetone Properties Meclofenamate Properties Piroxicam Properties Clinical use Menu II

Overview: Inflammation

Inflammation: Three Phases --
- Acute inflammation
  - initial response to injury
  - mediators: autacoids release
    - histamine
    - serotonin
    - bradykinin
    - prostaglandins
    - leukotrienes
  - precedes immune response development

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Immune response
- activation of immune cells and responds to antigenic substances/ organisms
- acute or chronic inflammatory responses
- Inflammation may be beneficial or harmful (chronic)

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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
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- 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.
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- Leukotrienes Effects:
  - Chemotactic:
    - eosinophils
    - neutrophils
    - macrophages
  - Vascular permeability changes
  - Bronchoconstriction

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Therapeutic approaches

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

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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)

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Nonsteroidal Anti-inflammatory Drugs

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

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Aspirin and some Nonsteroidal Anti-inflammatory Agents
aspirin	salicylate	apazone	diclofenac
diflusnisal	etodolac	fenoprofen	flubiprofen
ibuprofen	indomethacin	ketoprofen	ketorolac
oxaprozin	meclofenamate	nabumetone (pro-drug)	naproxen

piroxicam

sulindac

tolmetin

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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
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- 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

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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
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- 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
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- 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
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- 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
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- 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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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

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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

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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
  - fecal blood loss: slightly increased with aspirin (normal one ml® four mls)
  - Management:
    - appropriate buffering (food; antacids)

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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

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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

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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

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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

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