Nonsteroidal Anti-inflammatory Drugs: Safety, Toxicity, and Clinical Implications

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Nonsteroidal Anti-inflammatory Drugs Safety,
Toxicity, and Clinical Implications

• Brett A. Roth, MD, FACEP, FACMT

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The Need Epidemiology

• The most frequently prescribed agents in the
  world
• Used by 30-50 million persons daily
• 10-20 of persons gt65 yo have a current
  prescription
• 40 of elderly Medicaid patients received at
  least one NSAID prescription

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Uses

• Mild to Moderate Pain
• Inflammation
• Fever

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Classification

• Para-aminophenol derivatives
• Acetaminophen, Phenacetin, Acetanilide
• Salicylic acid derivatives
• Acetylsalicylic acid, diflunisal, salsalate, etc.
• Other Non-selective NSAIDs
• Ibuprofen, Indomethacin, Sulindac,
• COX-2 inhibitors
• Celecoxib, Rofecoxib, Meloxicam

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Overview

• Common denominator
• All NSAIDs inhibit cyclooxygenase (COX)
• Differences
• Anti-inflammatory effects
• COX selectivity
• Toxicity
• Cost
• Drugs interactions

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Mechanisms of Action

• Steroids
• Dec. production lipooxygenase / Cyclic
  Endoperoxides
• NSAIDs
• Dec. production prostaglandins/ prostacyclins/
  thromboxane
• LTRA
• Act directly on leukotriene pathway

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Toxicology Acetaminophen
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Acetaminophen Acute Toxicity

• Toxic dose
• Minimal hepatotoxic dose 7.5 g in adults gt150
  mg/kg body weight in children severe toxicity
  possible if dose gt20 g
• Mechanism
• Toxicity depends on metabolism to an active
  metabolite (NAPQI)
• Antidote
• N-acetylcysteine is universally effective if
  given within 8 hours
• Epidemiology
• 200 deaths/ yr in the US reported to AAPCC

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Acetaminophen Acute Toxicity
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APAP Acute Toxicity

• Clinical Implications
• Beware of the different products that may contain
  acetaminophen (analgesics, cold remedies,
  products for cramping)
• Check serum APAP levels on all pts with acute
  overdose
• Administer antidote within 10 hours prior to
  glutathione depletion if toxic

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APAP Susceptible Individuals

• APAP Hepatotoxicity in Alcoholics A Therapeutic
  Misadventure
• 25 cases accidental overdose.
• 17/24 reported taking doses
• that exceeded the maximum
• recommended dose of 4.0 gm/d
• Measurement of APAP levels
• not described for any patient
• Conclusion Alcoholics may be
• more susceptible to overdose

Seef et al, 1986 Ann Inter Med, 104 399-404
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APAP Susceptible Individuals

• Alcoholics
• 200 alcoholics admitted to Denver detoxification
  center
• 1 gm APAP vs. placebo for four doses x2 days
• Conclusion alcoholic patients treated maximal
  therapeutic daily doses of acetaminophen did not
  develop evidence of hepatoxicity

Kuffner E, et al Clin Tox 37 p 641 143
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APAP Susceptible Individuals

• Cirrhosis/ Hepatitis
• Limited data
• Two small studies
• Recommended doses were not associated with
  hepatotoxicity
• Down regulation of cytochrome p450
• Insufficient generation of reactive intermediate

Benson GD, Clin Pharmacol Ther 198333(1)
95-101 Jorup-Ronstrom, et al. Clin
Pharmacokinet 198611(3)250-6
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Chronic Liver Disease and Acetaminophen
Benson et al. Pilot study in six subjects with
advanced cirrhosis
Benson et al, Clin Phar Ther, 1983,33(1) 95-101
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Chronic Liver Disease and Acetaminophen
Benson et al .20 pts assigned to either 4.0 gm of
APAP daily or placebo for 13-d period.
Benson et al, Clin Phar Ther, 1983,33(1) 95-101
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APAP Toxicity Susceptible Individuals
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Acetaminophen Preparations

• Acetaminophen drops (Tylenol, Anacin-3,
  Liquiprin, Panadol, or Tempra)
• Strength 80 mg per dropper
• Acetaminophen syrup
• Strength 160 mg per 1.0 tsp (5.0 mL)
• Chewable acetaminophen
• Strength 80 mg tablets and 160 mg tablets
• Suppositories
• Strength 120 mg, 325 mg, and 650 mg

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APAP Chronic Toxicity

• Analgesic nephropathy syndrome
• Histopathology
• Papillary necrosis/ chronic interstitial
  nephritis
• Mechanism
• Repetitive daily ingestion of compound analgesic
  mixtures

Perneger et al. NEJM. 19943311675-1579 Sandler
et al. Ann Intern med 1991 115165-172
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APAP Renal Toxicity

• Analgesic nephropathy syndrome
• Acetaminophen may be involved but study results
  vary and most implicate phenacetin, and analgesic
  mixtures taken over years
• National Kidney Foundation still recommends APAP
  as the non-narcotic analgesic of choice for
  episodic use in patients with underlying renal
  disease
• Clinical Implication
• Supervise long-term analgesic use

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Salicylate Overdose

• Toxic dose
• 150-200 mg/kg produce mild toxicity
• 300-500 mg/kg produce severe intoxication
• Mechanism
• Uncoupling oxidative phosphorylation and
  interruption of glucose and fatty acid metabolism
• Antidote
• Sodium bicarbonate, multiple dose activated
  charcoal, hemodialysis

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Salicylate Overdose

• Clinical Manifestations
• Acute ingestion
• Mixed respiratory alkalemia and metabolic
  acidosis, coma seizures, hypoglycemia,
  hyperthermia, pulmonary edema
• Death cardiovascular collapse, CNS failure
• Chronic intoxication
• Young/ confused elderly, nonspecific
  presentation confusion, dehydration, metabolic
  acidosis. High mortality (up to 25), lower
  serum levels
• Death Cerebral and pulmonary edema

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Salicylates Acute Toxicity

• Anaphylaxis
• Clinical Scenario
• 25 of adult asthmatics with nasal polyps or
  chronic urticaria manifest an acute asthmatic
  attack minutes after NSAID exposure
• 2.5 cross-reactivity noted in patients allergic
  to tartrazine dyes
• Mechanism
• increased production of LTC4, LTD4, LTE4

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Salicylate Exposure/ Overdose
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NSAIDs Acute Toxicity

• Overdose
• Clinical manifestations N/V, metabolic acidosis,
  CNS and respiratory depression, acute renal
  failure, aseptic meningitis, hallucinations.
• Toxic Dose Generally large doses gt6 gms
• Villains Phenylbutazone and mefenamic acid are
  considered the most toxic due to their ability to
  provoke all the above symptoms, as well as
  seizures
• Mechanism of toxicity poorly understood

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NSAID Overdose
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NSAIDs GI Toxicity

• Prevalence of gastric and duodenal ulcers
• 9-22
• Bleeding, perforation, or obstruction
• 1/10 NSAID-induced peptic ulcer
• GI bleeding
• 35 of all peptic ulcer complications
• Most common serious ADE in US
• 10,000-20,000 deaths/year
• Economic implications
• 200,000-4000,000 hospitalizations each year in US
• gt 4 billion health care cost

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NSAIDs- Epidemiology
Singh G, et al. J Rheumatol 1999 26Suppl
2618-24.
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Mechanism of GI toxicity
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Risk Factors For NSAID-Mediated GI Bleeding
Piper et al. Ann Intern Med. 1991114735.Shorr
et al. Arch Intern Med. 19931531665. Silverstein
et al. Ann Intern Med. 1995123241.
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NSAIDs Age as a risk factor
Percent of NSAID users among patients
hospitalized with bleeding peptic ulcers
Somerville et al. Lancet 19861462-464
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• Partial selectivity GI toxicity

/

• Comparison of the toxicity of five NSAIDs at
  endoscopy
• with the COX-2/COX-1 inhibition ratios

Geis et al J Rheumatol 199118 suppl 28
11-4 Vane et al Imporoved NSAIDs. Boston, Mass
Kluwer publisher
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NSAIDs GI Toxicity
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Wolfe et al. NEJM1999, 30(24)1888-1899
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NSAIDs Renal Toxicity

• Epidemiology
• 90 drug-induced toxicity caused by
  aminoglycosides, contrast materials, or NSAIDs
  (15)
• 1-5 of patients taking NSAIDs develop a
  nephrotoxic syndrome
• 20 of NSAID using pts are considered at risk
  because of underlying conditions.

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NSAIDs Acute Renal Toxicity
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Risk Factors For NSAID-MediatedAdverse Renal
Effects
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NSAIDs Acute Deterioration in Renal Function

• Mechanism inhibition of important vasodilatory
  PGs (PGI2, PGE2)
• PGs become major factors in maintaining renal
  functions when circulating blood volume is
  reduced by hypotension or volume depletion,
• Histopathology Acute tubular necrosis
• Cardinal Signs
• Elevated BUN/ Cr, K, weight gain, oliguric or
  nonoliguric

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NSAIDs Acute Renal Toxicity
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NSAIDs Nephrotic Syndrome

• Mechanism
• Tubular inflammatory process through production
  of chemotactic-vasoactive leukotrienes.
• Histopathology
• minimal change glomerulonephritis /-
  interstitial nephritis
• Cardinal signs
• edema, elevated creatinine, proteinuria after
  months of therapy
• fever, drug rash, eosinophilia, and
  eosinophiluria are usually absent
• Not seen with acetaminophen

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NSAIDs Papillary Necrosis

• Acute Renal Papillary Necrosis
• Typical candidate overdose in a dehydrated
  individual with preexisting normal renal function
• Chronic Renal Papillary Necrosis
• Typical candidate abuser of OTC combination
  analgesic products for 20 to 30 years (Analgesic
  Abuse Nephropathy)
• Histopathology
• Ischemic necrosis due to extremely high local
  NSAID concentration in the renal papillae.
• Cardinal Signs
• Colicky flank pain, Inc. BUN/ Cr, K, diminished
  urine volume

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NSAIDs Renal Toxicity
National Kidney Foundation recommendation
Henrich et al. Am J Kidney Dis 1996 27162
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Selective COX-2 Inhibitors
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The COX hypothesis

• COX 1
• products are responsible for normal homeostasis
• COX-2
• Products are responsible for modulating dynamic
  processes such as inflammation
• Inhibition of COX-1 ? organ-specific toxicity
• Selective Inhibition of COX-2 ?safe
  anti-inflammatory therapy

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The COX hypothesis
COX-2
PAIN AND INFLAMATION
COX-1
Gastric protection Renal function Platelet
Activity
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The COX Dichotomy
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COX-2 Inducible regulatory effects
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The COX hypothesis reconsidered

• COX-2
• Stimulates Coronary Thrombosis
• ? Role in mucosal healing in chemical induced
  injury and colitis
• Promote cell proliferation
• Bone injury
• Reproduction
• Modulating renal function in some animals

• COX-1
• Animal models show COX-1 mediates some
  inflammation

Mandell B, 1999 66(5) Cleveland Clinic Journal
of Medicine
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COX-2 Inhibitors Cardiac Toxicity

• The regulatory approval of Vioxx was based on a
  safety database of Phase III studies which
  included approximately 5000 patients on
  rofecoxib.
• The data did not show an increased risk of heart
  attack or stroke.
• A double blind randomized, stratified, parallel
  group prospective clinical trial, VIGOR (VIOXX GI
  Outcomes Research), was conducted, with 8076
  patients to compare the occurrence of
  gastrointestinal toxicity of rofecoxib (50 mg
  daily) versus another NSAID, naproxen (1000 mg
  daily), during chronic treatment for patients
  with rheumatoid arthritis.
• This study was primarily designed to examine GI
  side effects of rofecoxib.
• The VIGOR study demonstrated that pts taking
  rofecoxib had fewer stomach ulcers and bleeding
  than patients taking naproxen, however, they also
  had greater number of heart attacks in patients
  taking rofecoxib.
• 0.1 percent vs. 0.4 percent
• Consequently, new safety information was added to
  the labelling for Vioxx in April 2002 that
  contraindicated using rofecoxib in obvious cases
  of ischemic heart disease.
• On September 30, 2004 Merck and Co. instituted an
  immediate voluntary worldwide withdrawal of Vioxx

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General Conclusions Regarding Cardiac Toxicity

• One cannot ignore the public need for NSAIDs with
  less gastrointestinal side effects than the
  traditional drugs.
• However, based on the rationale put forward, and
  unless more clear-cut data become available, the
  use of highly COX-2 selective NSAIDs without the
  use of a suitable COX-1 inhibitor, (e.g., low
  dose aspirin) may be best avoided.

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COX-2 Inhibitors GI Toxicity

• Endoscopy performed after 12 weeks of therapy
  (N1149)
• Ulcer any 3 mm diameter break in mucosa over a
  12 week period (most asymptomatic)
• GI Symptoms
• 19 placebo
• 26 celecoxib
• 31 naprosyn

Simon et al JAMA 1999,282 (20) 1921-1928
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COX-2 Inhibitors GI Toxicity

• Langman et al
• Meta-analysis of 8 studies (n-5435)
• Complicated ulcers with 12 m of therapy
• 1.33 / 100 pt-yr with rofecoxib
• 2.60 / 100 pt-yr with nonselective NSAIDs
• 0.49 relative risk reduction for developing
  complicated ulcer

Complicated ulcer perforated, painful, bleeding
Langman et al JAMA 1999 282(20),1929-1933
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COX-2 Inhibitors Renal Toxicity

• Results of well-controlled studies in at-risk
  renal/ hypertensive/congestive heart failure
  patients are necessary
• COX-2 is responsible for the synthesis of some
  renal prostaglandins
• Manufacturers data sheet reports acute renal
  failure in lt0.1 of pts (n7,400)

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COX-2 Inhibitors Cost
Retail price to the consumer from the 1999 Drug
Topics Red Book
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COX-2 Inhibitors Cost

• 500 low-risk pts would need to be treated to
  prevent one complicated ulcer
• Yearly incremental cost of celecoxib (200 mg/d)
  400,000/ ulcer
• 40 higher risk pts would need to be treated to
  prevent one complicated ulcer
• Yearly incremental cost 30,000/ ulcer

Assumptions COX-2 inhibitors decrease risk of
developing a complicated ulcer by 50 the
incidence of complicated ulcer is 0.4/ yr.
Peterson et al. JAMA, 1999 282(20), 1961-1963
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COX-2 Inhibitors
Reasons of cost, safety, and extensive clinical
experience using apap
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Summary

• Billions of tablets of NSAIDs are consumed
  annually making them responsible for more toxic
  deaths than any other pharmaceutical agent
• The vast majority of these deaths are from the GI
  toxicity from non-selective NSAIDs
• Overdosing of acetaminophen accounts for nearly
  all of its toxicity. In recommended doses it is
  remarkably safe.
• COX-2 inhibitors are costly and may be less toxic
  than other NSAIDs.
• Patient education, and and understanding of
  appropriate dosing/ risk factors can prevent
  needless deaths and morbidity