Salicylates

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ARTHRITIS AND GOUT

• NSAIDS, DMARDS, BRMs and Drug Therapy of
  Arthritis
• Drug Therapy of Gout

Garold S. Yost, Ph.D. Department of Pharmacology
and Toxicology 390C Biomedical Polymers 581-7956 g
yost_at_pharm.utah.edu
2
Aspirin for Thrombotic Diseases - decreases
platelet aggregation 24 reduction in major
vascular events (myocardial infarction) Prevention
of myocardial infarction in low-risk patients
may not compensate for possible increased risk of
hemorrhagic stroke.
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Ibuprofen Blocks Aspirin Anti-platelet Effects
Catella-Lawson, et al., New Engl. J. Med., 25,
1809-1817 (2001)
Concomitant administration of ibuprofen but not
acetaminophen or diclofenac inhibits
antiplatelet effect of aspirin
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Rheumatoid Nodules
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Cytokines Play Important Role
Anakinra
The Lancet Vol 358,Issue 9285, 15 Sep 2001, pg
903-911
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Cyclooxygenase Enzymes

• COX-1
• Constitutively expressed in most tissues
• Inhibition leads to GI, renal, other toxicities
• Not induced in response to cytokines
  (inflammation)
• COX-2
• Constitutively expressed at low levels
• Neurons, kidney, gastric mucosa
• Highly induced by inflammation (10 to 1000-fold)
  - IL-1 and TNF

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COX-3 Boom or Bust?

• Produced by alternate splicing of the COX-1 gene
• Was an exciting new discovery of a potential
  target for new analgesics, because dog form was
  inhibited by acetaminophen
• However, human form does not appear to be an
  active enzyme
• Search is intense to see if other splice variants
  exist in humans

Chandrasekharan et al. PNAS 99, 1396-31 (2002)
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Balancing Therapy and Toxicities of COX
Inhibition
Warner and Mitchell, PNAS, 99, 13371-13373 (2002)
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COX-2 Selective Drugs

• Celecoxib (Celebrex)
• Only COX-2 selective drug still available - Vioxx
  voluntarily withdrawn by Merck and Bextra was
  removed by FDA
• High doses (gt400 mg bid) may have increased
  cardiovascular risk
• Contraindicated in patients allergic to
  sulfonamides
• May be effective for cancer (colon, and possibly
  pancreas, lung, breast, and brain) or Alzheimers
  Disease

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COX-2 SELECTIVE DRUGS TOXICITIES?

• Cardiovascular 2.4 relative risk of major event
  with rofecoxib compared to naproxen (VIGOR -
  Vioxx study), but CLASS (celecoxib) study showed
  no increase in cardiovascular events
• High dose gt 25 mg/day of rofecoxib increased CHD
  (coronary heart disease) risk by 70-90
• Renal celecoxib associated with a few reports
  of acute renal failure (celecoxib - edema in 2
  patients) (refecoxib edema in 3.8 )

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Vioxx Recalled Due to Risk Of Heart Attacks and
Strokes !
Although the risk that an individual patient
would have a heart attack or stroke related to
Vioxx is very small, the study that was halted
suggests that, overall, patients taking the drug
chronically faced twice the risks of a heart
attack compared to patients receiving a placebo
..FDA News
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Recent fallout following the Adenomatous Polyp
Prevention on Vioxx (APPROVe) study
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Nonsteroidal Anti-Inflammatory Drugs

• All organic anions bound to plasma proteins
• All cause GI ulceration or bleeding and renal
  toxicity
• Misoprostol (Cytotec) used to prevent or treat GI
  injury
• Omeprazole (Prilosec) also effective prophylactic
  or treatment for gastritis
• All inhibit platelet aggregation, but reversibly
• All potentially cross-reactive with aspirin
  hypersensitivity including COX-2 selective drugs

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Specific NSAIDs

• ibuprofen (Motrin) naproxen (Naprosyn)
  diclofenac (Voltaren)
• indomethacin (Indocin) or phenylbutazone may be
  drugs of choice for gout inhibit neutrophil
  phagocytosis
• diclofenac available with misoprostol (Arthrotec)
  to decrease GI toxicity

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Anakinra
The Lancet Vol 358,Issue 9285, 15 Sep 2001, pg
903-911
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Slow-Acting Anti-Inflammatory Drugs
(Disease-Modifying Antirheumatic Drugs DMARD)

• methotrexate is first line therapy 2.5 mg/week
  maintenance dose. Monitor serum enzymes for
  hepatotoxicity
• gold aurothioglucose (Solganal) and
  aurothiomaleate (Myochrysine) are i.m. forms
• Bone marrow depression (blood counts mandatory),
  and renal toxicities
• auranofin (Ridaura) is oral form with latency 4-6
  months but 50 of patients have severe diarrhea
  during this period
• diet glucosamine and chondroitin may decrease
  pain and decrease progression of disease

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Less Frequently Used DMARDS

• hydroxychloroquine (Plaquenil)
• Retinal damage often major problem requires
  vision checks
• sulfasalazine (Azulfidine)
• D-penicillamine (Cuprimine)
• Mechanism may be to alter T-lymphocyte function
• Side effects include nephrotoxicity

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Newer Anti-Inflammatory Agents Biological
Response Modifiers (BRMs)

• leflunomide (Arava - oral) etanercept (Enbrel
  s.c.) infliximab (Remicade i.v.) anakinra
  (Kineret s.c.) adalimumab (Humira s.c.)
• leflunomide inhibits T-cell proliferation oral
  pyrimidine synthesis inhibitor slows joint
  damage carcinogen and teratogen
• etanercept is recombinant human TNF-a receptor

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Newer Anti-inflammatory (cont.)

• infliximab is a monoclonal antibody to TNF-a and
  inhibit its binding to cell surface receptors.
  Combination with methotrexate showed 100
  response (285 patients halt in progression of
  joint damage).
• anakinra is IL-1 receptor antagonist. Has been
  approved for severe rheumatoid arthritis when a
  DMARD drug doesnt work.
• adalimumab is another new TNF-a inhibitor
  (monoclonal antibody) for use in DMARD-refractive
  RA patients. All of the TNF-a inhibitors may
  cause lymphomas

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Key Concepts Arthritis Drugs

• NSAID inhibition of PGs still primary treatment
  for arthritis
• DMARDs can be helpful, but toxicities are major
  problems methotrexate is generally the
  exception, i.e. effective and lower toxicities
• New BRIs may provide dramatic, life-style
  altering therapy but immune system alterations
  are a concern

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The Gout
The Gout by James Gilray, 1799. Gout depicted as
an evil demon attacking a toe.
http//www.hopkins-arthritis.som.jhmi.edu/other/go
ut.html
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Thomas Sydenham (1624-1689)"the Shakespeare of
Medicine"

• The victim goes to bed and sleeps in good
  health. About 2 o'clock in the morning, he is
  awakened by a severe pain in the great toe more
  rarely in the heel, ankle or instep. This pain is
  like that of a dislocation, and yet the parts
  feel as if cold water were poured over them. Then
  follows chills and shiver and a little fever.

The pain which at first moderate becomes more
intense. With its intensity the chills and
shivers increase. After a time this comes to a
full height, accommodating itself to the bones
and ligaments of the tarsus and metatarsus. Now
it is a violent stretching and tearing of the
ligaments-- now it is a gnawing pain and now a
pressure and tightening. So exquisite and lively
meanwhile is the feeling of the part affected,
that it cannot bear the weight of bedclothes nor
the jar of a person walking in the room.
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Redness and Swelling of Acute Gouty Attack
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Tophaceous Deposits of Urate
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Causes of Gout Hyperuricemia Idiopathic Renal
retention of urate Unexplained associations
(hypertension, obesity, hypolipidemia) Increased
urate production Renal retention,
specific Drug effects (diuretics -
hydrochlorothiazide, acetylsalicylic
acid) Renal damage (glomerular or
tubular) Metabolic (lactate, ?-OH-butyrate) Inc
reased nucleic acid turnover (polycythemias,
myeloproliferative disorders) Specific
enzyme defects Hypoxanthine-guanine
phosphoribosyl transferase Phosphoribosylpyropho
sphate synthetase Local Factors Local decrease
in urate solubility (pKa 5.6) Low
temperature Low pH Possible tissue
factors Possible local increase in urate
concentration
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Purines in the Diet

• Highest purine content (150-1000 mg/g) herring,
  sardines, mussels, liver, kidney, meat extracts
  (gravy)
• High purine content (75-150 mg/g) bacon, beef,
  pork, scallops, trout, turkey, veal, salmon, ham,
  beans, lobster, mushrooms, oysters, peas, spinach
• Low purine content (0-15 mg/g) vegetables,
  fruits, milk, cheese, eggs, cereal

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Drugs Used for Therapy of Gout

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• Rational Therapeutic Strategies
• Inhibit PMN Function Colchicine
• Inhibit Prostaglandin Formation NSAIDS
• Increase Urate Excretion Probenecid
• Inhibit Urate Formation - Allopurinol

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Colchicine

• Mechanism interferes with neutrophil function
• Uses acute gout
• Combination therapy with allopurinol and
  probenecid

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Normal Urate Excretion
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Probenecid and Sulfinpyrazone

• Treatment of choice for chronic gout
• Initiation of therapy may induce acute attack
• Caused by mobilization of urate from other sites
  to inflammed joints
• Prophylactic use of NSAIDs prevent pain and
  inflammation when probenecid started
• Decreases secretion of anionic drugs causes
  significant drug interactions

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Mechanism of Allopurinol Action
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Side Effects of Allopurinol
D. Toxicity and Problems   Acute attacks may
be observed during initiation of therapy and may
be treated with an NSAID.   E. Interactions  
Xanthine oxidase inactivates 6-mercaptopurine
and azathioprine doses of these drugs must be
reduced to one-fourth of usual dose when the
patient is also taking allopurinol.  
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• Key Concepts
• Rational Treatment in Two Phases
•  
• Phase I control pain and inflammation
•     NSAIDs (ibuprofen may use indomethacin) or
  colchicine
•  
• Phase II decrease the serum urate (lt 4.0 mg/dL)
• gt 800 mg in 24 hr urine suggests overproduction
  use allopurinol
• lt 500 mg in 24 hr urine suggests decreased renal
  clearance use probenecid