• Overview:indomethacin

  • indole derivative

  • well absorbed (oral route)

  • substantial plasma protein binding

  • hepatic metabolism

  • inactive metabolites & unchanged parent compound: excreted in bile and urine

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• Clinical Uses:indomethacin

  • not recommended for analgesia

  •  not recommended for use in children, except:

    •   treatment of patent ductus arteriosus in premature infants

    • prostaglandin production keeps the structure open;accelerated closure, in a premature newborn can be accomplished by intravenous infusion of indomethacin

      • may avoid surgery

      • renal toxicity may occur

    • COX-I dependent

  • Effective in clinical management of:

    • acute gouty arthritis

      • may replace colchicine in initial treatment

      • ankylosing spondylitis

      • extra-articular inflammation, e.g.:

        • pericarditis

        • pleurisy

        • Bartter's syndrome

  •  Controversial Use: tocolytic in preterm labor < 32 weeks gestation

    • Rationale: reduced prostaglandin synthesis ® reduced strength/frequency all of uterine contractions

    •  Difficulty: fetal/maternal drug toxicity

    • Alternative Medication: calcium channel blockers

•  Adverse Effects:indomethacin

  •  at higher dosages: about 33% have reactions sufficient to require withdrawal of indomethacin

  • Gastrointestinal disturbances:

    •  abdominal pain

    •  GI hemorrhage

    •  pancreatitis

    •  diarrhea

  •  Headache common: frequency = 15%-25% (including dizziness, depression, confusion)

  • Hyperkalemia, secondary to renal prostaglandin synthesis inhibition

  •  Contraindicated in patients with:

    • nasal polyps

    • angioedema

    • asthma

    • pregnancy

  •  Cautious Use: -- peptic ulcer disease; psychiatric disorder

• Properties:phenylbutazone

  • pyrazolone derivative

  •  Hematologic toxicities: ® withdrawal from North American markets

    • agranulocytosis/aplastic anemia ® deaths

    • hemolytic anemia

    • many other non-hematologic toxicities

• Properties:Ketorolac

  • intermediate duration NSAID

  • marketed for analgesia; not for inflammation (but has typical NSAIDs' properties)

  • Significant analgesic effects --sufficient to replace morphine in mild/moderate post surgical pain

  • parenteral administration route most common

  • ophthalmic preparation available

• Clinical Pharmacological Issues:NSAIDs

  • NSAIDs:less gastric irritation; easier dosing schedule, e.g. better patient compliance

  • NSAIDs: safer than aspirin, more expensive

  •  NSAIDs: gastric ulceration patients taking anti-inflammatory doses --

    • approaches to reduce gastric irritation leading to ulceration:

      •  concurrent administration of misoprostol

      •  misoprostol (prostaglandin E1 analog) reduces (a) gastric acid secretion and (b) the increases gastric mucosal protective factors, e.g. bicarbonate

  •  NSAIDs: increased incidence of acute renal failure; nephrotic syndrome

    •  insidious development

    •  not dose-dependent; not related to drug use duration

  • NSAIDs -- Prescribing Decisions:

    • cost

    • adverse effects

    • dosing schedules-- patient compliance issues

      • once a day/twice a day dosing:

        • piroxicam

        • naproxen

        • sulindac

        • oxaprozin

    • For patients taking hypoglycemic agents or warfarin:

      • ibuprofen--no potentiation of hypoglycemic/warfarin effects

      • tolmetin--no potentiation of hypoglycemic/warfarin effects

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• Overview: (DMARDS)

  • Rheumatoid arthritis:(DMARDS)

    •  reduces mobility

    •  reduces quality of life

    •  reduces life span

    • NSAIDs: symptomatic relief (reduction: inflammation, pain) -- limited effect on progressive bone & cartilage loss

  •  Disease modifying antirheumatic drugs (selecting -- six weeks to six months for effects) slow or possibly stop disease progression.

• Immunosuppressive drugs (DMARDs): useful in --

  • lupus nephritis

  • seropositive, progressive rheumatoid arthritis

  • vasculitis syndromes (Wegener's gramulomatosis & panarteritis)

• Toxicities associated with immunosuppressive drug use (suggest safer agents should be prescribed first):

  •  oncogenic effects

  •  bone marrow depression

  •  hepatoxicity

• Mechanisms of action (rheumatic disease doses):

  • Inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase, thymidylate synthase and increased adenosine release.

• 70% absorbed (oral route administration)

• Primary excretion pathway: urine; secondary, bile

•  Most common toxicities: Methotrexate

  • mucosal ulcers

  • nausea

•  Dose-related hepatotoxicity (enzyme changes): common

• Reduction in methotrexate toxicity:

  • Post-treatment (24 hours after methotrexate): with leucovorin or using daily folic acid

• Other immunosuppressive drugs that had been used for treating arthritis:

  • mechlorethamine

  • cyclophosphamide

  • chlorambucil

  • azathioprine -- purine antagonist -- FDA-approved for rheumatoid arthritis  infrequent use due to toxicities: hematologic, hepatic, possible increased incidence of non-Hodgkin's lymphoma).

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