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NSAIDs: Special Indications Indomethacin Overview Clinical Uses Adverse Effects Cautious Use Phenylbutazone Properties Ketorolac Properties Clinical Pharmacology Issues Prescribing Considerations Disease Modifying Antirheumatic Drugs (DMARDs) Overview Rheumatoid Arthritis Disease Modifying Antirheumatic Drugs (DMARDs) Immunosuppressive Drugs Toxicities Methotrexate Mechanisms of Action Toxicities Hepatotoxicity Management Antimalarial Drugs: Chloroquine Overview Clinical Indications Gold Overview Chemistry Pharmacokinetics Pharmacodynamics Clinical Uses/Contraindications Major Contraindication Adverse Effects Penicillamine Overview Pharmacokinetics Pharmacodynamics Clinical Indications Adverse Effects Contraindications Glucocorticoids Overview Pharmacodynamics Adverse Effects Clinical Use Diet	Acetaminophen Overview Pharmacokinetics Clinical Uses Adverse Effects Gout Introduction, Disease Definition, Etiology Clinical Manifestation Usual Patient Differential Diagnosis Pharmacological Management Mechanistic Rationale Sequence of Pathophysiological Events Colchicine Overview Pharmacokinetics Pharmacodynamics Mechanism of Action Clinical Indications Adverse Effects NSAIDs Overview Rationale Uricosuric Drugs: Probenecid & Sulfinpyrazone Chemistry Pharmacokinetics Pharmacodynamics Adverse Effects Allopurinol Overview Chemistry Pharmacokinetics Pharmacodynamics Clinical Use/Issues Adverse Effects Drug-Drug Interactions

NSAIDs: Special Indications

Indomethacin

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

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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

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Phenylbutazone

Properties:phenylbutazone
- pyrazolone derivative
- Hematologic toxicities: ® withdrawal from North American markets
  - agranulocytosis/aplastic anemia ® deaths
  - hemolytic anemia
  - many other non-hematologic toxicities

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Ketorolac

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

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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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Disease Modifying Antirheumatic Drugs (DMARDs)

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

Disease Modifying Antirheumatic Drugs (DMARDs)
methotrexate	azathioprine	penicillamine	hydroxycholoroquine

chloroquine

organic gold compounds

sulfasalazine

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Immunosuppressive drugs (DMARDs): useful in --
- lupus nephritis
- seropositive, progressive rheumatoid arthritis
- vasculitis syndromes (Wegener's gramulomatosis & panarteritis)

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Toxicities associated with immunosuppressive drug use (suggest safer agents should be prescribed first):
- oncogenic effects
- bone marrow depression
- hepatoxicity

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Methotrexate: as a disease modifying antirheumatic drug

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

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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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