Indomethacin

• Overview: indomethacin

  • Indole derivative

  • Well absorbed (oral route)

  • Substantial plasma protein binding

  • Hepatic metabolism

  • Inactive metabolites and unchanged parent compound: excreted in bile and urine

• 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

Phenylbutazone

• Properties:phenylbutazone

  • Pyrazolone derivative

  • Hematologic toxicities: ® withdrawal from North American markets

    • Agranulocytosis/aplastic anemia ® deaths

    • Hemolytic anemia

    • Many other non-hematologic toxicities

• 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

  • 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

  Disease Modifying Antirheumatic Drugs (DMARDs)

  • Overview: (DMARDS)

    • Rheumatoid arthritis:(DMARDS)

      • Overview:

        • Chronic multisystem disease

        • Unknown cause

        • Characteristic feature:

          • Persistent inflammatory synovitis, usually involving peripheral joints (symmetric distribution)

        • Consequences of synovial inflammation:Disease Hallmarks--

          • Cartilage destruction

          • Bone erosion

          • Joint integrity change

        • Range of Disease Manifestations:

          • Mild (brief, oligoarticular illness; minimal joint damage)

          • Substantial (progressive, relentless, polyarthritis ®significant functional impairment)

      • Epidemiology

        • Prevalence of rheumatoid arthritis: 0.8%

        • women: affected about 3X more often than men

        • Prevalence increases with age

        • RA:

          • Affects all races

          • Seen worldwide

          • Most frequent onset: age--forties to fifties

      • Genetic Predispositions:

        • Severe RA: four times expected rate in first-degree relatives of individuals with disease associated with auto antibody, rheumatoid factor

        • About 10% of patient with RA -- affected first-degree relative

        • Monozygotic twins: at least four times more likely to be concordant for RA than dizygotic twins

        • About 15% to 20% of monozygotic twins -- concordant for RA suggesting other than genetic factors play an important role

      •  Genetic Factors-- RA etiology and other considerations:

        •  Class II major histocompatibility complex (MHC) gene product HLA-DR4

        •  Approximately 70% of patients with definitive RA express HLA-DR4 (compared to 28% of controls)

        •  Genes outside HLA complex contributes, probably including genes controlling T cell antigen receptor expression and the expression of immunoglobulin heavy and light chains

        •  Genetic component associated with drug-induced toxicities -- For example:

          •  presence of the HLA-DR3 (DRß1*0301) allele: highly correlated with side effect development to gold therapy including:

            •  Proteinuria (similar relationship between allele presence and  proteinuria associated with D-penicillamine treatment)

            •  Skin rash

            •  Thrombocytopenia

      • Non-genetic factors:

        • Analysis of epidemiologic studies in Africa;indicative of additional factors including

          • Climate

          • Urbanization

      •  Pathology and pathogenesis

        • Earliest lesions in rheumatoid synovitis:

          • Increased number of synovial lining cells

        • Subsequent changes:

          • Increased number of synovial lining cells + mononuclear cell perivascular infiltration

          • Synovium: edematous; protruding into the joint cavity

            • Rheumatoid arthritis (RA), pannus, low power photomicrograph

              "Pannus in rheumatoid arthritis, showing finger-like projections of synovium that are infiltrated by chronic inflammatory cells" Ó 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

        • Microscopic features:

          • Synovial lining cell hyperplasia and hypertrophy

          • Focal/segmental vascular change --

            • Microvascular injury

            • Thrombosis

            • Neovascularization

            • Edema

            • Mononuclear cell infiltration (aggregates around small blood vessels)

          • Rheumatoid synovium endothelial cells:

            • Resemble high endothelial venules of lymphoid organs

            • Altered by cytokine exposure

            • elaboration of adhesion molecules

          • Infiltrating cell types:

            •  Predominant -- T lymphocytes

              • CD4+ memory T cells more common then CD8+ cells

              • T cell's express early activation antigen CD69

            • Significant B-cell proliferation:

              • local differentiation into antibody-producing plasma cells

              • produce both polyclonal immunoglobulin and autoantibody rheumatoid factor ® local immune complexes formation.

            • HLA-DR+ macrophages

            • Dendritic cells

        • Synovial fibroblasts are activated producing: collagenase/cathepsins ® articular matrix degradation

          • Activated fiberglass: prominent:

            • Lining layer

            • Bone/cartilage interface -- osteoclasts prominent

            • At bone erosion sites

        •  Rheumatoid synovium:

          • Secreted products of activated lymphocytes, macrophages, fibroblasts

          • Local cytokine/chemokine production responsible for many clinical and pathological presentations of rheumatoid arthritis

        • Rheumatoid Arthritis: Clinical Manifestations

          • Onset:two-thirds of patients -- following symptoms:

            •  Fatigue, anorexia, weakness, vague musculoskeletal symptoms

            •  Specific symptoms appear gradually:

              • symmetrical effects on joints of the hands, wrists, knees, feet

          • Symptoms of Articular disease

            •  Most common manifestation of established RA:

              • pain and affected joints

              • worsened by movement

              • morning stiffness

            • Synovial inflammation: swelling, tenderness, motion limitations.

            • With persistent inflammation: characteristic deformities:

              • Rheumatoid arthritis (RA), hand, X-ray

                "Radiograph of a hand in late-stage rheumatoid arthritis showing subluxation of the metacarpo-phalangeal joints and ulnar deviation of the fingers, x-ray." © 1999 KUMC Pathology and the University of Kansas, used with permission; courtesy of Dr. James Fishback, Department of Pathology, University of Kansas Medical Center.

      •  Reduces mobility

      •  Reduces quality of life

      •  Reduces life span

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

    •  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

  • Immunosuppressive drugs (DMARDs): useful in:

    • lupus nephritis

    • seropositive, progressive rheumatoid arthritis

    • vasculitis syndromes (Wegener's gramulomatosis and panarteritis)

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

    •  Oncogenic effects

    •  Bone marrow depression

    •  Hepatoxicity

   

  • 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

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

      • Mechlorethamine

      • Cyclophosphamide

      • Chlorambucil

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

  Primary Reference: Katzung, B. G. and Furst, D. E. Nonsteroidal Anti-Inflammatory Drugs; Disease-Modifying Antirheumatic Drugs; Nonopioid Analgesics; Drugs Used in Gout, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 578-602.

  Lipsky, P.E. Rheumatoid Arthritis, In Harrison's Principles of Internal Medicine 14th edition, (Isselbacher, K.J., Braunwald, E., Wilson, J.D., Martin, J.B., Fauci, A.S. and Kasper, D.L., eds) McGraw-Hill, Inc (Health Professions Division), 1998, pp 1880-1888.Agudelo, C.A.

  Gout in Medicine for the Practicing Physician, Fourth edition, (Hurst, J. Willis, editor in chief) Appleton and Lange, 1996, pp 223-226.