Drugs

1. Drugs used in joint diseases
Dr Sanjeewani Fonseka
Department of Pharmacology

2. OBJECTIVES
• List the classes of drugs that are used in
the treatment of RA
• Describe the mechanism of action,
pharmacokinetics and adverse effects of
the above drugs
• Explain the basis of disease modifying
drugs
• Explain the basis of drug treatment of OA
and gout

3. Rheumatoid arthritis
• Chronic synovial inflammation
• Autoimmune
• Cytokine networks are responsible for
inflammation & joint destruction
– Tumor Necrosis Factor-α (TNF-α)
– Interleukins - 1,6,17

7. Disability in Early RA
• Inflammation
– Swollen
– Stiff
– Sore
– Warm
• Fatigue
• Potentially
Reversible

10. Periarticular Osteopenia
Joint Space Narrowing
Erosions
Mal-Alignment

11. Disability in RA
• Most of the disability in RA is a result of
the INITIAL burden of disease
• People get disabled because of:
– Inadequate control
– Lack of response
– Compliance
• GOAL: control the disease early on!

12. Drugs for RA
• Nonsteroidal anti-inflammatory drugs
(NSAIDs)
• Disease-modifying anti-rheumatic drugs
(DMARDs)
– Synthetic
– Biologic
• Glucocorticoids

13. NSAIDs
• Cyclo-oxygenase inhibitors
• Do not slow the progression of the disease
• Provide partial relief of pain and stiffness

15. NSAIDs
• Non-selective COX inhibitors
– Ibuprofen
– Diclofenac sodium
• COX–2 inhibitors
– celecoxib

16. COX-2 Inhibitors
• COX-2 inhibitors appear to be as effective
NSAIDs
• Associated with less GI toxicity
• However increased risk of CV events

17. Read
Side effects of
• non selective NSAID
• COX – II inhibitors

18. Drugs for RA
• Nonsteroidal anti-inflammatory drugs
(NSAIDs)
• Disease-modifying anti-rheumatic drugs
(DMARDs)
– Synthetic
– Biologic
• Glucocorticoids

19. 90% of the joints involved in RA are
affected within the first year
SO TREAT IT EARLY

20. Disability in Late RA (Too Late)
• Damage
– Bones
– Cartilage
– Ligaments and
other structures
• Fatigue
• Not Reversible

21. DMARDs
Disease Modifying Anti-Rheumatic Drugs
• Reduce swelling & inflammation
• Improve pain
• Improve function
• Have been shown to reduce radiographic
progression (erosions)

22. DMARDs
• Synthetic
• Biologic

23. Synthetic DMARDs
• Methotrexate
• Sulphasalazine
• Chloroquine
• Hydroxychloroquine
• Leflunomide

24. Synthetic DMARDs
• Methotrexate
• Sulphasalazine
• Chloroquine
• Hydroxychloroquine
• Leflunomide

25. Methotrexate (MTX)
• Dihydrofolate reductase inhibitor
• ↓ thymidine & purine nucleotide synthesis
• “Gold standard” for DMARD therapy
• 7.5 – 30 mg weekly
• Absorption variable
• Elimination mainly renal

27. MTX adverse effects
• Hepatotoxicity
• Bone marrow suppression
• Dyspepsia, oral ulcers
• Pneumonitis
• Teratogenicity
• Folic acid reduces GI & BM effects
• Monitoring
– FBC, ALT, Creatinine

28. Synthetic DMARDs
• Methotrexate
• Sulphasalazine
• Chloroquine
• Hydroxychloroquine
• Leflunomide

29. Sulphasalazine
• Sulphapyridine + 5-aminosalicylic acid
• Remove toxic free radicals
• Remission in 3-6 month

30. • Elimination hepatic
• Dyspepsia, rashes, BM suppression

31. Synthetic DMARDs
• Methotrexate
• Sulphasalazine
• Chloroquine /Hydroxychloroquine
• Leflunomide

32. Chloroquine, Hydroxychloroquine
• Mechanism unknown
– Interference with antigen processing ?
– Anti- inflammatory and immunomodulatory
• For mild disease

33. Chloroquine cont
• Take a month to see the effect

34. Chloroquine cont
Side effects
• Irreversible Retinal toxicity, corneal
deposits
• Ophthalmologic evaluation every 6 months

36. Synthetic DMARDs
• Methotrexate
• Sulphasalazine
• Chloroquine
• Hydroxychloroquine
• Leflunomide

37. Leflunomide
• Competitive inhibitor of dihydroorotate
dehydrogenase (rate-limiting enzyme in de
novo synthesis of pyrimidines)
• Reduce lymphocyte proliferation

38. Leflunomide cont
• Oral
• T ½ - 4 – 28 days due to EHC
• Elimination hepatic
• Action in one month
• Avoid pregnancy for 2 years

39. Side effects of leflunomide
• Hepatotoxicity
• BM suppression
• Diarrhoea
• rashes

41. Combination therapy (using 2 to 3)
DMARDs at a time works better
than using a single DMARD

42. Common DMARD
Combinations
• Triple Therapy
– Methotrexate, Sulfasalazine, Hydroxychloroquine
• Double Therapy
– Methotrexate & Leflunomide
– Methotrexate & Sulfasalazine
– Methotrexate & Hydroxychloroquine

43. DMARDs
• Synthetic
• Biologic

44. BIOLOGIC THERAPY
• Complex protein molecules
• Created using molecular biology methods
• Produced in prokaryotic or eukaryotic cell
cultures

45. Biologics
• Monoclonal Antibodies to TNF
– Infliximab
– Adalimumab
• Soluble Receptor Decoy for TNF
– Etanercept
• Receptor Antagonist to IL-1
– Anakinra
• Monoclonal Antibody to CD-20
– Rituximab

46. Tumour Necrosis Factor (TNF)
• TNF is a potent inflammatory cytokine
• TNF is produced mainly by macrophages and
monocytes
• TNF is a major contributor to the inflammatory
and destructive changes that occur in RA
• Blockade of TNF results in a reduction in a
number of other pro-inflammatory cytokines (IL-
1, IL-6, & IL-8)

47. Macrophage
Any Cell
Trans-Membrane
Bound TNF
TNF Receptor
Soluble TNF
How Does
TNF Exert Its
Effect?

49. Trans-Membrane
Bound TNF
Soluble TNF
Strategies for
Reducing
Effects of TNF
Macrophage
Monoclonal Antibody (Infliximab & Adalimumab)

50. Side Effects
• Infection
–Common (Bacterial)
–Opportunistic (Tb)
• Demyelinating Disorders
• Malignancy
• Worsening CHF

51. Drugs for RA
• Nonsteroidal anti-inflammatory drugs
(NSAIDs)
• Disease-modifying anti-rheumatic drugs
(DMARDs)
– Synthetic
– Biologic
• Glucocorticoids

52. Glucocorticoids
• Potent anti-inflammatory drugs
• Serious adverse effects with long-term use
• To control the diaseas
• Indications
– As a bridge to effective DMARD therapy
– Systemic complications (e.g. vasculitis)

53. Route of steroid
• Oral
• Intra- articular
• IM - depot

54. Osteoarthritis

55. Osteoarthritis
• Most common joint disorder worldwide
• Diagnosed on clinical presentation and
supported by radiography.

57. Clinical Features
• Age of Onset > 40
years
• Commonly Affected
Joints

58. Goals of Treatment
• Control pain and swelling
• Minimize disability
• Improve the quality of life
• Prevent progression

59. NSAIDs
• Tend to avoid for long-term use
• Indomethacin should be avoided for long-
term use in patients with hip OA
–associated with accelerated joint
destruction

60. • Read – different classes of NSAID that
can be used in OA

61. Topical NSAIDs
• Effect was not apparent at three to four
weeks
• Topical NSAIDs were generally inferior to
oral NSAIDs
• Topical route was safer than oral use
• Topical Diflofenac (1% gel or patch)

62. • Corticosteroid – intra- articular injections

63. Glucosamine Sulfate
• Glycoprotein derived from marine
exoskeletons or produced synthetically
• Found - tendons, ligaments, cartilage,
synovial fluid
• ? disease modifying agent in osteoarthritis.

64. • orally, intravenously, intramuscularly, and
intra-articularly
• provide pain relief, reduce tenderness, and
improve mobility in patients with OA

65. Hyaluronic acids
– Injected into the joint capsule to reduce
friction and improves articulation (act as
synovial fluid)

66. GOUT

68. GOUT

69. TREATMENT GOALS
• Rapidly end acute flares
• Protect against future flares

70. Acute Flare
• NSAIDS
• Colchicine
• Corticosteroids

71. Colchicine
Colchicine- reduces pain, swelling, and
inflammation; pain subsides within 12 hrs
and relief occurs after 48 hrs
Prevent migration of neutrophils to joints

72. Side effects
• Nausea
• Vomiting
• Diarrhea
• Rahes

73. TREATMENT GOALS
• Rapidly end acute flares
Protect against future flares

75. URICOSURIC AGENTS
• Probenecid
• Increased secretion of urate into urine
• Reverses most common physiologic
abnormality in gout ( 90% pt.s are
underexcretors)

77. • Hypoxanthine
• Xanthine
• Uric acid
XO

78. • Hypoxanthine
• Xanthine
• Uric acid
XO ALLOPURINOL

79. XANTHINE OXIDASE
INHIBITOR
• Allopurinol
• Effective in overproducers
• May be effective in underexcretors
• Can work in pt.s with renal insufficiency

80. Summary

81. Drugs for RA
• Nonsteroidal anti-inflammatory drugs
(NSAIDs)
• Disease-modifying anti-rheumatic drugs
(DMARDs)
– Synthetic
– Biologic
• Glucocorticoids

82. RA

83. OA
• Pain relief
• Glucosamine Sulfate
• Hyaluronic acids injections
• Surgery

84. TREATMENT OF GOUT
• Colchicine, NSAID, steroids – acute attack
• Allopurinol- decreases the production of uric
acid
• Probenecid - prevent absorption of uric acid in
the tubules of kidney

85. OBJECTIVES
• List the classes of drugs that are used in
the treatment of RA
• Describe the mechanism of action,
pharmacokinetics and adverse effects of
the above drugs
• Explain the basis of disease modifying
drugs
• Explain the basis of drug treatment of OA
and gout