Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
Musculoskeletal disorders therapeutics
By: Tsegaye Melaku
[B.Pharm, MSc, Clinical Pharmacist]
02, January, 2017
tsegayemlk...
Learning objectives
Upon completion of the chapter, you will be able to:
Explain the pathophysiologic mechanisms for rheu...
Mini case
A. A, a 37 year-old woman with a 5-year history of rheumatoid arthritis who
presented with fatigue and dyspnea f...
4
Introduction: RA
Most common systemic inflammatory disease characterized by
symmetrical joint involvement
Chronic, progr...
Epidemiology
Prevalence in US: 1%, 1-2% of the world’s population.
Can occur at any age, with increasing prevalence up t...
Etiology
Cause of RA is unknown.
Genetic: account for 50% of the risk.
Environmental, hormonal, immunologic, and infect...
Pathophysiology
 It results from a complex interaction between genes and environment
 breakdown of immune tolerance and...
Immune system: complex network of checks and balances
designed to discriminate self from non-self (foreign) tissues.
It ...
 The characteristics of a synovium affected by RA are:
a) Presence of a thickened, inflamed membrane lining called pannus...
T-Lymphocytes
 Development and activation of T lymphocytes!!
Maintain protection from infection without causing harm to ...
 Activation of T lymphocytes  
Stimulates the release of macrophages or monocytes,
release of inflammatory cytokines...
Cytokines
Are proteins secreted by cells (serve as intercellular mediators).
Can be
a) Pro-inflammatory: IL-1, IL-6, IL-...
14
B Lymphocytes
 Serve as
APCs to T lymphocytes.
Produce pro-inflammatory cytokines and antibodies.
 Antibodies of signi...
16
17
Clinical Presentation
Pale yellow
18
19
20
RA versus OA
Diagnostic work-up
 P/E & history (extra-
articular manifestations)
 Lab. Investigations
RF, ESR, CRP, anti-CCP
antibod...
22
23
Joint Involvement
24
Dx of Juvenile Idiopathic Arthritis (JIA)
Age <16 years at disease onset
Arthritis in one or more joints for more than 6...
Systemic (10%):
Girls : boys ; 1:1
X-tic fever spikes twice daily
(>38.3°C)
Presence of a pale, pink,
transient rash.
...
Poor prognosis indicators
The most clinically important features associated with poor long-
term outcomes:
Functional li...
Extra-articular Involvement
Rheumatoid Nodules
Occur in 20% of patients with RA.
Commonly on the extensor surfaces of t...
Pulmonary Complications
Pleural effusions, Interstitial pneumonitis and arteritis, nodules
Smoking increase the risk.
...
Malignancy
Increased risk of developing lymphoproliferative
malignancy (e.g., lymphoma, leukemia, and
multiple myeloma) ...
Treatment
Desired Outcomes
Reduce or eliminate pain,
Protect articular structures,
Control systemic complications,
Pre...
General Approach to Treatment
Early dx and early aggressive Rx necessary (reduce disease
progression and prevent joint da...
Non-pharmacologic Therapy
 Rest: alleviation of pain
 Occupational therapy, physical
therapy: skills and exercises
neces...
 Early RA with low disease activity: non-biologic DMARD monotherapy
(initial Rx)
 Hydroxychloroquine, minocycline, leflu...
35
Recommendations for the treatment of early RA (disease duration less than 6 months)
bCombination DMARD therapy:
methot...
 Biologic DMARDs : Consider in patients with established RA following
inadequate response to non-biologic.
Switch: in a ...
37
Recommendations for the treatment of
established RA (disease duration 6 month or
longer)
bCombination DMARD therapy
me...
38
Poor prognosis: limitation in function, extra-articular findings (rheumatoid nodules, vasculitis, Felty
syndrome, Sjogr...
Algorithm for Rx of RA using biologic agents
39
NSAIDS
 Analgesic and anti-inflammatory benefits for joint pain and swelling.
 Don’t prevent joint damage or change the ...
 Adverse event of NSAIDS:
GI ulcers or hemorrhage, fluid retention, exacerbation of existing
hypertension, and decreased...
 Increased risk of NSAID-induced adverse reactions: use gastro-protection:
PPI: preferred, greater acid suppression, pre...
43
Dosage Regimens for Nonsteroidal Anti-inflammatory Drugs
Drug Adult Children Dosing Schedule
Aspirin 2.6–5.2 g 60–100 m...
Corticosteroids
 Anti-inflammatory and immunosuppressive properties.
 Interfere with antigen presentation to T lymphocyt...
 Patients with difficult-to-control disease: low-dose, long-term corticosteroid(control
their symptoms).
 Alternate-day ...
 IV steroids: Patient with large amounts of drug during a steroid burst to
control severe symptoms.
 Intra-articular dep...
DMARDs
 Non-biologic and biologic
 Mainstay of RA treatment (modify the disease process and prevent or
reduce joint dama...
Non-biologic DMARDs
 Inhibit of dihydrofolate reductase, which causes the inhibition of purines and
thymidylic acid and b...
Methotrexate: concern!!!
 Contraindication
 Pregnant and nursing women, DC 3 months prior to attempting conception.
 Ch...
Leflunomide
 Inhibits pyrimidine synthesis  decrease in lymphocyte proliferation and
modulation of inflammation.
 Inhib...
 If conception is desired, leflunomide must be discontinued.
 Because leflunomide undergoes enterohepatic circulation, t...
Hydroxychloroquine
 Exact MOA unknown
 Immunomodulatory activity in T helper 17 (Th17) cytokines.
 Diminish the formati...
Sulfasalazine
A prodrug (cleaved in to sulfapyridine and 5-aminosalicylic acid) by
bacteria in the colon (azoreductase)
...
 Other side effects of sulfasalazine:
 Rash, urticaria, and serum sickness-like reactions: use
antihistamines/corticoste...
Biologic DMARDs
Genetically engineered protein molecules that block the pro-
inflammatory cytokines
TNF-α (infliximab, e...
Selecting a Biologic DMARD
 The risk of infection in patients treated with biologic DMARDs must be considered
when select...
57
58
Monitoring and evaluation
 Clinically (signs and symptoms) & lab. for effectiveness and safety
59
Drug Toxicities Requiri...
60
Upcoming SlideShare
Loading in …5
×

Rheumatoid Arthritis

  • Be the first to comment

Rheumatoid Arthritis

  1. 1. Musculoskeletal disorders therapeutics By: Tsegaye Melaku [B.Pharm, MSc, Clinical Pharmacist] 02, January, 2017 tsegayemlk@yahoo.com or tsegaye.melaku@ju.edu.et +251913765609 Chapter 1 Rheumatoid Arthritis 1
  2. 2. Learning objectives Upon completion of the chapter, you will be able to: Explain the pathophysiologic mechanisms for rheumatoid arthritis. List the symptoms associated with rheumatoid arthritis (RA). List the extra-articular manifestations of RA. List the laboratory tests used in diagnosing RA. Components of non-drug approaches to assist in the management of RA. Create a stepwise plan for treatment of RA in a patient who does not respond to therapy. Design a therapeutic & monitoring plan to treat RA. 2
  3. 3. Mini case A. A, a 37 year-old woman with a 5-year history of rheumatoid arthritis who presented with fatigue and dyspnea from Jimma. One month before her admission to JUMC , she developed pleuritic chest pain and was treated by her primary care provider for “bronchitis” with Amoxicillin. Over the next five days her pain worsened and she became short of breath. She was admitted to Shenen Gibe hospital , where she was found to be in new-onset atrial fibrillation with an elevated troponin level of 4.4 ng/ml. Echo showed a small pericardial effusion. Past Medical History: HTN, Gastritis.  What other investigation should be done?  Complication from RA?  How can we treat optimally?? DOC, safety concern!!!  Any drug interaction and pharmaceutical care revision??  Monitor and evaluate?? 3
  4. 4. 4
  5. 5. Introduction: RA Most common systemic inflammatory disease characterized by symmetrical joint involvement Chronic, progressive inflammatory disorder of unknown etiology. x-zed by poly-articular symmetric joint involvement and systemic manifestations. 5
  6. 6. Epidemiology Prevalence in US: 1%, 1-2% of the world’s population. Can occur at any age, with increasing prevalence up to the 7th decade of life. More common in women (3x) From ages 15 to 45 yrs; women :men6:1; otherwise equal. 6
  7. 7. Etiology Cause of RA is unknown. Genetic: account for 50% of the risk. Environmental, hormonal, immunologic, and infectious factors may play significant roles. 7 HLA-DR-4: present peptide to T cells
  8. 8. Pathophysiology  It results from a complex interaction between genes and environment  breakdown of immune tolerance and synovial inflammation.  Given the heterogeneous response to therapy, RA in not just a single disease.  The initiation of RA is a combination of pre-determined (genetic) and stochastic (random) events.  Susceptibility to RA is clearly defined by a pattern of inherited genes, with the HLA major histocompatability genes as the most important.  However, scores of minor genes : cytokine promoters, T cell signaling genes, and many others, contribute to susceptibility and severity. 8 Genetic or infectious antigen?!!
  9. 9. Immune system: complex network of checks and balances designed to discriminate self from non-self (foreign) tissues. It helps rid the body of infectious agents, tumor cells, and products associated with the breakdown of cells. In RA, this system no longer can differentiate self from non-self tissues  attacks the synovial tissue and other connective tissues. 9 Cont’d…
  10. 10.  The characteristics of a synovium affected by RA are: a) Presence of a thickened, inflamed membrane lining called pannus. b) Development of new blood vessels; and c) Influx of inflammatory cells in the synovial fluid, predominantly T lymphocytes.  The pathogenesis of RA is driven by T-lymphocytes, but the initial catalyst causing this response is unknown. Components of the immune system and their involvement: T-lymphocytes, cytokines, and B-lymphocytes 10 Cont’d…
  11. 11. T-Lymphocytes  Development and activation of T lymphocytes!! Maintain protection from infection without causing harm to the host.  Activation of mature T lymphocytes requires two signals. Presentation of an antigen by APC to the T-lymphocyte receptor. A ligand-receptor complex (i.e., CD80/CD86) on antigen- presenting cells binds to CD28 receptors on T-lymphocytes.    activation of inflammatory cascade. 11 APC: antigen-presenting cells
  12. 12.  Activation of T lymphocytes   Stimulates the release of macrophages or monocytes, release of inflammatory cytokines Activates osteoclasts Activates the release of matrix metalloproteinases or enzymes responsible for the degradation of connective tissue. Stimulates B lymphocytes and the production of antibodies. 12
  13. 13. Cytokines Are proteins secreted by cells (serve as intercellular mediators). Can be a) Pro-inflammatory: IL-1, IL-6, IL-17,TNF-α (high concentrations in synovial fluid) b) Anti-inflammatory: IL-4, IL-10, and IL-1 receptor antagonist  Imbalance  inflammation and joint destruction. Pro-inflammatory cytokines   activation of other cytokines and adhesion molecules  recruitment of lymphocytes to the site of inflammation. 13
  14. 14. 14
  15. 15. B Lymphocytes  Serve as APCs to T lymphocytes. Produce pro-inflammatory cytokines and antibodies.  Antibodies of significance: rheumatoid factors (RFs) and antibodies against cyclic citrullinated peptide (CCP).  RFs are not present in all patients with RA Its presence indicate: disease severity, likelihood of extra-articular manifestations, and increased mortality!!  CCPs: produced early in the course of disease. High levels of anti-CCP antibodies: indicative of aggressive disease and a greater likelihood of poor outcomes. 15
  16. 16. 16
  17. 17. 17 Clinical Presentation Pale yellow
  18. 18. 18
  19. 19. 19
  20. 20. 20 RA versus OA
  21. 21. Diagnostic work-up  P/E & history (extra- articular manifestations)  Lab. Investigations RF, ESR, CRP, anti-CCP antibodies CBC Synovial fluid analysis  Imaging (MRI, X-ray) 21 DDx
  22. 22. 22
  23. 23. 23 Joint Involvement
  24. 24. 24
  25. 25. Dx of Juvenile Idiopathic Arthritis (JIA) Age <16 years at disease onset Arthritis in one or more joints for more than 6 weeks Exclusion of other types of arthritis. 25
  26. 26. Systemic (10%): Girls : boys ; 1:1 X-tic fever spikes twice daily (>38.3°C) Presence of a pale, pink, transient rash. The peak onset :1 and 6 years. Polyarticular (40%): Girls >boys (3:1) Arthritis of ≥ 5 joints. Resembles adult RA Pauciarticular (50%): Girls > >boys (5:1). Uveitis is more likely Arthritis of ≤ 4 joints. Categorized:  Early onset (more in girls)  Late onset (more in boys) 26 Types of JIA
  27. 27. Poor prognosis indicators The most clinically important features associated with poor long- term outcomes: Functional limitation (Health Assessment Questionnaire [HAQ] score) Extra-articular disease Positive rheumatoid factor Positive anti-CCP antibodies, and/or Bony erosions by radiography. 27
  28. 28. Extra-articular Involvement Rheumatoid Nodules Occur in 20% of patients with RA. Commonly on the extensor surfaces of the elbows, forearms, and hands. Also in lung or pleural lining, meninges Vasculitis: invasion of blood vessel walls by inflammatory cells In patients with long-standing RA Results in an obliteration of the vessel infarction of tissue distal to the area (ends of the fingers or toes) 28
  29. 29. Pulmonary Complications Pleural effusions, Interstitial pneumonitis and arteritis, nodules Smoking increase the risk. Cardiac Involvement Pericarditis  accumulation of fluid. Aggressive management of systemic inflammation and traditional cardiovascular risk factors (e.g., blood pressure, cholesterol, tobacco use) Felty's Syndrome: splenomegaly + neutropenia Also thrombocytopenia More susceptible to infection 29
  30. 30. Malignancy Increased risk of developing lymphoproliferative malignancy (e.g., lymphoma, leukemia, and multiple myeloma) and lung cancer. Osteoporosis Increased osteoclast activity; Inhibit osteoblast activity. Renal involvement Rare (associated NSAIDs, gold salts, and penicillamine). 30
  31. 31. Treatment Desired Outcomes Reduce or eliminate pain, Protect articular structures, Control systemic complications, Prevent loss of joint function, Improve or maintain quality of life. Maintaining normal growth, development, & activity level(for JIA/JRA). 31
  32. 32. General Approach to Treatment Early dx and early aggressive Rx necessary (reduce disease progression and prevent joint damage). Aggressive treatment: use of 1 or more DMARDs at effective doses. Disease severity and presence of poor prognostic features DMARD should be started within the first 3 months of symptom onset. Options: NSAIDs Glucocorticoids Non-biologic DMARDs, Biologic DMARDs. 32 DMARDs: disease-modifying anti-rheumatic drugs Treat based on  Activity level of the patient’s disease,  Presence or absence of poor prognostic features,  Duration of disease activity (early vs. established).  Early introduction of DMARDs results in a more favorable outcome
  33. 33. Non-pharmacologic Therapy  Rest: alleviation of pain  Occupational therapy, physical therapy: skills and exercises necessary to increase or maintain mobility  Use of assistive devices: Canes, walkers, and splints  Weight reduction:  Surgery : 33
  34. 34.  Early RA with low disease activity: non-biologic DMARD monotherapy (initial Rx)  Hydroxychloroquine, minocycline, leflunomide, methotrexate, or sulfasalazine.  Moderate/high disease activity but without poor prognostic features:  DMARD monotherapy or methotrexate+ hydroxychloroquine (initial Rx).  Moderate/high disease activity and evidence of poor prognostic features:  Combination: methotrexate +hydroxychloroquine, methotrexate+ sulfasalazine or methotrexate+ sulfasalazine+ hydroxychloroquine.  Alternative: started on anti-TNF therapy with or without methotrexate. 34 Early RA Rx
  35. 35. 35 Recommendations for the treatment of early RA (disease duration less than 6 months) bCombination DMARD therapy: methotrexate + leflunomide, methotrexate + hydroxychloroquine, methotrexate + sulfasalazine, sulfasalazine + hydroxychloroquine. Triple DMARD therapy: methotrexate + hydroxychloroquine + sulfasalazine.
  36. 36.  Biologic DMARDs : Consider in patients with established RA following inadequate response to non-biologic. Switch: in a patient who experiences an inadequate response or adverse event. Combination is mandatory in most of cases. 36 Established RA Rx
  37. 37. 37 Recommendations for the treatment of established RA (disease duration 6 month or longer) bCombination DMARD therapy methotrexate + leflunomide, methotrexate + hydroxychloroquine, methotrexate + sulfasalazine, sulfasalazine + hydroxychloroquine. Triple DMARD therapy: methotrexate + hydroxychloroquine + sulfasalazine. cReassess after 3 months of adequate therapy. dReassess after 6 months of adequate therapy
  38. 38. 38 Poor prognosis: limitation in function, extra-articular findings (rheumatoid nodules, vasculitis, Felty syndrome, Sjogren syndrome, rheumatoid lung findings, erosions on radiograph). Algorithm for treatment of RA using non-biologic DMARDs
  39. 39. Algorithm for Rx of RA using biologic agents 39
  40. 40. NSAIDS  Analgesic and anti-inflammatory benefits for joint pain and swelling.  Don’t prevent joint damage or change the underlying disease.  As “bridge therapy” to provide symptomatic relief until the therapeutic effect of the DMARD is observed.  If a patient does not receive relief from one NSAID, it is acceptable to try a second one (interpatient variability in response) 40 NSAIDs and/or corticosteroids may be used for symptomatic relief  provide relatively rapid improvement in symptoms compared with DMARDs (weeks to months)
  41. 41.  Adverse event of NSAIDS: GI ulcers or hemorrhage, fluid retention, exacerbation of existing hypertension, and decreased renal function  Factors that place a patient at a higher risk of GI-related adverse reactions include: History of PUD. High doses of NSAIDs. Concomitant use of other medications with an increased risk of GI hemorrhage or ulcers (e.g., anticoagulants, corticosteroids, use of multiple NSAIDs) Age greater than 75 years 41
  42. 42.  Increased risk of NSAID-induced adverse reactions: use gastro-protection: PPI: preferred, greater acid suppression, prevention of both gastric and duodenal ulcers, and a tolerable adverse-effect profile Misoprostol: effective in reducing the occurrence of gastric and duodenal ulcers (but, diarrhea limit its use) H2RA: prevent duodenal ulcers (but not gastric ulcers)  NSAIDs may accentuate the increased risk of CV events inherent in patients with RA. Increases in blood pressure and fluid retention may exacerbate existing CV disease. 42
  43. 43. 43 Dosage Regimens for Nonsteroidal Anti-inflammatory Drugs Drug Adult Children Dosing Schedule Aspirin 2.6–5.2 g 60–100 mg/kg 4x daily Celecoxib 200–400 mg – Daily to twice daily Diclofenac 150–200 mg 3-4x daily; Extended release twice daily Diflunisal 0.5–1.5 g – Twice daily Etodolac 0.2–1.2 g (max. 20 mg/kg) – Twice daily to 4 times daily Fenoprofen 0.9–3.0 g – Four times daily Flurbiprofen 200–300 mg – 2-4x daily Ibuprofen 1.2–3.2 g 20–40 mg/kg 3-4x daily Indomethacin 50–200 mg 2–4 mg/kg (max. 200 mg) T2-4x daily Extended release daily Meclofenamate 200–400 mg – 3-4x per day Meloxicam 7.5–15 mg – Daily Nabumetone 1–2 g – Daily to twice daily Naproxen 0.5–1.0 g 10 mg/kg 2x Extended release–daily Naproxen sodium 0.55–1.1 g – Twice daily Nonacetylated salicylates 1.2–4.8 g – 2-6x per day Oxaprozin 0.6–1.8 g (max. 26 mg/kg) – 1- 3 x a day Piroxicam 10–20 mg – Daily Sulindac 300–400 mg – Twice daily Tolmetin 0.6–1.8 g 15–30 mg/kg Twice daily to 4 times daily
  44. 44. Corticosteroids  Anti-inflammatory and immunosuppressive properties.  Interfere with antigen presentation to T lymphocytes,  Inhibit prostaglandin and leukotriene synthesis,  Inhibit neutrophil and monocyte superoxide radical generation.  Impair cell migration redistribution of monocytes, lymphocytes, and neutrophils blunting the inflammatory and autoimmune responses. Used in bridging therapy, continuous low-dose therapy, and short- term, high-dose bursts to control flares. 44 Control pain and synovitis
  45. 45.  Patients with difficult-to-control disease: low-dose, long-term corticosteroid(control their symptoms).  Alternate-day dosing not recommended (due to flares).  High-dose corticosteroid bursts: to suppress disease flares.  Sustained for several days until symptoms are controlled taper to the lowest effective dose.  Intramuscular steroids: in patients with adherence problems for short-term therapy.  Long-acting depot steroids:  Provides the patient with 2 to 6 weeks of symptomatic control.  Provides a physiologic taper, avoiding withdrawal reaction  Triamcinolone acetonide, triamcinolone hexacetonide, and methylprednisolone acetate. 45
  46. 46.  IV steroids: Patient with large amounts of drug during a steroid burst to control severe symptoms.  Intra-articular depot forms steroids: treat synovitis and pain when a small number of joints are affected.  Fewest number of systemic adverse effects (preferred to IV/IM)  If effective, may be repeated every 3 months  No one joint should be injected more than 2 to 3 times per year (joint destruction and atrophy of tendons).  Side effects: Bone loss, Cushing's syndrome, PUD/gastritis, hypertension, weight gain, infection, mood changes, cataracts, dyslipidemia, and hyperglycemia, skin atrophy 46
  47. 47. DMARDs  Non-biologic and biologic  Mainstay of RA treatment (modify the disease process and prevent or reduce joint damage).  Initial choice depends on: disease severity, patient characteristics (i.e., comorbidities, likelihood of adherence), cost, and clinician experience with the medication.  Methotrexate alone or in combination: initial treatment.  Early, mild disease: monotherapy of sulfasalazine, leflunomide or hydroxychloroquine.  Agents: azathioprine, penicillamine, gold salts, and rarely used today(toxicity and reduced efficacy). 47
  48. 48. Non-biologic DMARDs  Inhibit of dihydrofolate reductase, which causes the inhibition of purines and thymidylic acid and by inhibiting the production of certain cytokines.  Once-weekly doses within 3 months of dx  increased steadily until the patient has symptomatic improvement or a maximum dose of 20 mg/week is reached.  Concomitant folic acid necessary : to prevent (e.g., stomatitis, diarrhea, nausea, alopecia, myelosuppression, and elevations in liver function tests)  Effect may be seen early as 2 to 3 weeks after starting therapy; maximal response in 3 to 6 months 48 Methotrexate Oral or IM: 7.5–15 mg q wk 5 -15 mg/m2 q wk in JIA If dose >15mg give parenteral, decreased BA of oral, due to saturable kinetics
  49. 49. Methotrexate: concern!!!  Contraindication  Pregnant and nursing women, DC 3 months prior to attempting conception.  Chronic liver disease, immunodeficiency,  Pleural or peritoneal effusions,  Leukopenia, thrombocytopenia, preexisting blood disorders,  CrCL < 40 mL/min.  Side effects:  Stomatitis (3% to 10%) D, V, N(10%, thrombocytopenia (1% to 3%),Leukopenia  Pulmonary fibrosis, pneumonitis ( rare, severe)  hepatotoxicity (15%), cirrhosis (rare) 49
  50. 50. Leflunomide  Inhibits pyrimidine synthesis  decrease in lymphocyte proliferation and modulation of inflammation.  Inhibits Dihydroorotate dehydrogenase** inhibits the T-lymphocyte response  LD 100 mg daily for 3 days, followed by a MD of 20 mg daily Long elimination t1/2 (14–16 days); so take time to reach steady state.  Use low dose if GI intolerance, complain of hair loss.  Side effects: hepatotoxicity, bone marrow toxicity  Teratogenic (use contraceptive) 50 ** Enzyme supplies T lymphocytes with the necessary components to respond to cytokine stimulation
  51. 51.  If conception is desired, leflunomide must be discontinued.  Because leflunomide undergoes enterohepatic circulation, the drug takes many months to drop to a plasma concentration.  Use cholestyramine: 240 mg/kg/day  To rapidly clear the drug from plasma.  In the event of severe toxicity. 51 UMP: uridine monophosphate
  52. 52. Hydroxychloroquine  Exact MOA unknown  Immunomodulatory activity in T helper 17 (Th17) cytokines.  Diminish the formation of peptide-MHC protein complexes required to stimulate CD4+ T cells  in down-regulation of the immune response against auto antigenic peptides.  Its onset delayed up to 6 weeks (wait 6 months of therapy to say therapeutic failure).  Advantage: lack of myelosuppressive, hepatic, and renal toxicities  Side effects: N, V, D, accommodation defects, benign corneal deposits, blurred vision, rash, alopecia, and increased skin pigmentation; headache, vertigo, and insomnia 52
  53. 53. Sulfasalazine A prodrug (cleaved in to sulfapyridine and 5-aminosalicylic acid) by bacteria in the colon (azoreductase) Sulfapyridine moiety: responsible for its antirheumatic properties. Antirheumatic effects should be seen in 2 months. GI adverse effects (N, V, D, and anorexia) limit its use. Start with low doses and titrating gradually to higher doses, Dividing the dose more evenly throughout the day, or Use enteric-coated preparations. 53 In older than 6 years is 30 to 50 mg/kg/day in 2 doses
  54. 54.  Other side effects of sulfasalazine:  Rash, urticaria, and serum sickness-like reactions: use antihistamines/corticosteroids.  Hypersensitivity reaction occurs: stop immediately and another DMARD substituted.  Leukopenia, alopecia, stomatitis, and elevated hepatic enzymes.  Urine and skin to turn a yellow-orange color (adherence??)  Its absorption can be decreased,  if antibiotics used (effect on colonic bacteria).  Binds iron supplements  Potentiate warfarin's effects by displacing it from protein-binding sites. 54
  55. 55. Biologic DMARDs Genetically engineered protein molecules that block the pro- inflammatory cytokines TNF-α (infliximab, etanercept, adalimumab, golimumab, and certolizumab), IL-1 (anakinra), & IL-6 (tocilizumab), Deplete peripheral B cells (rituximab), or Bind to CD80/86 on T cells to prevent the co-stimulation needed to fully activate T cells (abatacept). 55
  56. 56. Selecting a Biologic DMARD  The risk of infection in patients treated with biologic DMARDs must be considered when selecting and monitoring therapy.  Use of TNF-α antagonists in patients with a history of tuberculosis exposure.  Reactivated infection of latent TB!!??  Initiated after at least 1 month of anti-tuberculosis treatment.  Patients with untreated hepatitis B should not receive them.  Should not be initiated during an acute, serious infection and should be discontinued temporarily during times of infection  Cost consideration  Rituximab should be discontinued 1 year prior to planned conception.  Abatacept should be discontinued 10 weeks prior to planned conception. 56
  57. 57. 57
  58. 58. 58
  59. 59. Monitoring and evaluation  Clinically (signs and symptoms) & lab. for effectiveness and safety 59 Drug Toxicities Requiring Monitoring Symptoms to Inquire About NSAIDs and salicylates GI ulceration and bleeding, renal damage Blood in stool, black stool, dyspepsia, nausea/vomiting, weakness, dizziness, abdominal pain, edema, weight gain, SOBC Corticosteroids Hypertension, hyperglycemia, osteoporosis Blood pressure if available, polyuria, polydipsia, edema, SOB, visual changes, weight gain, headaches, broken bones or bone pain Azathioprine Myelosuppression, hepatotoxicity, lymphoproliferative disorders Symptoms of myelosuppression (extreme fatigue, easy bleeding or bruising, infection), jaundice Gold (intramuscular or oral) Myelosuppression, proteinuria, rash, stomatitis Symptoms of myelosuppression, edema, rash, oral ulcers, diarrhea Hydroxychloroquine Macular damage, rash, diarrhea Visual changes including a decrease in night or peripheral vision, rash, diarrhea Methotrexate Myelosuppression, hepatic fibrosis, cirrhosis, pulmonary infiltrates or fibrosis, stomatitis, rash Symptoms of myelosuppression, SOB, nausea/vomiting, lymph node swelling, coughing, mouth sores, diarrhea, jaundice Leflunomide Hepatitis, GI distress, alopecia Nausea/vomiting, gastritis, diarrhea, hair loss, jaundice Penicillamine Myelosuppression, proteinuria, stomatitis, rash, dysgeusia Symptoms of myelosuppression, edema, rash, diarrhea, altered taste perception, oral ulcers Sulfasalazine Melosuppression, rash Symptoms of myelosuppression, photosensitivity, rash, nausea/vomiting Etanercept, adalimumab, golimumab, certolizumab, tocilizumab anakinra Local injection-site reactions, infection Symptoms of infection Infliximab, rituximab, abatacept Immune reactions, infection Postinfusion reactions, symptoms of infection
  60. 60. 60

×