Date post: | 03-Apr-2018 |
Category: |
Documents |
Upload: | drashua-ashua |
View: | 222 times |
Download: | 0 times |
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 1/16
รศ.ดร. บญเกด คงย งยศ ภาควชาเภสัชวทยา คณะแพทยศาสตร
มหาวทยาลัยขอนแกน 2555
DISEASE-MODIFYING
ANTIRHEUMATIC DRUGSDMARDs
DISEASE-MODIFYING
ANTIRHEUMATIC DRUGSDMARDs
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 2/16
2
• Purpose of drug therapy in rheumatoid arthritis
OBJECTIVES : DMARDs
• Notes on important drug groups:
- Hydroxychloroquine, chloroquine - Sulfasalazine
- Immunosuppressants:- Methotrexate, tacrolimus,
- Leflunomide
- Biologic agents:
- Anti-TNF: Infliximab, Adalimumab, Etanercept
- IL-1 inhibitor : Anakinra
- Immunomodulators: Abatacept, Rituximab Mechanism of action Adverse effects
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 3/16
3
• Rheumatoid Arthritis (RA)
Incidence increases with age Female : Male = 3 : 1 1% of world population Aged 40-70 years
incomplete known causes & unclear pathogenesis
• Genetic influence •
Autoimmune disease
A systemic inflammatory disorder movable joints
• Environmental factors: smoking?
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 4/16
4
Symptoms: pain, stiffness, swelling of peripheral joints Variable clinical course: remission continuing progression
joint deformity functional disability increased mortality
20% Mild RA 5% Disabilty
75% Continue havingInflammed joint
• Rheumatoid Arthritis (RA)
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 5/16
• Therapy of RA
• Main purpose of using DMARDs in RA
- Slow /stop the course of disease progression
2. Pharmacological :
no known cure pain & prevent destruction
definite diagnosis :
- DMARD initiation - immediate use- monotherapy- if poor response add DMARD Biologic DMARDs
NSAIDs, corticosteroids:
- before DMARD onset, during DMARD therapy
1. Non-pharmacological :
rest, weight, light & regular exercise
5
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 6/16
6
Improvement of symptoms & reduce disease activity reduce rheumatoid factor, anti CCP in serum
Unclear mechanism of action except biologic agents
some effective in other chronic inflammatory diseases
e.g. SLE, psoriasis, atopic dermatitis, Crohn’s disease, etc.
Effective as monotherapy, more effective in combination (2-3)
remission is possible (Individualization) Efficacy loss over time
tDMARDs
Slow onset (after 6 weeks – 6 months)
The use must be weighed against serious adverse effects
toxicity limits dose/duration of therapy
No general anti-inflammatory action
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 7/16
7
Hypothesized(auto) antigen
triggering events
Geneticpredisposition
Biologic DMARDRituximab
Biologic DMARDAbatacept
TraditionalDMARDs
MethotrexateLeflunomideSulfasalazine
Biologic DMARDs
Infliximab, AdalimumabEtanercept, Anakinra
Mechanism of action of drugs in RA
7
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 8/16
8
Sulfasalazine
Adverse effects: nausea, diarrhea, headache, folate absorption
Serious toxicities: granulocytopenia, hemolytic anemia (G6PD def.),
anaphylactic reactions 30% discontinue
Monitoring: CBC, LFT, G6PD level
Chloroquine, Hydroxychloroquine
Mechanism ?
- pH in lysosomes immune cell function
- stimulation of TLR (innate immune sys.)
Few side effects: nausea, diarrhea, headache, rashes
Serious toxicities: irreversible retinopathy dose & duration
- hydroxychloroquine < chloroquine
- ophthalmologic test every 6-12 months
colon bacteria sulfapyridine + 5-amino salicylic acid, poor absorbed
Mechanism ? - scavenge toxic oxygen metabolites of neutrophils
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 9/16
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 10/16
10
Tacrolimus: Macrolide (fungus)
• Calcineurin inhibitor ciclosporin but more potent
- T-cell proliferation ( IL-2 syn & IL-2-Rc), B-cell response• po, iv, ointment, 99% metabolized by liver , t1/2 7 h
• Adverse effects: ciclosporin but more severe
- higher nephrotoxicity & neurotoxicity, lower incidence of
hirsutism, GI effects, hyperglycemia
Leflunomide intestine, plasma active A77-1726
• inhibits dihydroorotate dehydrogenase (pyrimidine syn.)
• specific inhibitory effect on activated T-cells,
B-cell-autoAb production• oral active, well absorbed (80%), t1/2-19 days
• efficacy methotrexate
• Adverse effects: alopecia, diarrhea (25%)
- serious: hepatotoxicity, BM suppression
Immunosuppressants
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 11/16
11
Other DMARDs
• Minocycline
• Gold compounds
• Penicillamine
• Other immunosuppressants:
- Azathioprine- cyclosporine
In RA : variable success, unfavorable toxicities
rarely use now
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 12/16
12
Biologic agents
Infliximab
- chimeric mouse-human IgG1 monoclonal Ab TNF-a- binds both soluble & membrane bound TNF-a; iv, q8w, t1/2 9-12 d
macrophage, T-cell function
• recombinant engineered Ab or receptor
targeted at specific cytokines
• difficult and expensive to produce
• for inadequate response to tDMARD
Anti-cytokine: TNF-a, IL-1
Adalimumab - human IgG1 monoclonal Ab, sc, q2w
- similar to infliximab, t1/2 10-20 d,
Infliximab Adalimumab
Golimumab, Certolizumab
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 13/16
13
- a recombinant protein- two TNF p75 (sol.) Rc fused to Fc-IgG1
binds TNF-a (soluble & cell bound), sc, twice a week, t1/2 4.5 d
- efficacy comparable to methotrexate with earlier onset
Etanercept
Biologic agents
Adverse effects:
- risks of bacterial, fungal infection (URI)
- reactivation of latent TB
- rare leucopenia, hepatitis, SLE,neurologic deficits
- increase in Ab against the drugs
by + methotrexate
- injection site reactions antihistamines
- initial PPD skin test - a recombinant human IL-1 receptor antagonist (E. coli), sc, od
- Adverse effects: bacterial, viral infection, TB reactive, neutropenia
- Not with anti-TNF-a, not use live-virus vaccine
Anakinra
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 14/16
14
Immunomodulators in RA refractory to anti-TNF
Rituximab
- a chimeric monoclonal Ab against CD20 B-lymphocytes
- 2 i.v. infusion separated by 2 weeks, repeated after 6-9 m
- Adverse effects:
1st infusion reactions (urticaria, HT, angioedema) stop
IgG & IgM - gradually decrease, bacterial, viral infections
hepatitis B reactivation
Biologic agents
Abatacept : a costimulation modulator - A soluble recombinant fusion protein
competes with CD28 for binding on CD80/86 protein on APC
inhibits the activation of T cells
- i.v. infusion in 3 doses (d 0, w 2, & w 4) monthly infusions,
- Adverse effects: headache, infection (URI), nausea, Ab,not + anti-TNF, anakinra
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 15/16
15
ADCC = Ab-dependent cell-mediated cytotoxicity
7/28/2019 Anti RA Drugs
http://slidepdf.com/reader/full/anti-ra-drugs 16/16
16