Disease-Modifying anti-rheumatoid drugs Flashcards
What is Rheumatoid arthritis and what are its pathogenic mechanisms?
Chronic progressive autoimmune disorder of joints Pathogenic mechanisms: ◦ Inflammatory changes; ◦ The proliferation of the synovial membrane, erosions of cartilage and bone.
Main pathogenic role – TNF-α
and IL1
What role do TNF-alpha and IL1 play in RA?
Main pathogenic role – TNF-α
and IL1
TNF- alpha= systemic and synovial inflammation, increase endothelial adhesion molecules, T&B cell proliferation, increased bone destruction, increased IL-1 and IL-6 production.
IL-6 = increased CRP, T&B cell stimulation
IL-1 = increased recruitment of inflammatory cells, increased metalloproteases, increased osteoclast maturation (bone destruction)
How are DMARDs classified?
1) Classical drugs
◦ Sulfasalazine
2) Immunosuppressants
◦ Methotrexate
◦ Leflunomide
3) Biologic drugs
1. TNF-α–blocking agents
Etanercept
Infliximab
Golimumab
Adalimumab
Certolizumab
2. Anti–IL-6 receptor antibody
Tocilizumab
3. T-cell–modulating biologic drug
Abatacept
4. B-cell cytotoxic agent
Rituximab
5. IL-1–inhibiting agents
Anakinra
What are the clinical effects of DMARDS?
Slow onset and long duration of action
Clinical effects:
◦ Reduction of pain and stiffness of the joints
◦ Retardation of the disease progression
◦ Induction of remission
The current concepts of treatment favor an
aggressive early treatment and the use of drug
combinations.
What is sulfasalazine?
A complex of sulfapyridine and 5-aminosalicylic acid
What is the PK of sulfasalazine?
PK
◦ Cleavage of the molecule to both constituents in the colon under the action
of bacterial enzymes
◦ Absorption of sulfapyridine, while 5-aminosalicylic acid is not absorbed
What is the mechanism of action of sulfasalazine?
Mechanism of action: sulfapyridine – probably the active ingredient:
◦ Suppression of T-cell responses
◦ Inhibition of B-cell proliferation
◦ Inhibition of the release of inflammatory cytokines produced by monocytes or
macrophages, eg, IL-1, -6, and -12, and TNF-α.
what are the adverse reactions of sulfasalazine?
ADR – severe and common (30% of patients stop treatment)
◦ Nausea, vomiting, headache, skin rashes
◦ Neutropenia (reversible after drug discontinuation)
◦ Reversible infertility in men, without effect on fertility in women
The drug does not appear to be teratogenic.
What is methotrexate?
Anticancer drug, folic acid antagonist (anti-metabolite)
The first-line DMARD for treating rheumatoid arthritis and is used in 50–70% of patients.
Relatively rapid onset of effect (4-6 weeks)
What is the PK and mechanism of action of methotrexate?
PK: orally administered, once weekly
Mechanism of action:
◦ Intracellular accumulation of AMP which is released and converted
extracellularly to adenosine – a potent inhibitor of inflammation.
As a result, the inflammatory functions of neutrophils, macrophages, and
lymphocytes are suppressed.
◦ Inhibition of polymorphonuclear chemotaxis
◦ Direct inhibitory effect on proliferation and stimulation of apoptosis of
immune-inflammatory cells
◦ Inhibition of proinflammatory cytokines linked to rheumatoid synovitis
What are the adverse reactions of methotrexate?
ADR: relatively well tolerated because it is given in lower doses than in
cancer patients.
◦ Nausea and mucosal ulcers – the most common toxicities
◦ Dose-dependent hepatotoxicity ( liver enzymes)
◦ Bone marrow toxicity (leucopenia)
Contraindicated in pregnancy
What is leflunomide?
A newer drug, an immunomodulator
Undergoes rapid conversion, both in the intestine and in the plasma, to its active
metabolite, A77-1726(A77-1726), which:
◦ Inhibits dihydroorotate dehydrogenase, leading to a decrease in ribonucleotide synthesis and the arrest of
stimulated cells in the G1 phase of cell growth.
◦ Consequently, leflunomide inhibits T-cell proliferation and reduces production of autoantibodies by B cells.
◦ Secondary effects include increases of IL-10 receptor mRNA, decreased IL-8 receptor type A mRNA, and
decreased TNF-α-dependent nuclear factor kappa B (NF-κB) activation.
What are the PK, clinical use, and adverse reactions of leflunomide?
PK: good oral absorption; t1/2 = 19 days; similar is the t1/2 of the active metabolite;
administered orally once daily
Clinical use:
◦As effective as methotrexate in rheumatoid arthritis
◦Rapid onset of effect (4 weeks)
ADR: ◦ Diarrhea (25%) ◦ Elevation of liver enzymes ◦ Others: alopecia, weight gain, hypertension Contraindicated in pregnancy
What are biological drugs used in RA?
Biologics and biosimilars are special types of disease-modifying antirheumatic drugs
What are TNF-alpha-blocking agents?
Their development is based on the current
understanding of the role TNF-α.
They:
◦ Act faster than the classical DMARD;
◦ Are at least as effective as methotrexate;
◦ Could repair structural damage.
