MSK 01 and 05: DMARDs Flashcards
What is the mechanism of action of DMARDs?
- slow progression of rheumatoid arthritis
- decrease immune cell response, therefore decrease inflammation and joint injury
What are TH1 (T helper) lymphocytes?
- produce interferon-γ, interleukin-2 (IL-2), and tumour necrosis factor-β (TNF-β)
- activate macrophages, cytotoxic T cells, and natural killer cells
What are TH2 (T helper) lymphocytes?
- produces IL-4, IL-5, IL-6, and IL-10
- induces B cell proliferation and differentiation into antibody-secreting plasma cells
What is the mechanism of action of methotrexate?
- inhibits dihydrofolate reductase (which normally converts folate to dihydrofolate to tetrahydrofolate) – important for production of purines and thymidine, and likely underlies anti-proliferative effects
- increases extracellular adenosine levels, which suppresses inflammatory functions of neutrophils, macrophage, dendritic cells, and other lymphocytes
What are the toxicities of methotrexate?
- leucopenia, anemia, oral and GI ulcerations, and alopecia – due to inhibition of cellular proliferation
- hepatic toxicity (steatosis and fibrosis) – may be due to adenosine release
- fatigue – may be due to release of adenosine, which is somnogenic
What can folic acid be used for while taking methotrexate?
can be used weekly to decrease GI and hepatic toxicity without effects on efficacy
Describe the metabolism of methotrexate.
oxidized to 7-hydroxyl-MTX – both parent drug and metabolite are cleared by kidney (interaction with NSAIDs)
Describe the ADME of sulfasalazine (SASP).
- 5-ASA bond to antibiotic sulfapyridine (SP) d removed by azoreductase (bacterial colonic enzyme), which converts SASP into 5-ASA and SP in colon
- ## 15% of SASP is absorbed from small intestine, SP freely absorbed from colon, 5-ASA minimally absorbed
What is the mechanism of action of sulfasalazine (SASP)?
- decreases T cell responsiveness, B cell proliferation, and cytokine production (IL 2 and INFγ, IL1, TNFa and IL6)
- TNFa receptor antagonist
- increases adenosine concentrations (like methotrexate)
What does caffeine do in rheumatoid arthritis?
promotes IFN-γ release by TH1 cells – this is reversed by adenosine
What are the adverse effects of sulfasalazine?
- nausea, GI upset, headaches, arthralgias, myalgias, bone marrow suppression, and malaise (30% cannot tolerate drug)
- oligospermia (reversible low sperm count)
- impairs folate absorption and processing
- often dose related, with slow acetylators of sulfapyridine at greater risk for ADRs
What is the mechanism of action of hydroxychloroquine?
- antimalarial drug
- immunomodulatory (decrease B and T cell activity, cytokine production), but mechanisms for effect in rheumatoid arthritis remain uncertain
What are the adverse effects of hydroxychloroquine?
- irreversible retinopathy and ototoxicity at cumulative total doses > 1 g of base/kg body weight
- reversible myopathy and peripheral neuropathy
- headache, nightmares, psychosis, seizure, vertigo
- abdominal cramping, anorexia, nausea, vomiting, diarrhea, abnormal liver function
- alopecia, pigmentation changes (skin and mucosal, black-blue colour)
- anemia, leukopenia, thrombocytopenia
What is the mechanism of action of leflunomide (prodrug)?
pyrimidine biosynthesis inhibitor (anti-proliferative agents)
- inhibition of dihydroorotate dehydrogenase depletes uridine monophosphate (UMP)
- activated T- and B-lymphocytes depend strongly on de novo synthesis, therefore proliferation is greatly attenuated
What are the adverse effects of leflunomide?
- no significant leukopenia or thrombocytopenia
- diarrhea, nausea, abdominal pain, vomiting – transient or dose related
- hepatotoxicity – rare, but sometimes fatal (active metabolite cleared by liver)
- drug-related hypertension – increase in sympathetic drive or displacement of free fraction of concomitant diclofenac or ibuprofen from protein binding increases NSAID effect on BP
What are janus kinases (JAK)?
group of 4 tyrosine receptor kinases involved in cytokine receptor signalling pathways
What are the 3 JAK inhibitors and their mechanism of action?
reduce inflammatory cell influx into joints
- tofacitinib: selective inhibitor all 4 JAKs, but most potent at JAK3 which is critical for immune response
- baricitinib: relatively selective inhibitor of JAK1/2
- upadacitinib: relatively selective inhibitor of JAK 1 (but also inhibits JAK 2)
What are the adverse effects of janus kinase inhibitors?
- thrombosis – including deep venous thrombosis, pulmonary embolism, arterial thrombosis
- lymphoma and other malignancies
- neutropenia, anemia – due to effects on erythropoietin signalling
- increased serious infections (ie. opportunistic tuberculosis, cryptococcus, pneumocysti) and marked increase in reactivation of Herpes Zoster, which causes shingles
- nasopharyngitis, hypercholesterolemia
- strong CYP3A4 inhibitors (ie. ketoconazole) will increase levels of tofacitinib and upadacitinib
How does methotrexate act as a folic acid analogue?
- 4-amino group on methotrexate forms H-bonds with backbone carbonyl oxygen atoms of Ile7 and Val115 on DHFR, which accounts for better binding affinity than between DHFR and folic acid
- 4-amino group on methotrexate provides additional electron density within pteridine ring, which is fully aromatic and difficult to reduce
What is the proposed mechanism of action of methotrexate?
- inhibits dihydrofolate reductase, therefore no production of DHF to THF
- inhibition of THF production prevents dTMP formation from dUMP (thymineless death) – blocks B cell proliferation by interfering with DNA synthesis, repair, and replication
- inhibition of enzyme glycinamide ribonucleotide (GAR) tranformylase (key enzyme in synthesis of purine nucleotides (ie. AMP and GMP)
- inhibition of polyamine (ie. spermine production – polyamines are basic compounds responsible for inducing tissue damage and activation of NF-kB (release of inflammatory mediators) in disease
What is the pyrimidine biosynthetic step of leflunomide?
- rate-limiting step is conversion of dihydroorotic acid to orotic acid by catalytic activity of enzyme dihydroorotate dehydrogenase (DHODH)
- proposed mechanism of DHODH enzyme involves stereospecific deprotonation (5 position) by catalytic serine residue and hydride transfer (6 position) to FMNOX, fumarate, NAD+, or coenzyme Q10 depending on DHODH class and subclass
How is leflunomide activated?
- prodrug that is rapidly metabolized (half-life < 1 hour) after oral administration to teriflunomide by CYP1A2
- teriflunomide binds to DHODH enzyme
How is DHODH inhibited?
- teriflunomide binds to DHODH enzyme and exhibits non-competitive inhibition toward DHODH
- DHODH inhibition by teriflunomide prevents B and T cell proliferation by interfering with cell cycle progression
