DMARDs Flashcards
Methotrexate (MTX) description
DMARD
DOC -> first DMARD prescribed for mild, moderate or severe RA
Decreases purine synthesis
Decrease toxicity with leucovorin or folic acid
Methotrexate Mechanism
DMARD
Inhibits AICAR transformylase -> final step in de novo purine synthesis forming IMP
Also leads to the accumulation of adenosine which is a potent anti inflammatory mediator -> decrease NF-kB
Methotrexate PK/PD
DMARD
Requires much lower dose than what is needed to CA chemotherapy -> inhibits DHF reductase
Methotrexate AE/contraindications
Nausea, ulcers
Hepatotoxicity (dose related)
Pseudolymphomatous rxn
Contraindicated in pregnancy
Leflunomide description
DMARDS
Prodrug converted to an active metabolite
Cells are arrested in G1
Decreases pyrimidine synthesis
Leflunomide mechanism
DMARDS
Inhibits dihydroorotate dehydrogenase -> decrease UMP
Inhibits autoimmune T&B cell proliferation which have increased need for DNA precursors (other cell are able to maintain basal pyrimidine requirements through salvage pathways)
Leflunomide PK/PD
DMARDS
Can cause severe hepatotoxicity when combine with MTX
Monitor CBC and LFT’s
Leflunomide AE/contraindications
DMARDS
Frequent diarrhea Alopecia, rash Myelosuppression Increase aminotransferase activity *Contraindicated in pregnancy*
Hydroxychloroquine description
DMARDS
Often used with MTX and sulfasalazine
Hydroxychloroquine PK/PD
DMARDS
Ophthalmology exam before treatment and annually thereafter for high risk pts
Hydroxychloroquine AE/contraindications
DMARDS
- *Hemolysis in patients with decreased G6PD**
* *Retinal damage** is rare
Sulfasalazine description
DMARDS
In contrast to use for the treatment of ulcerative colitis, Sulfapyridine is the active DMARD
Sulfasalazine PK/PD
DMARDS
Diazo bond metabolized by bacteria in colon to sulfapyridine and 5-ASA
Sulfasalazine AE/contraindications
DMARDS
Nausea, anorexia, rash Hepatitis, leukopenia *Lupus like syndrome* *Hemolysis in decrease G6PD* ****Safe in pregnancy*****
Cyclosporine description
DMARDS
Inhibits Ag triggered signal transduction in T cells
Only used in severe cases
Cyclosporine mechanism
DMARDS
Forms a comlpex with cyclophilin -> prevents calcineurin from desphosphorylating NFAT -> decrease IL-2
Cyclosporine PK/PD
DMARDS
Many drug interactions and widespread nephrotoxicity -> limited use
Cyclosporine AE/contraindications
DMARDS
Nephrotoxicity
Hirsutism & gum hyperplasia
Tremor, HTN, hyperglycemia, hyperlipidemia, osteoporosis
Azathioprine description
DMARDS
Purine antimetabolite
Only used in cases of refractory RA
Azathioprine mechanism
DMARDS
Converted to 6-MP -> inhibition of de novo purine synthesis -> suppression of T & B cells
Azathioprine PK/PD
DMARDS
Reduce dose in pts taking allopurinol due to inhibition of xanthine oxidase
Azathioprine AE/contraindications
DMARDS
BM suppression
GI disturbance
Infection and malignancy risk
Cyclophosphamide description
DMARDS
Generally limited to the most severe cases of RA
Cyclophosphamide mechanism
DMARDS
Alkylating agents -> cross links DNA -> prevents cell replication
Cyclophosphamide PK/PD
DMARDS
Mesna is used to treat hemorrhagic cystitis caused by cyclophosphamide
Cyclophosphamide AE/contraindications
DMARDS
BM suppression, infertility
Hemorrhagic cystitis
Infection and malignancy risk
Fanconi’s anemia
Gold sodium thiomalate & Auranofin description
DMARDS
Macrophage poisons with high toxicity rendering them basically obsolete
Gold sodium thiomalate & Auranofin mechanism
DMARDS
Suppress phagocytosis and lysosomal enzyme activity
Gold sodium thiomalate & Auranofin PK/PD
DMARDS
GST is given IM
Auranofin is oral
Adalimumab description
DMARDS
Fully human IgG1 anti-TNF Ab
Adalimumab mechanism
DMARDS
Binds to soluble TNF alpha preventing is interaction with receptors -> downregulation of T-cell and macrophage function
Infliximab mechanism
DMARDS
Binds to soluble TNF alpha preventing is interaction with receptors -> downregulation of T-cell and macrophage function
Etanercept mechanism
DMARDS
Binds to soluble TNF alpha preventing is interaction with receptors -> downregulation of T-cell and macrophage function
Anakinra mechanism
DMARDS
IL-1 receptor antagonist
Adalimumab PK/PD
DMARDS
Pts need to be screened for latent TB prior to and during treatment with any TNF alpha inhibitor (also used in IBD)
Infliximab PK/PD
DMARDS
Pts need to be screened for latent TB prior to and during treatment with any TNF alpha inhibitor (also used in IBD)
Etanercept PK/PD
DMARDS
Pts need to be screened for latent TB prior to and during treatment with any TNF alpha inhibitor (also used in IBD)
Infliximab description
DMARDS
Chimeric anti TNF alpha
mouse and human
Etanercept description
DMARDS
Recombinant fusion protein -> 2 TNF receptors linked to IgG1
Adalimumab AE/contraindications
DMARDS
Cytopenia -> monitor CBC
Serious infection
Do not give to patients with active infection
Etanercept AE/contraindications
DMARDS
Cytopenia -> monitor CBC
Serious infection
Do not give to patients with active infection
Infliximab AE/contraindications
DMARDS
Cytopenia -> monitor CBC
Serious infection
Do not give to patients with active infection
Glucocoritcoids description
DMARDS
Prompt and dramatic effect, but use is controversial
Not real DMARDS
Glucocorticoids mechanism
DMARDS
Used for short term symptomatic relief until beneficial effects of DMARDs become apparent
Inhibit PLA2 and COX-2
Glucocorticoids PK/PD
DMARDS
AE associated with long term use
Do not affect CV risk
Glucocorticoids ae/contraindications
DMARDS
Osteoporosis, weight gain, ulcers, HTN, hyperglycemia, etc.
DMARD therapy
More effect if combination than monotherapy without significanly increasing toxicity
Combo typically includes MTX and another agent
MTX + leflunomide can increase risk for hepatoxicity
Never use multiple biological agents in combination therapy
DMARD biological agents
Adalimumab
Infliximab
Etanercept
Anakinra
Relief of RA
DMARDs
NSAIDs off symptomatic relief of RA, but have little effect on progression of disease
DMARDs have no immediate analgesic effect, but can control symptoms and delay progression of disease
Typically takes 6 weeks to 6 months for DMARD clinical effects to be seen, but some of the biologic DMARDs can have effects within 2 weeks
