Pharm-RA-DMARDS-nonBiologics Flashcards
What is a DMARD?
Disease-Modifying AntiRheumatic Drugs
What are the DMARD-non-Biological Agents? (4)
- Methotrexate
- Hydroxychloroquine
- Leflunomide
- Sulfasalazine
(No-Body Hates Meth-heads Like Salazar=Non-biologics→Hydroxychloroquine, Methotrexate, Leflunomide Sulfasalazine)
How were non-biologic DMARDs developed?
They are from many drug classes, and many were developed/used for the Rx of cancer and other diseases but were inadvertently found to treat RA.
What properties do non-biological DMARDs have in common? (2)
a. They improve inflammatory symptoms
b. They slow the progression of joint erosions
(they suppress inflammatory disease activity and produce quantifiable alterations in synovial tissue morphology)
How are non-biologic DMARDs used in the Rx of Rheumatoid Arthritis (RA)? Why is their use limited?
They are the cornerstone of RA Rx Regimens, especially as MONOTHERAPY.
However, toxicity and inadequate response limit use.
Often these agents (primarily MTX) are used in combination therapy w/ newer biologic DMARDs.
What is the MoA of MTX?
Immunosuppression, primarily via: A→B→C→5
a. Inhibition of AICAR Transformylase (the last step in de novo synthesis of IMP)→ Leads to accumulation of AICA Riboside→inhibits ADA→ increased circulating Adenosine concentration
b. Adenosine does several things: (5)
1) inhibits lymphocyte proliferation
2) suppresses secretion of IL-1, IFN-gamma, and TNF
3) increases secretion of IL-4
4) impairs release of histamine from basophils
5) decreases chemotaxis of neutrophils
What is unique about MTX that allows it to maintain high intracellular levels?
Upon entry into the cell, MTX undergoes POLYGLUTAMATION, which retains the drug intracellularly.
Metabolism of MTX? Therefore, contraindicated with what?
Hepatic metabolism and enterohepatic recirculation which increases its half-life; therefore, contraindicated with alcoholism, alcoholic hepatic ds, chronic hepatic ds
Elimination of MTX? What aids its elimination? What reduces its elimination
Primarily renal, especially tubular secretion; caution in renal failure
Alkalinization and hydration reduce renal damage and aid in elimination
Probenecid and weak acids compete for secretion and may reduce its elimination
ADE of MTX? (8)
HIV-LIX-GD
- CI’d in Hepatitis/alcoholism
- Immunosuppression Bone Marrow Suppression (leukopenia/thrombocytopenia) or Anemia→CI’d in immunosuppressed/HIV→increased risk of opportunistic infections and bleeding
- Interstitial pulm toxicity (Interstitial pneumonitis/pulm fibrosis→may be irreversible)
- cat. X teratogen; CI’d in breastfeeding
- avoid Vaccinations (Ab response is suboptimal)
- malignant Lymphomas
- severe Dermatologic rxns (SJS)
- GI toxicity, esp pt’s w/ PUD/ulcerative colitis and when used in conjunction with NSAIDs.
What 4 parameters need to be monitored in a pt taking MTX?
- CBC (immunosuppression/lymphoma)
- LFTs (liver/EtOH)
- SrCr/BUN
- Serum Uric Acid (tubular secretion)
Route/MoA of Sulfasalazine?
It’s an oral drug metabolized by bacteria in colon to active components:
a. Sulfapyridine (sulfonamide)
b. Mesalamine (5-aminosalicylic acid)→responsible for the beneficial effects
What is the future of Sulfapyridine?
Once absorbed, it is acetylated and hydroxylated in the liver
What type of pt’s need to be monitored for increases serum sulfapyridine levels?
Poor acetylators
What is the future of Mesalamine (5-ASA)?
It is responsible for most of the beneficial effects;
Anti-inflammatory properties b/c it inhibits PG and LT production.
Elimination of Sulfasalazine/Mesalamine?
Renal; caution in pt’s with renal failure; accumulation may occur with repeated dosing
ADEs of Sulfasalazine? (2)
- Hypersensitivity to 5-ASA, SA, or sulfonamide drugs
2. Hematotoxicity→potentially fatal blood dyscrasias
What needs to be monitored in pt’s taking Sulfasalazine? (4)
- CBC
- LFTs
- SrCr/BUN
- Urinalysis
Route/MoA of Leflunomide?
Oral; Its active primary metabolite A77-1726 inhibits Dihydroorotate Dehydrogenase (DHODH), a miitochondrial enzyme that catalyzes a key step in de novo PYRIMIDINE synthesis→T&B cell cycle progression and interaction is arrested/interrupted and Ig production is suppressed.
Leflunomide is cytotoxic or cytostatic?
Cytostatic at normal clinical doses
Leflunomide metabolism/elimination?
M=hepatic glucuronidation; may cause hepatotoxicity
E= in feces and renally→Uricosuric effect
Leflunomide ADEs/CIs? (3)
- Alcoholics/Liver damage (alcoholic hepatitis) due to its hepatic metabolism
- Severe immunodeficiency, BM dysplasia, or uncontrolled infection due to its immunosuppressive effects
- Cat. X Teratogen
What needs to be monitored in pt’s taking leflunomide? (4)
- CBC
- LFTs
- Pregnancy Testing
- Serum Electrolytes
UNIQUE*** MoA of Hydroxychloroquine?
a. It increases intracellular vacuole pH (altering processes such as protein degradation by acidic hydrolases in lysosomes, assembly of macromolecules in endosomes, and PTM’s of proteins in Golgi)
b. Acidic cytoplasmic compartments are required for antigen digestion and assembly of peptides onto MHC Class II alpha/beta chains.
c. Thus, this drug diminishes formation of peptide-MHC protein complexes required to to stimulate CD4+T cells are presented, resulting in down-regulation of the immune response to auto-antigenic peptides.
