Pharm: Drugs for Rheumatic Diseases Flashcards
Hydroxychloroquine - HCQ
Nonbiologic DMARDs-
**ok for pregnancy, but less effective than MTZ and LEF
MOA: unsure, but may suppress T cells responses, decreased leukocyte chemotaxis, inhibition of DNA/RNA synthesis and trapping of radicals
- takes 3-6 mos
AE’s:
- ocular toxicity, need opthalmalogic monitoring
- dyspepsia, nausea, vomiting, ab pain, rashes, nightmares
Leflunomide - LEF
Nonbiologic DMARDs
** as effective as MTX **
MOA: prodrug converted to active matbolite, A77-1726, in the intestine and plasma –> inhibits dihydroorotate dehydrogenase, leading to reduced ribonucleotide synthesis and cell arrest at G1
__ ultimately T cell and B cell production of autoAbs are inhibited ___
reponds in 6-12 weeks
response rates are better with MTX + LEF (but hepatotoxicity is increased)
AEs: diarrhea is very common! **liver enzymes elevated, mild alopecia, weight gain, increased BP, leukopenia, thrombocytopenia
CI in pregnancy!!!
** Methotrexate - MTX
Nonbiologic DMARDs
** first line DMARD for RA**
MOA: inhibits dihydrofolate reductase that results in impaired DNA synthesis causing cell death
- at low levels works as anti-inflammatory w/ increased extracellular levels of adenosine
- also inhibits proliferation and stimulates apoptosis in immune-inflamm. cells
- works within 4-6 weeks
AE’s: common: nausea, upset stomach, loose stools, stomatitis or soreness of mouth, alopecia, fever, macular punctate rash (usually on extremities); headache, fatigue
- hepatic enzymes elevated, should discourage drinking alcohol: hepatotoxicity
- pulmonary damage rare
- myelosupression is less frequent with low-dose therapy (red blood cell macrocytosis, leukopenia, anemia, thrombocytopenia)
- nephrotoxicity rare
** Folic acid used to reduce SE **
CI in pregnancy !!
Sulfasalazine - SSZ
Nonbiologic DMARDs -
**ok for pregnancy, but less effective than MTZ and LEF
MOA: ?? decreased IgA and IgM RF production, supression of T and B cell proliferation
- takes 1-3 mos.
AE: causes MORE toxicity than HCQ
- nausea, vomiting, h/a, anorexia, rash
- reversible infertility in men
- safe in pregnancy
Rarely used DMARds
- Azathioprine: immunosuppressive purine, reserved for pts. w/ refractory RA, risk of lymphoma, CI in pregnancy
- Cyclosporine: peptide antibiotic that inhibits T cell activation - has nephrotoxicity and DDI’s
- Gold salts: can induce remission, but has lots of SE’s: enterocolitis, anaplastic anemia, interstitial pneumonitis
- only used in severe disease if can’t tolerate other things - minocycline: unlabeled use
Adalimumab
TNF-alpha blocking Biologic DMARDs
Certolizumab
TNF alph blocking Biologic DMARDs
Etanercept
TNF alph blocking Biologic DMARDs
Golimumab
TNF alph blocking Biologic DMARDs
Infliximab
TNF alph blocking Biologic DMARDs
Abatacept
Biologic DMARDs: T-cell Fc fusion
MOA: prevents T cell activation
- genetically engineered fusion protein composed of the extracellular domain of the CTLA-4 receptor and the Fc region of human IgG1; CTLA-4 is normally expressed by Helper T cells and binds to CD80 and CD86 on antigen-presenting cells resulting in inhibition of T cells; CD28 is similar to CTLA-4 and also binds CD80 and CD86, but transmits a stimulatory signal; abatacept binds to CD80 and CD86, inhibiting binding to CD28 and preventing T-cell activation
response time: nearly immediately, but can take 6 mos. for full effect
Uses: if refractory to nonbiologic DMARDs or anti-TNF agents
AE’s: HTN, H/a, dizziness, anaphylactoid rxns
- increased risk of pneumonia, pyelonephritis, cellulitis, diverticulitis
Rituximab
Biologic DMARDs: anti-CD20 mAb
MOA: chimeric monoclonal antibody that depletes CD20-expressing B lymphocytes through cell-mediated and complement-dependent cytotoxicity and stimulation of apoptosis; B cell depletion reduces inflammation by decreasing the presentation of antigens to T cells and inhibiting the secretion of proinflammatory cytokines
response time is 6 weeks
USE: pts refractory to nonbio DMARDs or TNF-alpha agents
AE’s: infusion rashes, increased risk of infections
Tocilizumab
Biologic DMARDs: anti-IL-6 mAb
MOA: humanized monoclonal Ab that inhibits signaling of IL-6 receptor
takes 6-12 weeks
Use: refractory pts.
AEs: infusion rxns, HTN, neutropenia, dysplipidemia, GI perforation, serious infections
Celecoxib
NSAID - COX2 specific inhibitor, decreased GI problems
used as adjunct for anti-inflammatory, and decreased pain
Ibuprofen
NSAID - management of pain and inflammatory process in RA
** has higher GI toxicity **
Naproxen
NSAID - - management of pain and inflammatory process in RA
Prednisone
Corticosteroid (oral)
Systemic AE’s: osteoporosis, weight gain, fluid retention, cataracts, glaucoma,poor wound healing, hyperglycemia, hypertension, adrenal suppression and increased risk of infection
Use: syptomatic relief of RA, slows progression
Methylprednisolone
Corticosteroid (oral and also IV)
Systemic AE’s: osteoporosis, weight gain, fluid retention, cataracts, glaucoma,poor wound healing, hyperglycemia, hypertension, adrenal suppression and increased risk of infection
Use: syptomatic relief of RA, slows progression
Triamcinolone
Corticosteroid (intra-articular)
Use: syptomatic relief of RA, slows progression
Drugs used in acute gout?
NSAIDs (naproxen, indomethacin, NOT aspirin)
Colchicine
Corticosteroids - provide rapid pain relief
Colchicine
used for acute gout
toxic! but used in pts. with NSAID CI’s (GI adverse effects)
** relieves pain and inflamm. of gouty arthritis in 12-24 hours
MOA: binds to tubulin and prevents polymerization into MT’s, leading to inhibition of leukocyte migration and phagocytosis
Use: second-line therapy for acute gout (behind NSAIDs), should be initiated w/in 12-24 hours or onset of sx
AE’s: more toxic!!!
- diarrhea, nausea, vomiting, ab. pain
hepatic necrosis, ARF, DIC, seizures
OD = burning throat pain, bloody diarrhea, shock, hematuria, CNS depression
Allopurinol
prevention of recurrent gout (don’t use for acute attack, can cause precipitation of urate in the beginning)
MOA: purine analog that competitively and irreversibly inhibits xanthine oxidase (prevents formation, thus effective in ALL cases)
**standard of care therapy for gout during the period b/w acute episodes
AE’s: acute gouty arthritis, GI intolerance, nausea, vomiting, diarrhea, allergic rash
Febuxostat
prevention of recurrent gout
MOA: non-purine xanthine oxidase inhibitor (prevents formation)
AE’s: precipitate acute gouty arthritis, well tolerated - some diarrhea, h/a, nausea
Pegloticase
prevention of recurrent gout - recombinant uricase for tx of severe chronic gout refractory to conventional antihyperuricemic therapy
MOA: recombinant mammalian uricase - uricase converts uric acid to allantoin (normally absent in humans) - IV dosing every 2 weeks reduces urate levels
AE’s: acute gouty arthritis, infusion reactions, Ab formation
** don’t use if have G6PD deficiency for concern of hemolytic anemia
Probenecid
prevention of recurrent gout
- only potent uricosic agent
- indicated in pts. w/ impaired renal excretion of uric acid (85-90% of cases)
MOA: an organic acid that acts at the anionic transport sites of the renal tubules to reduce reabsorption of uric acid; tophaceous deposits of urate are reabsorbed
AE’s:
** likelihood of renal stone formation d/t increased uric acid secretion
GI irritation and rash
38 y/o woman presents w/ 2 mos hx of pain and swelling in both hands, generalized fatigue, body weight loss, body aches, tenderness in MCP and PIP joints in hands. imaging shows erosions in MCP joints/PIPs, labs are RF+, Anti-CCP +
tx includes MTX, what is the main goal for use of MTX?
Slow, stop and possibly reverse joint pathology in RA
DMARDs
slow, stop and possibly reverse damage of joint pathology in RA - most common is MTX
- suppress the immune system possibly at low levels
- in general pretty slow acting (1-6 mos) after initiating therapy
common AE: low dose causes stomatitis
4 main DMARDs: MTX, LEF, HCQ, SSZ!!! – lots of combinations of these 4
MTX and LEF are MOST effective: but worry about elevation of liver enzymes (or pregnant pt.) when used together
- these are both CI’s in pregnancy!!! category X
HCQ and SSZ are safe in pregnancy: category B
- but overall less effective than MTX and LEF
what reduces the SE of MTX?
Folic Acid supplementation
or
Folinic Acid (Leukovorin)
role of NSAIDs in tx of RA?
have immediate analgesic and anti-inflamm effects, but don’t effect disease progression
typically used during DMARD induction, during transition to a different DMARD, or during disease flares
- ibuprofen, naproxen, diclofenac
** worry about GI irritation **
(Celecoxib has less GI problems)
- no oral NSAID is consistently more effective than others; choice based on toxicity
which TNFalpha blocking agent is best?
there is no single one! adalimumab, certolizumab, enanercept, golimumab and infliximab all used equally
AE of etanercept most likely?
opportunistic infection — must screen for latent TB before starting therapy!!!
first line therapy for tx of acute gout?
NSAIDs!!
naproxen and indomethacin are most commonly used
** don’t use aspirin b/c can inhibit urate excretion!!
what if can’t use NSAIDs for tx of acute gout d/t active peptic ulcer disease?
use Colchicine
MOA: inhibits microtubule polymerization
- used to be first line, but is pretty toxic - can cause hepatic necrosis, ARF, DISC, diarrhea, nausea, vomiting, abdominal pain
which agent most likely to be effective in lowering urate levels, regardless of the pathophysiology of hyperuciemia?
allopurinol
(MOA: Xanthine oxidase inhibitor, works through decreased uric acid production) - effective in ALL cases
not as often used: probenecid- (whereas uricosuric agents inhibit the reabsorption of uric acid - they act at transporters in renal tubules, thus don’t prevent the production of uric acid) - these are indicated in 90%, but wouldn’t be indicated in cases where there is increased production of uric acid
- also they are CI in those with renal stones
NEVER GIVE THEM DURING AN ACUTE ATTACK!!! can result in increased precipitaiton of uric acid in the beginning
std tx for RA?
MTX and/or LEF (HCQ and SSZ are safer, less efficacious) \+ corticosteroid to relive joint sx \+ NSAID for pain relief and anti-inflamm.
add biologic DMARD (etanercept, infliximab, adalimumab, golimumab, certolizumab) after inadquate response to non-biologic DMARD
- etancercept is common first choice b/c rapid onset of action and shorter half-life
TNF alpha inhibitors
= Biologic DMARD’s
- mab (monoclonal Abs) and etanercept
TNF is a pro-inflamm. cytokine predominent in RA - regulates immune cells by binding to TNFR - can induce cell death and inflammation
MOA: prevent binding of TNF-alpha to TNF receptors, resulting in down-regulation of macrophages and T-cells
** much faster response than nonbiologic DMARDs** 1-2 week response time
- often used in combo w/ MTX (do NOT use in combination w/ each other)
Common AE’s:
- cytopenias: CBC should be monitored regularly
- SERIOUS INFECTION! bacterial sepsis and TB (must be screened for TB first)
- increased dissemination of infection
Rare AE’s:
- malignancies, lymphomas
- lupus
- heart failure
- demylinating syndromes
xanthine oxidase inhibitors vs. uricosuric agents
xanthine oxidase inhibitor: allopurinol
- MOA: decreased uric acid production - first line for tx of gout, used in ALL gout
ucircosuric agents: probenecid
- inhibits reabosorption of uric acid in kidney
- increased likelihood of renal stone formation
response time in DMARDs?
Nonbiologic DMARDs are slowest (1-6 months)
Biologic DMARDs are faster (1-2 weeks); some patients report improvement after the first dose
