Pharm: Drugs for Rheumatic Diseases

Question 1

Hydroxychloroquine - HCQ

Answer 1

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

Question 2

Leflunomide - LEF

Answer 2

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!!!

Question 3

** Methotrexate - MTX

Answer 3

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 !!

Question 4

Sulfasalazine - SSZ

Answer 4

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

Question 5

Rarely used DMARds

Answer 5

1. Azathioprine: immunosuppressive purine, reserved for pts. w/ refractory RA, risk of lymphoma, CI in pregnancy
2. Cyclosporine: peptide antibiotic that inhibits T cell activation - has nephrotoxicity and DDI’s
3. 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
4. minocycline: unlabeled use

Question 6

Adalimumab

Answer 6

TNF-alpha blocking Biologic DMARDs

Question 7

Certolizumab

Answer 7

TNF alph blocking Biologic DMARDs

Question 8

Etanercept

Answer 8

TNF alph blocking Biologic DMARDs

Question 9

Golimumab

Answer 9

TNF alph blocking Biologic DMARDs

Question 10

Infliximab

Answer 10

TNF alph blocking Biologic DMARDs

Question 11

Abatacept

Answer 11

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

Question 12

Rituximab

Answer 12

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

Question 13

Tocilizumab

Answer 13

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

Question 14

Celecoxib

Answer 14

NSAID - COX2 specific inhibitor, decreased GI problems

used as adjunct for anti-inflammatory, and decreased pain

Question 15

Ibuprofen

Answer 15

NSAID - management of pain and inflammatory process in RA

** has higher GI toxicity **

Question 16

Naproxen

Answer 16

NSAID - - management of pain and inflammatory process in RA

Question 17

Prednisone

Answer 17

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

Question 18

Methylprednisolone

Answer 18

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

Question 19

Triamcinolone

Answer 19

Corticosteroid (intra-articular)

Use: syptomatic relief of RA, slows progression

Question 20

Drugs used in acute gout?

Answer 20

NSAIDs (naproxen, indomethacin, NOT aspirin)
Colchicine
Corticosteroids - provide rapid pain relief

Question 21

Colchicine

Answer 21

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

Question 22

Allopurinol

Answer 22

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

Question 23

Febuxostat

Answer 23

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

Question 24

Pegloticase

Answer 24

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

Question 25

Probenecid

Answer 25

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

Question 26

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?

Answer 26

Slow, stop and possibly reverse joint pathology in RA

Question 27

DMARDs

Answer 27

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

Question 28

what reduces the SE of MTX?

Answer 28

Folic Acid supplementation or Folinic Acid (Leukovorin)

Question 29

role of NSAIDs in tx of RA?

Answer 29

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

Question 30

which TNFalpha blocking agent is best?

Answer 30

there is no single one! adalimumab, certolizumab, enanercept, golimumab and infliximab all used equally

Question 31

AE of etanercept most likely?

Answer 31

opportunistic infection --- must screen for latent TB before starting therapy!!!

Question 32

first line therapy for tx of acute gout?

Answer 32

NSAIDs!! naproxen and indomethacin are most commonly used ** don't use aspirin b/c can inhibit urate excretion!!

Question 33

what if can't use NSAIDs for tx of acute gout d/t active peptic ulcer disease?

Answer 33

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

Question 34

which agent most likely to be effective in lowering urate levels, regardless of the pathophysiology of hyperuciemia?

Answer 34

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

Question 35

std tx for RA?

Answer 35

``` 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

Question 36

TNF alpha inhibitors

Answer 36

= 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

Question 37

xanthine oxidase inhibitors vs. uricosuric agents

Answer 37

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

Question 38

response time in DMARDs?

Answer 38

Nonbiologic DMARDs are slowest (1-6 months) Biologic DMARDs are faster (1-2 weeks); some patients report improvement after the first dose