Caldwell Drugs RA and Gout

Question 1

Colchicine

Answer 1

tx of acute gout

inhibits microtubule assembly. Suppresses inflammasome-driven caspase 1 activation, IL-1beta precessing and L selectin expression

common adverse effects may include GI sx (D abd pain, N, V) and readily reversible peripheral neuropathy. More severe colchicine tox (eg blood cytopenias, severe cutaneous eruption) has only rarely been reported in pts being treated for acute gout flare

contradindication: pts with advanced renal or hepatic impairment
notes: used in pts who have contraindications to NSAIDs (actuve peptic ulcer dz, or a hx of NSAID intolerance

Question 2

allopurinol

Answer 2

tx of chronic gout

xanthine oxidase inhibitor- inhibits uric acid synth

side effects: mild rash; can cause leukopenia or thrombocytopenia; diarrhea; can precipitate acute gouty arthritis

caution: pts with renal insufficiency
contraindication: known hypersensativity

Note: although reduced renal uric acid excretion is responsible for the majority (80-90%) of cases of promary or secondary hyperuricemia, allopurinol, which inhibits production of uric acid, is the first line pharmacologic

Question 3

febuxostat

Answer 3

tx of chronic gout

xanthine oxidase inhibitor

side effects: incidence of liver function test abnormalities, nausea, arthralgia, and rash, increased risk of acute gouty attack

caution: periodic monitering of liver function, principally hepatic transaminase enzyme levels, is suggested by the manufacturer

more expensive than allopurinol

Question 4

probenecid

Answer 4

tx of chronic gout

promotes renal clearace of uric acid by inhibiting urate-anion exhangers ( including URAT1) in the proximal tubule that mediates urate reabsorption- ie it increases urate excretion (a urosuric agent)

side effects: rash, precipitation of acute gouty arthritis, GI intolerance, and uric acid stone formaiton

Contraindications: pts in whom nephrolithiasis or uric acid nephropathy may occut

caution: interferes with the renal transport of various drugs that are organic acids (eg penecillin, ampicillin) and which undergo transport in the kidney; consequently, there is a need to adjust dosage of these drugs

NOTES:

efficacy is reduced in pts with impaired renal fn

relatively short half life requires dosing 2-4 times a day

mult drug interactions due to inhibition of organic anion transporter 1 (OAT1) and OAT3. In addition to uricosuric drugs, OAT1 and OAT 3 interact with several classes of drugs, including ace inhibitors, angiotensin II receptor antagonists, diuretics, HMG CoA reductase inhibitors, beta-lactum abx, antineoplastics and antiviral drugs

Question 5

Lesinurad

Answer 5

chronic gout tx

inhibits activity of URAT 1 and OAT 4 in vitro
does not inhibit GLUT9 or ABCG2
unlike probenecid, lesinurad does not inhibit OAt1 or OAT3

most common adverse reactions in clinical trials were HA< influenza, highter levels of blood creatanine, and gastroesophageal reflux

pts need to be cautioned to stay well hydrated

Warning: increased risk of acute renal failure. Contraindicaitons in pts with severe renal impairment, end stage renal dz, kidney transplant, or pts on dialysis

note: often administered with allopurinol

Question 6

Pegloticase

Answer 6

recombinant uricase, which converts uric acid to allantoin

increased risk of acute gouty attack

caution: infusion reaction can occur

Contraindicated: pegloticase is contraindicated in pts with G6PD deficiency

Caution: pts may develop anti-pegloticase abs, resulting in a loss of urate lowering effect of the drug. Other urate lowering therapies should not be given to pts recieving this drug, because they may mask recognition of the increasing serum urate levels associated with an increased risk for infusion related reactions and loss of effectiveness resulting from the effects of high titer pegloticase abs

Question 7

Treatement of acute gout

Answer 7

NSAIDS, excluding low dose ASA, are used to treat acute attacks of gout.

Question 8

ASA and gout

Answer 8

at low doeses (<2-3g per day) ASA causes uric acid retention by the kidney, whereas at higher doses ASA has a uricosuric effectin most individuals, low dose ASA that is being administered for CV protective effects does not need to be discontinued

Question 9

Treatment of chronic gout

Answer 9

urate lowering therapy aims to prevent and recerse the deposition of urate crystals in joints (gouty arthropathy), urinary tract (nephrolithiasis), renal interstitium (rarely producing renal failure due to urate nephropathy) and tissues and parenchymal organs (tophi)

Question 10

Rituxumab

Answer 10

inhibitor of B cell function

approved for pts that fail to respond to anti-TNF-a therapy

Approved for tx of nonhodgekins lymphoma

chimeric mab against CD20 antigen found on the surface of normal and malignant B lymphocytes. IgG1 and k immunoglobulin

2-1000mg IV infusions separated by 2 weeks

admin of glucocorticoid recommended prior to infusion to reduce incedence severity of infusion reaction

Question 11

abatacept

Answer 11

inhibitor of t cell activation

fusion protein of the extracellular domain of the CTLA4 molecule and the Fc doman of human IgG1

approved for pts who do not respond well to methotrexate and for pts who do not respond or cannot tolerate TNA antagonists

30 minute infusion given at 2 and 4 weeks after 1st infusion, every 4 weeks thereafter. Fixed dose. 10mg/kg

MOA: blocing the costimulatory molecule required for T cell activation B7 (CD80/86)

Question 12

apremilast

Answer 12

PDE-4 inhibitor

indicated for moderate to severe plaque psoriasis

increases intracellular cAMP, decreased TNAa production

Most common adverse affect N and D in first year of tx, nasopharyngitis, URI

Metabolized by CYP3A4 with subsequent glucuronidation and non-CYP mediated hydrolysis

excretion: 58% urine, 39% feces, severe renal impairment

associated with increased risk depression

Question 13

Tofacitinib

Answer 13

JAK inhibitor

Blocks JAK 1 and 3 and to a lesser degree 2

approved for moderate to severe RA for pts that do not respond well to methotrexate

Side effects: inflammation of nasal passages and upper pharynx, URI, Increased risk TB and lymphoma, HA

Metabolized by CYP3A4

Question 14

Anakinra

Answer 14

cytokine blocker

inhibitor of IL-1

recombinant, nonglycosylated synthetic form of the human IL-1 receptor antagonist (IL-1Ra), an endogenous regularot of IL 1 action

Question 15

Infliximab

Answer 15

cytokine blocker

inhibitor of TNF-a

chimeric mAb (human contant, mouse variable)

given IV

increased risk for TB

Question 16

Entanercept

Answer 16

cytokine blocker

inhibitor of TNF-a

Human TNF receptor linked to the Fc portion of human IgG1

Basically sponge for TNF-a. Like a decoy recep.

Given 2x/ week

Question 17

Methotrexate

Answer 17

folate antagonisht; exterts cytotoxic effects

mechanism of anti-inflammatory activity in RA is uncertain; may inhibit T cell activation and/or suppress expression of adhesion molecules on T cells

80-90% excreted unchanged in the urine; t1/2 influenced by glomerular filtration rate

most common side effects at doses used to treat RA: N/V, mouth sores, HA, fatigue, alopecia, rash

low incidence but significant side effects: life threatening hepatotoxicity, pulmonary damage and myelosuppression

Question 18

Hydroxychloroquine

Answer 18

mechanism of action in treating RA unceartain; possible mechanism:

1) inhibition of toll like receptors (esp TLR-9)
2) block antigen processing in macrophages and presentation of antigen MHC complex to CD4+ cells

may increase penicillamine plasma levels

relatively low efficacy as antirheumatic agent; onset of therapeutic effects is relatively slow; commonly combines with other therapies

(not used often in RA. If so often combined)