Drugs to treat RA/Gout Flashcards
What three types of drugs are used to treat the acute joint pain in RA?
NSAIDS
Analgesics
Glucocorticoids
Provides symptomatic relief only
What two class of drugs used in the treatment of RA inhibit the progression of the disease?
Disease modifying anti-rheumatic drugs (DMARDS)
Biologic Response Modifiers (BRM)
What is the purpose of using NSAIDS, analgesics, and glucocorticoids in RA?
Minimize symptomatic effects while waiting for clinical effects of slow acting DMARDS and BRMs.
Used for ACUTE joint pain
List three analgesics used in the treatment of acute RA
Acetaminophen
Capsaicin
Opioids
List the four DMARDS.
hydroxychloroquine
sulfasalazine
methotrexate
leflunomide
Nonspecific inhibitors of the immune system
Name three anti-TNF drugs used in the treatment of RA
Etanercept
Adalimumab
Infliximab
Name two anti-cytokine drugs used in the treatment of RA
anakinra
tocilizumab
Name a drug used in the treatment of RA that inhibits T cells
abatacept
Name a drug used in the treatment of RA that inhibits B cells
Rituximab
Name a chemical inhibitor of cytokine signaling used in the treatment of RA
Tofacitinib
How long does it take before DMARDs are effective against RA?
slow acting
Takes weeks to months to show efficacy
What is the most commonly used DMARD?
Methotrexate
Name 5 of the less frequently used DMARDS in the treatment of RA
Azathioprine D-Penicillinamine Gold Salts Cyclosporine Cyclophosphamide
What type of RA may be treated with hydroxycholoquine
Mild arthritis
Is hydroxychloroquine safe in pregnancy and lactation?
Yes
List a rare/serious side effect of hydroxychloroquine
Ocular toxicity–> can result in total blindness
Increased risk with age > 60, treatment > 5 years and high doses
Is sulfasalazine safe to use during pregnancy
Yes
What are adverse effects associated with sulfasalazine?
Agranulocytosis within 2 weeks (very rare)
Hepatotoxicity (fully reversible)
What is the time to effect of hydroxychloroquine?
3-6 months
What is the time to effect of sulfasalazine?
1-3 months
What is the MOA of sulfasalazine?
Unclear- thought to interfere with immune system activation through NF-kappa B
What is the active component of sulfasalazine?
sulfapyridine
Is sulfasalazine administrated as a monotherapy?
NO- generally given with hydroxychloraquine
What is the drug of choice for patients with active/severe RA?
Methotrexate
What is the effect of methotrexate in RA?
Reduces the rate of new bone erosions
How long does it take for the effects of methotrexate to begin?
4-6 months
What is the low dose MOA of methotrexate (as opposed to high dose MOA for cancer tx)
indirectly increases production of adenosine –> immunosuppressive properties
Why do patients on methotrexate need to avoid alcohol?
Methotrexate commonly causes dose-related hepatotoxicity
List three rare side effects of methotrexate that requires clinical monitering
Pulmonary toxicity
Bone marrow suppression
Risk of lymphoma
What is the metabolism of methotrexate?
80-90% excreted renally
Is methotrexate safe in pregnancy?
NO- it is actually used an as abortifactant
Methotrexate is contraindicated in patients with which two underlying diseases?
Liver disease
Renal impairment
What is the efficacy of leflunomide?
as effective as either sulfasalazine or methotrexate
Used as an alternative to methotrexate
What is the time to onset for leflunomide?
1-2 months
What is the MOA of leflunomide?
Inhibits dihydroorotate dehydrogenase –> inhibits uridine synthesis –> inhibits both T-cell proliferation and production of autoantibodies by B cells
Which side effect of leflunomide requires monitoring?
Hepatotoxicity
Also associated with GI upset and HTN
Is leflunomide safe during pregnancy?
No
In general, how to BRMs work?
Specific inhibition of cytokines or B-cells/T-cells
How do etanercept, infliximab and adalimumab work?
They are all antibodies against the TNF-alpha receptor
What is the time to effect for Etanercept?
1-4 weeks
Are the anti-TNF alpha drugs used as a monotherapy or in tandem with other drugs?
Used either as a monotherapy or combined with methotrexate
It is often added to patients who are not responding adequately to methotrexate
List the adverse effects associated with the anti-TNFalpha drugs
Increased risk for bacterial and fungal infections
Reactivation of latent TB and latent HBV
Cannot be used for patients with a chronic infection
List three rare but serious side effects of the anti-TNF alpha drugs
Exacerbation of heart disease
Onset of MS
Onset of lymphoma
What is the MOA of abatacept?
binds with high affinity to CD80/CD86 (recombinant fusion protein of CTLA4)
–> inhibits T-cell activation by blocking CD28 co-stimulatory signals essential for T-cell activation
WHen are patients given abatacept?
Patients who are non-responsive to TNF-alpha inhibitors
What are the adverse effects associated with abatacept?
REactivation of latent TB and HBV
screen before administration
Can any of the BRMs be combined with each other?
NO
Can only be given in combo with DMARD drugs
What is the MOA of rituximab?
Binds CD20 on human B cells
–> depletes B cells from the blood
How long do effects from a rituximab injection last?
Although onset of benefit is not seen for 3 months, the effect can last for up to 2 years with a single infusion
Which patients receive rituximab?
Patients who are unresponsive to TNF alpha inhibitors
Which is a rare adverse effect associated with rituximab?
PML (demyelinating disease associated with reactivation of the JC virus)
What is the MOA of anakinra?
Inhibits IL-1 (decreases pro-inflammatory effects)
What is the relative efficacy of IL-1 inhibitors (anakinra?)
Decreased efficacy as compared to anti- TNF alpha agents
Also must be given subQ daily
Who should not receive anti-IL-1 (anakinra)/
patients with acute/chronic infections
Increased risk of infections/neutropenia
What is MOA of tocilizumab?
IL-6 cytokine receptor antagonist
Who receives tocilizumab?
Patients unresponsive to TNF inhibitors
May be used in combo with methotrexate
What are unique adverse effects associated with Tocilizumab?
Bone marrow suppression
Increased hypercholesterolemia
What is the MOA of Tofacitinib?
inhibits Jak tyrosine kinase
involved in immune cell cytokine signaling
List the tx strategies for mild, moderate and severe RA
Mild: hydroxychloroquine or sulfasalazine or combo
Moderate: methotrexate (alt, leflunomide) or combo therapy of DMARDS + TNF alpha inhibitors
Severe: Switch to biologics
Are tophi present in acute gout?
No- they form in chronic gout
Which two drugs are used to relieve the symptoms of an acute gouty attack?
Colchicine
NSAIDS
list two drugs that increase uric acid excretion
Probenecid
Lesinurad (newly approved)
List two drugs that lower uric acid synthesis
Allopurinol
Febuxostat
List a drug that directly degrades uric acid
Pegloticase
Which two NSAIDS can induce gout?
Aspirin and salicylates – they inhibit uric acid secretion
Is colchicine an analgesic?
No- antiinflammatory but no analgesic properties
When is colchicine effective?
When given within the first 24-48 hours of an attack
Limited used due to side effects (GI upset)
What is the MOA of colchacine?
Inhibits microtubule rearrangements –> inhibits leukocyte migration and phagocytosis
What is the therapeutic window of colchicine?
Very narrow- leads to GI upset
What is the MOA of probenecid?
Blocks the URATE1 ion transporter in the renal tubules –> decreased reabsorption and increased uric acid excretion
Most gout is due to underexcretion of uric acid
When should probenecid NOT be administered?
Within 2-3 weeks following an acute gouty attack.
The drug will disrupt uric acid homeostasis and can increase risk of a second attack
Administer with prophylactic colchicine or NSAID
In what type of patients is probenecid contraindicated?
In patients with increased uric acid synthesis
Probenecid will increase the risk of kidney stones
What is the MOA of allopurinol and Febuxostat
Inhibitors of xanthine oxidase
Hypoxanthine cannot be converted to uric acid
Patients with tophi should be treated with which drug?
Allopurinol (or febuxostat)
What is the rare but potentially deadly side effect of allopurinol?
Rash, fever, hepatitis, eosinophilia and acute renal failure
Occurs in patients with pre-existing renal failure, patients taking excessive doses
NOT induced by febuxostat (which is 50% hepatic elimination)
What race is more susceptible to the life threatening allopurinol side effect?
Thai, Korean, Han Chinese
Allopurinol has a DDI with which two other drugs?
6-mercaptopurine and azathioprine
What is the goal of treating chronic gout?
Reduce uric acid levels to <6 mg/dl
How long do you treat someone with gout?
Life long - goal to prevent acute gouty attacks
What is the MOA of pegloticase?
Pig enzyme that converts uric acid to allanatoin which can be readily excreted
What are the downsides of pegloticase?
It must be administered by IV every two weeks, requires NSAID/colchicine prophylaxis
Self-limited as anti-drug antibodies may develop
