RAA Drugs and DMARDs Flashcards
Differentiate the ability of NSAIDs, DMARDs (disease modifying anti-rheumatic drugs), and Biologicals in their ability to treat rheumatic disease.
NSAIDs - there are anti-inflammatories that only treat pain
DMARDs - systemic drugs that modify the disease process
Biological - a type of DMARD that targets specific epitopes
Note: only biologicals and DMARDs have the ability to slow disease progression in rheumatoid disease
Note: DMARDs are really just steroids and immunosuppressive drugs
Note: DMARDs are really just steroids and immunosuppressive drugs
What DMARDs are used in the treatment of RA?
Non-steroidal DMARDs:
Methotrexate
Hydroxychloroquine
Lefunomide
Sulfasalazine
Steroidal DMARDs:
Betamethasome
Cortisone
Dexamethasone
Hydrocortisone
Methylprednisone
Prednisolone
Prednisone
Triamcinolone
What biological DMARDs are used in the treatment of RA?
Abatacept
Adalimumab
Anakinra
Apremilast
Certolizumab
Etanercept
Golimumab
Infliximab
Rituximab
Tofacitinib
Tocilizumab
Ustekinumab
Regardless what type of DMARD you treat with, what is the key to good treatment outcomes in patients with RA?
You must treat aggresively and treat early
What is the typical progression of drug prescription to a patient with RA?
- Start with Methotrexate ± NSAIDS ± Corticosteroids; IF the condition is mild you may yse Hydroxychoroquine
- After treatment 1 fails go with a First line biological (etanercept, infliximab, adalimumab, golimumab, or certolizumab) as a MONOTHERAPY OR in conjunction with MTX.
- If this fails then go with 3rd line drugs or non-TNF-alpha targeted drugs like Anakinra, Rituximab, or Tocilizumab
Methotrexate
• What are 3 MOAs?
• why is this useful for RA treatment?
Methotrexate:
First it comes into the cell and must be polyglutamated via FPGS so it is retained in the cell
1. DHFR inhibition as a folate analogue
- Depletion of THF leads to a lack of Methyl-THF needed to make Methionine (first amino acid in proteins)
- AICAR transformylase inhibition causes a buildup of AICAR and feedback inhibition occurs on AMP deaminase and Adenosine deaminase. This leads to a buildup of adenosine and AMP that bind to Gs GPCRs on the cell surface and deactivate inflammatory processes
As a result of Adenosine inhibition in the 3rd MOA we see reduced: IL-1, INF-gamma, and TNF and increased IL-4 that impairs histamine resase from basophils and decreases neutrophil chemotaxis
Methotrexate:
• how is it metabolized and extreted?
• what are some adverse effects?
Metabolism and Excretion:
• Metabolized in the liver so its contraindicated in liver disease. It also undergoes enterohepatic recirculation. Excretion occurs mainly in the kidney with filtration and secretion so watch out using this in patients with renal failure.
On-target adverse effects:
• Immunosuppresion from MTX means vaccinations won’t be useful in treating this disase and Lymphomas may arise.
Off-target advese effects:
• Irreversible interstitial pneumonitis and pulmonary fibrosis may occur. GI toxicity.
Methotrexate:
• Can this drug be given to breast-feeding mothers?
• What commmon drug interactions should you watch out for?
Do not give chemo drugs like MTX (category X) to breastfeeding mothers
• NSAIDs + MTX = potential GI toxicity
Sulfasalazine:
• Metabolism
• MOA
Sulfasalazine is metabolized in the Liver via Acetylation and Hydroxylation. However, metabolism to ACTIVE products required GI bacteria that metabolize sulfasazine to sulfapyridine (sulfanamide) and mesalamine (5-aminosalicylic acid).
Most of the beneficial effects are a result of Mesalamine (5-aminosalicyclic acid) that inhibits both PROSTAGLANDIN and LEUKOTRIENE production. (this makes sense given its name - must just be more promiscuous than asprin interacting with both COX an LOX)
Sulfasalazine:
• what patients might you want to watch closely for drug toxicity in?
• How is the drug excreted?
• What are some side effects?
Patients that are a slow acetylators may have this drug build up to toxic doses (asians may need more of the drug).
Sulfasalazine is excreted renally so metabolites may accumulate with repeated dosing.
NEVER give this drug to anyone who has asprin sensitivity or sulfanamide allergy.
Side Effects: BLOOD DYSCRASIAS (these are rare)
Leflunomide
• MOA
• what is the outcome of this MOA?
MOA:
• Leflunomide inhibits dehydroorotate dehydrogenase DHODH
• DHODH is an enzyme located in the mitochondria that is key in de novo PYRIMADINE synthesis
OUTCOME:
• Inhibition of dehydroorotate reductase by leflunomide instigates cell cycle arrest in T and B Lymphocytes (so less Ig is produced)
Leflunomide:
• Metabolism
• On-target and Off-target side effects?
• Can you give this to pregnant/breastfeeding ladies?
Metabolism:
• Occurs mainly in the liver so don’t give to patients with potential liver problems.
On-target adverse effects:
• Leflunomide causes immunosuppresion (via DHODH inhibition) this there is a risk of infection
Off-target effects:
• URICOSURIC effect increase renal elimination of uric acid (good if you have gout, bad if you’re prone to kidney stones)
CATEGORY X (like MTX) don’t give this to pregnant or breastfeeding women
Hydroxychloroquine:
• MOA
• what diseases besides RA can it treat?
MOA: • Hydroxychloroquine I**NCREASES pH in intracellular vacuoles** needed for digestion of proteins. • **Loss of protein digestion in APCs** results in **inability to elicit CD4+ T-cell response** b/c there are no proteins to present on MHC class II
Other Dz:
• Can also be used to treat Systemic Lupus Erythematosus (SLE) and Malaria
Hydroxychloroquine:
• Patients that this drug is contraindicated with?
• Side Effects
Don’t give this drug to people with Hepatic Dysfunction (alcoholics, NASH, Hepatitis etc.) or people with OCULAR disease
SIDE EFFECTS:
• Blood Dyscrasias and CNS Toxicity (polyneuritis, ototoxicity, seizures, or neuromyopathy)
• EYE ISSUES (rare) - Corneal opacities, keratopathy, retinopathy
Which of the non-steroidal DMARDs are okay to use in patients with liver dysfunction?
• name these drugs
Don’t give ANY of these drugs to people with hepatic dysfunction
Non-steroidal DMARDs include:
• Methotrexate
• Sulfasalazine
• Leflunomide
• Hydrochloroquine
How might you want to monitor a patient who is on methotrexate?
**Additionally in MTX you’ll want to do pregnancy testing
How might you want to monitor a patient that is on sulfasalazine?
How might you want to monitor a patient that’s on leflunomide?
How might you want to monitor a patient that’s on Hydrochlroquine?
How do Corticosteroids work as DMARDs?
• what potential bone related side effects may present?
DMARD effect or Corticosteroids:
• DMARD effect of these drugs lies in the fact that they inhibit the activator protein (AP-1) of NfkB and Nf-AT which causes decreased production of TNF-alpha, IL-1, and IL-6.
Excessive Bone Resorption may occur:
• this is due to UPREGULATION of RANKL and M-CSF in osteoBlasts causing increased osteoClastic activity.
Explain why corticosteroids lead to decreased bone density in short and long term scenarios.
Short Term:
• Corticosteroids lead to upregulation of M-CSF and RANKL on osteoblasts and you get hyperactivity of osteoclasts via increased differentiation of osteoclast precursors and lifespan
Long Term:
• You get increase PPARgamma2 expression and decreased Wnt/ß-cateninin signaling that leads to activation of caspase 3 and you get apoptosis of both osteoclasts and osteoblasts.
Reminder of Wnt/APC/ß-cateninin interaction that allows for cancer formation
What are some things you might suggest your RA patient to do after placing them on corticosteroids?
• how will you monitor and treat these patients?
RA patients chronically using corticosteroids should be encouraged to eat lots of Ca2+, Vitamin D. You also want to start them on anti-osteoporotic medications ASAP. Monitor these people with DEXA and do extra scans if you suspect that they’re becoming symptomatic.
Review of Consequences of Medium/High Dose Corticosteroid Therapy.
• Note that many RA pts. on this therapy may start to take on show a cushings-like appearance
What disease is more prominent in patients with RA and why might this be related to treatment?
• how should you take this into consideration with looking at treatment options for an RA patient?
Patients with RA have 2x the risk of having a CV event, this may be related to widespread corticosteroid use in these patients.
Adverse CV effects of corticosteroids include Adverse Lipid Profile, Blood glucose regulation, Insulin production and resistance, and obesity.
What is an effective way to continue steriod use in RA patients while limiting systemic effects?
• Are adverse effects of corticosteroids cumulative or Daily Dose Dependent?
Direct injection into the joint cavity with slow-releasing steroids is a good option
• Side effects of corticosteroids is BOTH Daily Dose Dependent and Cumulative use dependent.
Should we monitor patients that are on low-dose corticosteroids? If so, how?
• can corticosteroids be used in combination with other DMARDs
Low Dose Pts. need to be monitored to by Osteoporosis screeing, Determining Pre-treatment fasting blood levels, Glaucoma risk, and Ankle edema.
*Concurrent administration of other DMARDs may increase the risk of experiencing adverse effects from corticosteroids
Auranofin
• MOA
• Adverse Effects
MOA:
• Auranofin suppresses inflammaiton and stimulates cell-mediated immunity
Adverse Effects:
• GI dysfunction (40% of the time), Skin Rashes (20%), Stomatitis and mouth ulcerations (1-12%), Conjunctivitis, and Proteinurea.
Name all of the drugs that act as TNF-alpha inhibitors.
Adalimumab
Certolizumab pegol
Etanercept
Golimumab
Infliximab
What drugs inhibit IL-1?
Anakinra
What RA drugs act on IL-6?
Tocilizumab
What RA drugs work on CD20?
Rituximab
What RA drugs work on CTLA4/B7?
Abatacept
What RA drugs work on IL-23?
Ustekinumab
Abatacept
• Route of Delivery
• MOA
Adalimumab
• Route of Delivery
• MOA
Anakinra
• Route of Delivery
• MOA
Certolizumab pegol
• Route of Delivery
• MOA
Etancercept
• Route of Delivery
• MOA
Golimumab
• Route of Delivery
• MOA
Infliximab
• Route of Delivery
• MOA
Rituximab
• Route of Delivery
• MOA
Tocilizumab
• Route of Delivery
• MOA
Remember patients taking Biologicals that you need to watch out for them getting bacterial, fungal, and parasitic infections, what patients might these problems be particularly pronounced in?
• what group of drugs carries an additional risk of malignancy?
Upper respiratory infections in people with Asthma or COPD may be especially problematic
TNF-alpha drugs have an increased risk of malignancy (etanercept, Adalimumab, Certolizumab pegol, Golimumab, and Infliximab)
What Biologics are associated or contraindicated with CHF, hypotension/angina/dysrhythmia?
Associated with posstible problems are:
• (TNF-alpha atangonists) Adalimumab, Golimumab, Infliximab, and (CD20 antagonists) Rituximab
Infliximab is contraindicated in patients with moderate-severe CHF
What Biologics used in RA may cause a lupus like syndrome?
Adalimumab
Certolizumab
Etanercept
Infliximab
Which biologic is associated with Steven-Johnson Sydrome, or Toxic Epidermal Necrolysis?
Rituximab
Which biological RA drug may interfere with blood-glucose testing in diabetics?
Abatacept IV solution contains maltose which may cause falsely elevated blood glucose tests
What biological RA drug must women use reliable contraception with and why?
• should you continue contraceptives after this drug is discontinued?
Rituximab may cross the placental barrier using the brambell receptor and deplete B-cells in the developing child
Because this is an IgG mAb women should continue contraception for 4-6 months following therapy
What RA biologicals may cause blood dyscrasias?
• what should you do to monitor this?
Akakinra, Certolizumab, Rituximab, Toclilmumab
You need to get regular CBCs in patients taking these drugs
With what RA biologics should you get routine LFTs?
Golimumab, Infliximab, and Tocilimumab
Which biologic may drastically change your serum lipid profile?
Tocilizumab
Which drugs are self administered SC?
• what advise should you give these patients?
Abatacept
Adalimumab
Anakinra
Certolizumab
Etanercept
Golimumab
*You need to tell these patients to rotate the injection site or they might get injection site reactions
Adalimumab
• Target
• Adverse Effects
Target: TNF-alpha
AEs: Malignancy, CV risks, Lupus, Self-Administration Advise
Certolizumab Pegol
• Target
• Adverse Effects (AEs)
Target: TNF-alpha
AEs: Malignancy, Lupus, Blood Dyscrasias, Self Admin. Advise
Etanercept
- Target
- Adverse Effects (AEs)
Target: TNF-alpha
AEs: Malignancy, Lupus, Self Admin
Golinmumab
• Target
• Adverse Effects (AEs)
Target: TNF-alpha
AEs: Malignancy, CV risk, LFTs, Self Adiministration
Infliximab
• Target
• Adverse Effects (AEs)
Target: TNF-alpha
AEs: Malignancy, CV risk, Lupus, LFTs
Rituximab
• Target
• Adverse Effects (AEs)
Target: CD20
AEs: CV risk, Lupus/Stephen Johnson Syndrome/Toxic Epidermal Necrolysis, Pregnancy, Blood Dyscrasias
Abatacept
• Target
• Adverse Effects (AEs)
Target: B7/CTLA4 interuption
AEs: Blood Glucose may be affected by IV administration, Self Admin. Advise
Anakira
• Target
• Adverse Effects (AEs)
Target: IL-1
AEs: Blood Dyscrasias, Self Admin advise
Tocilizumab
• Target
• Adverse Effects (AEs)
Target: IL-6
AEs: Blood Dyscrasias, LFTs, Serum Lipids
Tofacitinib
• Administration
• MOA
• this is a TKI so administration is oral and there is potential for CYP drug interactions
MOA:
• is JAK3/JAK1 inhibitor that blocks the effects of IL-2, 4, 7, 9, 15, and 21.
• Also causes CRP levels to drop rapidly
Tofacitinib
• Adverse Effects
Apremilast
• Indication
• MOA
• Adverse Effects
Apremilast is indicated for use in psoriatic arthritis and plaque psoriasis
MOA:
• PDE4 (phosphodiesterase-4) inhibitor causing increased cAMP and reduced proinflammatory mediators (TNF-alpha, IL-17, IL-23) and increased anti-inflammatory mediators.
Adverse Effects:
• Nausea, weight loss, headache, andn rarely depression or suicidal ideation
Apremilast Metabolism
Apremilast undergoes extensive hepatic metabolism
**Remember you need to monitor WEIGHT LOSS in patients taking Apremilast**
What is the advantage to using IgG antibodies and/or pegalated drugs?
Pegalation keeps drugs from being degraded for longer periods of time. IgG antibody is a long lasting antibody so this is also advantageous
If administering steroids long term, what other drug might you give patients who are at increased risk for osteoporosis?
Bisphosphonates are often given with chronic steroids to reduce osteoclastic activity
What is TAILS?
TNF-alpha induced lupus-like syndrome, this type of drug induced lupus often involves the kidneys cause LUPUS NEHPRITIS (diffuse proliferative glomerulonephritis) too
