Arthritis & Gout MT2 Flashcards
what is rheumatoid arthritis
- autoimmune disease that causes chronic inflammation of the joints
- affects joints first, then surrounding tissues may become affected
- usually occurs between 40 and 60 years of age
- 2 to 3 times more common in women
- genetic basis
what type of disease is RA directly linked to?
cardiovascular disesae
- increase in MI, stroke, heart failure and hypertension than non-RA patients
what are some symptoms of RA
- joint inflammation (swelling, redness, pain and stiffness)
chronic inflammation can lead to damage and deformity of joints
what are some tests that may be done to diagnosis someone with rheumatoid arthritis
- rheumatoid factor test
- anti-CCP antibody test
- complete blood count
- CRP (C-reactive protein)
- ESR (eryhtocyte sedimentation rate)
- ultrasound/MRI/X-ray
- synovial fluid analysis
what are some causes of RA
- infectious agents that deposit into the joints and cause inflammation
- genetic link/genetic inheritance
- environmental factors (smoking)
what is the difference between the 1980 pyramid approach of treatment of RA and how RA is treated now
1980 pyramid approach was that topical NSAIDs and aspirin were on the bottom of the pyramid. 2nd line therapy was initiated after a patient had proven radiographic damage. RA was considered a nuisance disease and the treatment of the disease was worse than its natural course, therefore symptomatic treatment only.
currently, pharmacological intervention is necessary early in order to prevent structural damage. multi drug therapy is not only well tolerated but is necessary. the goal is to put disease into remission
what are some non-pharmacological treatment options for RA
- patient education on nature of RA, coping mechanisms
- physical and occupational therapy for joint-strengthening and joint protection
- prevention of osteoporosis is RA and antiresorptive therapy for those who receive chronic corticosteroids
what are the “first line” drugs used to reduce inflammation in RA
NSAIDS and corticosteroids
what are the “second line” drugs used to promote remission of the disease and prevent progressive joint damage in RA
DMARDs and biologics or biologic response modifiers
corticosteroids are any of the steroidal hormones made by the _______ of the adrenal gland (e.g. cortisol)
cortex (outer layer)
true or false: steroids inhibit the synthesis of almost all known cytokines
true
what is the MOA of corticosteroids
they stimulate the synthesis of IF-kappa beta alpha, which is a protein that traps and therefore inactivates nuclear factor kappa B (NF-kB)
this is an activator of cytokine genes and mediator of the pro-inflammatory action of tumour necrosis factor and IL-1
nuclear factor kappa beta (NF-kB)
what are some possible side effects of corticosteroids
- increased appetite and weight gain
- deposits of fat in chest, face, upper back and stomach
- swelling and edema due to water and salt retention
- high blood pressure, diabetes
- slower healing of wounds
- black and blue marks
- osteoporosis
- increased susceptibility to infections
- cataracts
- muscle weakness
- thinning of the skin
- stomach ulcers
- increased sweating
- mood swings
what is the route of administration for corticosteroids
- oral
- topical (for eczema, allergic conjunctivitis, or rhinitis)
- parenteral/injection
- aerosol (for asthma)
do corticosteroids bind to proteins?
yes, bind to corticosteroid binding globulin (CBG) and albumin in the blood and then enter cells by diffusion
what is the half life of hydrocortisone
90 min. main effect lasts for 2-8 hrs
cortisone and prednisone are inactive until converted in vivo to ______________
hydrocortisone
what organ metabolizes corticosteroids
liver
what are some examples of medications that should be taken with NSAIDs to offset side effects
-antacids (Sucralfate)
- PPIs (lansoprazole, etc)
- PG analogues (misoprostol)
examples include methotrexate, chloroquine, hydroxychloroquine, sulfasalazine, leflunomide, biologics, gold salts, penicillamine, cyclosporin and cyclophosphamide
DMARDs - disease modifying anti-rheumatic drugs
this specific DMARD is classified as an anti-metabolite, but in RA the MOA seems more anti-inflammatory than anti-metabolite. it is an inhibitor of folate (vit. b6) metabolism
methotrexate (Rheumatrex, Trexall)
what is the MOA of methotrexate for RA
- it inhibits leukotriene synthesis and dihydrofolate reductase
- decreases TNF concentrations
net effect: a decrease in T and B cell proliferation and a decrease in rapidly dividing synoviocytes. there is promotion of apoptosis of activated peripheral T cells
how much methotrexate is absorbed orally
70% but variable depending on dose
in terms of distribution, how much methotrexate is bound to proteins
50% bound to plasma proteins
how and how fast is methotrexate excreted
primarily by urine within 48 hrs (clearance may be diminished in elderly and those with decreased renal fxn)
what are some side effects of methotrexate
contraindicated in pregnancy
- generally well tolerated, but may see some of the following SE’s with high doses
- mouth sores
- headaches
- dizziness
- hair loss
- stomtitis
- drowsiness
- itching, rash
- low WBCs
- folate deficiency
- accelerated rheumatoid nodulosis
- can also have severe liver and bone marrow toxicity, therefore patients need to be monitored
this is an isoxazole derivative
Leflunomide (Avara)
what the MOA of leflunomide
it completely inhibits dihydroorotate dehydrogenase which is required for de novo synthesis of pyrimidines. this blocks the proliferative lymphocyte response in inflammation
true or false: lefluonomide is a prodrug that is converted to active metabolite A77 1726
true
this is highly protein bound and has a half life of 15-18 days. it undergoes extensive enterohepatic recirculation. persisting drug levels seen 1-2 years after discontinuation. not recommended in patients with advanced renal disease
leflunomides active metabolite (A77 1726)
what are some adverse effects and side effects of leflunomide
adverse effects: hepatotoxicity. contraindicated in preganancy - d/c 2 years before attempts at pregnancy
side effects: diarrhea, hair loss, reduction in WBC and RBC, hypertension, peripheral neuropathy, itching, rash
this is generally used in the treatment of inflammatory bowel diseases such as UC and chrons, and used as an antimicrobial agent. it is converted by bacteria in the colon into 5-aminosalicylic acid (5-ASA) and sulfapyridine.
sulfasalazine (Azulfadine)
what is the MOA of sulfasalazine
- does not appear to inhibit COX even if 5-ASA is the therapeutic agent
appears to inhibit TNF-alpha, IL-1 and NF-kB. also scavenges free radical and oxygen species
what are some side effects of sulfasalazine
GI (N/V), dizziness, change in color of skin or urine, can cause reduction of WBCs and RBCs
what is the MOA of chloroquine/hydroxychloroquine (Plaquenil)
suggested MOAs
- inhibits sulfhydryl-disulfide interchange (which is important for proliferation of immune cells)
- inhibits enzyme reactions (decreased phospholipase action)
- binds to DNA and interferes with replication in immune cells
- decreases chemotaxis, phagocytosis, fibroblast growth, and WBC proliferation
this has a very favourable safety profile
- rapidly absorbed
- plasma levels plateau in 8-14 days
- long plasma half-life (3-10 days depending on dosing regimen)
- slow urinary excretion
- tissue levels are higher than plasma levels
- concentrates in pigmented ocular tissue
cloroquine/hydroxychlorquine (Plaquenil)
what are some side effects of chloroquine/hydroxychloroquine (Plaquenil)
relatively safe
- GI
- skin and hair lesions
- muscle weakenss
- ocular defects (including retinopathy)
true or false: combination of methotrexate and other compounds (such as leflunomide, sulfasalazine and hydroxychloroquine) is common
true
this is a class of biologic response modifiers Etanercept (Enbrel), Infliximab (Remicade), Adalimumab (Humira), Certolizumab pegol (Cimizia), Golimumab (Simponi)
TNF inhibitors
this is a class of biologic response modifiers
Abatacept (Orencia)
CTLA4 fusion to IgG1 (CD4 antagonist)
this is a class of biologic response modifiers
Rituximab (Rituxan)
chimeric, anti CD20 monoclonal antibodies
this is a class of biologic response modifiers
anakinra (Kineret)
IL-1 receptor inhibitors
this is a class of biologic response modifiers
Tocilizumab and Sarilumab
IL-6 receptor inhibitors
_________ are a class of drugs that work by blocking the action of janus kinase enzymes which are involved in the inflammation that causes the symptoms of RA
JAK inhibitors
this is a JAK inhibitor that blocks JAK1 and 2
Baricitinib
this is a JAK inhibitor that blocks JAK1 and 3
tofacitinib
_________ focus is on methods of action in the cytokine cascade. they reduce signs/symptoms of RA and inhibit. structural damage in patients with moderate.severe to severe RA. they are often given i.v. or sc and either along or in combination with methotrexate for better disease control
biologic response modifiers
________ either “sponge the excess TNF (Etanercept), prevent cell surface and soluble TNF binding to its receptor (infliximab), or bind directly to TNF, blocking TNF receptors (Adalimumab)
TNF inhibitors
_______ selectively inhibits T cells (similar to CTLA4)
Abatacept
________ was originally developed and used for B cell non-Hodgkins Lymphoma and is an anti-CD20 monoclonal antibody
Rituximab
this is an immunosuppressant agent that may be used in RA. the exact MOA is not understood. it used used in patients that have not responded to other medications or in combination therapy
azathioprine (Imuran, Azasan)
this is an immunosuppressant agent that may be used in RA. it primarily affects T cell signalling
cyclosporine (Gengraf, Neoral, Sandimmune)
true or false: treatment with single non-biological DMARDs can achieve remission
true
when are combinations of non-biological DMARDs indicated?
for patients with moderate or high disease activity or prolonged disease duration or for those who fail to respond to a single compound
_________ are reserved for patient with persistent moderate ro high disease activity and indicators of poor prognosis
biologic DMARDs
__________ are often used to bing the level of inflammation quickly under control
short term glucocorticoids
why are glucocorticoids not suitable for long term use
due to adrenal suppression and severe side effects
this is characterized biochemically by hyperuricemia and clinically by episodes of severe, acute arthritis. acute attacks occur as a result of an inflammatory reaction to crystals of uric acid that are deposited in the joint
gout
explain uric acid metabolism
xanthine oxidase breaks down hypoxanthine to xanthine to the keto form of uric acid and finally to the enrol form of uric acid
explain the MOA of allopurinol
this is an analog of hypoxanthine, therefore is serves as a substrate for the enzyme xanthine oxidase and further stops the production of uric acid.
is allopurinol used to treat acute gout attacks or used for prophylaxis
prophylaxis
is allopurinol absorbed well?
rapid oral absorption
is allopurinol bound to plasma proteins
no
where does allopurinol distribute
in total body water (2/3 less in brain)
what are some side effects of allopurinol
GI irration -> diarrhea
this gout agent is an antibiotic: it interferes with mitotic spindles and arrests cells in metaphase. it causes depolymerization and disappearance of fibrillar microtubules in granulocytes and other motile cells. decreases intracellular translocation involved in histamine release therefore less inflammation
colchicine
is colchicine used to treat acute gout or prophylaxis
acute
is colchicine absorbed well?
rapid oral absorption (peak plasma concentration in 30min - 2hrs)
where is colchicine distributed in the body
high concentration in liver, spleen and kidneys; excluded from heart, muscle and brain
how is colchicine excreted
fecal excretion of metabolites
which population is colchicine less tolerated in
elderly
what are some side effects of colchicine
- GI (N/V/D)
- acute poisoning (GI hemorrhage, vascular damage, CNS paralysis)
- chronic poisoning (bone marrow effects)
this is a uricosuric agent used to treat gout. it blocks the reabsorption of uric acid, therefore it leaves the body instead of building up
Probenecid (Benemid)
this is a uricosuric agent used to treat gout. it inhibits uric acid reabsorption in the proximal tubule of the kidney
Sulfinpyrazone (Anturane)
what is the MOA of uricosuric agents
inhibition of the URAT1 (anion exchanger) in the kidneys and thus blocking reabsorption
this is another agent that may be used for gout. includes indomethacin or naproxen
NSAIDs
this is another agent that may be used for gout. it inhibits xanthine oxidase
Febuxostat
this is another agent that may be used for gout. it is an anti-hyperlipidemic drug that is most commonly used in combination with allopurinol
fenofibrate
this is another agent that may be used for gout. is is an angiotensin II receptor antagonist. it also blocks uric acid reabsorption. usually used to treat gout in patients who have hypertensions
losartan
this is another agent that may be used for gout. 4g of ascorbic acid daily nearly doubles the fractional excretion of uric acid
vitamin C
