Flashcards in RA & Gout Deck (32)
Disease-Modifying Anti-rheumatic Drugs (DMARDS)
NSAIDS provide mainly symptomatic relief for patients with rheumatoid arthritis; they reduce inflammation and pain and often preserve function but have little effect on the progression of bone and cartilage destruction. DMARDS may take 6 weeks to 6 months for their effects to become evident, i.e., they are slow-acting compared to NSAIDS. DMARDS are used primarily for rheumatic disorders, especially in cases where the inflammation does not respond to cyclooxygenase inhibitors. These drugs cannot repair existing damage but prevent further injury.
***These drugs do not have any effect upon cyclooxygenase****
Gold salts aurothioglucose & auranofin moa & use
M.O.A.: unknown; are probably taken up by macrophages where they suppress phagocytosis and lysosomal enzyme activity
therapeutic use: rheumatoid arthritis not responding to NSAIDS
Gold salts aurothioglucose & auranofin kinetics & adverse
pharmacokinetics: aurothioglucose (Solganol) is given IM; auranofin (Ridaura) orally; gold compounds concentrate in synovial membranes, liver, kidney, spleen, and bone marrow which allows for long half-lives (months, half-life increases with continued dosing); prolonged treatment is acceptable
adverse effects: about 1/3 of patients experience toxicity; dermatitis is the most common, proteinuria, nephrosis, metallic taste in the mouth; nitritoid reactions (sweating, fainting, flushing, and headaches) may occur due the vehicle used
Chloroquine & Hydroxychloroquine moa & use
M.O.A.: unknown; stabilize lysosomal membranes, inhibit RNA and DNA synthesis, and trap free radicals
Therapeutic use: rheumatoid arthritis, systemic lupus erythematosus, malaria
D-Penicillaminemoa & use
therapeutic use: reserved for patients who have not responded to gold therapy; not given for prolonged periods due to toxicity; also used as a chelating agent for heavy metal poisoning
Methotrexate moa & use
M.O.A: is an immunosuppressant that competitively inhibits the enzyme dihydrofolate reductase, which catalyzes the reduction of dihydrofolate to FH4, this blocks the regeneration of FH4 and prevents the synthesis of purines and pyrimidines. (folic acid is essential for enzyme catalyzed reactions that transfer methyl groups during purine and pyrimidine synthesis.
therapeutic use: patients with severe rheumatoid arthritis that have not responded to NSAIDS and one other slow-acting agent; patients typically respond 3-6 weeks after starting treatment; also used for cancer chemotherapy but doses are much higher than those used for arthritis
Adverse Effects: mucosal ulceration most common, however cirrhosis of the liver and an acute pneumonia syndrome may occur after chronic administration.
Cytopenia (particularly depression of the white blood cell count) may occur after chronic use. Take Leucovorin (folic acid derivative that acts as an antidote to drugs that antagonize folic acid)
Sulfasalazine moa & use
therapeutic use: rheumatoid arthritis, ulcerative colitis
Is an isoxazole immunomodulatory agent
M.O.A. : preferentially causes cell arrest of the autoimmune lymphocytes through its action on dihydroorotate dehydrogenase (DHODH). Stimulation of a T Cell by an antigen-presenting cell drives the lymphocyte into its replicative cycle. Many enzymes including those required for de novo purine, pyrimidine, RNA and membrane synthesis, are upregulated in the G1 phase of the cycle. Dihydrooratate dehydrogenase which catalyzes the formation of orotate (a precursor of the pyrimidines) from dihydrooratate in the mitochondria. Inhibition of DHODH deprives the cell of the precursor for uridine monophosphate (UMP) – a necessary component for RNA synthesis, and a precursor of the thymidine-containing nucleotide required for DNA synthesis.
The inhibition of DHODH is reversible
Leflunomide kinetics & adverse
Pharmacokinetics : a prodrug, has to biotransformed to an active metabolite.
Half-life is 14 to 18 days, because of the long half life loading doses are necessary
Adverse Effects: flu-like syndrome, skin rash, alopecia (allergic reactions)
Teratogenic in experimental animals
Use caution in patients with liver disease
Etanercept, Infliximab, Adalimumab (Humira)
Tumor necrosis factor (TNF) plays a key role in the host’s immune system. Its inflammatory and immune regulating activities are varied.
The actions of TNF result after binding to two different receptors that are found on neutrophils, vascular endothelial cells, and fibroblasts. These receptors also exist in the serum and synovial fluid . The targeting of TNF rests on the observation that cytokines produced by macrophages predominate in the rheumatoid synovium.
Etanercept is a genetically engineered fusion protein composed of two identical chains of the recombinant human TNF- receptor p75 monomer fused with the Fc domain of the human IgG1. This soluble fusion protein binds two molecules of TNF, and prevents then from binding to cellular receptors. The protein does not discriminate between TNF-a and TNF-B(lymphotoxin).
Infliximab is an anti-TNF-a monoclonal antibody that prevents TNF binding to cellular receptors.
******because TNF is important in modulating cellular immune responses to infection and tumors, there is some concern about the long-term use*****
Etanercept & Infliximab adverse
Both agents- do not give to patients with life-threatening infection such as sepsis.
Infliximab has a high risk of causing hepatotoxicity
M.O.A.- Adalimumab is fully human IgG ant-TNF monoclonal antibody. This compound complexes with soluble TNF-a and preventsits interaction with p55and p75 cell surface receptors. This results in down regulation of macrophage and T cell function.
Phamacokinetics- ½ life of 10 to 20 days
Adverse effects- do not give if patient has serious infection
******with all anti-TNF agents be sure you give your patient
M.O.A- Interleukin-1 receptor antagonist
Reserved for patients who have failed at least one DMARD, increased incidence of serious infections
Drugs for the Treatment of Gout
Gout is a metabolic disorder characterized by high levels of uric acid in the blood. This hyperuricemia results in the deposition of sodium urate crystals in tissues, especially the kidneys and joints. Hyperuricemia does not always lead to gout, but gout is always preceded by hyperuricemia. Uric acid forms from purine metabolism. Urate is taken up by granulocytes which then release prostaglandins, lysosomal enzymes, and interleukin-1. The cause of hyperuricemia is an overproduction of uric acid relative to the patient’s ability to excrete it. Therapeutic Goal: lower uric acid level below saturation point for elimination
1. Block uric acid synthesis with allopurinol
2. Increase uric acid excretion with probenecid or sulfinpyrazone
3. Block leukocyte entry into the affected joint with colchicine
4. Administer NSAIDS (non-salicylates)
Acute gout treatment
results from excessive alcohol consumption,
a diet rich in purines, or kidney disease; treat with colchicine to
decrease movement of granulocytes into the affected area, and
with NSAIDS to decrease pain and inflammation
Chronic gout treatment
caused by 1) a genetic defect causing
increased purine synthesis, 2) renal deficiency, 3) Lesch-Nyhan
Syndrome, (no hypoxanthine guanine phosphoribosyl transferase – increase of purines) or 4) excessive synthesis of uric acid associated with cancer chemotherapy; treat with uricosuric drugs, probenecid or sulfinpyrazone, which increase excretion of uric acid, and
use allopurinol to inhibit uric acid synthesis
These drugs do not alter the course of an acute
gout attack nor supplant the use of anti-inflammatory agents in
gout management. In fact, acute gout attacks may increase in
frequency or severity during the early months of therapy when
urate is being mobilized from affected joints. Therapy should not be initiated during an acute gout attack where indomethacin and
naproxen are effective drugs
Colchicine moa & use
M.O.A: binds to tubulin causing its depolymerization which disrupts mobility of granulocytes; also blocks cell division by binding to mitotic spindles; prevents the synthesis and release of leukotrienes (B4)
therapeutic use: specific for gout and relieves acute gouty
arthritis attacks within 12 hours; not effective for other types
Colchicine kinetics & adverse
pharmacokinetics: oral; also available as part of a
combination with probenecid (Colbenemid, Proben-C)
adverse effects: nausea, vomiting, abdominal pain, diarrhea;
myopathy, agranulocytosis, aplastic anemia, alopecia
Allopurinol moa & use
M.O.A.: is a purine analog that is a non-competitive inhibitor of the last two steps of uric acid biosynthesis, both of which are catalyzed by xanthine oxidase (NOTE: uric acid is not very water-soluble while xanthine and hypoxanthine are and are less likely to precipitate)
therapeutic use: treatment of primary hyperuricemia and hyperuricemia secondary to other conditions (where large amounts of purines are produced); often given with NSAIDS
Allopurinol kinetics & adverse
pharmacokinetics: oral; alloxanthine (oxypurinol) is the primary metabolite and it also inhibits xanthine oxidase; t ½ of allopurinol = 2 hrs, oxypurinol = 15 hrs
adverse effects: well tolerated; skin rashes in 3% of patients
M.O.A- a potent & selective inhibitor of xanthine oxidase which results in the reduction of uric acid.
ADVERSE EFFECTS: well tolerated but liver function abnormalities have occurred.
Probenecid moa & use
M.O.A.: increases the excretion of uric acid by inhibiting its tubular reabsorption; these drugs actually inhibit tubular secretion of other acids (aspirin, penicillin) which causes increased plasma levels of these drugs
therapeutic use: chronic gout; liberal fluid intake should be maintained during therapy because of a tendency to cause renal uric acid stones; increasing the urine pH also reduces the likelihood of stone formation
TUMOR LYSIS SYNDROME
Tumor lysis syndrome occurs in malignancies that are highly proliferative and have high tumor burdens, such as lymphomas and leukemias. Metabolic abnormalities—including hyperphosphatemia, hyperkalemia, hyperuricemia and/or hypocalcemia, and renal dysfunction—usually accompany tumor lysis syndrome. Often, hyperuricemia (generally a uric acid level ≥8 mg/dL) is a hallmark finding of tumor lysis syndrome. The current strategies to prevent tumor lysis syndrome are the recognition of risk factors and preventive treatment. In the USA, the standard therapy for preventing tumor lysis syndrome is hydration, alkalinization of the urine with sodium bicarbonate, and allopurinol however, allopurinol only prevents the formation of uric acid and does not affect the uric acid developed prior to treatment.
Rasburicase is derived..
from a cDNA code from a modified Aspergillus flavus strain and expresssed in a modified yeast strain of Saccharomyces cerevisiae A recombinant urate oxidase enzyme, rasburicase converts existing uric acid to allantoin, which is 5 to 10 times more soluble in urine than uric acid. Rasburicase differs from allopurinol since it can affect existing plasma uric acid; allopurinol affects only the future production of uric acid by inhibiting xanthine oxidase The oxidation of uric acid to allantoin by rasburicase produces hydrogen peroxide and carbon dioxide
the overall elimination half-life of rasburicase is 18 hours. Clearance of rasburicase is independent of renal and hepatic function because it is degraded via peptide hydrolysis Because of limited pharmacokinetic evaluation in the adult and geriatric populations, no definitive data can be presented for these groups
The most serious adverse reactions attributed to rasburicase were anaphylaxis, rash, hemolysis, and methemoglobinemia, which all occurred in