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27 Cards in this Set
- Front
- Back
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Colchicine
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Specific for the prevention and treatment of gout. Little effect on other inflammatory conditions and no inherent analgesic properties
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Mechanism of Colchicine:
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-Arrests mitosis in metaphase by binding to tubulin and prevents mitotic spindle formation in granulocytes and other motile cells
Colchicine inhibits microtubule formation and, at high enough concentration, disrupts microtubules. Inhibits migration of granulocytes into inflamed areas and decrease their metabolic and phagocytic activities. - Prevents elaboration of urate-induced glycoprotein in joints |
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Gout formation pathway
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What is the underlying metabolic disorder in gout?
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Hyperuricemia
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What are the two ways that Pharmocologic agents reduce the amount of uric acid in the blood?
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- Reducing acid production through the inhibition of of xanthine oxidase (allopurinol)
- Increasing uric acid clearance through an inhibition of its renal tubular reabsorption (probenecid) or through metabolic conversion to a more soluble compound (urate oxidase) |
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Drug interactions for Colchicine
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Erythromycin, simvastatin, and cyclosporine can increase the risk of colchicine-induced toxic effects. Cyclosporine and verapamil inhibit MDR and ↑colchicine in systemic circulation leading to toxicity without diarrhea
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Mechanism of action for steroids
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- Glucocorticoids suppress the induced expression of COX-2 and thus COX-2 mediated prostaglandin production
- Inhibit the action of PLA2 which releases arachidonic acid from cell membranes. |
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What is the treatment of choice of acute crystal induced arthritis
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Non-salicylate NSAIDS are the drugs of choice in the treatment of acute crystal induced arthritis. No clear advantage of one NSAID over another but large initial doses are recommended
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How do NSAIDS work against gout
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NSAIDs exert their anti-inflammatory effects mainly through inhibition of COX which catalyses the conversion of arachidonic acid to proinflammatory prostaglandins, particularly PGE2. These play a major role in crystal induced inflammation, and act synergistically with other mediators (bradykinin, leukotriene B4) to enhance capillary dilatation, pain sensitivity, and neutrophil chemotaxis
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What are the roles of the two COX enzymes?
Which do you want to inhibit more? |
- COX-1 is constitutively expressed in most tissue and is unaffected by inflammatory mediators. It supports biosynthesis of prostanoids required for housekeeping functions such as renal blood flow and maintaining the gastric mucosa
- COX-2 is constitutively expressed in a few tissues but is highly inducible in response to cytokines, endotoxins, mitogens, and growth factors, implying a role in inflammation, infection, and cellular proliferation |
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What is the primary target of NSAIDS
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NSAIDs exert their anti-inflammatory effects mainly through inhibition of COX-2 and most adverse effects, particularly GI effects results from inhibition of COX-1. Newer NSAIDs (celecoxib, rofecoxib, valdecoxib, and etoricoxib) are highly COX-1 sparing.
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What does Indomethacin inhibit?
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- Inhibition of COX-1 and COX-2
- Inhibition of PMN leukocyte migration - Relieves inflammation, fever and pain. Useful antipyretic in Hodgkins disease when fever is refractory to other agents. - Rapidly absorbed from GI tract, metabolized by liver and excreted in urine - GI problems (anorexia, abdominal pain, ulceration). CNS problems include (frontal headache, dizziness, confusion), rare aplastic anemia and impaired platelet function common to nonselective COX inhibitors. - Contraindicated in pregnancy, psychiatric disorders, epilepsy, Parkinsonism, renal disease, gastric or intestinal ulcers and operation of machinery. |
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Sulindac
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- The prodrug of sulindac sulfide
- Inhibit COX enzyme (sulfide metabolite is 500x more potent than the parent drug) -Half life of the drug is 7hr, but it is oxidized to the sulfone, then reduced to the sulfide with a half life of 18hr. Excreted in urine and feces. |
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Naproxen
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- Oral absorption accelerated by sodium bicarbonate
- Oral absorption reduced by MgO or Al(OH)3 - Many patients prefer for analgesia and morning stiffness - Long half life (14hr) determine dosing: q12hr - Side effects similar to indomethacin but better tolerated |
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Selective COX-2 inhibitors
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- Celecoxib, rofecoxib, valdecoxib, etoricoxib
- Developed to inhibit prostacyclin synthesis at sites of inflammation without interfering with COX-1 found in GI tract, kidney and platelets - They do not affect platelet function and cause less GI side effects |
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What is the problem with selective COX-2 inhibitors?
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- COX-2 is constitutively active in the kidney and these agents do cause renal problems similar to nonselective COX inhibitors.
- PGI2 is a key COX-2 dependent product in the endothelium that inhibits platelet aggregation, causes vasodilatation, and prevents proliferation of vascular smooth muscle cells - In contrast, TXA2 is a COX-1 derived product that causes platelet aggregation, vasoconstriction, and vascular proliferation. - Inhibition of COX-2 will suppress formation of PGI2, leaving TXA2 unopposed to promote vasoconstriction, thrombosis, and atherogenesis. Hence these agents are associated with an increased risk of cardiovascular events. |
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Rofecoxib
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- Selectively inhibits COX-2
- No effect on platelet function - Less gastric irritation than ibuprofen - Treat osteoarthritis, acute pain and dysmenorrhea - Metabolized by cytosolic reductases to dihydro derivatives. - Excreted in urine and feces. - Interactions with rifampin, methotrexate and warfarin - Edema and hypertension at high dose |
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Selective COX-2 inhibtiors (Coxibs)
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Celecoxib: similar to rofecoxib
- Interactions with fluconazole and lithium - Metabolized by CYP2C9, so interacts with warfarin - Contain sulfonamide group so may cause rash Other Agents - Etoricoxib - Valdecoxib---contains sulfonamide group so rxn in sulfonamide sensitive patients. |
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Purine Metabolism
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The final two steps have the same enzyme:
- So if we inhibit xanthine oxidase, it will significantly effect the formation of uric acid. |
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Allopurinol
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- An analog of hypoxanthine, metabolized to active agent oxypurinol (t1/2 of 18-30h)
Mechanism: - Interference with xanthine oxidase, thus blocking uric acid synthesis - Xanthine oxidase enzyme contains molybdenum Which goes between +4 and +6. allopurinol freezes the enzyme so that it cannot cycle Therapeutic uses: - Hyperuricemia (add C or N 1st 4-6 m - Gout - Prevention of hyperuricemia in patients receiving antineoplastic drugs - Adverse effects are mainly hypersensitivity rxn (pruritic, erythematous or maculopapular rash)(may develop to SJ syndrome |
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Other effects of Allopurinol
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- Increases t1/2 for probenecid and enhance its uricosuric effect.
- Probenecid increases the clearance of oxypurinol and so increase the dose requirement of oxypurinol - Allopurinol decrease metabolism and clearance of mercaptopurine (and derivative azathioprine) Decrease dose of azathioprine and mercaptopurine when given with allopurinol - Allopurinol also increase the accumulation of the active metabolite of theophylline (1-methylxanthine) - Contraindicated in patients with serious hypersensitivity rxns. |
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Agents that enhance uric acid metabolism
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Rasburicase (ELITEK):
- A recombinant urate-oxidase that catalyze the enzymatic oxidation of uric acid into soluble and inactive metabolite allantoin. Lower urate levels more effectively than allopurinol. Useful in tumor lysis syndrome Adverse effects -Efficacy is reduced by production of antibodies against the drug. Hemolysis in G6PD-deficient patients, methemoglobinemia, acute renal failure and anaphylaxis Pegloticase: - Recently approved for gout refractory to conventional therapy |
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Uricosuric Agents used in the treatment of gout
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These agents increase the rate of excretion of uric acid
Probenecid: - Mechanism: Inhibition of uric acid reabsorption in the proximal tubule. Action blunted by salicylate. Competition with urate for the anion exchange mechanism (URAT1 anion transporter) (IF a pt. doesn’t have URAT1 then the don’t respond to uricosuric agents – tells that URAtT1 is the main transporter that reabsorbs uric acid. And tells us that URAT1 is target for the uricosuric acid.) |
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Probenecid
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Given orally
- Moderately analgesic and anti-inflammatory - Fluid intake must be generous to avoid formation of renal urate stones (NaHCO3 or Cacitrate) Adverse effects: - An attack of acute gouty arthritis may be precipitated; administer an NSAID along with the probenecid - GI irritation - Also used to inhibit the active secretion (not the reabsorption) of penicillin G (OAT). Uric acid levels < 6-6.5mg/dL supports crystal dissolution in synovial joints |
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Sulfinpyrazone
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Mechanism:
- Inhibition of uric acid reabsorption in the proximal tubule - Small doses inhibit uric acid secretion - Also inhibits platelet aggregation Adverse effect: GI irritation - Fluid intake must be generous to avoid formation of renal urate stones |
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Methotrexate
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- Disease modifying Antirheumatic Drug (DMARD) of choice to treat RA
- Much lower doses needed to treat RA than cancer - Inhibit aminoimidazolecarboxamide (AICAR) transformylase resulting in accumulation of adenosine which binds to A2 receptors to increase cAMP. Increased cAMP decrease TNF, IL2 etc. Also inhibit dihydrofolate reductase. |
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stoped on
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slide 41
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