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18 Cards in this Set
- Front
- Back
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a. Know the physiologic and intracellular mechanism involved in the anti-inflammatory effects of glucocorticoids
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Naturally originate from the HPA as corticotrophin, which activates the adrenal cortex to produce glucocorticoids (cortisol, corticosterone). They upregulate hepatic glucose output by stimulating catabolism of peripheral fat/protein to promote gluconeogenesis. Increases blood glucose levels allows body to survive stressful stimuli but downregulates immune system. This is how GCs act as anti-inflammatories: fewer immune cells are made, and necessary mediators are downregulated intracellularly by 4 pathways:
i. Inhibits nF-kB, an intracellular signal to produce cytokines, adhesion molecules, chemotactic proteins, etc. which stimulate COX-2 ii. Promotes Annexin-1, which inhibits cPLA2a (normally catalyzes phospholipid transformation to arachidonic acid) iii. Promotes MAPK phosphatase-1, which dephosphorylates and inactivates MAPKs (these are activated by cytokines, hormones, endotoxin, antigens and promote cPLA2a as well) 1. MAPKP-1 also downregulates Jun N-terminal kinase, which are activated by cytokines and produce cytokines iv. Inhibits c-Jun, which is normally phosphorylated by Jun N-terminal kinase (above) Overall effects on arachidonic cascade: inhibits PLA2 and COX2 |
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b. Be familiar with durations (short, medium, long)
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Short-acting: cortisol/hydrocortisone, prednisone, cortisone
Medium: triamcinolone, paramethosone Long: betamethosone, dexamethosone |
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c. Be familiar with adverse effects with long-term use
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Most important: long-term synthetic GC use results in a feedback inhibition of the adrenal gland production of endogenous cortisol. This means the patient is less likely to respond to stress from surgery/trauma. Need to taper off dosage slowly to allow accommodation.
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d. Be able to identify anti-inflammatory glucocorticoid drugs listed below
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Cortisone, betamethosone, dexamethosone, hydrocortisone, prednisolone, triamcinolone
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a. Be familiar with the synthesis of prostaglandins, leukotrienes, and thromboxan
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Arachidonic acid is released from damaged cells by PLA-2, and can go one of four ways (two of which are important)
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i. Understand the role of cyclooxygenase and lipoxygenase
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1. COX pathway
1) Arachidonic acid is converted to PGH by COX1/2 2) COX-1 promotes synthesis of thromboxane A (TXA), a prothrombin. 3) COX-2 promotes synthesis of prostacyclin (PGI), an anticoagulant 4) Both promote PGF2a, PGD, PGE1, PGE2 2. LOX pathway (5-lipooxygenase is a single enzyme and is active in mainly stimulated inflammatory cells [significant in asthma and anaphylactic shock] good target for drug action) 1) Arachidonic acid is converted to HPETEs (hydroxyperoxyeicosatetraenoic acids), leukotrienes (LT) 2) LTA is unstable, and is converted to LTB or LTC, which can be further converted to LTD and LTE i. LTC/D are potent bronchoconstrictors and induce mucus secretion ii. Primary components of slow-reacting substance of anaphylaxis (SRS-A) |
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b. Be familiar with the eicosanoid receptors, their intracellular signaling cascade
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PGI, PGD, and PGE1 all trigger the Gs complex and increase cAMP, leading to smooth muscle relaxation by inhibiting MLCK. PGE2, TXA, and PGF2a (and LTB) all cause smooth muscle contraction by triggering the Gq complex and increasing intracellular Ca and MLCK activity.
i. PGI binds IP 1. Causes vasodilation and capillary fluid outflow ii. PGD binds DP1 1. Causes immune cell chemoattraction, activation, and T cell modulation iii. PGE1 binds EP2/4 iv. PGE2 binds EP1/3 1. In addition to triggering Gq, also triggers Gi, which has same overall effect by inhibiting adenylyl cyclase. 2. Causes vasodilation, capillary fluid outflow, increases vascular permeability, secretion, and endothelial gaps v. TXA binds TP 1. Causes immune cell chemoattraction, activation, and T cell modulation vi. PGF2a binds FP vii. LTB binds BLT (nice) |
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c. Be familiar with the effects of prostaglandins, thromboxane, and leukotrienes in smooth muscle, bone, GI, lung, kidney, platelet, reproductive function, and temperature regulation in the CNS
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GI: smooth muscle contraction by TXA, PGE2-EP3, PGF2a, and LTs; mucosal acid release is inhibited by PGE1 (important!)
Lungs: smooth muscle relaxation by PGE2, PGI2; contraction by TXA, PGD, PGF2a, and LTs Kidney: stimulate renin release (a pre-angiotensin), regulate Na secretion, maintain blood flow by PGE2, PGI Female repro: uterine smooth muscle contraction by PGE2-EP3, PGF2a, TXA Male repro: relaxation of vascular smooth muscle in corpora cavernosum by PGE1 Neuronal: Fever is increased by PGE2-EP3; Pain is increased by PGD/I/F2a Bone: Healing and bone turnover increased by PGE2-EP4 (stimulates osteoclast activity [macrophages of the bone]) Eye: Vasoconstriction increases aqueous humor outflow via uveoscleral pathway by PGF2a Cancer: PGE2 is oncogenic |
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d. Know the role of prostaglandins, thromboxane, and leukotrienes in inflammation and immunity.
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This is addressed above, but I’ll summarize:
PGE2: increases vascular permeability, endothelial gaps, and secretion as well as vasodilation and capillary blood outflow (leads to inflammation) PGI: increases vasodilation and capillary blood outflow (leads to inflammation) TXA and PGD: immune cell chemoattractants, activation, and T cell modulation LTs: phagocyte attraction, activation, and T cell modulation; also increases vascular permeability, endothelial gaps, and secretion |
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e. Know the use of the various prostaglandins in labor, dysmenorrhea, erectile dysfunction, pulmonary hypertension, patency of ductus arteriosus.
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Labor: can be induced by triggering the PGE2-EP3 complex in the uterine smooth muscle use dinoprostone
Dysmenorrhea: abnormal amount of blood/pain during menses can be due to too much PGE2/PGF2a causing contractions; prevent with NSAIDs or PG inhibition Erectile dysfunction: Lack of PGE1 to allow erection can be corrected with alprostadil Pulmonary hypertension: improved by extra PGI (eprostenol) which is an anticoagulant and relaxes smooth muscle Patent ductus arteriosus: can be corrected with indomethacin, or kept open with extra PGE1 if there is transposition of the great vessels and surgery is necessary GI: cytoprotection can be increased with extra PGE1 via misoprostol (prevents hemorrhaging and ulceration) Eye: glaucoma can be alleviated with PGF2a via latanoprost Lungs: Alleviate asthma with PGE2 aerosol |
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f. Know the role of thromboxane in thrombosis.
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Thromboxane is a platelet aggregation promoter; it is produced by the COX-1 pathway, and therefore, if the COX-2 pathway is inhibited without balancing with COX-1 inhibition, extra TXA will be synthesized and cause more thromboses; however, inhibiting both (like with aspirin) will generally prevent thromboses.
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Know the effects of NSAIDs on lipoxygenase, cyclooxygenase (COX1 & COX2):
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increases lipoxygenase since only open pathway; can inhibit COX2 or both COX1&2
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Know the importance of COX2 vs COX1 inhibition:
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We want to inhibit COX2 because this is responsible for inflammation. We need to be careful when inhibiting COX1 because it is responsible for the ‘housekeeping’ of the body. When blocked, things get messy – decreases GI mucosal integrity, decreases platelet aggregation, decreases renal function
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Know everything about aspirin
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Aspirin is a nonspecific irreversible inhibitor of COX1 & COX2 enzymes. Its pKa is 3.5.
MOA: irreversible inhibition which is great for anti-platelet effects (blocking COX1 enzymes) Dose duration is 6-12 hours Clinical uses: decrease rate of temporary ischemic attacks, unstable angina, coronary artery thrombosis with myocardial infarction & thrombosis after coronary artery bypass grafting Children <19yrs should not take aspirin, as it is linked with Reye’s Syndrome Most important side effects: GI – abdominal pain, dysplasia, nausea, vomiting, ulcers/bleeding (rarely); hematologic – antiplatelet activity, rare thrombocytopenia, neutropenia or even aplastic anemia; renal: renal insufficiency, renal failure, hyperkalemia, proteinuria Contraindications: gout, hemophilia, most pregnancies |
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Know the toxicity of aspirin, NSAIDs and coxibs**
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aspirin and NSAIDs are more toxic in renal function, coxibs are linked to increased cardiovascular disorders
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Be able to identify major NSAIDs and coxibs listed below
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NSAIDs:
Nonselective reversible: ibuprofen, nabumetone (long half-life), oxaprozin (longest half-life), piroxicam (long half-life) Nonselective irreversible: aspirin Coxibs: celecoxib, meloxicam (long half-life) |
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Know common DMARDs listed below, MOA, use & toxicities
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1st choice DMARD = methotrexate
Use: Stop the progression of rheumatoid arthritis, but requires that drugs must be taken for life MOA: immunosuppressive drugs; inhibit function and division of immune cells (or other rapidly dividing cell populations) Many ways: antimetabolites (methotrexate), purine antagonist, agents that suppress B/T cell function (sulfasalazine – mainly for inflammatory bowel disease), agents that prevent cellular replication, DNA crosslinker (leflunamide), antimalarial (hydroxychloroquine), gold (aurothioglucose + auranofin), penicillamine (for copper poisoning possibly via metal chelation), drugs that are protein-based must be humanized to bypass the body’s immune system (anti-TNF-alpha drugs) Toxicities: liver, so make sure to monitor liver function after treatment started |
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Know common anti-gout medications listed below, MOA, use & toxicities
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Acute: indomethacin (NSAID), ketorolac, colchicine (microtubule polymerization inhibitor by binding to tubulin, also inhibits leukocyte migration, caused diarrhea)
Chronic: allopurinol (used in conjunction w/ NSAID or colchicine; inhibits XO, and prevents urate formation from dietary purines, increases acute gouty arthritis, GI intolerance, bone marrow depression and skin rashes), febuxostat, sulfinpyrazone, probenecid (last 2 for several acute attacks, work by decreasing the body’s store of uric acid; patient must maintain high urine volume to avoid crystal precipitation, also can cause GI irritation) |
