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121 Cards in this Set
- Front
- Back
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Which cells synthesize eicosinoids?
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All EXCEPT erythrocytes
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How do eicosinoids function?
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locally at site of synthesis through receptor mediated G-protein linked signaling pathways leading to increase in cAMP levels
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What are the eicosinoids and where do they come from?
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arachodinic acid metabolites: prostaglandins, thromboxanes (COX dependent pathway of production), leukotrienes (lipoxygenase dependent pathway of production)
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Prostaglandins?
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-made from phospholipid membrane derived fatty acids (arachidonic acid)
-made on demand and act locally -degraded quickly either by enzymes or "autocoid" change into inactive forms |
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Dinoprostone?
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PGE2 used to induce labor and for second trimester abortion
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Misoprostol?
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PGE1 used to decrease gastric ulceration, can prevent or reverse gastric side effects of NSAIDS
also abortifacient properties |
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PGE1?
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harvesting and storage of platelets
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Alprostadil?
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PGE1 that improves blood flow in peripheral vascular disease (vasodilator, platelet anti-aggregant)
-also maintains an open ductus arteriosis in the newborn -treatment for male impotence |
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Latanoprost?
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PGF-2a applied topically for glaucoma
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Epoprostenol?
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prostacyclin PGI2 used for rapid reversal of pulmonary hypertension
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Do COX inhibitors affect leukotrienes?
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NO because leukotrienes dependent on lipoxygenase pathway
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Where is COX-1 found?
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Blood vessels, GI, mucosa
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Where is COX-2 found?
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macrophages, mast cells, other immune and inflammatory cells
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Alprostadil can maintain an open patent ductus arteriosis but what can close it?
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indomethacin, COX blocker
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Why do COX blockers have analgesic effects?
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because prostaglandins function to sensitize nociceptive (pain) receptors to mechanical stimuli and chemical stimuli from bradykinin and histamine
so block prostaglandin synthesis, block pain sensitization |
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Why do COX blockers have antipyretic effects?
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PGE2 increases the temperature set point set by the hypothalamus, PGE2 inhibition returns temp to normal and excess heat dissipated via sweating and centrally mediated peripheral vasodilation
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Why do COX blockers have anti-inflammatory properties? And which one is the exception?
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mediated via a COX-2 block which reduces leukocyte activation and interaction with endothelial cells
exception: acetaminophen!! only analgesic and antipyretic |
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What is the PGH synthase system and what reaction does each enzyme catalyze?
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consists of cyclooxygenase and peroxidase
COX converts arachidonic acid into PGG2 peroxidase converts PGG2 into PGH2 |
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What is asprin's mechanism of action?
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acetylates a serine of COX which IRREVERSIBLY inhibits it
but asprin readily metabolized to salicylic acid which is a REVERSIBLE inhibitor |
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What are the most common side effects of asprin?
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GI: burning, cramps, nausea, vomiting, gastric ulceration but NOT duodenal
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How do asprin and salicylic acid cause GI side effects?
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-direct irritants since pH causes drugs to get trapped in mucosal cells
-via block of PGI2 and PGE2 create loss of mucus barrier |
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Can platelets replace COX?
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NO, so thromboxane inhibition by aspirin lasts for the life of the platelet
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What is aspirin's effect on the respiration?
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-at therapeutic doses stimulates respiratory center (but at toxic doses inhibits it! leads to resp. acidosis)
-uncouples oxidative phosphorylation (inc CO2, inc depth & rate of breathing, resp. alkalosis) |
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Aspirin effects in acid/base balance?
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to compensate for resp alkalosis kidneys excrete bicarb, Na, & K; so on sustained therapeutic doses in state of compensated resp alkalosis
but kiddies can bypass & enter toxic zone of resp and metabolic acidosis |
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Regular use of aspirin in last trimester of pregnancy can lead to?
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prolonged gestation
prolonged labor increased maternal blood loss |
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Aspirin effects on liver?
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acute, dose dependent, reversible hepatotoxicity
patients at risk: juvenile arthritis, active SLE, rheumatic fever |
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Salicylism?
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mild to chronic salicylate intoxication; symptoms of tinnitus, hearing loss, vertigo
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Salicylate poisoning?
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inhibition of respiratory center, rate and depth of respiration slows so get accumulation of CO2 and uncompensated respiratory acidosis, central respiratory paralysis and circulatory collapse
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What are the toxic effects of aspirin on acid/base balance?
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displacement of bicarbonate by ionized salicylic acid; interference with carb metabolism; impaired renal function leading to accumulation of metabolic acids; inhibition of Krebs cycle & inc of acidic byproducts
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What are some of the consequences of uncoupling oxidative phosphorylation by aspirin?
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ATP not produced
Fats mobilized to FFA and ketones Tissue glycolysis inc leading to fever Glycogen stores mobilized |
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Which patients have a higher incidence of aspirin hypersensitivity?
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with triad of asthma, nasal polyps, and chronic rhinitis
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Where is aspirin absorbed?
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upper small intestine
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Do OTC NSAIDs effect prothrombin time or whole blood clotting time?
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NO
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Why isn't acetominophen an anti-inflammatory drug?
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reactive oxygen species at site of inflammation modifies drug; weak inhibitor of COX in presence of peroxides
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Why does COX-1 inhibition lead to mucosal bleeding?
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mediates PGE2 production, which is cytoprotective
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What are COX 2 inhibitors side effects?
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abdominal pain
diarrhea nausea headache upper respiratory infections cardiotoxicity! (why rofecoxib and valdecoxib have been pulled) |
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Where else can COX-2 be expressed besides macrophages and similar inflammation mediators?
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blood vessel endothelial cells in response to shear stress
COX-2 causes release of prostacyclin (PGI2) from these cells which is anti-thrombotic and balances the pro-thrombotic activity of COX-1 dependent Thromboxane A2 |
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Why do COX-2 inhibitors have cardiotoxicity?
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because COX-2 normally helps vessels release anti-thrombotic factors after shear stress
without COX-2, COX-1 mediated thrombosis uninhibited so greater chance of clotting and cardiotoxicity |
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Why is aspirin cardio-protective?
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namely, the imbalance between PGI2 (anti-clot) and thromboxane 2
inhibits both irreversibly but endothelial cells can make more PGI2 while platelets thromboxane inhibited for LIFE (life of the platelet) |
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Why is Aspirin cardioprotective but the other non-selective NSAIDs are not?
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other NSAIDs are reversible, so platelet thromboxane 2 inhibition will be overcome and imbalance with PGI2 not maintained
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How is aspirin's effect on COX-2 different from other COX-2 inhibitors?
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aspirin acetylates COX-2 and changes its SPECIFICITY
ENHANCES COX-2 production of 15-epi-lipoxin from arachidonic acid and the production of resolvins from omega-3 FA EPA (these help resolve inflammation) |
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Which non-selective NSAIDs are appropriate for RA Tx?
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All EXCEPT ketorolac
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Ibuprofen?
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non-selective propionic acid NSAID used for dysmenorrhea
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Indomethacin?
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non-selective acetic acid NSAID, closes PDA
may cause ACUTE RENAL FAILURE |
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Ketorolac?
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non-selective acetic acid NSAID
NOT used for RA |
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Naproxen?
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non selective propionic acid NSAID used for dysmenorrhea
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Piroxicam?
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carboxylic acid/oxicam structured non-selective NSAID
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Sulindac?
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acetic acid structured non selective NSAID
used for RA |
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NSAIDs with carboxylic acid structure?
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oxicams (piroxicam)
salicylic acid (aspirin) anthranilic acid (meclofenamate, mefenamic acid) |
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NSAIDs with propionic acid structure?
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fenoprofen
flurbiprofen ibuprofen ketoprofen naproxen oxaprozin |
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NSAIDs with acetic acid structure?
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indomethacin
sulindac etodolac nabumetone tolmetin ketorolac diclofenac |
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What is Arthrotec?
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combination drug containing diclofenac and misoprostol (PGE1 analog)
this reduces the GI ulceration effect of the NSAID (diclo) |
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What role do PGE1 and PGE2 play in the kidney?
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both vasodilatory (afferent)
their inhibition by NSAIDs in patients with CHF, cirrhosis, chronic renal may cause decreased GFR & RBF and lead to acute renal failure |
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How do NSAIDs affect salt and water balance?
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tend to promote retention of salt and water by the kidney
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Is inhibition of platelet aggregation by NSAIDs therapeutic benefit or a side effect?
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BENEFIT with aspirin (most pronounced with aspirin)
considered side effect with other NSAIDs because they have weaker inhibitory effect on platelet aggreation |
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If you have a hypersensitivity reaction with aspirin should you switch to another NSAID?
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it is a contraindication
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What are some factors that make rheumatoid arthritis difficult to diagnose clinically?
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-may be rheumatoid factor negative for first year of disease
-10% of normal population is RF positive -synovitis may be subclinical and more widespread than can be detected on exam -early erosions not apparent on X-ray |
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In step down combination therapy approach to RA which drugs are used?
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sulfasalazine
methotrexate (taper down and d/c) prednisone (taper down and d/c) |
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Methotrexate?
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DMARD
immunosuppressive inhibits dihydrofolate reductase at high doses may inhibit adenosine and TNFa at therapeutic doses |
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Sulfasalazine?
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DMARD with unknown MOA for RA
impairs secretions of myofibroblasts that prevent break down of scar tissue |
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Gold Salts?
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DMARD
taken up by macrophages: inhibits phagocytosis, dec RF, dec IgG levels |
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Hydroxy-chloroquine?
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DMARD
may suppress T cell activation can cause hemolysis in G6PD deficiency |
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Leflunoamide?
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DMARD
inhibits synthesis of uridine phosphate |
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What macrophage secretion is a major contributor to synovial inflammation in RA?
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TNF-alpha, hence the anti-TNF drugs
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Infliximab?
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anti-TNF
used in RA and Crohn's binding site mouse derived clears TNFa from joint and blood used with methotrexate to reduce antibody formation against drug |
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Adalimumab?
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anti-TNF drug
same mechanism as infliximab BUT all human in sequence less likely to have AB response less of a problem with TB |
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Etanercept?
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-anti-TNF drug
-soluble dimeric form of p75 TNF receptor -used as initial RA Tx, ankylosing spondylitis, and psoriatic arthritis -abdominal pain, sepsis/infection are side effects |
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Anakinra?
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Anti- IL-1 drug
IL-1 receptor blocker -indicated for moderate to severe RA when other drugs have failed -LESS efficient than TNF block, but may slow bone erosions -can be used with other DMARDs but NOT TNFa inhibitors -neutropenia side effect |
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How do infliximab and adalimumab help treat RA?
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anti-TNF antibodies
-reduced activation/infiltration of inflammatory cells -reduced clinical manifestations of disease and slowing/halting radiographic progression |
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Two classes of steroids made by adrenal cortex?
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corticosteroids (gluco- and mineralo-)
androgens |
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What is the rate limiting step in steroid synthesis?
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conversion of cholesterol to pregnenolone
ACTH activates the enzyme that cleaves cholesterol's side chain in this step |
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What is the MOA of glucocorticoid SAIDs?
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stimulate synthesis of lipocortin
lipocortin then inhibits phospholipaseA2 this reduces arachidonic acid production which is starting point of prostaglandin, leukotriene synthesis |
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How are steroid receptors maintained inactive?
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form complex with heat shock protein 90
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Anti-inflammatory effects of glucocorticoids?
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-increase apoptosis in activated lymphocytes
-inhibit cytokine production -inhibit activation of neutrophils and leukocytes -stabilize leukocyte lysosomal membranes -reduction in capillary permeability and edema -antagonism to histamine activity and edema |
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What are specific structural components necessary for glucocorticoid and mineralocorticoid activity?
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C3 keto
double bond at delta 4 |
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What are specific structural features needed for glucocorticoid function?
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-C11 ketone or hydroxyl (ketone gets reduced to hydroxyl in vivo anyway)
-C17 hydroxyl enhances activity C3 keto and double bond at delta 4 also needed but these are common with mineralocorticoids too |
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What are two structural features that serve as enhancements for glucocorticoid activity?
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-double bond at C1
-F9 or C16 methyl or hydroxyl |
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Of the glucocorticoids which drug is the most potent anti-inflammatory? And the least potent?
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most potent: dexamethasone, followed by bethamethasone
least potent: cortisone, followed by hydrocortisone (cortisol) |
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Of the glucocorticoids which has the strongest mineralocorticoid action?
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fludrocortisone, rest are all comparably low
fludro has unique structure of mineralo activity enhancing F9 methyl or hydroxyl and lacks the gluco enhancing double bond at C1 |
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How are uses of cortisol are different between physiologic and pharmacologic doses?
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physiologic: replacement of deficient hormones
pharmacologic: anti-inflammatory and immune suppression (may have some of these effects at physiologic doses as well) |
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What are the symptoms of steroid withdrawal syndrome and how is it related to the hypothalamus pituitary axis?
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presents with fever, myalgia, anthralgia, and malaise
rarely pseudo tumor cerebri it is NOT related to hypothalamus pituitary axis |
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How can a primary adrenal cortical insufficiency (Addison's) be distinguished from a secondary cause?
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ACTH levels
HIGH in Addison's LOW in secondary cause (pituitary fails to make adequate ACTH in response to low cortisol usually due to steroid use) |
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What are symptoms of hypocortism?
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weakness
fatigue hypotension hypoglycemia Na wasting apathy depression psychosis arthralgia hyperpigmentation |
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Difference between Cushing's syndrome and disease?
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Disease: inc ACTH and thus cortisol due to bilateral adrenal hyperplasia secondary to ACTH secreting PRIMARY ademona - REPSONSIVE to high doses of glucocorticoids
Syndrome: nodular hyperplasia of adrenal gland itself (just inc cortisol, not ACTH); OR ectopic production of ACTH by other tumors - NOT RESPONSIVE to glucocorticoids |
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What is the test for Cushing's syndrome vs. disease?
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dexamethasone
low doses distinguish normal from Cushing's patients high doses finds those who are sensitive and show reduction in cortisol metabolites in their urine, these have the disease insensitive to high doses have syndrome, ectopic ACTH |
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Aminoglutethimide?
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steroid synthesis inhibitor (corticosteroid antagonist)
-blocks conversion of cholesterol to pregnelone (rate limiting step) -given with hydrocortisone and prevents over-ride of block by inc ACTH -reduces all hormonally active steroids |
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Metyrapone?
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steroid synthesis inhibitor: inhibits 11B-hydroxylation
interferes with cortisol and corticosterone synthesis treatment of cushing's |
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Trilostane?
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steroid synthesis inhibitor: inhibits 3B-dehydorgenase
treatment of Cushing's |
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Beta 2 MOA on asthmatics?
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-relax bronchial smooth muscles, physiologic antagonism preventing contraction by various stimuli
-increases mucus clearance -prevent mast cell mediator release |
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Inhaled bronchodilators of choice for acute asthma?
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metaproterenol
albuterol terbutaline |
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Do mast cell stabilizers have bronchodilator or antihistaminic activity?
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NO; just prevent release of histamine (and degranulation) by mast cells
also reduces the effect of chemoattractant peptides to woo PMN, eosinophils, and monocytes |
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Corticosteroid MOA for asthmatics?
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-reduce number and activity of inflammatory cells in the airway
-inhibit release of arachidonic acid metabolites in the airway -prevent inc in vascular permeability -suppress IgE binding -dec severity of disease and inc bronchodilator efficacy -NOT bronchodilators |
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What are the therapeutic uses for corticosteroids for asthmatics?
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-for patients who use B2 adrenergic agonists more than 4x per week
-suppresses late repsonse, little effect on early response -used for long term prevention of symptoms: suppression, control, and reversal of inflammation |
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What is theophylline and what is its MOA?
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xanthine used for asthmatic treatment
-inhibits phosphodiesterases with minor effect of increased intracellular cAMP -adenosine receptor antagonism (blocks adenosine receptor that mediates bronchoconstriction) |
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When useful, Ipratropium may be prescribed along with which class of asthmatic drugs for enhanced effectiveness?
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Beta 2 agonists
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Why are leukotriene modifiers beneficial in aspirin sensitive asthma?
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aspirin blocks COX and arachidonate gets diverted to alternative lipoxygenase pathway thus making more leukotrienes
leukotrienes happen to be more potent bronchoconstrictors, so this is bad |
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What is the MOA of leukotriene modifiers?
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zafirlukast is selective LKT4 receptor antagonist
zileuton is a 5 lipoxygenase inhibitor thus decreasing leukotriene synthesis |
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What causes hypersecretion of serotonin and how does it manifest?
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-malignant growth of enterochromaffin calls (usually in small intestine)
-also causes inc substance P, prostaglandins, and bradykinin -results in hypermotility, diarrhea, bronchial constriction, hyptension, cardiac fibrosis |
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Ritanserin?
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5H2 receptor antagonist with antiplatelet effects (prevents serotinin influence on platelet aggregation)
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Cyproheptadine?
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5H2 receptor antagonist: controls skin allergies, itching, cold induced uticaria, and for smooth muscle actions of serotonin in carcinoid tumor and gastrectomy
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Methysergide?
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5HT2 receptor partial agonist/antagonist
prophylatic use for migraines |
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Ondansteron?
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5HT3 receptor antagonist; prophylatic for nausea and vomiting in cancer chemo
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H1 receptors?
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vasodilation
bronchoconstriction smooth muscle activation (gastric) pain and itching at peripheral receptors AV node conduction |
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H2 receptors?
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located in parietal cells, regulate gastric acid secretion
also capillary dilation SA nodal rate, ionotropic activity, and atrial and ventricular automaticity |
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H3 receptors?
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primarily on presynaptic neuronal cells, affect NT release of histamine, acetylcholine, norepi, serotonin
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For treatment of gout which NSAID is preferred and which is contraindicated?
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indomethacin preferred
aspirin should NEVER be used, exacerbates condition by partially blocking active secretion of urate in the kidney |
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Colchicine?
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anti-inflammatory drug of choice for acute phase of gouty arthtitis
NOT an NSAID, is not general analgesic, does not inhibit PG synthesis binds to tubulin and inhibits granulocyte motility so dec phagocytosis, granule release, granulocyte lysis, cytokine release |
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Side effects of Colchicine?
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diarrhea, N/V, ab pain most common
alopecia, bone marrow depression, peripheral neuritis acute toxicity: hemorrhagic gastroenteritis, vascular damage, nephrotoxicity, ascending paralysis of CNS |
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Allopurinol?
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suicide inhibitor of xanthine oxidase (final enzyme in pathway from purine to uric acid) drug is substrate for the enzyme but has slow reaction, used for CHRONIC gout
get accumulation of more water soluble purine end products: hypoxanthine and xanthine |
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What are some drug interactions associated with allopurinol?
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-inhibits oxidation of 6-mercaptopurine and azathioprine
-inhibits metabolism of anticoagulants and probenecid |
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Peobenecid?
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reduces uric acid pool by inhibiting its reabsorption in the proximal convoluted tubule
causes inc chance of renal stones due to inc uric acid excretion use 2-3 weeks AFTER acute attack also used to retain antibiotics |
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What are some drug interactions associated with probenecid?
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-salicylates decrease its effectiveness
-inhibits renal excretion of antibiotics like penicillins, cephalosporins, fluoroquinolones |
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Rasburicase?
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NOT used for gout but inactivates uric acid by catalyzing its oxidation into allantonin
used for initial management of uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumors because anti-cancer therapy causes tumor lysis and thus purine level elevation |
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What can probenecid toxicity cause?
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GI irritation
allergic dermatitis nephrotic syndrome |
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Cimetidine?
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H2 blocker, directly inhibits histamine binding to receptors on parietal cells
also inhibits CYP450 so may have drug-drug interactions! may have anti-androgenic activity and increase prolactin secretion |
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Why are H2 blockers used for gastric acid control only available in low doses?
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H2 receptors also have functions in the heart!
effect SA nodal rate, ionotropic activity, atrial and ventricular automaticity, and capillary dilation |
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What is better at healing NSAID induced gastric ulcers: H2 antagonists, PPI, or misoprostol?
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PPI!
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What pathway so atropine and glycopyrrolate block to inhibit gastric acid secretion?
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parasympathetic stimulation of parietal cells that results in increased Ca which leads to inc cAMP and activation of H/K ATPase
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Which patient group is misoprostol contraindicated for?
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pregnant woman
it is a PGE1 analog so has potential abortifacient properties |
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How is misoprostol cytoprotective?
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PGE1 analog so increases mucus and bicarbonate secretion in the stomach
decreases cAMP which decreases acid ONLY effective for ulcers due to NSAIDs |
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How does sucralfate work?
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cytoprotective agent which polymerizes into sticky gel under acetic conditions
has affinity for exposed protein found in crater of an ulcer and the gel inhibits back diffusion of H+ and reduces pepsin activity |
