Non-narcotic analgesics and NSAIDs Flashcards Preview

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Flashcards in Non-narcotic analgesics and NSAIDs Deck (21):

Metabolism of aspirin

-Not a prodrug, salicylate is metabolized by liver into 2 conjugated forms for renal excretion
-Aspirin is broken into salicylate (in liver, plasma and RBCs), which still has some activity
-Unconjugated aspirin is not excreted (lipophilic)


Analgesic action of aspirin

-Good for post-op and inflammatory pain, does not help pain from hollow viscera
-Acts to irreversibly inhibit COX (acetylates COX1 and COX2), thereby inhibiting the synthesis of prostaglandins
-Do not affect the prostaglandin receptor
-Prostaglandin increases pain by inducing hyperanalgesia by lowering the threshold of polymodal nociceptors
-Does not change the perception of other modalities
-Salicylate and other NSAIDs reversibly inhibit COX


Antipyretic, antithrombitic, and gastric affects of aspirin

-Elevated body temp is due to pyrogens form bacteria and IL1 from macs during inflammation
-Aspirin blocks the action of pyrogens and IL1 in the hypothalamus by inhibiting prostaglandin synthesis (COX)
-The preoptic region then facilitates vasodilation
-By inhibiting COX1 aspirin lowers the synthesis of thromboxane, thus preventing platelet aggregation/thrombus generation
-COX1 also is found in the stomach where it facilitates protection from gastric acid, thus inhibiting COX1 can lead to gastric irritation


Acute overdose of aspirin

-Due to saturation of salicylate metabolizing nzs in liver and limited ability of kidney to excrete salicylate
-Leads to fluid, electrolyte and acid-base disturbances


Metabolic and respiratory abnormalities

-Uncoupling of oxidative phosphorylation increases heat production
-This increases O2/glc consumption and thus CO2 production
-Metabolic acidosis occurs due to lactic acid generation
-CO2 exchange from RBCs to air in alveoli inhibited by salicylate
-Overall, increase in CO2 leads to stimulation of medulla to induce hyperventilation
-Hyperventilation results in respiratory alkalosis: increases renal excretion of Na, K, and HCO3


Therapy for aspirin poisoning

-Urine alkalization to increase salicylate excretion via sodium bicarb
-This also corrects the metabolic acidosis
-Hypokalemia by giving K separately from NaHCO3
-Also IV glucose


Aspirin and Reye's syndrome in children

-Reye's syndrome develops from a virus-host reaction, mostly from varicella and influenza
-Salicylate can modify the course of the syndrome
-Aspirin not given to children under 12, or to children w/ chickenpox or the flu


Actions of acetaminophen (tylenol)

-Analgesic and antipyretic action equal to aspirin/other NSAIDs, but does not reduce inflammation (is not an NSAID)
-Does not inhibit peripheral COX thus does not affect inflammation (not used in RA)
-However this also means it doesn't have some of the side effects NSAIDs have
-Preferred choice for pregnant women or children w/ influenza or chickenpox (no reyes syndrome)


Overdose of acetaminophen

-Overdose (10g) can produce a delayed (3-5 days) hepatic necrosis
-This results from the way acetaminophen is metabolized and excreted
-CYP450 in the liver converts acetaminophen to quinoneimine, which conjugates w/ glutathione and is excreted
-In high doses, this process depletes the liver of glutathione, resulting in large amount of apoptosis and necrosis of hepatocytes


Rx of acetaminophen OD

-Goal is to restore glutathione in liver
-Giving glutathione will not work b/c it cannot pass the membrane
-Must give one of the following, all of which are precursors to glutathione
-N-acetylcysteine is the first choice
-Then go to methionine, then cysteamine


Commonalities/differences of NSAIDs

-All inhibit COX, thus reducing the synthesis of prostaglandins and prostacyclins (both vasodilate and induce inflammation) and some reduce the synthesis of thromboxane (vasoconstricts and causes platelet activation)
-Most prostaglandins/prostacyclins are made in response to local inflammatory stimuli, thus are mainly produced by COX2
-Thromboxane is made from COX1
-Some NSAIDs can also inhibit LOX, thereby reducing the synthesis of leukotrienes


Selective COX2 inhibitors (NSAIDs)

-COX2 activity is usually low in peripheral tissues, but rapidly increases in response to local inflammatory stimuli
-Celecoxib, a selective COX2 NSAID, has lower gastric irritation and platelet function disturbances due to not having any function on COX1


Common side effects of NSAIDs: antithrombotics

-Inhibition of platelet functioning comes from inhibiting COX1, thereby reducing thromboxane synthesis (thereby increasing vasodilation and reducing platelet activation)
-This increases the bleeding time but also decreases chance of thrombosis (antithrombotic)
-COX2 inhibitors do not have this effect, and instead they reduce PC synthesis, which increases vasoconstriction and are therefore prothrombotic


Common side effects of NSAIDs: gastric irritation

-Inhibition of COX1 reduces synthesis of PGs in the gastric mucosa
-PGs in the stomach promotes the secretion of mucus and bicarb, thus inhibiting PGs reduces the secretion of these
-All NSAIDs have a direct acid affect on the gastric mucosa causing irritation (proton doesn't dissociate until w/in the epithelial cells)
-Inhibition of platelet aggregation prolongs the bleeding time of GI bleeds


Common side effects of NSAIDs: hypersensitivity rxn

-Caused by COX1 inhibition, only in pts w/ asthma or nasal polyps
-All NSAIDs are contraindicated for these pts
-Causes bronchoconstriction and anaphylactic shock


Common side effects of NSAIDs: renal function

-Due to inhibition of COX2, which leads to a decrease in renal blood flow/GFR in pts w/ CHF or hepatic cirrhosis
-This leads to edema via retention of salt and water and enhanced action of ADH


Common side effects of NSAIDs: reproduction

-Due to COX2 inhibition, decreases ovulation (delays follicular rupture)
-Also prolongs gestation and risks closure of ductus arteriosus
-NSAIDs contraindicated for pregnancy


Common side effects of NSAIDs: CNS

-Cause tinnitus, decreased hearing, vertigo


Contraindications of NSAIDs

-Children can only take certain NSAIDs (ibuprofen, naproxen)
-Pregnant women (esp. in 3rd trimester)
-Hemophilia, hypoprothrominemia, hepatic damage
-Coagulopathy/CHF and COX2 inh
-Aspirin and gout
-Peptic ulcer
-Asthma or nasal polyps


Drug interactions of Aspirin

-Aspirin (and some NSAIDs) interact w/ MTX, warfarin, and sulfonylureas
-Aspirin/NSAIDs displace other drugs from albumin
-Thus they increase the tissue level of the drugs
-Use ibuprofen to prevent this
-Aspirin aslo interacts w/ uricosuric agents by preventing the secretion of uricosuric agents into the tubular lumen (which is the site of their action)


Commonly used non-Aspirin NSAIDs

-Indomethacin: most potent inhibitor of COX, not used in RA but is used in acute gout attacks
-Sulindac: a prodrug that is activated in liver and subjected to enterohepatic recirculation (active metabolite is not recirculated)
-Low GI irritation, low kidney toxicity, useful for those w/ renal complications
-Profens (ibuprofen, naproxen) have low GI complications and do not displace MTX, warfarin, sulfonylureas from albumin