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51 Cards in this Set
- Front
- Back
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NSAIDs indicated in treatment of? (3)
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-inflammation
-pain -fever |
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3 types of NSAIDS
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1. aspirin/salicylates
2. traditional NSAIDs 3. COX-2 specific inhibitors |
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General mechanism of action
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-inhibit COX activity, i.e. prevent production of prostaglandins
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How do NSAIDs inhibit COX activity?
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Preventing binding of arachidonic acid substrate (inhibition either reversible or irreversible)
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Aspirin and traditional NSAIDs inhibit which COX?
-COX-2 specific? (doy) |
COX-1 and COX-2
-just COX-2 |
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Describe Aspirin's mechanism of action:
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-covalently attach to acetyl group on active site of COX enzyme (irreversible inhibition of COX-1)
-Aspirin aacetylates COX-2, but active site is bigger, so there is less inhibition. |
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COX-1
-expression -function |
-constituitively expressed
-housekeeping functions |
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COX-2
-expression -function |
Induced in macrophages, synoviocytes, fibroblasts
-is proinflammatory -constituitive in kidney, brain, endothelium |
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Low dose aspirin effect?
how? |
antithrombotic agent.
-inhibits COX-1 in platelets (block production of thromboxane). -COX-1 resynthesized in endothelium, so low dose does not inhibit production of anti-thrombic prostacyclins (helps maintain effect, and shows why high dose wouldn't work) |
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NSAIDS or Cox-2 inhibitor, more effective?
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Equal! cox-2 inhib might be better in pts with history of GI bleed or ulcers
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Key feature of Ibuprofen
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rapid onset
ideal for fever/acute pain |
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key feature of naproxen
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rapid onset, long half life (14 hrs), less dosing
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Key features of Oxaproxin
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long half life (50-60 hrs), once a day dosing
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Indomethacin-key features
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potent antiinflam (>toxicity). used to close ptent ductus arteriosus. also good for rapid fever reduction
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Diclofenac- key features
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pretty selective for cox-2. incrased risk of MI/Stroke
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Ketorolac- key features
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mainly IV. replacement for opioid analgesics.
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Major NSAID side effects
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**get later when reread
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Stomach/GI problems with Aspirin and NSAIDs..cause?
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-inhibition of COX-1 (produces prostaglandins that prevent damage to gastric/intestinal epithelial cells).
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Contraindications for NSAIDs
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1. GI ulcers
2. bleeding disorders 3. renal disorders (elderly) 4. hypersensitivity to aspirin 5. pregnant women 6. increased risk of CVD 7. children with febrile viral infections (Aspirin, can cause Reye's) 8. aspirin contraindicated in gout (increase uric acid retention at low doses) |
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Drug interaction between low-dose aspirin and other NSAIDS (except celecoxib)
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antagonize antithrombic effects (prevents bindinf of aspirin to cox-1)
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drug interaction:
oral anticoag + all NSAIDs |
Increased risk of bleeding (plt cox-1 inhibition/protein displacement)
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Celecoxib- related to what enzyme?
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cyp2c9
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drug interaction:
antihypertensives (ACE inhib, B blockers) + all NSAIDS |
decreased antihypertensive effect
(NSAID promote renal vasoconstriction=increase BP) |
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drug interaction:
Diuretic agent + All nsaids |
increased risk of high BP (NSAIDS promote fluid retention too)
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drug reaction:
oral hypoglycemics + salicylates |
potentiate hypoglycemic effects
(sal displaces protein bound sulfonylureas, and independently enhance glucose utilization) |
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Acetaminophen- action and use
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-treat mild/moderate pain and fever
-does not inhibit COX-1 or COX-2 in periphery. |
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Metabolism of acetaminophen where?
-active metabolite? action? |
in brain
-to AM404 (inhibits COX-2 in CNS, and endogenous cannabinoid system in pain and thermoreg centers to reduce pain and fever) |
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Why doesn't acetaminophen not work as an anti-inflammatory or anti-platelet?
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no COX inhib in periphery (but is anti-pyretic and analgesic)
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side effects of tylenol?
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few (because there are no COX-1 interactions in periphery)
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Acetaminophen is prefered analgesic in 4 types of pts
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1. allergy to aspirin/salicylates
2. children with viral infection 3. pts with hemophilia/bleeding risk 4. pts with prior history of ulcer/GI upset |
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COX enzymes catalyze what reaction?
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arachidonic acid ===> prostaglandins + thromboxane
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COX-2 is constitutively expressed in what 6 places?
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-brain
-kidney -endothelium -ovaries -uterus -small intestine |
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main housekeeping functions of COX-1
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PLT regulation (blood clotting)
kidney function regulation of stomach acid/mucous production |
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symptoms of inflammation- mediators and process
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PGE2-PGI2 (increased by COX2)
-dilate blood vessels (increase red and heat) -PGE2- increase migration of phagocytes -PGE2-vascular permability=edema |
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why inflammation causes pain?
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-prostaglandins lower neuron afferents by lowering threshold for painful stimuli (specifically in dorsal horn)=enhance transmission of STT
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fever production?
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COX-2 in endothelium of hypothalamus increase PGE2. acts on OVLT of hypothalamus = fever
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prostaglandins in the stomach do what?
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-decrease acid
-increase bicarb -increase mucous -increase blood flow to stomach |
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COX-1 on platlets produces what?
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TXA2 (thromboxane)= vasoconstrictor and plt aggregation
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endothelial cells and thromboxane?
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-have COX1/2 but no TXA2 synthase. no production.
-do produce PGI2- vasodilation and inhibit platelet aggregation. RATIO OF PGI2 AND TXA-2 IS IMPORTANT IN CLOTTING! |
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Effect of prostaglandins on the kidney, and hence NSAIDs
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-increase renal blood flow (vasodilation)
-increase GFR -decrease salt and water retention **important in disease states, to help combat vasoconstriction** NSAIDs do opposite, and are thus bad for people with kidney problems and old people |
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Prostaglandins in pregnancy
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overproduction during menstruation (menstrual cramps)
-stimulates uterine contraction (NSAIDs delay labor) -ductus arteriosus is kept open in baby via prostaglandins (NSAIDs can close this in infants-indomethecin) |
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acetoaceylic acid breaks up into what?
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salcylic acid and acetic acid.
-salcylic acid works as competitive antagonist of COXs. aspirin works by irreversibly inhibiting cox1 and 2 by acetylating active site. this is more in 1 than 2. |
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cancer associated with reduction via aspirin use?
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colon cance (50% reducation)
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Diflusinal
-type of drug -limitation? |
salicylate
-cannot cross BBB, so no anti-pyretic effects |
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pharmacokinetics of salyciliates
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dose dependant (1st at low conc, zero and high conc)
-rapid stomach absorption (short half life) -most cross BBB, anti-pyretic -high protein binding (can effect other high protein bound drugs, ie warfarin) -metabolized in liver, cleared at kidney (pH of urine determines form) -low doses, aspirin decreases uric acid excretion (bad for gout pts) |
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Salicylate toxicity
early signs late signs |
-excessive consumption is toxic
-Early signs- n/v/ ap, lethargy, vertigo late signs: hyperthermia, hyperventilation, resp alkalosis, metabolic acidosis, hypoglycemia, altered mental status, coma |
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mechanism of salicylate toxicity:
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-trigger increased respiration initially (resp alk, followd by met acidosis)
-acidified blood= more salycilate into CNS (direct toxicity, resp depression, coma, hypoglycemia, edema, death) |
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Antidote for salycylate intoxication
mild case severe case |
mild case- symptomatic treatment and increase urinary pH to enhance elimination
severe case=gastric lavage and IV fluids/dyalisis |
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exacerbation of heart failure/ hypertension at what dose of aspirin?
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only at high doses (increases vasoconstriction, fluid retention)
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Liver effects of NSAIDs
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elevated liver enzymes
liver failure rare ELEVATED RISK WITH SULINDAC |
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HOW ACETAMINOPHEN WORKS
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metabolized in brain to AM404
-is a CNS COX-2 inhibitor (anti-pyretic, analgesic) -also acts on cannaboid system -limited effect on peripheral COX (no anti plt effects or anti-inflammatory effects) |
