Term
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Definition
-Oxygenation products of polyunsaturated long- chain fatty acids
• Found in animals and variety of plants
• Constitute a family of highly potent and diverse compounds
• Wide spectrum of biologic activity has therapeutic potential
- Arachidonic acid(AA)
• Most abundant of eicosanoid precursors
• Multiple pathways of AA release and metabolism |
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Term
| pathways of arachidonic acid diagram |
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Definition
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Term
| Prostaglandin Endoperoxides |
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Definition
• Two unique cyclooxygenases (COX) isozymes convert AA into prostaglandin endoperoxides
• COX-1 (PGH synthase-1) • Expressed in most cells
• COX-2 (PGH synthase-2)
• Expression dependent on stimulus |
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Term
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Definition
• Generates prostanoids for • “housekeeping” functions
- Gastric epithelial cytoprotection |
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Term
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Definition
-Immediate response upregulated by:
• Sheer stress
• Growth factors
• Tumor promoters • Cytokines
- Major source in inflammation
- Endothelial COX-2 primary source of vascular prostacyclin (PGI2)
- Renal COX-2 important for renal development and function |
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Term
| physiology of prostaglandins diagram |
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Definition
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Term
| physiology of prostaglandins effects |
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Definition
- Major effects on the smooth muscle
• Vasculature
• Airways
• Gastrointestinal (GI)
• Reproductive tracts
- Other important targets
• Kidneys, platelets, CNS, endocrine organs, eyes |
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Term
| Vascular physiology of prostaglandins |
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Definition
• TXA2, PGF2α,—potent vasoconstrictors
• Exposure to testosterone to upregulate smooth muscle cells |
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Term
| CNS, Inflammation, and Immunity of prostalgandins |
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Definition
• Fever
• PGE2, PGF2α, and PGI2 increases body temperature
• Interleukin-1promotes synthesis and release
• Enhance edema formation |
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Term
| Platelets prostaglandin physiology |
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Definition
- TXA2 is the major product of COX-1
• Only COX isoform in mature platelets
• Amplifies effects of platelet agonists such as thrombin |
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Term
| kidneys prostaglandin physiology |
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Definition
- Bowman’s capsule
• COX-1 mainly expressed • Promotes salt excretion in collecting ducts
- Renal medullary interstitial cells
• COX-2 • PGE2 and PGI2: maintain renal blood flow and GFR via vasodilation • Inhibiting may reduce blood pressure in these settings
- TXA2
• Vasoconstriction: decline in renal function
• Hypertension via increased TXA2 |
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Term
| NSAIDS Chemistry and Pharmacokinetics |
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Definition
• Weakorganicacids
• Absorption:excellentabsorption
• Food not required to change bioavailability
• Metabolism:CYP3AorCYP2Cfamilies • Most phase I metabolism
• Elimination:renal
-most protein bound (albumin) |
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Term
| NSAID pharmacodynamics diagram |
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Definition
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Term
| pharmacodynamics of NSAIDs |
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Definition
• Reversibly inhibits COX (including platelets)
• Selectivity for COX-1 vs. COX-2 is variable and incomplete for older, non-selective NSAIDS |
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Term
| pharmacodynamics of Non-selective NSAIDS vs.selective COX-2 |
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Definition
• COX-2: Platelet function not affected at usual doses
- Equivalent efficacy with non-selective NSAIDS
- GI safety may be improved with selective COX-2
• COX-2: increase the incidence of edema, hypertension, and possibly myocardial infarction
- Celecoxib: FDA Black Box warning concerning CV risk |
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Term
| Analgesic, anti-inflammatory, and antipyretic, and all inhibit platelet aggregation (except COX-2) |
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Definition
• Decrease sensitivity of vessels to bradykinin and histamine
• Affect lymphokine production from T- lymphocytes
• Reverse the vasodilation caused by inflammation |
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Term
| other pharmacodynamics of NSAIDs |
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Definition
• Gastric irritants associated with GI ulcers and bleeds
- Newer agents tend to cause less GI irritation than aspirin
• Nephrotoxicity
- Interference with autoregulation of renal blood flow modulated by prostaglandins
- Inhibit prostaglandin biosynthesis
• Hepatotoxicity |
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Term
| COX-2 Selective Inhibitors |
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Definition
• Developed to inhibit prostaglandin synthesis by COX-2 isozyme induced at sites of inflammation
- Without affecting the action of the COX-1 isozyme found in the GI tract, kidneys, and platelets
• No impact on platelet aggregation
- Mediated by thromboxane TXA2
• Inhibit COX-2 mediated prostacyclin synthesis in the vascular endothelium
- No cardioprotective effects of traditional non-selective NSAIDS • Refecoxib and valdecoxib :removed from market due to CV thrombotic events
• Renal toxicities similar to non-selective NSAIDs |
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Term
| non-selective NSAID agents and notes |
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Definition
| Aspirin (antiplatelet effects), Diclofenac, Etodolac, Ibuprofen, Indomethacin, Nabumetone, Naproxen, Ketorolac |
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Term
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Definition
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Term
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Definition
• All NSAIDs, including aspirin, equally efficacious with few exceptions
• Differentiated based on toxicity and cost-effectiveness
- Ketorolac: IV and limited to five days
- Indomethacin and tolmetin: associated with greatest toxicity
- Aspirin and ibuprofen: least toxic
• Renal insufficiency: nonacetylated salicylates may be preferential
• LFT abnormalities: diclofenac and sulindac associated with more abnormalities
• GI bleeding
- Celecoxib probably safest for high-risk patients for GI bleeding, but has
greatest risk for CV toxicity |
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Term
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Definition
• *Cardiovascular—fluid retention, hypertension, edema, MI and CHF (rarely)
**Gastrointestinal—abdominal pain, nausea, vomiting, ulcers or bleeding
**Renal—renal insufficiency, renal failure
• CNS—headaches, tinnitus, dizziness
• Hematologic—rare thrombocytopenia, neutropenia, or aplastic anemia
• Hepatic—abnormal LFTs
• Pulmonary—asthma
• Skin—rashes, pruritus |
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Term
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Definition
• Irreversibly inhibits platelet COX (1 and 2) activity and prostaglandin production
- Anti-inflammatory and anti-platelet effects
- Low doses (<100 mg/d) inhibit preferentially COX -1; higher doses inhibit COX-1 and COX-2
- Does not inhibit lipoxygenase pathways of AA metabolism
• Antiplatelet effects lasts 8–10 days |
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Term
| clinical utility of aspirin |
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Definition
| • Decreases incidence of TIA, unstable angina, coronary artery thrombosis with MI, and thrombosis after CABG |
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Term
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Definition
• Gastric upset (intolerance)
• Gastric and duodenal ulcers
• Hepatotoxicity
• Asthma
• Rashes
• GI bleeding |
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Term
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Definition
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Term
| Adverse Effects of Aspirin Therapy |
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Definition
-Inhibition of prostaglandinsynthesis
• Responsible for anti- inflammatoryeffectsofASA
• Alters protective prostaglandin functions leading to serious consequences• Gastric ulcers(e.g., indigestion, N/V, heartburn
-Hemorrhagic stroke
• Increased risk
-Renal
• Weak inhibitor of renal prostaglandin synthesis • No significance in affecting renal function or blood pressure in low doses |
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Term
| Pharmacokinetics of Acetaminophen |
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Definition
• Analgesia
- Inhibit synthesis of prostaglandins in CNS and work peripherally to block pain impulse generation
• Antipyretic
- Inhibition of hypothalamic heat-regulating center
• Lacks anti-inflammatory properties and platelet inhibiting effects
• Weak COX-1 and COX-2 inhibitor |
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Term
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Definition
• Undergoes glucuronidation (40–60%) and sulfation (20–40%) and is excreted in the urine
• Alternative cytochrome P450-dependent GSH conjugation pathway accounts for remaining 5–8%
- Potential production in hepatotoxic metabolite N-acetyl-p-benzoquinone imine (NAPQI)
- Pathway becomes extremely important during toxicity |
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Term
| acetaminophen and pregnancy |
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Definition
• Not associated with teratogenicity
- Pregnancy Category B in all stages
• Excreted in low concentrations in breast milk
- Compatible with breast milk
• First-line analgesic in pregnancy
- If non-pharmacological therapy fails |
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Term
| acetaminophen epidemiology |
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Definition
• Leading calls to poison control centers—>100,000/year
• 56,000 emergency room visits and 2,600 hospitalizations
• 450 deaths/year
• Acute liver failure ~50% of cases
- Leading cause in the U.S |
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Term
| Stages of Tylenol Toxicity |
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Definition
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Term
| Diagnosis: Tylenol Toxicity |
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Definition
- Toxic exposure to acetaminophen
• Adult: ingests > 10 grams (or 200 mg/kg single ingestion) over 24-hour period or ingest > 6 grams or 150 mg/kg/day for two consecutive days • 4 grams is associated with increased LFT abnormalities
- Confirm toxicity with Rumack-Matthew nomogram
• Plot serum acetaminophen concentration vs. time of ingestion • Only applies to setting of acute exposure and window between 4 hours and 24 hours post-ingestion
• Obtain laboratory studies
• BMP, transaminases, LFTs, CBC, urine toxicology screen as clinically indicated |
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Term
| tylenol mechanism of toxicity diagram |
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Definition
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Term
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Definition
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Term
| Tylenol Toxicity antidote |
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Definition
acetylcysteine
• Acts as glutathione substitute, binding the toxic metabolite as it is produced
• Binds and removes NAPQI
• Most effective when early administration (within 8–10 hours)
[image] |
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Term
| COX/Acetaminophen/Tylenol Summary |
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Definition
- COX-1vs.COX-2receptors
• Gastric cytoprotection vs. stimulus
- Prostaglandins and thromboxanes
• Major effects on smooth muscle in vasculature, airways, GI, and reproductive tracts
- NSAIDS reversible inhibition of COX enzymes
• Affects platelet aggregation
• COX-2 selective does not affect platelet aggregation
• Nephrotoxic, hepatotoxic, GI irritant
- Aspirin irreversibly inhibits COX enzymes
• Affects platelet aggregation
• GI toxic
- Tylenol toxicity
• GSH conjugation required for elimination and avoidance of toxic metabolite NAPQI
• NAPQI: hepatocellular damage and formation of radical oxygen species |
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Term
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Definition
| sheer stress, growth factors, and cytokines. |
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Term
| Which of the following prostanoid is correctly associated with their actions in the smooth muscle? |
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Definition
| TXA2: vascular and renal vasoconstriction |
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Term
| T/F COX-2 selective NSAIDs do not affect platelet function at usual dosages, but may increase incidence of hypertension and edema. |
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Definition
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Term
| Adverse effects of nonselective NSAIDS |
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Definition
| Renal insufficiency, Gastric irritation/ulcers, Abnormal liver function tests |
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Term
| T/F NSAIDs can induce asthma via inhibition of the lipoxygenase pathway to convert the metabolism over to cyclooxygenase. |
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Definition
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Term
T/F:
NSAIDs do not require food to increase absorption.
clear
NSAIDs are mostly protein bound to albumin.
clear
COX-2 inhibitors can have similar renal toxicities as traditional NSAIDs. |
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Definition
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Term
| What makes aspirin uniquely different from other NSAIDS? |
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Definition
| Irreversibly inhibits platelet COX and prostaglandin production |
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Term
| T/F Aspirin inhibits PGH2 synthase and prostaglandins I2, E2, and D2. |
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Definition
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Term
| Toxicities associated w aspirin |
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Definition
| hemorrhagic stroke, hepatotoxicity, GI toxicity due to loss of PGE2 protection in gastric mucosa and reduction of renal function (not reduces renal function) |
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Term
| T/F acetaminophen Inhibits the hypothalamic heat-regulating center |
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Definition
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