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Eicosonoids/nsaid
UVa med pharmacology block 2
| Question | Answer |
|---|---|
| Misoprostol | Eicosonoid agonist sim to PGE1 adjuvant to NSAID therapy protects stomach, induce abortion T1/2 20-40min by oral admin excr kidney CI: pregnancy |
| Carboprost | Eicos agonist 15-methyl PGF2alpha maintain postpartum tone, control bleeding, induce abortion physfx: stims smooth musc contr IM admin sidefx: nausea, vomiting, diarrhea |
| Dinoprostone | Eicos agonist PGE2 Cervical ripening to induce labor (local gel), induce abortion (IM) Sidefx nausea, vomiting, diarrhea |
| Alprostadil | Eicos agonist Prostacyclin receptor agonist (PGE1) ED (2nd line tx), maintain patent ductus arteriosus physfx: vasodilator most vascular beds injected/urethral suppos, IV for DA sidefx: penile pain |
| Caverject | Eicos agonist Prostacyclin receptor agonist (PGE1) ED (2nd line tx) physfx: vasodilator most vascular beds admin as sterile powder sidefx: penile pain |
| Prostacyclin | Eicos agonist PGI2 Primary/2ndary pulmonary hypertens, portopulmonary hypertens lowers periph pulm/coronary res Extremely short T1/2 via IV admin contin infusion via central line |
| TXA2 | Physfx: potent stimulus for platelet aggregation, very potent vasoconstrictor |
| PGI2 | Physfx: antagonist of TXA2 Bronch relax, vasodil, can cause hypotension decr pain thresh, cytoprotect in gastric mucosa, decr acid sec, incr mucosal bf, incr mucus secretion in bowel, induces fever, inhibs NE release, bone turnover, decr intraoc press |
| PGE2 | Uter contract lowdose, maintain patent DA in fetus, vasc bed vasodil, inhib ADH fx decr pain thresh, cytoprotect in gastric mucosa, decr acid sec, incr mucosal bf, incr mucus secretion in bowel, induces fever, inhibs NE release, bone TO, dec intraoc pres |
| PGF2alpha | physfx:uterine/bronchial contraction, vasoconstriction of pulm arteries/veins, may cause preg-induced hypertension, incr in menstruation |
| PGD2 | physfx: bronchial contraction, vasodilation (low concentration), vasonconstriction (high concentration) |
| LTC4/LTD4 (SRSA) | potent bronchoconstriction, incr secretion->mucosal edema, red cardiac contractility/Coronary BF |
| LTB4 | physfx: potent chemoattractant for PMNs, decr pain threshold, promotes inflammation |
| 12-S-HETE | physfx: role in athero (esp w/diabetes), meds Ang2 mediated aldosterone synthesis, reduces release of insulin in response to glucose |
| NSAIDs (generally) | COX inhibitors Antipyretic, analgesic, anti-inflammatory sidefx: GI ulceration/intolerance, block platelet aggregation, inhib uterine motility, inhib prosto-med renal function, hypersense rxns |
| Salicylic acid | active form of aspirin - irreversibly acetylates COX T1/2 low does: 2-4hrs, high dose: 12-15hrs met'd in liver, exc in urine sidefx: bleeding, bronchoconstrict, DNP mitochon uncoupling, CNS incr resp, excit, confusion, coma, convulsion, nausea, vomiting |
| Aspirin | aches/pains, RA, CAD/DVT irreversibly acetylates COX abs'd rapid in small int, incr pH=incr abs, deactyl'd->salicylic acid sidefx: bleeding, bronchoconstrict, DNP mitochon uncoupling, CNS incr resp, excit, confusion, coma, convulsion, nausea, vomiting |
| Diflunisal | irreversibly acetylates COX pain control in cancer, dental surg, oral lesions, RA oral/topical admin T1/2 like salicylate sidefx: pseudoporphyria CI: renal impairment (clearence depends on renal function) |
| Indomethacin | Indole Cox-1 spec inhibitor Fever, ankylosing spondylitis, osteoarthritis, acute gout attack, premature labor, ductus arteriosus T1/2 3 hrs oral admin excr liver, severe side fx |
| Sulindac | Indole Cox-1 spec inhibitor RA, osteoarthritis, ankylosing spondylitis T1/2 7hrs oral admin sidefx: decr GI toxicity/renal fx than indomethacin |
| Phenylbutazone | Pyrazolon deriv Cox-1 inhib Gout attacks (not pref'd), comp'd to aspirin incr anti-inflamm met'd to toxic metabolite, highly bound to protein (displaces other drugs) sidefx: same as other NSAIDs + occasional BM suppresion, agranulocytosis, aplastic ane |
| Ibuprofen | Propionic acid deriv Cox1/2 inhib (more cox-2) RA, osteoarthritis, ankyl spondyl, analgesic, dysmenorrhea T1/2 2hrs CI: pregnancy/breast feeding (crosses placenta) sidefx: tolerated better than aspirin |
| Naproxen | Propionic acid deriv Cox1=2 inhib RA, osteoarthritis, ankyl spondyl, analgesic, dysmenorrhea T1/2 14hrs sidefx: normal NSAID, more GI bleed than ibu |
| Ketoprofen | Propionic acid deriv Cox1,2, lipoxygenase inhib RA, osteoarthritis, ankyl spondyl, analgesic, dysmenorrhea t1/2 1.8hrs sidefx: normal NSAID plus GI tract and CNS fx |
| Meclofenamate | Anthranilic acid COX1/2 & phoslipase A rarely used toaday |
| Piroxicam | oxicam COX2>COX1 RA, osteoarthritis T1/2 50hrs exc urine>feces sidefx: Normal NSAID |
| Acetominophen | para-aminophenol deriv (not NSAID) inhibs Cox1/2 analgesic, antipyretic, no anti-inflamm T1/2 2hrs oral admin, exc liver w/ toxicity (p450 saturation) sidefx: minimal |
| Celecoxib | NSAID cox-2 inhib RA, osteoarthritis T1/2 11hrs by oral admin met'd by cytochrome P140 CI: sulfonamide allergy, aspirin hypersensitivity |
| How are eicosanoids stored in the body? | They are NOT stored in cells. They are synthesized by release of Arachidonic Acid from Phospholipids. |
| What is/are the physiologic response(s) to: TXA2 | Platelet Aggregation |
| How are PGEs related to body temperature? | An increase in PGEs (e.g. In response to IL-1 and TNF) in the hypothalamus can raise the temperature set point of the body. |
| What are some ways Eicosanoids are used to help Erectile Dysfunction? | Alprostadil (PGE1) is injected or used as urethral suppository (Works as vasodilator). Carerject is a sterile powder formulation of PGE1 that can also be used. |
| What is the main theraputic use for Carboprost? | Maintaining tone of uterus post-partum to control bleeding. Has also been used to induce abortion. |
| Which Eicosanoids cause pain by lowering nociceptor threshold? | PGE2 PGI2 LTB4 |
| What is a way to help prevent NSAID-induced ulceration of the stomach/duodenum? | Co-administration of Misoprostol (PGE1 analog) |
| Why were multiple COX-2 inhibitors pulled from the market? | There was evidence of increased MI and Stroke with their use. Celebrex (Celecoxib) remains on the market, despite its increased risk of CV events, because the risks are lower than those of Vioxx and Bextra. |
| Besides OTC pain medication, what else is Aspirin used for? | Coronary Artery Disease Post-Op DVT *This is due to Aspirins low-dose effect decreasing platelet function. |
| What makes Ketoprofen unique when compared to other NSAIDs? | It not only inhibits COX, but also Lipoxygenase. However, this has not been shown to make it a superior drug, and it still has the same side effects on the GI tract and CNS. It is mainly used to treat: R. and O. Arthritis, Gout, Dysmenorrhea. |
| Dinoprostone is a synthetic version of which Eicosanoid? | PGE2 |
| Indomethacin has strong anti-inflammatory capabilities. Why is it used so infrequently? | It has a higher incidence and severity of side effects over other NSAIDs. |
| What is the antidote to Acetominophen-induced Hepatic necrosis? | N-Acetylcysteine. It works by replenishing hepatic stores of Glutathione. |
| Which NSAID has the least amount of side effects on the GI tract? | Acetaminophen |
| Which Eicosanoid is seen to be elevated in asthmatics when not exposed to triggers? | LTC4 |
| What is the main contraindication of using Misoprostol as an adjuvant to NSAID therapy? | Pregnancy, due to uterotonic activity. *Because of uterotonic activity, it is sometimes used to induce labor, or to induce abortion (with an anti-progestin). Not in the notes, but I saw it used this summer during my Ob/Gyn research. |
| Which drug is unique in that it irreversibly inhibits COX (all others do so reversibly)? | Aspirin |
| What is Reye's Syndrome? | Fatal disease associated with Aspirin consumption by children with viral diseases (e.g. Chicken Pox). *Thus, Aspirin is contraindicated in children with Chicken Pox or the Flu, etc. |
| How do Salicylates affect Uric Acid excretion? | Low doses inhibit, intermediate doses have no effect, and High doses stimulate. |
| What is the only COX-2 inihibitor still on the market? | Celecoxib |
| Which NSAID is more effective than Aspirin for treating Dysmenorrhea? | Ibuprofen |
| What is the main theraputic use for Diflusinal? | Pain relief in Rheumatoid Arthritis, Cancer (Bone Metastases), and Wisdom Tooth Extraction. Oral Ointment is also useful for oral lesions. |
| What is the main theraputic use of Dinoprostone? | Used vaginally to promote cervical ripening (Shortened, softened in preparation for labor.) Can also induce abortion. |
| What is the main use for Misoprostol? | Adjuvant to NSAID therapy to stimulate cytoprotective mucus and inhibit gastric secretions. |
| Which Eicosanoid has 100-1000x the Bronchoconstrictor response of Histamine? | LTC4 |
| How is Platelet Activating Factor related to Arachidonic Acid liberation? | The same enzyme (PLA2) generates a precursor to Platelet Activating Factor (PAF). |
| What is the main use for Indomethacin? | Fever refractory to other agents (e.g. Hodgkins) Ankylosing Spondylitis / Osteoarthritis Acute Gout |
| Why is Aspirin sometimes a problem in asthmatics? | Hypersensitivity reactions may occur, probably due to Leukotriene formation (Because PG and Thromboxane pathway is reduced, more Arachadonic Acid goes through the Leukotriene pathway). |
| In which class of drugs does Aspirin and Diflusinal belong? | Salicylates |
| What is the advantage of using Propionic Acid Derivatives (Ibuprofen and Naproxen) over Aspirin and Indomethacin? | They are usually tolerated better. |
| Carboprost is a synthetic version of which Eicosanoid? | PGF2 |
| What is/are the physiologic response(s) to: LTB4 | Potent Chemoattractant for Polymorphonuclear Leukocytes Pain Promotes Inflammation |
| Which Eicosanoid is a potent chemoattractant for PML & Monocytes and also promotes all inflammatory processes? | LTB4 |
| Rank the following in terms of Anti-Inflammatory effects: - Ibuprofen - Acetominophen - Indomethacin | Highest: Indomethacin Medium: Ibuprofen Lowest: Acetominophen |
| What is the significance of NSAIDs decreasing TXA2 formation? | Inhibition of Platelet aggregation, causing increased bleeding time. |
| What is the most serious side effect of Acetominophen? | Dose-dependent, potentially fatal Hepatic necrosis. |
| Phenylbutazone is similar to Aspirin in its effects, except that it is more potent in its anti-inflammatory properties. Why is its use limited? | In addition to NSAID side effects, it causes occasional bone marrow suppression (agranulocytosis, and aplastic anemia) that may be fatal. |
| Which NSAID most commonly has hypersentivity reactions associated with it? | Aspirin *If a patient is allergic to Aspirin, all other NSAIDs are contraindicated. |
| What is the main reason to use Piroxicam over other NSAIDs such as Aspirin, Indomethacin, Naproxen, etc. for long-term treatment of Arthritis? | It has a half-life estimated at about 50hrs. It also may be tolerated slightly better. |
| Which Eicosanoids cause painful menstruation, camps, etc.? | PGF2 and PGE2. They cause Uterine contraction and are elevated during menstruation. |
| Misoprostol is a synthetic version of which Eicosanoid? | PGE1 |
| Which Eicosanoids have a protective effect on the gastric mucosa? | PGI2 PGE2 *Thus, Non-selective NSAIDs can have negative effects on gastric mucosa. |
| What is the leading cause of poisoning in children? | Aspirin. |
| What is the theraputic use for Sulindac? How does it differ from Indomethacin? | It is used for the same non-Obstetrical uses as Indomethacin (R. Arhtiris, Osteoarthritis, Ankylosing Spondylitis). It has a lower incidence of GI toxicity than Indomethacin, and fewer renal side effects. |
| What are the Obstetrical uses for Indomethacin? | Prevention of Premature Labor (not first choice due to ductus arteriosus effects) *Can be used to close a patent duct post-delivery. |
| Which Eicosanoids reduce Cardiac Contractility and Coronary Blood Flow? | LTC4 LTD4 |
| Which Eicosanoids are released in response to tissue damage? | Prostaglandins and Leukotrienes. PGE2 PGI2 LTB4 LTC4 LTD4 |
| What are possible side effects to pregnancy while using NSAIDs? | Delayed Labor. |
| What causes the mild analgesic properties of NSAIDs? | PGE2 and PGI2 sensitize nociceptic nerve endings to inflammatory mediators Bradykinin and 5-Hydroxytryptamine. NSAIDs block the synthesis of PGE2 and PGI2 |
| Why is ibuprofen not recommended for use in pregnancy or in breast-feeding mothers? | It readily crosses the placenta, and appears in breast milk. |
| What are the differences between Naproxen and Ibuprofen? | Naproxen has a longer half-life, but has a higher indicence of GI bleeding. It also has a higher free fraction in women. |
| How do you treat Salicylate Poisoning? | It is a medical emergency. External cooling (Hyperthermia), Fluids (Dehydration), Emesis, Gastric Lavage, Activated Charcoal (to block further absorption) |
| What are signs of Salicylate Toxicity? | Early: Tinnitis, Headache, Dizziness, Dim vision, Mental Confusion, Thirst, Hyperventilation, Nausea, Vomiting. More serious sxs: Convulsions, Fever, Dehydration, Petechial Hemorrhages, Coma, Cardiovascular Collapse, Respiratory Failure. |
| What is the Half-Life of Aspirin? | It is dose-dependent, and also urinary pH dependent. Low doses: 2-4hr. Can be as high as 12-15hr at high doses. Toxic Doses: 20+hrs. *Liver cannot keep up with metabolism at higher doses. |
| How do Salicylates affect the CNS? | At high doses can stimulate respiration, cause excitation, confusion, convulsions, coma. |
| Where are COX-1 and COX-2 enzymes expressed? | COX-1: Ubiquitously (Except RBCs) COX-2: Inflammatory Cells (eg. Macrophages) |
| What are the major Eicosanoid products of the Kidney? Their physiological responses in the kidney? | PGE2, PGI2 Renal vasodilators PGE inhibits effects of ADH. |
| What is the source of Arachidonic Acid in humans? | Diet. Either directly, or through Essential Fatty Acids (Linolenic, and Linoleic acids) Humans are unable to synthesize Arachidonic Acid de novo. |
| What is/are the physiologic response(s) to: PGD2 | Bronchial Contraction Vasodilation (at Low conc.) Vasoconstriction (at High conc.) |
| What OTC drugs can cause Analgesic-associated Nephropathy? | Aspirin Acetaminophen Ibuprofen Naproxen Sodium |
| Which Eicosanoids constrict Bronchial Smooth Muscle? Relax? | Constrict: PGF2 PGD2 LTC4 LTD4 Relax: PGI2 (Also antagonizes constrictors) |
| What contraindicates Celecoxib? | Allergic reactions to Sulfonamides, or Hypersensitivy to Aspirin |
| Which Eicosanoids are vasodilators? | PGE2 PGD2 (at low conc.) PGI2 (Injection can cause prominent Hypotension) |
| Which Eicosanoids typically Vasoconstrict? | PGF2 (Pulmonary Arteries and veins) PGD2 (at High concentrations) TXA2 (one of the most potent vasoconstrictors known) |
| Why is it necessary to be careful with NSAIDs in patients with CHF, Renal Disease, or Hypovolemia? | In these patients, pressor substances are often increased (Angiotensin II, Norepinephrine) and they rely on PGE-mediated renal vasodilation to maintain renal blood flow. NSAIDs can reduce renal function in these patients. |
| What is/are the physiologic response(s) to: LTC4 & LTD4 | Potent Bronchoconstriction (LTC4 more potent) Increased Secretion --> Mucosal Edema Reduce cardiac contractility and coronary flow |
| What are the most common side effects of NSAIDs? | Gastrointestinal intolerance and ulceration Blockade of Platelet aggregation Inhibition of Uterine motility Inhibition of Prostaglandin-mediated Renal Function Hypersensitivity Reactions |
| How do NSAIDs exert their Anti-Inflammatory effect? | PGE2 and PGI2 cause vasodilatation, allowing more histamine, bradykinin and leukotrienes to act on tissues. This increases vascular permeability. Thus, inhibition of PGE2 and PGI2 formation indirectly reduces edema associated with inflammation. |
| What is a possible side effect caused by NSAIDs blocking the ADH-inhibiting effects of PG's? | Sodium Retention, Edema --> Can reduce effectiveness of Anti-Hypertensives Also, can cause Hyperkalemia, due to decrease in Sodium concentration in distal tubule as well as reducing Renin (therefore Aldosterone) synthesis. |
Created by:
sam.mrosenfeld
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