what should i know pc 121 prostaglandins

1. 1

2. 2

3. 3 What should I KNOW? PC 121 Prostaglandins/NSAIDS (lecture 1)

4. 4 What should I KNOW? PC 121 Prostaglandins/NSAIDS (lectures 2&3)

5. 5 What should I KNOW? PC 121 Prostaglandins/NSAIDS (lecture 4)

6. 6 Inflammation Following insult/injury, cells secrete mediators or activate processes Responses vary with stimulus, responding cells, and downstream factors/targetsFollowing insult/injury, cells secrete mediators or activate processes Responses vary with stimulus, responding cells, and downstream factors/targets

7. 7 Acute Mediators Prostaglandins - Leukotrienes - Histamine - Bradykinin (pain) and serotonin TNF Interleukins Acute Mediators Prostaglandins - Leukotrienes - Histamine - Bradykinin (pain) and serotonin TNF Interleukins

8. 8 Blockade of Inflammation Goals of treatment: Remove cause of inflammation Prevention of further damage Comfort of patientGoals of treatment: Remove cause of inflammation Prevention of further damage Comfort of patient

9. 9 �Fast Mediators�The Eicosanoid Cascade Many cells produce small amounts of eicosanoids In response to insult, damaged cells or activated leukocytes produce large amounts of eicosanoids (locally) that mediate inflammation Production of inflammatory mediators is controlled by biosynthesis Rate limiting step is release of arachidonic acid from phospholipids Most eicosanoids either inherently unstable or rapidly degraded (t1/2 seconds to minutes) Eicosanoids produced after release depend on cell type, phenotype, stimulus, and type of fatty acidMany cells produce small amounts of eicosanoids In response to insult, damaged cells or activated leukocytes produce large amounts of eicosanoids (locally) that mediate inflammation Production of inflammatory mediators is controlled by biosynthesis Rate limiting step is release of arachidonic acid from phospholipids Most eicosanoids either inherently unstable or rapidly degraded (t1/2 seconds to minutes) Eicosanoids produced after release depend on cell type, phenotype, stimulus, and type of fatty acid

10. 10 Formation of Eicosanoids (1) Central source for synthesis of most eicosanoids in humans is arachidonic acid Several phospholipases: cytosolic PLA2 is dominant playerCentral source for synthesis of most eicosanoids in humans is arachidonic acid Several phospholipases: cytosolic PLA2 is dominant player

11. 11 Key Enzymes: Phospholipase A2 (PLA2) Phospholipase C (PLC) Phospholipase D (PLD)Key Enzymes: Phospholipase A2 (PLA2) Phospholipase C (PLC) Phospholipase D (PLD)

12. 12 Formation of Eicosanoids (2) After release, AA can enter four metabolic pathways 1) Lipoxygenases to give leukotrienes 2) Cyclooxygenases to give prostaglandins and thromboxanes 3) Epoxygenase (microsomal P450 monooxygenases) to give epoxides. Active on smooth muscles and important in renal function 4) Free radicals to peroxidize the fatty acid leading to spontaneous formation of isoprostanes. This occurs in the membrane prior to release of the fatty acids. They are potent vasoconstrictors. Shutting down one pathway can have the effect of shunting intermediates to other pathwaysAfter release, AA can enter four metabolic pathways 1) Lipoxygenases to give leukotrienes 2) Cyclooxygenases to give prostaglandins and thromboxanes 3) Epoxygenase (microsomal P450 monooxygenases) to give epoxides. Active on smooth muscles and important in renal function 4) Free radicals to peroxidize the fatty acid leading to spontaneous formation of isoprostanes. This occurs in the membrane prior to release of the fatty acids. They are potent vasoconstrictors. Shutting down one pathway can have the effect of shunting intermediates to other pathways

13. 13 The Eicosanoid Cascade:Intervention Sites Multiple possible sites of intervention: 1) Prevent release of fatty acids: corticosteroids 2) Change composition of fatty acids: dietary supplementation 3) Block oxidation (lipoxygenase or cyclooxygenase) 4) Block receptors for mediators 5) Block downstream effectors Multiple possible sites of intervention: 1) Prevent release of fatty acids: corticosteroids 2) Change composition of fatty acids: dietary supplementation 3) Block oxidation (lipoxygenase or cyclooxygenase) 4) Block receptors for mediators 5) Block downstream effectors

14. 14 Essential Fatty Acids &Fatty Acid Synthesis Linoleic or linolenic acids = �Essential Fatty acids� Mammals convert essential fatty acids to arachidonic acid, the common precursor for PG�s Normal source high in omega six: corn, safflower, chicken, pork Basis for dietary therapies based upon supplementation of particular fatty acids: omega 3 fatty acids (double bond 3 carbons from the last) such as eicosapentaenoic; these come from plants:nut oils, flax oil; certain fish (phytoplankton high in omega 3 FA).Linoleic or linolenic acids = �Essential Fatty acids� Mammals convert essential fatty acids to arachidonic acid, the common precursor for PG�s Normal source high in omega six: corn, safflower, chicken, pork Basis for dietary therapies based upon supplementation of particular fatty acids: omega 3 fatty acids (double bond 3 carbons from the last) such as eicosapentaenoic; these come from plants:nut oils, flax oil; certain fish (phytoplankton high in omega 3 FA).

15. 15 Naming Eicosanoids 1 Two components to naming eicosanoids: Ring & double bonds Rings: four classes 1) Prostaglandins (PGA - PGF): a single five membered ring 2) Endoperoxides (intermediates): a bridged bicycle with an O-O bond 3) Prostacyclins (PGI): two fused five membered rings 4) Thromboxanes (TXA): a bridged bicycle Of these, the prostaglandins have six major subtypes: A - FTwo components to naming eicosanoids: Ring & double bonds Rings: four classes 1) Prostaglandins (PGA - PGF): a single five membered ring 2) Endoperoxides (intermediates): a bridged bicycle with an O-O bond 3) Prostacyclins (PGI): two fused five membered rings 4) Thromboxanes (TXA): a bridged bicycle Of these, the prostaglandins have six major subtypes: A - F

16. 16 Naming Eicosanoids 2 For Leukotrienes -- Number refers to total number of double bonds For prostaglandins, prostacyclins, and thromboxanes: numbers imply particular types & locations of double bonds: 1 = trans 13,14 alkene 2 = cis 5,6 trans 13,14 diene 3 = cis 5,6 trans 13,14 cis 17,18 trieneFor Leukotrienes -- Number refers to total number of double bonds For prostaglandins, prostacyclins, and thromboxanes: numbers imply particular types & locations of double bonds: 1 = trans 13,14 alkene 2 = cis 5,6 trans 13,14 diene 3 = cis 5,6 trans 13,14 cis 17,18 triene

17. 17 Prostaglandin Synthesis 1 Prostaglandins, prostacyclins, and thromboxanes common intermediates: (PGG2, PGH2) Cyclooxygenases (COX), bifunctional enzymes Cyclooxygenase bifunctional: cyclizes and peroxidizes Peroxidase function then oxidizes the 15 position to PGH Both endoperoxides are unstable. Inhibition of COX as major therapeutic interventionProstaglandins, prostacyclins, and thromboxanes common intermediates: (PGG2, PGH2) Cyclooxygenases (COX), bifunctional enzymes Cyclooxygenase bifunctional: cyclizes and peroxidizes Peroxidase function then oxidizes the 15 position to PGH Both endoperoxides are unstable. Inhibition of COX as major therapeutic intervention

18. 18

19. 19 Prostaglandin Synthesis 2 PGH2 can be converted to many products depending on tissue, stimulus, and other factors Reduction of the ring ketone by PGH reductase can lead to the PGF seriesPGH2 can be converted to many products depending on tissue, stimulus, and other factors Reduction of the ring ketone by PGH reductase can lead to the PGF series

20. 20 Prostaglandin Synthesis 3 In certain settings, PGI synthase can convert PGH to the prostacyclin PGI PGI itself is relatively unstable and converts to 6 keto PGF structuresIn certain settings, PGI synthase can convert PGH to the prostacyclin PGI PGI itself is relatively unstable and converts to 6 keto PGF structures

21. 21 Thromboxane Synthesis In platelets, primary path involves thromboxane synthesis; converts PGH to TXA TxA unstable; converts to TxB2In platelets, primary path involves thromboxane synthesis; converts PGH to TXA TxA unstable; converts to TxB2

22. 22 Leukotriene Synthesis 1 Lipoxygenase enzymes Most active in platelets and leukocytes Lipoxygenase adds the hydroperoxide group to form HPETE class of eicosanoids HPETE rapidly converted by dehydrases to LTA series, central leukotriene intermediate LTA�s can be converted by the hydrolase enzyme to LTB series. Lipoxygenase enzymes Most active in platelets and leukocytes Lipoxygenase adds the hydroperoxide group to form HPETE class of eicosanoids HPETE rapidly converted by dehydrases to LTA series, central leukotriene intermediate LTA�s can be converted by the hydrolase enzyme to LTB series.

23. 23 Leukotriene Synthesis 2 Alternate route is conjugation with glutathione to give the LTC series LTC�s are sequentially degraded proteolyticaly to give the LTD and LTE series LTC4 and LTD4 are known as the slow reacting substance of anaphylaxis -- important in asthma, anaphylaxis, and allergic rhinitisAlternate route is conjugation with glutathione to give the LTC series LTC�s are sequentially degraded proteolyticaly to give the LTD and LTE series LTC4 and LTD4 are known as the slow reacting substance of anaphylaxis -- important in asthma, anaphylaxis, and allergic rhinitis

24. 24 Essential Fatty Acids &Fatty Acid Synthesis Normal (Western diet) FA sources high in omega six FA Supplementation of omega-3 fatty acids (e.g., eicosapentaenoic) Feeding omega-3 acids leads to production of PG3 rather than PG2Normal (Western diet) FA sources high in omega six FA Supplementation of omega-3 fatty acids (e.g., eicosapentaenoic) Feeding omega-3 acids leads to production of PG3 rather than PG2

25. 25 Eicosanoid Substrates Determine PG Formed

26. 26 Dietary Manipulation of PG�s Exogenous omega 3 FA (cold water fish, flax, nuts) Adding FA that cannot be made endogenously to diet can shift balance of membrane FA esters Starting PG synthesis with different FA leads to different PG�s Used to reduce risk of heart attack, stroke, and other cardiovascular disease Also appears to modulate autoimmune diseases, asthma, and arthritis (less joint swelling) Another more controversial approach: vegetable oils rich in gamma llinoleic acid (the normal omega 6 FA) - evening primrose, borrage, black currant oils. Approach being used for arthritis; believed to modulate fat deficiencies in older women. Exogenous omega 3 FA (cold water fish, flax, nuts) Adding FA that cannot be made endogenously to diet can shift balance of membrane FA esters Starting PG synthesis with different FA leads to different PG�s Used to reduce risk of heart attack, stroke, and other cardiovascular disease Also appears to modulate autoimmune diseases, asthma, and arthritis (less joint swelling) Another more controversial approach: vegetable oils rich in gamma llinoleic acid (the normal omega 6 FA) - evening primrose, borrage, black currant oils. Approach being used for arthritis; believed to modulate fat deficiencies in older women.

27. 27 Alternate PGD Structures

28. 28 Dinoprostone Synthetic PGE2 Strongly oxytocic; induces uterine contractions Used to induce abortion in first or second trimester Synthetic PGE2 Strongly oxytocic; induces uterine contractions Used to induce abortion in first or second trimester

29. 29 Epoprostenol Synthetic PGI2 Flolan or Cycloprostin Used to treat pulmonary hypertension Extremely short half life Disadvantage: central line Advantage: rapidly discontinuedSynthetic PGI2 Flolan or Cycloprostin Used to treat pulmonary hypertension Extremely short half life Disadvantage: central line Advantage: rapidly discontinued

30. 30 Alprostadil Synthetic PGE1 Caverject, Muse, Edex Used in the treatment of impotency Used to maintain an open ductus arteriosus in infants prior to surgical correction of some congenital heart diseases Synthetic PGE1 Caverject, Muse, Edex Used in the treatment of impotency Used to maintain an open ductus arteriosus in infants prior to surgical correction of some congenital heart diseases

31. 31 Misoprostol Synthetic analog to PGE Cytotec Increased stability: methyl group at C15 Used to prevent NSAID-induced ulcers �GI Cytoprotection�Synthetic analog to PGE Cytotec Increased stability: methyl group at C15 Used to prevent NSAID-induced ulcers �GI Cytoprotection�

32. 32 Prototype Non Steroidal Anti-inflammatory Drugs Still used for headache, malaise, fever, rheumatoid arthritis, inflammatory disease, coronary thrombosis SAR: Acid, Aryl Ring Tox: 1) GI Irritation - All NSAIDS 2) Clotting - Slows 3) Hypersensitivity - probably LT-mediated, (cross reactive/other NSAIDS) 4) Renal toxicity - not normally problematic; careful with CHF, chronic renal disease, or other renal stresses 5) Drug Interactions - Tightly binds plasma proteins, displaces other drugs - e.g. warfrin 6) Contraindicated in peds due to Reye�s syndrome (influenza/chicken pox) Use with Caution in pregnancy or with nursing (premature closure of ductus artereosis; acidosis)Still used for headache, malaise, fever, rheumatoid arthritis, inflammatory disease, coronary thrombosis SAR: Acid, Aryl Ring Tox: 1) GI Irritation - All NSAIDS 2) Clotting - Slows 3) Hypersensitivity - probably LT-mediated, (cross reactive/other NSAIDS) 4) Renal toxicity - not normally problematic; careful with CHF, chronic renal disease, or other renal stresses 5) Drug Interactions - Tightly binds plasma proteins, displaces other drugs - e.g. warfrin 6) Contraindicated in peds due to Reye�s syndrome (influenza/chicken pox) Use with Caution in pregnancy or with nursing (premature closure of ductus artereosis; acidosis)

33. 33 Modes of Action Aspirin unique as irreversible: duration dependent upon cyclooxygenase turnover All other NSAIDS are reversible: duration of action governed by drug turnoverAspirin unique as irreversible: duration dependent upon cyclooxygenase turnover All other NSAIDS are reversible: duration of action governed by drug turnover

34. 34 Other Salicylates Salicylamide can be used (for pain) in hypersensitve pts; less GI irritating Metal salts (Mg, Na) often less irritating Salsalate can be given to aspirin-sensitive pts Diflunisal is more potent and long lived; often used in arthritis Salicylamide can be used (for pain) in hypersensitve pts; less GI irritating Metal salts (Mg, Na) often less irritating Salsalate can be given to aspirin-sensitive pts Diflunisal is more potent and long lived; often used in arthritis

35. 35 Other Salicylates CHEMICAL STRUCTURES OF SOME ADDITIONAL SALICYLATES (attempts to decreaseGI toxicities) SODIUM SALICYLATE; Na salt; SODIUM THIOSALICYLATE: Note THIOL GROUP SUBSTITUTION CHOLINE SALICYLATE: CHOLINE GROUP AS THE SALTCHEMICAL STRUCTURES OF SOME ADDITIONAL SALICYLATES (attempts to decreaseGI toxicities) SODIUM SALICYLATE; Na salt; SODIUM THIOSALICYLATE: Note THIOL GROUP SUBSTITUTION CHOLINE SALICYLATE: CHOLINE GROUP AS THE SALT

36. 36

37. 37 NSAID Structure Activity Relationships (SAR) Three main elements to SAR: Acidic Group (red) - Can be a carboxylic acid, a hydroxyamidic acid, or an enolic acid. Analogous to the acid of arachidonic acid. Aryl Group (blue) - A large, flat, fatty group. Generally separated from the acid by one carbon. Distance is critical. Correlates with C-5 and C-8 double bonds of arachidonic acid. Alkyl Group (green) - Substitution of this position tends to increase anti-inflammatory activity. (S) isomer tends to be most active. Most commonly a methyl group as in the "profen" class. May correspond to the C-11 alkene of arachidonic acid.Three main elements to SAR: Acidic Group (red) - Can be a carboxylic acid, a hydroxyamidic acid, or an enolic acid. Analogous to the acid of arachidonic acid. Aryl Group (blue) - A large, flat, fatty group. Generally separated from the acid by one carbon. Distance is critical. Correlates with C-5 and C-8 double bonds of arachidonic acid. Alkyl Group (green) - Substitution of this position tends to increase anti-inflammatory activity. (S) isomer tends to be most active. Most commonly a methyl group as in the "profen" class. May correspond to the C-11 alkene of arachidonic acid.

38. 38 Aryl Propionic Acids Ibuprofen Naproxen Ibuprofen Naproxen

39. 39 More Aryl Propionic Acids Wide Variety available High degree of variation in aryl groups allowedWide Variety available High degree of variation in aryl groups allowed

40. 40 Profen NSAIDS

41. 41 Indole and Indene Acids Indomethacin Most Potent NSAID Cox I selective (relatively) Etodolac Lower GI toxicity than most Favored for ArthritisIndomethacin Most Potent NSAID Cox I selective (relatively) Etodolac Lower GI toxicity than most Favored for Arthritis

42. 42 Indene Acetic Acid Sulindac Prodrug; sulfoxide reduced to sulfide More potent analgesic than anti-inflammatory Sulindac Prodrug; sulfoxide reduced to sulfide More potent analgesic than anti-inflammatory

43. 43 Enol Acids Variation in acidic function also allowed Extremely long-lived Long term use in arthritisVariation in acidic function also allowed Extremely long-lived Long term use in arthritis

44. 44

45. 45

46. 46

47. 47 COX-II Selectivity Selectivity: differences around the binding site Large side pocket accommodates side chain (COX-2); H-bond to group on side chain Selectivity: differences around the binding site Large side pocket accommodates side chain (COX-2); H-bond to group on side chain

48. 48 COX-II Selective NSAIDS Celecoxib (Celebrex� - Pfizer) Concern now with all COX2 agents, or �coxibs�, regarding risks for cardiovascular events (MI) and thrombotic cardiovascular events Rofecoxib (Vioxx� - Merck) Also was approved for osteo and rheumatoid arthritis (removed) Long term trial to test GI safety (VIGOR) shows significant improvement in ulcerations and GI irritation between rofecoxib and naproxen (as did another coxib: lumiracoxib in TARGET trial) However, the incidence of thrombotic cardiovascular events is significantly higher (overall incidence remains less than 2%) Similar efficacy with most NSAIDSCelecoxib (Celebrex� - Pfizer) Concern now with all COX2 agents, or �coxibs�, regarding risks for cardiovascular events (MI) and thrombotic cardiovascular events Rofecoxib (Vioxx� - Merck) Also was approved for osteo and rheumatoid arthritis (removed) Long term trial to test GI safety (VIGOR) shows significant improvement in ulcerations and GI irritation between rofecoxib and naproxen (as did another coxib: lumiracoxib in TARGET trial) However, the incidence of thrombotic cardiovascular events is significantly higher (overall incidence remains less than 2%) Similar efficacy with most NSAIDS

49. 49 COX Isoform Functions: �Revised� COX-1: normal housekeeping functions COX-2: inflammatory response to insult; but also constitutive functions COX-1: normal housekeeping functions COX-2: inflammatory response to insult; but also constitutive functions

50. 50 COX-II Selective NSAIDS Valdecoxib (Bextra -Pfizer) First of the �second generation� coxibs Removed from market in April 2005: risk of cardiovascular and thrombotic SE Paracoxib: injectable, inactive prodrug; release of propionic acid to activate Etoricoxib Second Generation 15 to 20 h half life Valdecoxib (Bextra -Pfizer) First of the �second generation� coxibs Removed from market in April 2005: risk of cardiovascular and thrombotic SE Paracoxib: injectable, inactive prodrug; release of propionic acid to activate Etoricoxib Second Generation 15 to 20 h half life

51. 51 Analgesia (without Anti-Inflammation) As effective as aspirin for relief of pain and fever No anti-inflammatory effects No effects on platelet aggregation Acetaminophen toxic to liver at high doses Phenacetin is toxic to the kidney; is converted to Acetaminophen As effective as aspirin for relief of pain and fever No anti-inflammatory effects No effects on platelet aggregation Acetaminophen toxic to liver at high doses Phenacetin is toxic to the kidney; is converted to Acetaminophen

52. 52 Acetaminophen Toxicity Normally safely cleared as sulfate or glucuronide Minor pathway: oxidation by Cyp Large overdose: Cyp intermediate significantly increased. Intermediate reacts with thiols -- normally cleared by conjugation with glutathione Large doses: depletes glutathione then reacts with liver proteinsTreatment: N-acetylcysteine Pts with elevated Cyp levels (induced by drugs) or low glutathione levels (alcoholics) are at higher risk Common ingredient in OTC combinations (Colds) Normally safely cleared as sulfate or glucuronide Minor pathway: oxidation by Cyp Large overdose: Cyp intermediate significantly increased. Intermediate reacts with thiols -- normally cleared by conjugation with glutathione Large doses: depletes glutathione then reacts with liver proteinsTreatment: N-acetylcysteine Pts with elevated Cyp levels (induced by drugs) or low glutathione levels (alcoholics) are at higher risk Common ingredient in OTC combinations (Colds)

53. 53 LTD4 (Leukotriene) Receptor Antagonists Zafirlukast Less effective than corticosteroids Linked to Churg-Strauss Syndrome (inflammation of pulmonary blood vessels) Montelukast Less effective than corticosteroids; may allow reduction of steroid dose Both used for allergic rhinitis; less effective than corticosteroids Aspirin-intolerant asthmaZafirlukast Less effective than corticosteroids Linked to Churg-Strauss Syndrome (inflammation of pulmonary blood vessels) Montelukast Less effective than corticosteroids; may allow reduction of steroid dose Both used for allergic rhinitis; less effective than corticosteroids Aspirin-intolerant asthma

54. 54 Leukotriene Synthesis I 5-Lipoxygenase FLAP5-Lipoxygenase FLAP

55. 55 5-Lipoxygenase Inhibitors Maintenance treatment of Asthma Dual Action 5-LOX-COX inhibitors: in development as anti-thromboticsMaintenance treatment of Asthma Dual Action 5-LOX-COX inhibitors: in development as anti-thrombotics

56. 56 Histamine Histamine levels controlled by release from granules Histamine: two basic centers Edema, hives, bronchioconstriction associated with allergy Three receptor types H1- smooth muscle, endothelium, brain Tx for Allergy (anti-histamines) H2- gastric mucosa, cardiac muscle, mast cells, brain H3 - brain, neuronsHistamine levels controlled by release from granules Histamine: two basic centers Edema, hives, bronchioconstriction associated with allergy Three receptor types H1- smooth muscle, endothelium, brain Tx for Allergy (anti-histamines) H2- gastric mucosa, cardiac muscle, mast cells, brain H3 - brain, neurons

57. 57 Blocking Histamine Action Physiologic Antagonists Opposite action to histamine, but different receptors - Used in anaphylaxis Release Inhibitors Prevent degranulation of mast cells Used in asthma Receptor Antagonists Block histamine binding to receptor Dominant mode of Tx for H1 and H2 receptorsPhysiologic Antagonists Opposite action to histamine, but different receptors - Used in anaphylaxis Release Inhibitors Prevent degranulation of mast cells Used in asthma Receptor Antagonists Block histamine binding to receptor Dominant mode of Tx for H1 and H2 receptors

58. 58 Antihistamine SAR Nitrogen Base (Black) First Aryl Group (Red) - generally phenyl Second Aryl Group (Green) - a phenyl, benzyl, pyridyl, or thienyl group Linker (Blue) 1, 2, or 3 atoms; provides a 5-6 � distance between center of aryl rings and nitrogen X group - Carbon or Nitrogen Y group - Carbon, Oxygen, or omitted Alkyl Groups (pink) - typically methyl groups First Generation: Block other receptors, cross blood brain barrier, high affinity for CNS receptorsNitrogen Base (Black) First Aryl Group (Red) - generally phenyl Second Aryl Group (Green) - a phenyl, benzyl, pyridyl, or thienyl group Linker (Blue) 1, 2, or 3 atoms; provides a 5-6 � distance between center of aryl rings and nitrogen X group - Carbon or Nitrogen Y group - Carbon, Oxygen, or omitted Alkyl Groups (pink) - typically methyl groups First Generation: Block other receptors, cross blood brain barrier, high affinity for CNS receptors

59. 59 Amino Alkyl Ethers Diphenhydramine Prototype - Used for Allergy Carbinoxamine Doxylamine Diphenhydramine Prototype - Used for Allergy Carbinoxamine Doxylamine

60. 60 Ethylene Diamines Pyrilamine TripelennaminePyrilamine Tripelennamine

61. 61 Piperazine Antihistamines Hydroxyzine Cyclizine Meclizine Hydroxyzine Cyclizine Meclizine

62. 62 Alkyl Amines

63. 63 Phenothiazines

64. 64 �Second Generation� Antihistamines Generally weakly or non-sedating Typically do not cross blood brain barrier Often metabolized by CyP450�s (CYP) Astemizole and Terfenadine first introduced Both metabolized by CYPs Both removed from market due to induction of cardiac arrhythmia (long QT syndrome)Generally weakly or non-sedating Typically do not cross blood brain barrier Often metabolized by CyP450�s (CYP) Astemizole and Terfenadine first introduced Both metabolized by CYPs Both removed from market due to induction of cardiac arrhythmia (long QT syndrome)

65. 65 Terfenadine Toxicity Terfenadine is a prodrug; fexofenadine through CYP Terfenadine itself is toxic; cardiac arrythmia Inhibitors of CYP block conversion, increase toxicity of Terfenadine Terfenadine is a prodrug; fexofenadine through CYP Terfenadine itself is toxic; cardiac arrythmia Inhibitors of CYP block conversion, increase toxicity of Terfenadine

66. 66 Newer Antihistamines 1 General: all once per day dosing; all relatively non sedating Fexofenadine is the metabolic product of terfenadine Requires p-glycoprotein for excretion; p-gp inhibited by ketoconazoles; may be potential interaction Cetirizine is metabolic product of hydroxyzine. sedating in some patients even at therapeutic dosages Both appear more effective than loratadineGeneral: all once per day dosing; all relatively non sedating Fexofenadine is the metabolic product of terfenadine Requires p-glycoprotein for excretion; p-gp inhibited by ketoconazoles; may be potential interaction Cetirizine is metabolic product of hydroxyzine. sedating in some patients even at therapeutic dosages Both appear more effective than loratadine

67. 67 Newer Antihistamines 2 Loratadine � non-sedating � long half life Now OTC/genericLoratadine � non-sedating � long half life Now OTC/generic

68. 68 W-3 Fatty Acids, Aspirin, & 5-Lipoxygenase Pathway COX acetylation leads to HEPE formation (15R or 18R, depending upons cells/tissues involved) Then 5-Lipoxygenase (most active in platelets and leukocytes) adds the hydroperoxide group to 15R/18R-HEPE give the respective epoxy-HEPE HPETE are rapidly converted by dehydrases to the LTA5, or to ResolvinE1 (RvE1) RvE1 has anti-inflammatory propertiesCOX acetylation leads to HEPE formation (15R or 18R, depending upons cells/tissues involved) Then 5-Lipoxygenase (most active in platelets and leukocytes) adds the hydroperoxide group to 15R/18R-HEPE give the respective epoxy-HEPE HPETE are rapidly converted by dehydrases to the LTA5, or to ResolvinE1 (RvE1) RvE1 has anti-inflammatory properties

69. 69 Novel Anti-Inflammatory Approaches

70. 70 Novel Anti-Inflammatory Approaches

71. 71 Eicosanoid Physiologic Effects