430 likes | 758 Views
2. InflammationEicosanoid metabolismProstaglandinsThromboxanesLeukotrienesEicosanoid analogsNSAIDSSalicylatesAryl-Propionic AcidsIndole
E N D
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 Ĺ 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 Ĺ 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