1. Prostaglandins (PGs) and Thromboxanes (TXs)-Synthesis and Degradation Dr. Arthur Roberts Modified from course of Dr. Warren Beach

2. Materials ELCnew pharmwiki.org – updated lectures Notes on the updates – class notes from the current lectures – lectures and notes from previous years – study aids Anki (free flash card software) flash-based quizzes to practice for the test

3. Purpose: Clicker Questions Are you paying attention? New material Thought questions Assessment of teaching

4. Overview Synthesis and Degradation Drugs – Natural – Modified – Analogs

5. PG and TX nomenclature  chain  chain 8 9 10 11 12

6. The head group corresponds to which prostaglandin? A.PGE B.PGF 2  C.TXA D.PGG/PGH E.PGI :30

7. PG and TX PGE 2 PGF 2  PGI 2 TXA 2 PG and TX to know: PGE 1, PGE 2, PGF 2 , PGG 2, PGH 2, PGI 2, TXA 2

8. PGE 2, PGF , and PGI 2 RELAX VASCULAR SMOOTH MUSCLE PGE 2 and PGI 2 INCREASE RENAL BLOOD FLOW PGE 2 and PGI 2 RELAX BRONCHIAL SMOOTH MUSCLE; PGF  CONTRACTS IT PGE 2 and PGF  CONTRACT UTERINE SMOOTH MUSCLE; PGI 2 RELAXES IT PGE 2 and PGI 2 PROTECT GASTRIC MUCOSA TxA 2 PROMOTES PLATELET AGGREGATION; PGI 2 INHIBITS IT

9. PG and TX Signaling G-protein Coupled Receptor (GPCR) or Nuclear Receptor Circulation Nearby

10. PG signaling between 2 adjacent cells is? A.Endocrine B.Autocrine C.Paracrine D.Intracrine :30

11. PG and TX Signaling EP1= Prostaglandin E receptor 1 PPAR=Peroxisome proliferator-activated receptor RXR=Retinoid X receptor 9-cis retinoic acid COX=Cyclooxygenase GPCR=G-protein coupled receptor COX Protein Signaling Protein Synthesis GPCR

12. Specific Receptors DAG/IP3 G as = Activates cAMP Pathway G aq = Activates Diacylglycerol (DAG) and Inositol Triphosphate (IP3) Pathway G ai = Inhibits the production of cAMP from ATP Prostaglandin Receptor Nomenclature = Prostaglandin Type + P + Receptor Number (e.g. DP2)

13. The EP1 prostaglandin receptor binds to which general type of prostaglandin? A.PGA B.PGG C.PGH D.PGE :30

14. PG and TX Transport 1.Passive Diffusion 2.Active Efflux ABC transporters 3.Active Influx OATP transporters OATP = Organic Anionic Transporting Polypeptide ABC = ATP Binding Cassette Transporters

15. Progenitor of PG and TX (AA)

16. Synthesis of Arachidonic Acid (AA) 1 2 3 Phospholipase A2 Protein Kinase Stimulus + - Glucocorticoids

17. PGG 2 COX PGH 2 Peroxidase

18. Prostaglandin Synthesis: COX COX 1 5 15 20 10 15 1 20 10 5 COX = cyclooxygenases 9 11 9 9

19. PGH 2 COX II COX I Growth Factors Tumor Necrosis Factor (TNF) Endotoxins Cytokine IL-1 Luteinizing Hormone Mitogens Corticosteroids (cardiomyocytes) + Corticosteroids Mostly Cytokine IL-4 - NSAIDs -

20. Synthetases

21. Tissue Specific Synthetases COX-1 COX-2

22. The product of COX metabolism is? A.Arachidonic Acid B.PGE 2 C.TXA 2 D.PGG 2 E.PGI 2 F.PGH 2 :30

23. The product of Phospholipase A 2 metabolism is? A.Arachidonic Acid B.PGE 2 C.TXA 2 D.PGG 2 E.PGI 2 F.PGH 2 :30

24. PG and TX Enzymatic Degradation Specific alcohol dehydrogenases Specific reductases  -chain  -chain

25.  -chain  -chain 1  -Oxidation attach Coenzyme A degrade to acetyl Coenzyme A Coenzyme A

26.  -Oxidation: Step 1 Coenzyme A AMP  -chain  -chain 1

27.  -Oxidation: Step 2 Coenzyme A Citric Acid Cycle (Krebs Cycle) CO 2  -chain  -chain 1

28. The carboxylic acid of the  -chain forms a covalent link with what during  -oxidation? A.An enol B.An ester C.A methyl D.Coenzyme A :30

29.  -Oxidation CYP4A H2OH2O  -chain  -chain 1

30. Which Cytochrome P450 (CYP) is involved in  -oxidation? A.CYP1A1 B.CYP2C9 C.CYP3A4 D.CYP4A :30

31. PG and TX Chemical Degradation

32. Prostaglandins (PGs) and Thromboxanes (TXs) as Drugs Dr. Arthur Roberts Modified from course of Dr. Warren Beach

33. PGs as Drugs Natural Modified Analogs

34. Molecules that influence PG drug administration NSAIDs – inhibit COX-1 and COX-2 Corticosteroids – induce (cardiomyocytes) and repress COX-2 – glucocorticosteroids induce lipocortin (annexin)  inhibit PLA 2

35. Drugs Chemical Name Usage ADME Mechanism Formulation and Administration Common ADR

36. Natural PGs Aprostadil Dinoprostone Epoprostenol

37. Natural PGs: Pros and Cons ProsCons PotentElimination t 1/2 short SpecificRapid Degradation Orally Inactive Injected/Applied Directly GI side effects

38. Natural PG: Alprostadil

39. What prostaglandin is Alprostadil? A.PGE 1 B.PGE 2 C.TXA 2 D.Prostacyclin only E.PGI 2 only F.Prostacyclin and PGI 2 Aprostadil :30

40. Usage Erectile Dysfunction Congenital Heart Defect Congenital Defect Patent ductus Arteriosis (PDA) Normal Heart Ligamentum arteriosum

41. The ductus arteriosus in a fetus’s heart usually becomes A.a heart valve B.a vein C.an artery D.an arterial ligament :30

42. ADME Absorption – Bioavailability 98% (IV) Distribution – 93% Protein-bound Metabolism – 60-90% First Pass Metabolism Pulmonary Elimination – t 1/2 9-11 minutes

43. Mechanism via GPCR (EP) Increase Blood Flow PDE= Phosphodiesterase

44. Formulations and Administration Erectile Dysfunction Caverject® – Penile Injection Edex® – Penile Injection Muse® – Urethral Suppository Congenital Heart Defect Prostin VR® – IV Injection

45. ADR Erectile Dysfunction Erection 4-6 hours Penis Curving Pain/Rash Light Headed Bleeding/Bruising Flu Symptoms (e.g. nausea) Congenital Heart Defect Pain/Rash Light Headed Bleeding/Bruising Flu Symptoms (e.g. nausea)

46. Natural PG: Dinoprostone

47. What prostaglandin is Dinoprostone? A.PGE 1 B.PGE 2 C.TXA 2 D.Prostacyclin only E.PGI 2 only F.Prostacyclin and PGI 2 Dinoprostone :30

48. Usage Effect –Cervical Ripening –Uterine Contraction Use –Labor induction –2 nd Trimester Abortion –Evacuation of Fetus

49. ADME Absorption – Some Systematic Metabolism – 95% First Pass Pulmonary Elimination – Half Life 2-5 minutes

50. Mechanism EP2 PGE 2 cAMP + Cervical Ripening Uterine Contraction

51. Formulations and Administration Prepidil® – Cervical Gel Cervidil® – Vaginal Insert

52. Common ADR Fever Pain- Stomach and Back Diarrhea, Nausea and Vomiting (DNV) Abnormal Uterine Contractions

53. Natural PG: Epoprostenol

54. What is another name for Epoprostenol? A.PGE 1 B.PGE 2 C.TXA 2 D.Prostacyclin E.PGI 2 F.D and E Epoprostenol :30

55. Usage/Effects Scleroderma Hypertension (High Blood Pressure)

56. ADME Metabolism Half-life of 42 seconds Hydrolysis Elimination 6 minutes

57. PGI 2 vs TXA 2 (Mechanism) PGI 2 Prostaglandin I 2 receptor (IP 2 ) – GPCR PPAR nuclear receptor cAMP signaling pathway Platelet Inhibition Smooth Muscle Relaxation Vasodilator TXA 2 Thromboxane Receptor (TP) – GPCR + G aq Diacylglycerol (DAG) Inositol 1,4,5-triphosphate signaling pathway (IP3) – Increase Ca 2+ Platelet Activation Smooth Muscle Contraction Vasoconstrictor

58. Epoprostenol Formulations/Administration Flolan®, Veletri®-Continuous IV Infusion

59. Epoprostenol Common ADR Fever/Flu-like symptoms Diarrhea, Nausea and Vomiting (DNV) Pain Rapid Heart Rate

60. Modified PGs Carboprost Bimatoprost, Latanoprost, Talfuprost, Travoprost and Unoprostone Misoprostol

61. General Strategies for Modifying PGs Block  -oxidation – Methyls at 15 and/or 16 – Phenyl in 17-20 range Increase Lipophilicity – Add methyls, phenyls and esters

62. 15

63. What prostaglandin does Carboprost correspond to? A.PGE 1 B.PGE 2 C.TXA 2 D.PGF 2  E.PGI 2 F.15-methyl PGF 2  15 :30

64. Usage/Effects Effects – Uterine contraction Usage – Postpartum (Post-pregnancy) bleeding IV oxytocin, uterine massage or IM ergot – 2 nd Trimester abortions

65. ADME Duration of Action: 2 hours

66. Mechanism DAG/IP3 G as = Activates cAMP Pathway G aq = Activates Diacylglycerol (DAG) and Inositol Triphosphate (IP3) Pathway G ai = Inhibits the production of cAMP from ATP Carboprost Uterine contractions

67. Formulations/Administration Hemabate®- Intramuscular Injection

68. ADR Diarrhea, Nausea and Vomiting (DNV) Bronchoconstriction Increased Body Temperature

69. Tafluprost

70. These compounds are modified versions of what prostaglandin? A.PGE 1 B.PGE 2 C.TXA 2 D.PGF 2  E.PGI 2 F.15-methyl PGF 2  15 :30

71. Usage/Effects Effect – Decreases intra-ocular pressure Usage – Open Angle Glaucoma – Ocular Hypertension –Bimatoprost: Increase eyelash growth

72. ADME Absorption – Across Cornea Elimination – Latanoprost aqueous humor 4h and plasma 1h – Tafluprost low levels in systematic circulation – Unoprostone 1% unchanged in urine

73. ADME: Metabolism E=Esterase, O=Oxidation, R=Reduction,  =  -Oxidation,  =  -Oxidation, D=dealkylation, G=glucuronidation E E R 13 14 O 15 E R 13 14 15 O  D G  Talfuprost E R 13 14   

74. Mechanism DAG/IP3 G as = Activates cAMP Pathway G aq = Activates Diacylglycerol (DAG) and Inositol Triphosphate (IP3) Signaling Pathway G ai = Inhibits the production of cAMP from ATP Drug Eye Cross-Section Increase Outflow and Decrease Intra-Ocular Pressure Relaxation of Ciliary Muscles

75. Formulations/Administration Lumigan®, Latisse® (Bimatoprost) Xalatan® (Latanoprost) Zioptan® (Tafluprost) Travatan® (Travoprost) Rescula® D/C (Unoprostone) Treatment with Latisse®

76. ADR Brown pigmentation of iris Eye lid rim darkening Eye lash darkening and grow longer

77. Misoprostol (Prodrug)

78. Misoprostol is a modified version of what prostaglandin? A.PGE 1 B.PGE 2 C.TXA 2 D.PGF 2  E.PGI 2 F.15-methyl PGF 2  :30

79. Usage/Effects Prevention of NSAID ulcers Labor Induction (Uterine Contractions and Ripening) Terminate 1 st and 2 nd Trimester Pregnancies Post-partum hemorrhaging

80. ADME 80% Excreted through Urine Food and antacids decrease absorption Free acid (Active Form) Elimination: t 1/2 = 20-40 minutes E=Esterase, R=Reduction,  =  -Oxidation,  =  -Oxidation  E  R 13 14 PGF 9 R

81. What general prostaglandin is produced when the oxygen at C-9 is reduced? A.PGE B.PGF C.PGG D.PGH E.TXA 9 :30

82. Mechanism Misoprostol cAMP + Prostaglandin E 1 Receptor 1.Decrease gastric acid secretion 2.Increase mucus secretion 3.Increase bicarbonate excretion 4.Uterine contractions and ripening

83. Formulations/Administration Cytotec®- Oral Arthrotec® (with Diclofenac)- Oral Diclofenac

84. ADR Abdominal Pain Diarrhea, Nausea and Vomiting (DNV) Increased Body Temperature

85. PG Analogs Stable at Room Temperature and neutral pH Treprostinil Ileprost

86. These compounds are analogs of which prostaglandin? A.PGE 1 B.PGE 2 C.TXA 2 D.PGF 2  E.PGI 2 F.15-methyl PGF 2  :30

87. PG Analogs PGI 2 Treprostinil Ileprost

88. Usage/Effects Usage – Pulmonary Hypertension

89. ADME Absorption – Bioavailability: 100% subcutaneous – 91% trepostinil and 60% iliprost bound to human plasma Metabolism – Liver Cytochromes P450 (CYPs) and UDP- glucuronosyltransferases (UGTs) –  -oxidation of iliprost Excretion – t 1/2 =4 hours – Major elimination route is urine

90. The mechanism for these compounds is the same as which prostaglandin? A.PGE 1 B.PGE 2 C.TXA 2 D.PGF 2  E.PGI 2 F.15-methyl PGF 2  :30

91. Formulations/Administration Remodulin® ( Treprostinil )- Subcutaneous/IV injection Ventavis® (Iliprost)- Inhaled

92. ADR Treprostinil- Infusion site pain/reaction Hypotension

93. Overview Lecture 1: Synthesis and Degradation Lecture 2: PG as drugs – Natural – Modified – Analogs