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

2. Overview General PG as drugs – Natural – Modified – Analogs

3. PG and TX nomenclature  chain  chain 8 9 10 11 12

4. 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

5. 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

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

7. 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

8. Specific Receptors IP3 G as = Activates cAMP Pathway G aq = Activates Diacylglyceral (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)

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

10. Progenitor of PG and TX (AA)

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

12. PGG 2 COX PGH 2 Peroxidase

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

14. PGG 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 -

15. Synthetases

16. Tissue Specific Synthetases

17. PG and TX Enzymatic Degradation

18.  -Oxidation

19.  -Oxidation CYP4A

20. PG and TX Chemical Degradation

21. PGs as Drugs Natural Modified Analogs

22. Drug-drug Interactions NSAIDs Corticosteroids

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

24. Natural PGs Aprostadil Dinoprostone Epoprostenol

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

26. Natural PG: Aprostadil

27. Usage Erectile Dysfunction Congenital Heart Defect Normal HeartWith Defect

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

29. ADME (To Know) Absorption – Very Bioavailable Distribution – Protein Bound Metabolism – Mostly Pulmonary Elimination – Short

30. Mechanism via GPCR Increase Blood Flow

31. Formulations and Administration Erectile Dysfunction Caverject® – Penile Injection Edex® – Penile Injection Muse® – Urethral Suppository Congenital Heart Defect Prostin VR® – IV Injection Things to know: Generic and brand names.

32. ADR Erectile Dysfunction Erection 4-6 hours Penis Curving Pain/Rash Light Headed Bleeding/Bruising Flu Symptoms Congenital Heart Defect Pain/Rash Light Headed Bleeding/Bruising Flu Symptoms

33. Natural PG: Dinoprostone

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

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

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

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

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

39. Natural PG: Epoprostenol

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

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

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

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

44. Common ADR Fever/Flu-like symptoms Nausea/Vomiting/Diarrhea Pain Rapid Heart Rate

45. Modified PGs Carboprost Bimatoprost, Lantaprost, Talfuprost, Travoprost and Unoprostone Misoprostol

46. Modified PGs Block  -oxidation – Methyls at 15 and/or 16 – Phenyl in 17-20 range Increase Lipophilicity – Add methyls, phenyls and esters

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

49. ADME Duration of Action: 2 hours

50. 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 Carbaprost Uterine contractions

51. Formulations/Administration Hemabate®- Intramuscular Injection

52. ADR Nausea, Diarrhea, Vomiting Bronchoconstriction Increased Body Temperature

53. Talfluprost

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

55. ADME Absorption – Across Cornea Elimination – Lantaprost aqueous humor 4h and plasma 1h – Talfuprost low levels in systematic circulation – Unoprostone 1% unchanged in urine

56. 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   

57. 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

58. Formulations/Administration Lumigan®, Latisse® (Bimaprost) Xalatan® (Lantaprost) Zioptan® (Talfuprost) Travatan® (Travoprost) Rescula® D/C (Unoprostone) Treatment with Latisse®

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

60. Misoprostol (Prodrug)

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

62. 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

63. 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

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

65. ADR Abdominal Pain Nausea, Diarrhea, Vomiting Increased Body Temperature

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

67. PG Analogs PGI 2 Treprostinil Ileprost

68. Usage/Effects Usage – Pulmonary Hypertension

69. 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

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

71. ADR Treprostinil- Infusion site pain/reaction Hypotension

72. Overview General PG as drugs – Natural – Modified – Analogs