1. Prostaglandins (PGs) and Thromboxanes (TXs)
PHRM 4050 Fall 2011
Prostaglandins (PGs) and Thromboxanes (TXs)
Dr. Arthur Roberts
Modified from course of Dr. Warren Beach

2. Overview
General
PG as drugs
Natural
Modified
Analogs

3. PG and TX nomenclature a chain b chain PHRM 4050 Fall 2011 9 8 10 12
a chain
b chain

4. The head group corresponds to which prostaglandin?
PGE
PGF2a
TXA
PGG/PGH
PGI
:30

5. PG and TX PGE2 PGF2a TXA2 PGI2
PG and TX to know: PGE1, PGE2, PGF2a, PGG2, PGH2, PGI2, TXA2

6. PLATELET AGGREGATION;
PGE2, PGF, and PGI2
RELAX VASCULAR
SMOOTH MUSCLE
PGE2 and PGI2
INCREASE
RENAL BLOOD FLOW
RELAX BRONCHIAL
SMOOTH MUSCLE;
PGF CONTRACTS IT
PGE2 and PGF
CONTRACT UTERINE
PGI2 RELAXES IT
PROTECT
GASTRIC MUCOSA
TxA2 PROMOTES
PLATELET AGGREGATION;
PGI2 INHIBITS IT

7. PG and TX Signaling PHRM 4050 Fall 2011
G-protein Coupled Receptor (GPCR) or Nuclear Receptor
Circulation
Nearby

8. PG signaling between 2 adjacent cells is?
Endocrine
Autocrine
Paracrine
Intracrine
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9. PG and TX Signaling EP1= Prostaglandin E receptor 1
PHRM 4050 Fall 2011
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
GPCR
COX
GPCR
Protein Synthesis
COX
Protein Signaling

10. Specific Receptors IP3 PHRM 4050 Fall 2011
Gas= Activates cAMP Pathway
Gaq= Activates Diacylglyceral (DAG) and Inositol Triphosphate (IP3) Pathway
Gai= Inhibits the production of cAMP from ATP
Prostaglandin Receptor Nomenclature = Prostaglandin Type + P + Receptor Number (e.g. DP2)

11. The EP1 prostaglandin receptor binds to which general type of prostaglandin?
PGA
PGG
PGH
PGE
:30

12. PG and TX Transport Active Efflux ABC transporters Active Influx
PHRM 4050 Fall 2011
PG and TX Transport
Active Efflux
ABC transporters
Active Influx
OATP transporters
Passive Diffusion
OATP = Organic Anionic Transporting Polypeptide
ABC = ATP Binding Cassette Transporters

13. Progenitor of PG and TX (AA) PHRM 4050 Fall 2011
Arachidonic acid: 20 carbon poly-unsaturated fatty acid(tetra-ene)
Precursor to the PG’s, TX’s and Leukotrienes, which are involved in the regulation of tissues processes and responses to tissue injury
(AA)

14. Synthesis of Arachidonic Acid (AA)
PHRM 4050 Fall 2011
Synthesis of Arachidonic Acid (AA)
Glucocorticoids
Stimulus + - 1 2 3
Phospholipase A2
Protein Kinase
Position #1 Phospholipase A1
Position #2 Phospholipase C and D
Position #1 and #2 Phospholipase B
Protein Kinase is Mitogen-activated Protein Kinase- Which is a Serine/Threonine Kinase
Stimulus- tissue damage, toxin exposure and hormonal stimulation
Steroid Anti-inflammatory Drugs (Glucocorticosteroids)

15. COX
PGG2
Peroxidase
PGH2

16. Prostaglandin Synthesis: COX10 5 9 9 1
COX 15 11 20 11 10 5 9 1 15 11 20
COX = cyclooxygenases

17. - - + COX II COX I PGG2 NSAIDs PHRM 4050 Fall 2011 Growth Factors
Tumor Necrosis Factor (TNF)
Endotoxins
Cytokine IL-1
Luteinizing Hormone
Mitogens
Corticosteroids (cardiomyocytes)
Corticosteroids Mostly
Cytokine IL-4 + -
COX II
COX I
Growth Factors, Tumor Promoters, Cytokines and Endotoxins induce COX II
Corticosteroid is cortisol; Dexamethasone is another one.
Luteinizing Hormone -
PGG2
NSAIDs

18. PHRM 4050 Fall 2011
Synthetases are tissue specific
Synthetases

19. Tissue Specific Synthetases

20. The product of COX metabolism is?
Arachidonic Acid
PGE2
TXA2
PGG2
PGI2
PGH2
:30

21. The product of Phospholipase A2 metabolism is?
Arachidonic Acid
PGE2
TXA2
PGG2
PGI2
PGH2
:30

22. PG and TX Enzymatic Degradation

23. b-Oxidation

24. The carboxylic acid of the a-chain forms a covalent link with what during b-oxidation?
An enol
An ester
A methyl
Coenzyme A
:30

25. w-Oxidation
CYP4A

26. Which Cytochrome P450 (CYP) is involved in w-oxidation?
CYP1A1
CYP2C9
CYP3A4
CYP4A
:30

27. PG and TX Chemical Degradation

28. What is the chemical process called of using water to break a bond?
Reduction
Oxidation
Hydrolysis
Deprotonation
Protonation
:30

29. PGs as Drugs
Natural
Modified
Analogs

30. Drug-drug Interactions
NSAIDs
Corticosteroids

31. NSAIDs will interfere with PG drugs because they can
Inhibit PG synthetases
Induce COX 2 expression
Reduce COX 2 expression
Inhibit COX 1
Inhibit COX 2
D and E
diclofenac
:30

32. Corticosteroids will interfere with PG drugs because they
PHRM 4050 Fall 2011
Corticosteroids will interfere with PG drugs because they
Inhibit PG synthetases
Induce COX 2 expression
Reduce COX 2 expression
Inhibit COX 2
C and D
B and C
:30
dexamethasone

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

34. Natural PGs
Aprostadil
Dinoprostone
Epoprostenol

35. Natural PGs: Pros and Cons
PHRM 4050 Fall 2011
Natural PGs: Pros and Cons
Pros
Cons
Potent
Elimination T 1/2 short
Specific
Rapid Degradation
Orally Inactive
Injected/Applied Directly
GI side effects
GI side effects: Nausea, Vomiting, Diarhea and Cramping

36. Natural PG: Aprostadil

37. What prostaglandin is Aprostadil?
PGE1
PGE2
TXA2
Prostacyclin only
PGI2 only
Prostacyclin and PGI2
:30
Aprostadil

38. Usage Erectile Dysfunction Congenital Heart Defect Normal Heart
PHRM 4050 Fall 2011
Usage
Erectile Dysfunction
Congenital Heart Defect
Patent ductus arterioles usually closes at birth
Normal Heart
With Defect

39. The ductus arteriosus in a fetus’s heart usually becomes
a heart valve
a vein
an artery
an arterial ligament
:30

40. ADME Absorption Distribution Metabolism Elimination
PHRM 4050 Fall 2011
ADME
Absorption
Bioavailability 98% (IV)
Distribution
93% Protein-bound
Metabolism
60-90% First Pass Metabolism Pulmonary
Elimination
t1/ minutes

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

42. Mechanism
via GPCR
Increase
Blood
Flow

43. Formulations and Administration
PHRM 4050 Fall 2011
Formulations and Administration
Erectile Dysfunction
Congenital Heart Defect
Caverject®
Penile Injection
Edex®
Muse®
Urethral Suppository
Prostin VR®
IV Injection
Things to know: Generic and brand names.

44. ADR Erectile Dysfunction Congenital Heart Defect Erection 4-6 hours
PHRM 4050 Fall 2011
ADR
Erectile Dysfunction
Congenital Heart Defect
Erection 4-6 hours
Penis Curving
Pain/Rash
Light Headed
Bleeding/Bruising
Flu Symptoms
Pain/Rash
Light Headed
Bleeding/Bruising
Flu Symptoms

45. Natural PG: Dinoprostone

46. What prostaglandin is Dinoprostone?
PGE1
PGE2
TXA2
Prostacyclin only
PGI2 only
Prostacyclin and PGI2
:30
Dinoprostone

47. Usage Effect Use Labor induction 2nd Trimester Abortion
PHRM 4050 Fall 2011
Usage
Effect
Cervical Ripening
Uterine Contraction
Use
Labor induction
2nd Trimester Abortion
Evacuation of Fetus
Cervical Ripening-cervix softens and becomes more distensible (tendency to distend or swell wout)

48. ADME Absorption Metabolism Elimination Some Systematic
PHRM 4050 Fall 2011
ADME
Absorption
Some Systematic
Metabolism
95% First Pass Pulmonary
Elimination
Half Life 2-5 minutes

49. Mechanism + cAMP PGE2 PHRM 4050 Fall 2011 EP2 Cervical Ripening
Uterine Contraction

50. Formulations and Administration
PHRM 4050 Fall 2011
Formulations and Administration
Prepidil®
Cervical Gel
Cervidil®
Vaginal Insert

51. Common ADR Fever Pain- Stomach and Back
PHRM 4050 Fall 2011
Common ADR
Fever
Pain- Stomach and Back
Diarrhea, Nausea and Vomiting (DNV)
Abnormal Uterine Contractions

52. Natural PG: Epoprostenol

53. What is another name for Epoprostenol?
PGE1
PGE2
TXA2
Prostacyclin
PGI2
D and E
Epoprostenol
:30

54. Usage/Effects Hypertension (High Blood Pressure) Scleroderma
PHRM 4050 Fall 2011
Usage/Effects
Pulmonary Arterial Hypertension New York Heart Association (NYHA) 3 or 4
Hypertension (High Blood Pressure)
Scleroderma

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

56. PGI2 vs TXA2 (Mechanism) PGI2 TXA2 Prostaglandin I2 receptor (IP2)
PHRM 4050 Fall 2011
PGI2 vs TXA2 (Mechanism)
PGI2
TXA2
Prostaglandin I2 receptor (IP2)
GPCR
cAMP signaling pathway
PPAR nuclear receptor
Platelet Inhibition
Smooth Muscle Relaxation
Vasodilator
Thromboxane Receptor (TP)
GPCR
Diacylglycerol (DAG) Inositol 1,4,5-triphosphate signaling pathway (IP3)
Increase Ca2+
Platelet Activation
Smooth Muscle Contraction
Vasoconstrictor

57. Formulations/Administration
PHRM 4050 Fall 2011
Formulations/Administration
Flolan®, Veletri®-Continuous IV Infusion

58. Common ADR Fever/Flu-like symptoms Nausea/Vomiting/Diarrhea Pain
PHRM 4050 Fall 2011
Common ADR
Fever/Flu-like symptoms
Nausea/Vomiting/Diarrhea
Pain
Rapid Heart Rate

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

60. Modified PGs Block w-oxidation Increase Lipophilicity
Methyls at 15 and/or 16
Phenyl in range
Increase Lipophilicity
Add methyls, phenyls and esters

62. What prostaglandin does Carbopost correspond to?
PGE1
PGE2
TXA2
PGF2a
PGI2
15-methyl PGF2a 15
:30

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

64. ADME
Duration of Action: 2 hours

65. Mechanism DAG/IP3 PHRM 4050 Fall 2011 Carbaprost
Gas= Activates cAMP Pathway
Gaq= Activates Diacylglycerol (DAG) and Inositol Triphosphate (IP3) Pathway
Gai= Inhibits the production of cAMP from ATP
Uterine contractions

66. Formulations/Administration
Hemabate®- Intramuscular Injection

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

68. Talfluprost

69. These compounds are modified versions of what prostaglandin?
PGE1
PGE2
TXA2
PGF2a
PGI2
15-methyl PGF2a 15
:30

70. Usage/Effects Effect Usage Decreases intra-ocular pressure
PHRM 4050 Fall 2011
Usage/Effects
Effect
Decreases intra-ocular pressure
Usage
Open Angle Glaucoma
Ocular Hypertension
Bimatoprost: Increase eyelash growth
For use, for those that are refractory (i.e. resistant) and intolerant to other agents

71. ADME Absorption Elimination Across Cornea Lantaprost Talfuprost
PHRM 4050 Fall 2011
ADME
Absorption
Across Cornea
Elimination
Lantaprost
aqueous humor 4h and plasma 1h
Talfuprost
low levels in systematic circulation
Unoprostone
1% unchanged in urine
Low levels of the free acid and ester in the systematic circulation.

72. ADME: Metabolism E R O b E b E D b G w R E O b R
PHRM 4050 Fall 2011 E R 13 14 15 O b E b 15 E D b G w 14 R E 13 O b R 14 13
Talfuprost
E=Esterase, O=Oxidation, R=Reduction, b=b-Oxidation, w=w-Oxidation, D=dealkylation, G=glucuronidation

73. Mechanism Eye Cross-Section DAG/IP3 PHRM 4050 Fall 2011 Drug
Increase Outflow from the Aqueous Humor
Gas= Activates cAMP Pathway
Gaq= Activates Diacylglycerol (DAG) and Inositol Triphosphate (IP3) Signaling Pathway
Gai= Inhibits the production of cAMP from ATP
Increase Outflow and Decrease Intra-Ocular Pressure
Relaxation of Ciliary Muscles

74. Formulations/Administration
PHRM 4050 Fall 2011
Formulations/Administration
Lumigan®, Latisse® (Bimaprost)
Xalatan® (Lantaprost)
Zioptan® (Talfuprost)
Travatan® (Travoprost)
Rescula® D/C (Unoprostone)
All Ophthalmalic
Treatment with Latisse®

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

76. Misoprostol (Prodrug)

77. Misoprostol is a modified version of what prostaglandin?
PGE1
PGE2
TXA2
PGF2a
PGI2
15-methyl PGF2a
:30

78. Usage/Effects Prevention of NSAID ulcers
PHRM 4050 Fall 2011
Usage/Effects
Prevention of NSAID ulcers
Labor Induction (Uterine Contractions and Ripening)
Terminate 1st and 2nd Trimester Pregnancies
Post-partum hemorrhaging
Elderly patients
Patients with debilitating disease
Patients with a history of gastic ulcers

79. ADME 80% Excreted through Urine Food and antacids decrease absorption
PHRM 4050 Fall 2011
ADME
80% Excreted through Urine
Food and antacids decrease absorption
Free acid (Active Form)
Elimination: t1/2= minutes
PGF R b E 9 R w 14 13
E=Esterase, R=Reduction, b=b-Oxidation, w=w-Oxidation

80. What general prostaglandin is produced when the oxygen at C-9 is reduced?
PGE
PGF
PGG
PGH
TXA 9
:30

81. Mechanism + cAMP Misoprostol PHRM 4050 Fall 2011
Prostaglandin E1 Receptor
Decrease gastric acid secretion
Increase mucus secretion
Increase bicarbonate excretion
Uterine contractions and ripening

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

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

84. PHRM 4050 Fall 2011
PG Analogs
Ileprost
Treprostinil
Stable at Room Temperature and neutral pH

85. These compounds are analogs of which prostaglandin?
PGE1
PGE2
TXA2
PGF2a
PGI2
15-methyl PGF2a
:30

86. PG Analogs PGI2 PHRM 4050 Fall 2011
Treprostinil
Ileprost
PGI2

87. Usage/Effects Usage Pulmonary Hypertension PHRM 4050 Fall 2011
NYHA class II-IV

88. ADME Absorption Bioavailability: 100% subcutaneous
PHRM 4050 Fall 2011
ADME
Absorption
Bioavailability: 100% subcutaneous
91% trepostinil and 60% iliprost bound to human plasma
Metabolism
Liver Cytochromes P450 (CYPs) and UDP-glucuronosyltransferases (UGTs)
b-oxidation of iliprost
Excretion
t1/2=4 hours
Major elimination route is urine

89. The mechanism for these compounds is the same as which prostaglandin?
PGE1
PGE2
TXA2
PGF2a
PGI2
15-methyl PGF2a
:30

90. Formulations/Administration
PHRM 4050 Fall 2011
Formulations/Administration
Remodulin® (Treprostinil)- Subcutaneous/IV injection
Ventavis® (Iliprost)- Inhaled

91. ADR
Treprostinil- Infusion site pain/reaction
Hypotension

92. Overview
General
PG as drugs
Natural
Modified
Analogs