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Prostaglandins (PGs) and Thromboxanes (TXs)
Dr. Arthur Roberts
Modified from course of Dr. Warren Beach
Overview
• General• PG as drugs
– Natural– Modified – Analogs
PG and TX nomenclature
chain
chain
89
10
11
12
The head group corresponds to which prostaglandin?
A. PGEB. PGF2
C. TXAD. PGG/PGHE. PGI
PG and TXPGE2 PGF2
PGI2
TXA2
PG and TX to know: PGE1, PGE2, PGF2, PGG2, PGH2, PGI2, TXA2
PGE2, PGF, and PGI2
RELAX VASCULARSMOOTH MUSCLE
PGE2 and PGI2
INCREASERENAL BLOOD FLOW
PGE2 and PGI2
RELAX BRONCHIALSMOOTH MUSCLE;
PGF CONTRACTS IT
PGE2 and PGF
CONTRACT UTERINESMOOTH MUSCLE;
PGI2 RELAXES IT
PGE2 and PGI2
PROTECTGASTRIC MUCOSA
TxA2 PROMOTESPLATELET AGGREGATION;
PGI2 INHIBITS IT
PG and TX SignalingG-protein Coupled Receptor (GPCR) or Nuclear Receptor
Circulation
Nearby
PG signaling between 2 adjacent cells is?
A. EndocrineB. AutocrineC. ParacrineD. Intracrine
PG and TX SignalingEP1= Prostaglandin E receptor 1PPAR=Peroxisome proliferator-activated receptorRXR=Retinoid X receptor 9-cis retinoic acidCOX=CyclooxygenaseGPCR=G-protein coupled receptorCOX
COX
Protein Signaling
Protein Synthesis
GPCR
GPCR
Specific Receptors
IP3
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)
The EP1 prostaglandin receptor binds to which general type of prostaglandin?
A. PGAB. PGGC. PGHD. PGE
PG and TX Transport1. Active Efflux
ABC transporters2. Active Influx
OATP transporters3. Passive Diffusion
OATP = Organic Anionic Transporting PolypeptideABC = ATP Binding Cassette Transporters
Progenitor of PG and TX
(AA)
Synthesis of Arachidonic Acid (AA)
1
2
3
Phospholipase A2
Protein Kinase
Stimulus
+ -
Glucocorticoids
PGG2
COX
PGH2PGH2
Peroxidase
Prostaglandin Synthesis: COX
COX1
5
15
20
10
15
1
20
105
COX = cyclooxygenases
9
11
11
9
9
11
PGG2
COX II
COX I
Growth FactorsTumor Necrosis Factor (TNF)EndotoxinsCytokine IL-1Luteinizing HormoneMitogensCorticosteroids (cardiomyocytes)
+
Corticosteroids MostlyCytokine IL-4
-
NSAIDs
-
Synthetases
Tissue Specific SynthetasesTissue Specific Synthetases
The product of COX metabolism is?
A. Arachidonic AcidB. PGE2
C. TXA2
D. PGG2
E. PGI2
F. PGH2
The product of Phospholipase A2 metabolism is?
A. Arachidonic AcidB. PGE2
C. TXA2
D. PGG2
E. PGI2
F. PGH2
PG and TX Enzymatic Degradation
-Oxidation
The carboxylic acid of the -chain forms a covalent link with what during -
oxidation?A. An enolB. An esterC. A methylD. Coenzyme A
-Oxidation
CYP4A
Which Cytochrome P450 (CYP) is involved in -oxidation?
A. CYP1A1B. CYP2C9C. CYP3A4D. CYP4A
PG and TX Chemical Degradation
What is the chemical process called of using water to break a bond?
A. ReductionB. OxidationC. HydrolysisD. DeprotonationE. Protonation
PGs as Drugs
• Natural• Modified• Analogs
Drug-drug Interactions
• NSAIDs• Corticosteroids
NSAIDs will interfere with PG drugs because they can
A. Inhibit PG synthetasesB. Induce COX 2 expressionC. Reduce COX 2 expressionD. Inhibit COX 1E. Inhibit COX 2F. D and E
diclofenac
Corticosteroids will interfere with PG drugs because they
A. Inhibit PG synthetasesB. Induce COX 2 expressionC. Reduce COX 2 expressionD. Inhibit COX 2E. C and DF. B and C
dexamethasone
Drugs
• Chemical Name• Usage• ADME• Mechanism• Formulation and Administration• Common ADR
Natural PGs
• Aprostadil
• Dinoprostone
• Epoprostenol
Natural PGs: Pros and Cons
Pros Cons
Potent Elimination T 1/2 short
Specific Rapid Degradation
Orally Inactive
Injected/Applied Directly
GI side effects
Natural PG:Aprostadil
What prostaglandin is Aprostadil?
A. PGE1
B. PGE2
C. TXA2
D. Prostacyclin onlyE. PGI2 only
F. Prostacyclin and PGI2
Aprostadil
Usage
• Erectile Dysfunction• Congenital Heart Defect
Normal Heart With Defect
The ductus arteriosus in a fetus’s heart usually becomes
A. a heart valveB. a veinC. an arteryD. an arterial ligament
ADME
• Absorption– Bioavailability 98% (IV)
• Distribution– 93% Protein-bound
• Metabolism– 60-90% First Pass Metabolism Pulmonary
• Elimination – t1/2 9-11 minutes
ADME (To Know)
• Absorption– Very Bioavailable
• Distribution– Protein Bound
• Metabolism– Mostly Pulmonary
• Elimination – Short
Mechanism
via GPCR
Increase BloodFlow
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.
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
Natural PG:Dinoprostone
What prostaglandin is Dinoprostone?
A. PGE1
B. PGE2
C. TXA2
D. Prostacyclin onlyE. PGI2 only
F. Prostacyclin and PGI2
Dinoprostone
Usage
• Effect– Cervical Ripening– Uterine Contraction
• Use– Labor induction – 2nd Trimester Abortion– Evacuation of Fetus
ADME
• Absorption– Some Systematic
• Metabolism– 95% First Pass Pulmonary
• Elimination– Half Life 2-5 minutes
MechanismEP2
PGE2
cAMPcAMP
+
Cervical RipeningUterine Contraction
Formulations and Administration
• Prepidil®– Cervical Gel
• Cervidil®– Vaginal Insert
Common ADR
• Fever• Pain- Stomach and Back • Diarrhea, Nausea and Vomiting (DNV)• Abnormal Uterine Contractions
Natural PG: Epoprostenol
What is another name for Epoprostenol?
A. PGE1
B. PGE2
C. TXA2
D. ProstacyclinE. PGI2
F. D and E
Epoprostenol
Usage/Effects
SclerodermaHypertension (High Blood Pressure)
ADME
• Metabolism• Half-life of 42 seconds• Hydrolysis
• Elimination• 6 minutes
PGI2 vs TXA2 (Mechanism)
PGI2
• Prostaglandin I2 receptor (IP2)– GPCR
• cAMP signaling pathway• PPAR nuclear receptor• Platelet Inhibition• Smooth Muscle Relaxation• Vasodilator
TXA2
• Thromboxane Receptor (TP)– GPCR
• Diacylglycerol (DAG) Inositol 1,4,5-triphosphate signaling pathway (IP3)– Increase Ca2+
• Platelet Activation• Smooth Muscle Contraction• Vasoconstrictor
Formulations/Administration
• Flolan®, Veletri®-Continuous IV Infusion
Common ADR
• Fever/Flu-like symptoms• Nausea/Vomiting/Diarrhea• Pain• Rapid Heart Rate
Modified PGs
• Carboprost• Bimatoprost, Lantaprost, Talfuprost,
Travoprost and Unoprostone• Misoprostol
Modified PGs
• Block -oxidation– Methyls at 15 and/or 16– Phenyl in 17-20 range
• Increase Lipophilicity– Add methyls, phenyls and esters
What prostaglandin does Carbopost correspond to?
A. PGE1
B. PGE2
C. TXA2
D. PGF2
E. PGI2
F. 15-methyl PGF2
15
Usage/Effects
• Effects– Uterine contraction
• Usage– Postpartum (Post-pregnancy) bleeding
• IV oxytocin, uterine massage or IM ergot
– 2nd Trimester abortions
ADME
• Duration of Action: 2 hours
Mechanism
DAG/IP3
Gas= Activates cAMP Pathway Gaq= Activates Diacylglycerol (DAG) and Inositol Triphosphate (IP3) Pathway Gai= Inhibits the production of cAMP from ATP
Carbaprost
Uterine contractions
Formulations/Administration
• Hemabate®- Intramuscular Injection
ADR
• Nausea, Diarrhea, Vomiting• Bronchoconstriction• Increased Body Temperature
Talfluprost
These compounds are modified versions of what prostaglandin?
A. PGE1
B. PGE2
C. TXA2
D. PGF2
E. PGI2
F. 15-methyl PGF2
15
Usage/Effects
• Effect– Decreases intra-ocular pressure
• Usage– Open Angle Glaucoma– Ocular Hypertension – Bimatoprost: Increase eyelash growth
ADME
• Absorption– Across Cornea
• Elimination– Lantaprost
• aqueous humor 4h and plasma 1h
– Talfuprost• low levels in systematic circulation
– Unoprostone• 1% unchanged in urine
ADME: Metabolism
E=Esterase, O=Oxidation, R=Reduction, =-Oxidation, =-Oxidation, D=dealkylation, G=glucuronidation
E
E
R13
14
O
15
E
R13
1415
O
D
G
Talfuprost
E
R
13
14
Mechanism
DAG/IP3
Gas= Activates cAMP Pathway Gaq= Activates Diacylglycerol (DAG) and Inositol Triphosphate (IP3) Signaling Pathway Gai= Inhibits the production of cAMP from ATP
Drug
Eye Cross-Section
Increase Outflow and Decrease Intra-Ocular Pressure
Relaxation of Ciliary Muscles
Formulations/Administration
• Lumigan®, Latisse® (Bimaprost)
• Xalatan® (Lantaprost)
• Zioptan® (Talfuprost)
• Travatan® (Travoprost)
• Rescula® D/C (Unoprostone)
Treatment with Latisse®
ADR
• Brown pigmentation of iris• Eye lid rim darkening• Eye lash darkening and grow longer
Misoprostol (Prodrug)
Misoprostol is a modified version of what prostaglandin?
A. PGE1
B. PGE2
C. TXA2
D. PGF2
E. PGI2
F. 15-methyl PGF2
Usage/Effects
• Prevention of NSAID ulcers• Labor Induction (Uterine Contractions and
Ripening)• Terminate 1st and 2nd Trimester Pregnancies• Post-partum hemorrhaging
ADME
• 80% Excreted through Urine• Food and antacids decrease absorption• Free acid (Active Form)• Elimination: t1/2= 20-40 minutes
E=Esterase, R=Reduction, =-Oxidation, =-Oxidation
ER
13
14
PGF9
R
What general prostaglandin is produced when the oxygen at C-9 is reduced?
A. PGEB. PGFC. PGGD. PGHE. TXA
9
Mechanism
Misoprostol
cAMPcAMP
+
Prostaglandin E1 Receptor
1. Decrease gastric acid secretion2. Increase mucus secretion3. Increase bicarbonate excretion4. Uterine contractions and ripening
Formulations/Administration
• Cytotec®- Oral• Arthrotec® (with Diclofenac)- Oral
Diclofenac
ADR
• Abdominal Pain• Nausea, Diarrhea, Vomiting• Increased Body Temperature
PG Analogs
• Stable at Room Temperature and neutral pH
Treprostinil Ileprost
These compounds are analogs of which prostaglandin?
A. PGE1
B. PGE2
C. TXA2
D. PGF2
E. PGI2
F. 15-methyl PGF2
PG Analogs
PGI2
Treprostinil
Ileprost
Usage/Effects
• Usage– Pulmonary Hypertension
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– t1/2=4 hours
– Major elimination route is urine
The mechanism for these compounds is the same as which prostaglandin?
A. PGE1
B. PGE2
C. TXA2
D. PGF2
E. PGI2
F. 15-methyl PGF2
Formulations/Administration
• Remodulin® (Treprostinil)- Subcutaneous/IV injection
• Ventavis® (Iliprost)- Inhaled
ADR
• Treprostinil- Infusion site pain/reaction• Hypotension
Overview
• General• PG as drugs
– Natural– Modified – Analogs
