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Prostaglandins (PGs) and
Thromboxanes (TXs)-Synthesis
and Degradation
Dr. Arthur Roberts
Modified from course of Dr. Warren Beach
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
Purpose: Clicker Questions
•
•
•
•
Are you paying attention?
New material
Thought questions
Assessment of teaching
Overview
• Synthesis and Degradation
• Drugs
– Natural
– Modified
– Analogs
PG and TX nomenclature
9
10
8
12
11
a chain
w chain
The head group corresponds to which
prostaglandin?
A.
B.
C.
D.
E.
PGE
PGF2a
TXA
PGG/PGH
PGI
:30
PG and TX
PGE2
PGF2a
TXA2
PGI2
PG and TX to know: PGE1, PGE2, PGF2a, PGG2,
PGH2, PGI2, TXA2
TxA2 PROMOTES
PLATELET AGGREGATION;
PGI2 INHIBITS IT
PGE2, PGFa, and PGI2
RELAX VASCULAR
SMOOTH MUSCLE
PGE2 and PGI2
INCREASE
RENAL BLOOD FLOW
PGE2 and PGI2
RELAX BRONCHIAL
SMOOTH MUSCLE;
PGFa CONTRACTS IT
PGE2 and PGI2
PROTECT
GASTRIC MUCOSA
PGE2 and PGFa
CONTRACT UTERINE
SMOOTH MUSCLE;
PGI2 RELAXES IT
PG and TX Signaling
G-protein Coupled Receptor (GPCR) or Nuclear Receptor
Circulation
Nearby
PG signaling between 2 adjacent
cells is?
A.
B.
C.
D.
Endocrine
Autocrine
Paracrine
Intracrine
:30
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
COX
Protein
Signaling
Protein Synthesis
Specific Receptors
DAG/IP3
Gas= Activates cAMP Pathway
Gaq= Activates Diacylglycerol (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.
B.
C.
D.
PGA
PGG
PGH
PGE
:30
PG and TX Transport
1.
2.
3.
OATP = Organic Anionic Transporting Polypeptide
ABC = ATP Binding Cassette Transporters
Passive Diffusion
Active Efflux
ABC transporters
Active Influx
OATP transporters
Progenitor of PG and TX
5
1
CO OH
10
CH 3
20
15
Arachidonic Acid (AA)
[(5,8,11,14)eicosatetraenoic acid]
Synthesis of Arachidonic Acid (AA)
Glucocorticoids
Stimulus
Protein
Kinase
1
+
2
-
3
Phospholipase A2
5
1
CO OH
10
CH 3
20
15
Arachidonic Acid
[(5,8,11,14)eicosatetraenoic acid]
COX
Peroxidase
PGH2
PGG2
Prostaglandin Synthesis: COX
10
9
1
cyclooxygenase
COOH
COX
( COX
1 or COX 2) O
5
10
CH3
11
O
20
15
Arachidonic Acid
5
9
1
COOH
15
11
CH3
20
PROSTAGLANDIN G 2
OOH
[(5,8,11,14)eicosatetraenoic acid]
10
peroxidase
9
5
O
O
1
COOH
15
11
PROSTAGLANDIN H 2
CH3
20
OH
COX = cyclooxygenases
Growth Factors
Tumor Necrosis Factor (TNF)
Endotoxins
Corticosteroids Mostly
Cytokine IL-1
Cytokine IL-4
Luteinizing Hormone
Mitogens
Corticosteroids (cardiomyocytes)
+
-
COX II
COX I
NSAIDs
PGH2
Synthetases
COX-1
COX-2
Tissue Specific Synthetases
The product of COX metabolism is?
A.
B.
C.
D.
E.
F.
Arachidonic Acid
PGE2
TXA2
PGG2
PGI2
PGH2
:30
The product of Phospholipase A2
metabolism is?
A.
B.
C.
D.
E.
F.
Arachidonic Acid
PGE2
TXA2
PGG2
PGI2
PGH2
:30
PG and TX Enzymatic Degradation
HO
b-oxidation
a-chain
COOH
PG F2a
HO
w-chain
OH
Reduction
Specific
reductases
w-oxidation
alcohol dehydrogenation
(Oxidation)
Specific alcohol dehydrogenases
HO
COOH
COOH
HO
O
Ultimate metabolite
a-chain
Coenzyme A
b-Oxidation
1
w-chain
• attach Coenzyme A
• degrade to acetyl Coenzyme A
a-chain
Coenzyme A
b-Oxidation: Step 1
1
w-chain
AMP
a-chain
Coenzyme A
b-Oxidation: Step 2
1
w-chain
CO2
Citric Acid Cycle
(Krebs Cycle)
The carboxylic acid of the a-chain forms a
covalent link with what during b-oxidation?
A.
B.
C.
D.
An enol
An ester
A methyl
Coenzyme A
:30
a-chain
w-Oxidation
1
w-chain
CYP4A
H2O
Which Cytochrome P450 (CYP) is involved
in w-oxidation?
A.
B.
C.
D.
CYP1A1
CYP2C9
CYP3A4
CYP4A
:30
PG and TX Chemical Degradation
OH
COOH
O
COOH
H2O
HO
O
O
OH
OH
THROMBOXANE B2
THROMBOXANE A2
COOH
COOH
O
O
HO
H2O
HO
HO
OH
PG I2
OH
6-Keto PG F1 a
Prostaglandins (PGs) and
Thromboxanes (TXs) as Drugs
Dr. Arthur Roberts
Modified from course of Dr. Warren Beach
PGs as Drugs
• Natural
• Modified
• Analogs
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 PLA2
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:
Alprostadil
What prostaglandin is Alprostadil?
A.
B.
C.
D.
E.
F.
PGE1
PGE2
TXA2
Prostacyclin only
PGI2 only
Prostacyclin and PGI2
Aprostadil
:30
Usage
• Erectile Dysfunction
• Congenital Heart Defect
Patent ductus
Arteriosis (PDA)
Congenital Defect
Ligamentum
arteriosum
Normal Heart
The ductus arteriosus in a fetus’s
heart usually becomes
A.
B.
C.
D.
a heart valve
a vein
an artery
an arterial ligament
:30
ADME
• Absorption
– Bioavailability 98% (IV)
• Distribution
– 93% Protein-bound
• Metabolism
– 60-90% First Pass Metabolism Pulmonary
• Elimination
– t1/2 9-11 minutes
Mechanism
via GPCR (EP)
PDE= Phosphodiesterase
Increase
Blood
Flow
Formulations and Administration
Erectile Dysfunction
• Caverject®
– Penile Injection
• Edex®
– Penile Injection
• Muse®
– Urethral Suppository
Congenital Heart Defect
• Prostin VR®
– IV Injection
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)
Natural PG:
Dinoprostone
What prostaglandin is
Dinoprostone?
A.
B.
C.
D.
E.
F.
PGE1
PGE2
TXA2
Prostacyclin only
PGI2 only
Prostacyclin and PGI2
Dinoprostone
:30
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
Mechanism
PGE2
EP2
+
cAMP
Cervical Ripening
Uterine 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.
B.
C.
D.
E.
F.
PGE1
PGE2
TXA2
Prostacyclin
PGI2
D and E
Epoprostenol
:30
Usage/Effects
Hypertension (High Blood Pressure)
Scleroderma
ADME
• Metabolism
• Half-life of 42 seconds
• Hydrolysis
• Elimination
• 6 minutes
PGI2 vs TXA2 (Mechanism)
PGI2
• Prostaglandin I2 receptor
(IP2)
– GPCR
•
•
•
•
•
PPAR nuclear receptor
cAMP signaling pathway
Platelet Inhibition
Smooth Muscle Relaxation
Vasodilator
TXA2
• Thromboxane Receptor (TP)
– GPCR + Gaq
• Diacylglycerol (DAG) Inositol
1,4,5-triphosphate signaling
pathway (IP3)
– Increase Ca2+
• Platelet Activation
• Smooth Muscle Contraction
• Vasoconstrictor
Epoprostenol
Formulations/Administration
• Flolan®, Veletri®-Continuous IV Infusion
Epoprostenol Common ADR
•
•
•
•
Fever/Flu-like symptoms
Diarrhea, Nausea and Vomiting (DNV)
Pain
Rapid Heart Rate
Modified PGs
• Carboprost
• Bimatoprost, Latanoprost, Talfuprost,
Travoprost and Unoprostone
• Misoprostol
General Strategies for Modifying
PGs
• Block w-oxidation
– Methyls at 15 and/or 16
– Phenyl in 17-20 range
• Increase Lipophilicity
– Add methyls, phenyls and esters
HO
COOH
15
HO
HO
CH 3
Carboprost
What prostaglandin does
Carboprost correspond to?
A.
B.
C.
D.
E.
F.
PGE1
PGE2
TXA2
PGF2a
PGI2
15-methyl PGF2a
HO
COOH
15
HO
HO
CH 3
Carboprost
:30
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
Carboprost
DAG/IP3
Gas= Activates cAMP Pathway
Gaq= Activates Diacylglycerol (DAG) and Inositol Triphosphate (IP3) Pathway
Gai= Inhibits the production of cAMP from ATP
Uterine contractions
Formulations/Administration
• Hemabate®- Intramuscular Injection
ADR
• Diarrhea, Nausea and Vomiting (DNV)
• Bronchoconstriction
• Increased Body Temperature
HO
HO
CH 3
CH 3
CO 2
CO 2
CH 3
CH 3
HO
O
OH
HO
OH
CF 3
Travoprost
HO
H
N
CH 2
Latanoprost
CH3
HO
CH 3
CO 2
O
CH 3
HO
OH
HO
O
Bimatoprost
Unoprostone
HO
O
O
O
HO
F
Tafluprost
F
These compounds are modified
versions of what prostaglandin?
A.
B.
C.
D.
E.
F.
PGE1
PGE2
TXA2
PGF2a
PGI2
15-methyl PGF2a
15
:30
Usage/Effects
• Effect
– Decreases intra-ocular pressure
• Usage
– Open Angle Glaucoma
– Ocular Hypertension
– Bimatoprost: Increase eyelash growth
ADME
• Absorption
– Across Cornea
• Elimination
– Latanoprost
• aqueous humor 4h and plasma 1h
– Tafluprost
• low levels in systematic circulation
– Unoprostone
• 1% unchanged in urine
ADME: Metabolism
b
HO
E
b
HO
CH 3
E
CH 3
CO 2
14
13
HO
CO 2
CH 3
15
O
R
HO
O
CF 3
HO
H
N
14
13
OH
OH
Travoprost
HO
CH 3
15
R
O
G
E
Latanoprost
D
CH 2
b
HO
CH 3
CH3
w
CO 2
CH 3
HO
O
OH
O
b
Unoprostone
HO
E
O
R
Bimatoprost
HO
13
14
O
O
F
F
Talfuprost
E=Esterase, O=Oxidation, R=Reduction, b=b-Oxidation, w=w-Oxidation, D=dealkylation, G=glucuronidation
Mechanism
Drug
Eye Cross-Section
DAG/IP3
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
Relaxation of Ciliary Muscles Decrease Intra-Ocular
Pressure
Formulations/Administration
•
•
•
•
•
Lumigan®, Latisse® (Bimatoprost)
Xalatan® (Latanoprost)
Zioptan® (Tafluprost)
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)
O
COOCH3
CH 3
HO
OH
Misoprostol( racemic)
Misoprostol is a modified version
of what prostaglandin?
A.
B.
C.
D.
E.
F.
PGE1
PGE2
TXA2
PGF2a
PGI2
15-methyl PGF2a
O
COOCH3
CH 3
HO
OH
Misoprostol( racemic)
:30
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
PGF
R
b
O
9
E
COOCH3
R
HO
14
CH 3
w
13
OH
E=Esterase, R=Reduction, b=b-Oxidation, w=w-Oxidation
Misoprostol( racemic)
What general prostaglandin is produced
when the oxygen at C-9 is reduced?
A.
B.
C.
D.
E.
PGE
PGF
PGG
PGH
TXA
O
9
COOCH3
CH 3
HO
OH
Misoprostol( racemic)
:30
Mechanism
Misoprostol
Prostaglandin E1 Receptor
+
cAMP
1.
2.
3.
4.
Decrease gastric acid secretion
Increase mucus secretion
Increase bicarbonate excretion
Uterine contractions and ripening
Formulations/Administration
• Cytotec®- Oral
• Arthrotec® (with Diclofenac)- Oral
Diclofenac
ADR
• Abdominal Pain
• Diarrhea, Nausea and Vomiting (DNV)
• Increased Body Temperature
PG Analogs
COOH
O
O-
COOH
O
O
CH3
HO
HO
HO
Treprostinil
• Stable at Room Temperature and neutral pH
HO
OH
OH
Ileprost
HO
These compounds are analogs of
which prostaglandin?
A.
B.
C.
D.
E.
F.
PGE1
PGE2
TXA2
PGF2a
PGI2
15-methyl PGF2a
:30
PG Analogs
COOH
O
O
OHO
COOH
HO
O
COOH
OH
PGI2
O
CH3
HO
HO
Treprostinil
HO
OH
HO
OH
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 UDPglucuronosyltransferases (UGTs)
– b-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.
B.
C.
D.
E.
F.
PGE1
PGE2
TXA2
PGF2a
PGI2
15-methyl PGF2a
:30
Formulations/Administration
• Remodulin® (Treprostinil)- Subcutaneous/IV
injection
• Ventavis® (Iliprost)- Inhaled
ADR
• Treprostinil- Infusion site pain/reaction
• Hypotension
Overview
• Lecture 1: Synthesis and Degradation
• Lecture 2: PG as drugs
– Natural
– Modified
– Analogs