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Prostaglandins (PGs) and Thromboxanes (TXs)-Synthesis
and DegradationDr. Arthur Roberts
Modified from course of Dr. Warren Beach
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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
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Purpose: Clicker Questions
• Are you paying attention?• New material• Thought questions• Assessment of teaching
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Overview
• Synthesis and Degradation• Drugs
– Natural– Modified – Analogs
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PG and TX nomenclature
a chain
w chain
89
10
11
12
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The head group corresponds to which prostaglandin?
A. PGEB. PGF2a
C. TXAD. PGG/PGHE. PGI
:30
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PG and TXPGE2 PGF2a
PGI2
TXA2
PG and TX to know: PGE1, PGE2, PGF2a, PGG2, PGH2, PGI2, TXA2
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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
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PG and TX SignalingG-protein Coupled Receptor (GPCR) or Nuclear Receptor
Circulation
Nearby
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PG signaling between 2 adjacent cells is?
A. EndocrineB. AutocrineC. ParacrineD. Intracrine
:30
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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
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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)
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The EP1 prostaglandin receptor binds to which general type of prostaglandin?
A. PGAB. PGGC. PGHD. PGE
:30
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PG and TX Transport1. Passive Diffusion2. Active Efflux
ABC transporters3. Active Influx
OATP transporters
OATP = Organic Anionic Transporting PolypeptideABC = ATP Binding Cassette Transporters
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Progenitor of PG and TX
(AA)
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Synthesis of Arachidonic Acid (AA)
1
2
3
Phospholipase A2
Protein Kinase
Stimulus
+ -
Glucocorticoids
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PGG2
COX
PGH2
Peroxidase
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Prostaglandin Synthesis: COX
COX1
5
15
20
10
15
1
20
105
COX = cyclooxygenases
9
11
11
9
9
11
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PGH2
COX II
COX I
Growth FactorsTumor Necrosis Factor (TNF)EndotoxinsCytokine IL-1Luteinizing HormoneMitogensCorticosteroids (cardiomyocytes)
+
Corticosteroids MostlyCytokine IL-4
-
NSAIDs
-
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Synthetases
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Tissue Specific Synthetases
COX-1 COX-2
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The product of COX metabolism is?
A. Arachidonic AcidB. PGE2
C. TXA2
D. PGG2
E. PGI2
F. PGH2
:30
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The product of Phospholipase A2 metabolism is?
A. Arachidonic AcidB. PGE2
C. TXA2
D. PGG2
E. PGI2
F. PGH2
:30
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PG and TX Enzymatic Degradation
Specific alcohol dehydrogenases
Specificreductases
a-chain
w-chain
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a-chain
w-chain
1
b-Oxidation
• attach Coenzyme A• degrade to acetyl Coenzyme A
Coenzyme A
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b-Oxidation: Step 1Coenzyme A
AMP
a-chain
w-chain
1
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b-Oxidation: Step 2Coenzyme A
Citric Acid Cycle(Krebs Cycle)
CO2
a-chain
w-chain
1
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The carboxylic acid of the a-chain forms a covalent link with what during b-
oxidation?A. An enolB. An esterC. A methylD. Coenzyme A
:30
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w-Oxidation
CYP4A
H2O
a-chain
w-chain
1
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Which Cytochrome P450 (CYP) is involved in w-oxidation?
A. CYP1A1B. CYP2C9C. CYP3A4D. CYP4A
:30
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PG and TX Chemical Degradation
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Prostaglandins (PGs) and Thromboxanes (TXs) as Drugs
Dr. Arthur Roberts
Modified from course of Dr. Warren Beach
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PGs as Drugs
• Natural• Modified• Analogs
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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
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Drugs
• Chemical Name• Usage• ADME• Mechanism• Formulation and Administration• Common ADR
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Natural PGs
• Aprostadil• Dinoprostone• Epoprostenol
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Natural PGs: Pros and Cons
Pros Cons
Potent Elimination t 1/2 short
Specific Rapid Degradation
Orally Inactive
Injected/Applied Directly
GI side effects
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Natural PG:Alprostadil
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What prostaglandin is Alprostadil?
A. PGE1
B. PGE2
C. TXA2
D. Prostacyclin onlyE. PGI2 only
F. Prostacyclin and PGI2
Aprostadil
:30
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Usage
• Erectile Dysfunction• Congenital Heart Defect
Congenital Defect
Patent ductusArteriosis (PDA)
Normal Heart
Ligamentumarteriosum
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The ductus arteriosus in a fetus’s heart usually becomes
A. a heart valveB. a veinC. an arteryD. an arterial ligament
:30
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ADME
• Absorption– Bioavailability 98% (IV)
• Distribution– 93% Protein-bound
• Metabolism– 60-90% First Pass Metabolism Pulmonary
• Elimination – t1/2 9-11 minutes
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Mechanism
via GPCR (EP)
Increase BloodFlow
PDE= Phosphodiesterase
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Formulations and Administration
Erectile Dysfunction• Caverject®
– Penile Injection
• Edex®– Penile Injection
• Muse®– Urethral Suppository
Congenital Heart Defect• Prostin VR®
– IV Injection
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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)
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Natural PG:Dinoprostone
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What prostaglandin is Dinoprostone?
A. PGE1
B. PGE2
C. TXA2
D. Prostacyclin onlyE. PGI2 only
F. Prostacyclin and PGI2
Dinoprostone
:30
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Usage
• Effect– Cervical Ripening– Uterine Contraction
• Use– Labor induction – 2nd Trimester Abortion– Evacuation of Fetus
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ADME
• Absorption– Some Systematic
• Metabolism– 95% First Pass Pulmonary
• Elimination– Half Life 2-5 minutes
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MechanismEP2
PGE2
cAMP
+
Cervical RipeningUterine Contraction
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Formulations and Administration
• Prepidil®– Cervical Gel
• Cervidil®– Vaginal Insert
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Common ADR
• Fever• Pain- Stomach and Back • Diarrhea, Nausea and Vomiting (DNV)• Abnormal Uterine Contractions
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Natural PG: Epoprostenol
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What is another name for Epoprostenol?
A. PGE1
B. PGE2
C. TXA2
D. ProstacyclinE. PGI2
F. D and E
Epoprostenol
:30
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Usage/Effects
SclerodermaHypertension (High Blood Pressure)
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ADME
• Metabolism• Half-life of 42 seconds• Hydrolysis
• Elimination• 6 minutes
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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
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Epoprostenol Formulations/Administration
• Flolan®, Veletri®-Continuous IV Infusion
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Epoprostenol Common ADR
• Fever/Flu-like symptoms• Diarrhea, Nausea and Vomiting (DNV)• Pain• Rapid Heart Rate
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Modified PGs
• Carboprost• Bimatoprost, Latanoprost, Talfuprost,
Travoprost and Unoprostone• Misoprostol
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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
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15
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What prostaglandin does Carboprost correspond to?
A. PGE1
B. PGE2
C. TXA2
D. PGF2a
E. PGI2
F. 15-methyl PGF2a
15
:30
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Usage/Effects
• Effects– Uterine contraction
• Usage– Postpartum (Post-pregnancy) bleeding
• IV oxytocin, uterine massage or IM ergot
– 2nd Trimester abortions
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ADME
• Duration of Action: 2 hours
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Mechanism
DAG/IP3
Gas= Activates cAMP Pathway Gaq= Activates Diacylglycerol (DAG) and Inositol Triphosphate (IP3) Pathway Gai= Inhibits the production of cAMP from ATP
Carboprost
Uterine contractions
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Formulations/Administration
• Hemabate®- Intramuscular Injection
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ADR
• Diarrhea, Nausea and Vomiting (DNV)• Bronchoconstriction• Increased Body Temperature
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Tafluprost
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These compounds are modified versions of what prostaglandin?
A. PGE1
B. PGE2
C. TXA2
D. PGF2a
E. PGI2
F. 15-methyl PGF2a
15
:30
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Usage/Effects
• Effect– Decreases intra-ocular pressure
• Usage– Open Angle Glaucoma– Ocular Hypertension – Bimatoprost: Increase eyelash growth
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ADME
• Absorption– Across Cornea
• Elimination– Latanoprost
• aqueous humor 4h and plasma 1h
– Tafluprost• low levels in systematic circulation
– Unoprostone• 1% unchanged in urine
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ADME: Metabolism
E=Esterase, O=Oxidation, R=Reduction, b=b-Oxidation, w=w-Oxidation, D=dealkylation, G=glucuronidation
E
E
R13
14
O
15
E
R13
1415
O
b
D
G
b
Talfuprost
E
R
13
14
b
b
w
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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
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Formulations/Administration
• Lumigan®, Latisse® (Bimatoprost)• Xalatan® (Latanoprost)• Zioptan® (Tafluprost)• Travatan® (Travoprost)• Rescula® D/C (Unoprostone)
Treatment with Latisse®
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ADR
• Brown pigmentation of iris• Eye lid rim darkening• Eye lash darkening and grow longer
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Misoprostol (Prodrug)
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Misoprostol is a modified version of what prostaglandin?
A. PGE1
B. PGE2
C. TXA2
D. PGF2a
E. PGI2
F. 15-methyl PGF2a
:30
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Usage/Effects
• Prevention of NSAID ulcers• Labor Induction (Uterine Contractions and
Ripening)• Terminate 1st and 2nd Trimester Pregnancies• Post-partum hemorrhaging
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ADME
• 80% Excreted through Urine• Food and antacids decrease absorption• Free acid (Active Form)• Elimination: t1/2= 20-40 minutes
E=Esterase, R=Reduction, b=b-Oxidation, w=w-Oxidation
w
EbR
13
14
PGF9
R
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What general prostaglandin is produced when the oxygen at C-9 is reduced?
A. PGEB. PGFC. PGGD. PGHE. TXA
9
:30
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Mechanism
Misoprostol
cAMP
+
Prostaglandin E1 Receptor
1. Decrease gastric acid secretion2. Increase mucus secretion3. Increase bicarbonate excretion4. Uterine contractions and ripening
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Formulations/Administration
• Cytotec®- Oral• Arthrotec® (with Diclofenac)- Oral
Diclofenac
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ADR
• Abdominal Pain• Diarrhea, Nausea and Vomiting (DNV)• Increased Body Temperature
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PG Analogs
• Stable at Room Temperature and neutral pH
Treprostinil Ileprost
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These compounds are analogs of which prostaglandin?
A. PGE1
B. PGE2
C. TXA2
D. PGF2a
E. PGI2
F. 15-methyl PGF2a
:30
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PG Analogs
PGI2
Treprostinil
Ileprost
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Usage/Effects
• Usage– Pulmonary Hypertension
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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
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The mechanism for these compounds is the same as which prostaglandin?
A. PGE1
B. PGE2
C. TXA2
D. PGF2a
E. PGI2
F. 15-methyl PGF2a
:30
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Formulations/Administration
• Remodulin® (Treprostinil)- Subcutaneous/IV injection
• Ventavis® (Iliprost)- Inhaled
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ADR
• Treprostinil- Infusion site pain/reaction• Hypotension
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Overview
• Lecture 1: Synthesis and Degradation• Lecture 2: PG as drugs
– Natural– Modified – Analogs