Prostaglandins (PGs) and Thromboxanes (TXs)-Synthesis

and DegradationDr. 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

a chain

w chain

89

10

11

12

The head group corresponds to which prostaglandin?

A. PGEB. PGF2a

C. TXAD. PGG/PGHE. PGI

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PG and TXPGE2 PGF2a

PGI2

TXA2

PG and TX to know: PGE1, PGE2, PGF2a, 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

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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

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. PGAB. PGGC. PGHD. PGE

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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

Progenitor of PG and TX

(AA)

Synthesis of Arachidonic Acid (AA)

1

2

3

Phospholipase A2

Protein Kinase

Stimulus

+ -

Glucocorticoids

PGG2

COX

PGH2

Peroxidase

Prostaglandin Synthesis: COX

COX1

5

15

20

10

15

1

20

105

COX = cyclooxygenases

9

11

11

9

9

11

PGH2

COX II

COX I

Growth FactorsTumor Necrosis Factor (TNF)EndotoxinsCytokine IL-1Luteinizing HormoneMitogensCorticosteroids (cardiomyocytes)

+

Corticosteroids MostlyCytokine IL-4

-

NSAIDs

-

Synthetases

Tissue Specific Synthetases

COX-1 COX-2

The product of COX metabolism is?

A. Arachidonic AcidB. PGE2

C. TXA2

D. PGG2

E. PGI2

F. PGH2

:30

The product of Phospholipase A2 metabolism is?

A. Arachidonic AcidB. PGE2

C. TXA2

D. PGG2

E. PGI2

F. PGH2

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PG and TX Enzymatic Degradation

Specific alcohol dehydrogenases

Specificreductases

a-chain

w-chain

a-chain

w-chain

1

b-Oxidation

• attach Coenzyme A• degrade to acetyl Coenzyme A

Coenzyme A

b-Oxidation: Step 1Coenzyme A

AMP

a-chain

w-chain

1

b-Oxidation: Step 2Coenzyme A

Citric Acid Cycle(Krebs Cycle)

CO2

a-chain

w-chain

1

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

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w-Oxidation

CYP4A

H2O

a-chain

w-chain

1

Which Cytochrome P450 (CYP) is involved in w-oxidation?

A. CYP1A1B. CYP2C9C. CYP3A4D. CYP4A

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PG and TX Chemical Degradation

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. PGE1

B. PGE2

C. TXA2

D. Prostacyclin onlyE. PGI2 only

F. Prostacyclin and PGI2

Aprostadil

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Usage

• Erectile Dysfunction• Congenital Heart Defect

Congenital Defect

Patent ductusArteriosis (PDA)

Normal Heart

Ligamentumarteriosum

The ductus arteriosus in a fetus’s heart usually becomes

A. a heart valveB. a veinC. an arteryD. an arterial ligament

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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

Mechanism

via GPCR (EP)

Increase BloodFlow

PDE= Phosphodiesterase

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. PGE1

B. PGE2

C. TXA2

D. Prostacyclin onlyE. PGI2 only

F. Prostacyclin and PGI2

Dinoprostone

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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

cAMP

+

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

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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

• 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

15

What prostaglandin does Carboprost correspond to?

A. PGE1

B. PGE2

C. TXA2

D. PGF2a

E. PGI2

F. 15-methyl PGF2a

15

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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

Carboprost

Uterine contractions

Formulations/Administration

• Hemabate®- Intramuscular Injection

ADR

• Diarrhea, Nausea and Vomiting (DNV)• Bronchoconstriction• Increased Body Temperature

Tafluprost

These compounds are modified versions of what prostaglandin?

A. PGE1

B. PGE2

C. TXA2

D. PGF2a

E. PGI2

F. 15-methyl PGF2a

15

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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

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

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® (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)

Misoprostol is a modified version of what prostaglandin?

A. PGE1

B. PGE2

C. TXA2

D. PGF2a

E. PGI2

F. 15-methyl PGF2a

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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

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

What general prostaglandin is produced when the oxygen at C-9 is reduced?

A. PGEB. PGFC. PGGD. PGHE. TXA

9

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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

Formulations/Administration

• Cytotec®- Oral• Arthrotec® (with Diclofenac)- Oral

Diclofenac

ADR

• Abdominal Pain• Diarrhea, Nausea and Vomiting (DNV)• 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. PGF2a

E. PGI2

F. 15-methyl PGF2a

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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)– 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. PGE1

B. PGE2

C. TXA2

D. PGF2a

E. PGI2

F. 15-methyl PGF2a

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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