Prostaglandins (PGs) and Thromboxanes (TXs) Dr. Arthur Roberts Modified from course of Dr. Warren...

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