Download PGI 2

Prostaglandins (PGs) and
Thromboxanes (TXs)
Dr. Arthur Roberts
Modified from course of Dr. Warren Beach
1
Overview
• General
• PG as drugs
– Natural
– Modified
– Analogs
PG and TX nomenclature
9
10
8
12
11
a chain
b chain
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 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
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)
PG and TX Transport
1.
2.
3.
OATP = Organic Anionic Transporting Polypeptide
ABC = ATP Binding Cassette Transporters
Active Efflux
ABC transporters
Active Influx
OATP transporters
Passive Diffusion
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
PGG2
Synthetases
Tissue Specific Synthetases
PG and TX Enzymatic Degradation
b-oxidation
HO
COOH
PG F2a
HO
OH
Reduction
w-oxidation
alcohol dehydrogenation
(Oxidation)
HO
COOH
COOH
HO
O
Ultimate metabolite
b-Oxidation
w-Oxidation
CYP4A
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
PGs as Drugs
• Natural
• Modified
• Analogs
Drug-drug Interactions
• NSAIDs
• Corticosteroids
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
Usage
• Erectile Dysfunction
• Congenital Heart Defect
Normal Heart
With Defect
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
Blood
Flow
Formulations and Administration
Erectile Dysfunction
• Caverject®
– Penile Injection
Congenital Heart Defect
• Prostin VR®
– IV Injection
• Edex®
– Penile Injection
• Muse®
– Urethral Suppository
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
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
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
•
•
•
•
•
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 w-oxidation
– Methyls at 15 and/or 16
– Phenyl in 17-20 range
• Increase Lipophilicity
– Add methyls, phenyls and esters
HO
COOH
HO
HO
CH 3
Carboprost
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
Carbaprost
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
• Nausea, Diarrhea, Vomiting
• 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
Talfluprost
F
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
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® (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)
O
COOCH3
CH 3
HO
OH
Misoprostol( racemic)
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)
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
• Nausea, Diarrhea, Vomiting
• 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
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
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