Prostaglandin Pharmacology

Endocrine 1 Module

Dr. Mary Thomas, Ph.D.

Visiting Professor, Biochemistry, Pharmacology, Physiology
mthomas@rossu.edu
 For help with Endocrine Pharmacology

I’ll be in Knoxville through July 26 and available by email after that.

I am happy to meet with you to go over any difficulties and answer

questions . The most reliable way to be sure that I will be available to talk
with you is to arrange an appointment by email: mthomas@rossu.edu .
This can be arranged on short notice – I will try to check my email
frequently.

For all my lectures, there are practice questions with explicated answers
posted in Canvas.
Reading and Supplementary Materials

• Review Dr. Lawson’s lecture (this module) concerning

prostaglandins

• Access Medicine supplemental reading:

• Clinical Pharmacology of Eicosanoids section of Chapter 18, The
Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, &
Related Compounds. In: Basic & Clinical Pharmacology, 14e, by
Bertram Katzung.
http://accessmedicine.mhmedical.com/content.aspx?bookid=224
9&sectionid=175218286#1148435285

• Practice questions in Canvas

 Drug List

Prostaglandin Drug Classes

PGE1 PGE2 PGF2a PGI2
alprostadil* dinoprostone* latanoprost epoprostenol*
misoprostol bimatoprost iloprost
tafluprost treprostinil
travoprost

carboprost

* Drugs that are chemically the same as the indicated endogenous prostaglandin

Note: these drugs are all either actual prostaglandin compounds or analogs of
the indicated prostaglandin; be sure you know what “analog” means.
Learning Objectives
For each drug in the Drug List:

1. Assign each drug to the appropriate class (prostaglandin type)

2. Describe the therapeutic uses and associated routes of

administration (note that for this and subsequent Endocrine
Pharmacology lectures, a point will be made about route of
administration if the drug is not administered orally for a given
indication; otherwise, assume oral administration)

3. Describe the important pharmacokinetic properties

4. Describe the main adverse effects, contraindications, and

precautions
Prostaglandins as drugs

Not hormones - autocrine and paracrine factors

• Produced locally – often not very selective
• Native compounds have short half-life than analogs
• Many different receptors
• Prostaglandin analogs have been designed to improve pharmacokinetic
properties and/or receptor selectivity

Pharmacological relevance of the above?

Katzung chapter does a good job of summarizing the prostaglandins;
organizes the therapeutic uses by organ system.

This lecture will give you a second way to address prostaglandin

pharmacology, organized according to each prostaglandin type and
focusing on specific uses of a few key drugs of each type of
prostaglandin
 PGE1 Drugs – alprostadil
PGE1 Drugs – alprostadil
Alprostadil - PGE1
Therapeutic uses:
• Causes relaxation of arterial smooth muscle, producing vasodilation
• Erectile dysfunction
• In the male reproductive system alprostadil enhances penile
erection
• for this indication, the drug is administered locally, either by the
intraurethral (suppository) or intracavernosal (injection) route

• Patency of the ductus arteriosus

• In the heart of neonates, alprostadil is used to maintain
patency of the ductus arteriosus (even though in vivo PGE2 is
probably the primary factor responsible for keeping the ductus
arteriosus open, PGE1 is also involved in vivo)
• For this indication, alprostadil is administered by continuous IV
infusion
 PGE1 Drugs – alprostadil

Alprostadil pharmacokinetics

• Widely distributed when given IV, but limited when given locally
• Extensive metabolism in the lungs
• t1/2 ~ 0.5-10 min
• Primarily excreted in urine
 PGE1 Drugs – alprostadil
Alprostadil Adverse Effects and Contraindications

Adverse effects (penile administration):

• penile pain
• urethral burning (when given by intraurethral route)
Contraindications :
• conditions predisposing to priapism (e.g. sickle cell anemia),
• anatomical deformation or fibrotic conditions of the penis
• penile implants
• men for whom sexual activity is inadvisable or contraindicated
• children or neonates
• intraurethral use in sexual intercourse with a pregnant woman unless a
condom barrier is used

IV administration (not recommended except in maintenance of ductus

arteriosus)
• Potential apnea risk in neonates
 PGE1 Drugs – misoprostal
Misoprostol - PGE1 analog
Therapeutic uses:
• Used as a protective agent in NSAID therapy; (previously covered in
GI-1 module)
• Used with mifepristone (progesterone receptor antagonist) for
termination of early pregnancy – uterine contraction

Routes of administration:
• Oral administration preferred for pregnancy termination, but can be
administered intravaginally (higher risk of sepsis)
Pharmacokinetics
• t1/2 ~ 20-40 min
• Extensive metabolism in the liver
• Metabolites primarily excreted in urine
Adverse effects – primarily cramping and diarrhea
 PGE2 Drugs – dinoprostone

Dinoprostone - PGE2
Dinoprostone will cause uterine contraction at any time during
pregnancy, with increased activity as pregnancy advances. It also has
direct effects on cervical collagenase, promoting cervical softening.
Therapeutic Uses

Most common use:

Ripening cervix for induction of labor at or near term

Also:
Inducing abortion in the second trimester
Missed abortion
Benign hydatidiform mole
 PGE2 Drugs – dinoprostone

Dinoprostone (PGE2)– Routes of Administration and Pharmacokinetics

Routes of administration
• Ripening of cervix: by locally-applied gel or controlled-release vaginal insert

• Induction of labor – intravaginal or intravenous (titrated hourly)

(prostaglandins have not been clearly shown to be superior to oxytocin
alone for initiation of labor)

Pharmacokinetics

• Widely distributed after IV, but limited after given locally

• Extensive metabolism in the lungs
• t1/2 ~ 2.5-5 min
• Primarily excreted in urine
 PGE2 Drugs – dinoprostone

Dinoprostone (PGE2) – Adverse Effects and Contraindications

Adverse Effects
• vomiting
• transient fever
• diarrhea, nausea
• headache, chills
• transient diastolic blood pressure decreases of >20 mm Hg
• possible uterine hyperstimulation depending on dose and gestational
uterine effects (uterus more responsive later in pregnancy)

Contraindications
• acute pelvic inflammatory disease; with active cardiac, pulmonary,
renal, or hepatic disease

• specific obstetrical conditions that would make induction of labor

dangerous
 PGF2a intraocular drugs

PGF2a Drugs – (All of the PGF2a drugs on the drug list are analogs of PGF2a)

Intraocular Applications

• latanoprost, travoprost, tafluprost, bimatoprost

Used to treat elevated intraocular pressure due to open-angle
glaucoma or ocular hypertension by increasing outflow of aqueous
humor from the anterior chamber via the uveoscleral pathway

• bimatoprost -
To treat hypotrichosis of the eyelashes (lack of adequate eyelashes)by
increasing the percent of eyelashes in growth phase and prolonging
the growth phase
 PGF2a intraocular drugs
PGF2a Intraocular Drugs: pharmacokinetics, adverse effects, contraindications
Latanoprost, tafluprost, travoprost, bimatoprost
Eye drops (ophthalmic solutions)
• Administered as pro-drugs
• Must be hydrolyzed by esterases of the cornea to be converted into
the biologically active form
• t1/2 ~ 17 - 45 min; peak effect 8 to 12 hrs

Adverse effects
• Latanoprost, tafluprost, travoprost, bimatoprost: Irreversible brown
pigmentation of the iris and eyelashes, drying of the eyes, and conjunctivitis.

• Bimatoprost: Increased growth of eyelashes

Contraindications and precautions

• Latanoprost, tafluprost, travoprost, bimatoprost: No recorded contraindications
 PGF2a drugs - carboprost
PGF2a Drugs – carboprost,
(analog of PGF2a modified to increase duration of action)

Therapeutic use
• stimulates uterine contraction
• Induction of 2nd trimester abortion
• Refractory postpartum uterine bleeding that has not responded to other
methods of management

Route of administration: administered IM

Pharmacokinetics: t1/2 ~ 3 hrs

Contraindications: Acute pelvic inflammatory disease, active cardiac,

pulmonary, renal, or hepatic disease
Adverse effects Diarrhea, vomiting, nausea (33-67% of patients),
cardiovascular events, pulmonary edema, endometritis, septic shock,
incomplete abortion, uterine hemorrhage, uterine rupture, hypersensitivity
reaction, anaphylactic shock
 PGI2 Drugs

PGI2 Drugs – Therapeutic Use, Pharmacokinetics, and Administration

Pulmonary arterial hypertension - To improve exercise tolerance,

symptoms, and diminish clinical deterioration by directly relaxing vascular
smooth muscle cells
o epoprostenol requires continuous IV perfusion through a central
line (due to t1/2 3-5’) for chronic treatment, which decreases it’s
usefulness (expensive and inconvenient)
o iloprost (t1/2 ~30’) is usually inhaled 6-9 times per day with a
nebulizer
o treprostinil (t1/2 ~4 hrs) can be given by subcutaneous or IV
infusion or inhalation
 PGI2 Drugs

PGI2 Drugs – Adverse Effects and Contraindications

PGI2 Drugs - Common adverse effects include headache, flushing,

hypotension, diarrhea, nausea, and jaw pain.

Iloprost may additionally cause cough and bronchoconstriction because

direct airway exposure sensitizes airway sensory nerves.
Summary of Prostaglandin Drugs –
some points to help you organize your study

We have primarily discussed the use of prostaglandins and their analogs for the
following indications:

Uterine contraction/cervical ripening – primarily as an adjunct in induced

labor or pregnancy termination

Patency of ductus arteriosus

Erectile dysfunction
Pulmonary hypertension

Open angle glaucoma

All of these uses involve smooth muscle tone (contraction or relaxation)

In many (most) cases, “local” administration is preferred