DEBRE TABOR UNIVERSITY

Pharmacology of pituitary hormones and their

hypothalamic releasing hormones for second
year medicine students

By Tezera Jemere
(MSC in pharmacology)

College Of Health Sciences

7/25/17 09:18:22 AM TJA March, 2017

1
Presentation outline
Hypothalamic hormones
Growth Hormone- Releasing Hormone
Somatostatin (Growth hormone- releasing
inhibiting hormone(GHRIH):
Thyrotropin- Releasing Hormone (TRH)
Corticotropin Releasing Hormone (CRH)
Gonadotropin-Releasing Hormone (GnRH)
Oxytocin and vasopressin
Anterior pituitary hormones
Prolactin and its antagonists
Gonadotropins, their analogues and
antagonists
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Objectives
At the end of the course students will be able
to:
1. List the hypothalamic releasing hormones
2. Discuss the MOA of hypothalamic and
pituitary hormones.
3. Explain the common adverse effects of
hypothalamic and pituitary hormones.
4. Appreciate the therapeutic uses of pituitary
hormones.
5. Appreciate the therapeutic uses of
hypothalamic hormone analogues and their
antagonists.
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Hypothalamic-pituitary endocrine
system

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 Hypothalamic hormones

1-Growth Hormone- Releasing Hormone(GHRH)

Together with somatostatin controls release of the GH

It is released from hypothalamus in a pulsatile fashion.

Diagnostic Uses of GHRH (Sermorlin)

To test pituitary function in patient with GH deficiency

Therapeutic Uses of GHRH

It has been used to stimulate GH release in patients with

GH deficiency that is not of pituitary origin.

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 2.Somatostatin(Growth hormone- releasing
inhibiting hormone(GHRIH):
Inhibits GH release and TSH from the ant.
pituitary .
Inhibits release of most GI hormones, reduces
gastric acids and pancreatic secretion.
Therapeutic Uses of Somatostatin:
Excess GH disorders mainly benign pituitary
tumor
3. Thyrotropin- Releasing Hormone (TRH):
Stimulates release of Thyrotropin (TSH) from
the ant pituitary.
Is used in diagnostic testing of thyroid
dysfunction
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4.Corticotropin Releasing Hormone (CRH)
It stimulates secretion of both ACTH &
endorphin from the ant. pituitary .
CRH can be used in the diagnoses of
abnormalities of ACTH secretion .
5.Gonadotropin-Releasing Hormone (GnRH):
Pulsatile Stimulate the gonadotroph cell to
produce and release LH & FSH
Sustained non pulsatile administration of GnRH or
GnRH analogs inhibits the release of FSH and LH.
Synthetic analogs of GnRH include: Buserelin,
Goserelin, Nafarelin, Triptorelin and Leuprolin
They are more potent and longer acting than
natural GnRH
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 Anterior pituitary (adenohypophysis), the
master endocrine gland, elaborates a
number of important regulatory
hormones.
All are peptide in nature and act at
extracellular receptors located on their
target cells.
Their secretion is controlled by the
hypothalamus through releasing and
release-inhibitory hormones that are
transported via hypothalamohypophyseal
portal system and is subjected to
feedback inhibition by hormones of their
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 GROWTH HORMONE (GH)
It is a 191 A.A, single chain peptide of MW 22000.
Physiological functions
GH promotes growth of all organs by inducing
hyperplasia.
There is a proportionate increase in the size & mass of all
parts, but in the absence of gonadotropins, sexual
maturation does not take place.
It promotes retention of nitrogen and other tissue
constituents.
The positive nitrogen balance results from increased
uptake of AAs by tissues & their synthesis into proteins.
GH promotes utilization of fat and spares carbohydrates:
uptake of glucose by muscles is reduced while its output
from liver is enhanced; fat is broken down.
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 The growth promoting, nitrogen retaining and
certain metabolic actions of GH are exerted
indirectly through elaboration Somatomedins
or Insulin-like growth factors (mainly IGF-1
also IGF-2) which are extracellular mediators of
GH response.
Liver is the major source of circulating IGF-1,
while IGF-1 produced by other target cells acts
locally in a paracrine manner.
Like insulin, IGF-1 promotes lipogenesis and
glucose uptake by muscles.
The IGF-1 receptor also is structurally and
functionally analogous to the insulin receptor
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 Regulation of secretion of GH
The hypothalamus produces GH releasing (GHRH)
& release inhibitory (somatostatin) hormones.
Somatostatin is also produced by D cells of islets
of Langerhans in the pancreas and by few other
tissues.
Receptors for GHRH and somatostatin are G
protein coupled receptors which enhance or
inhibit GH secretion by increasing or decreasing
cAMP formation respectively in pituitary
somatotropes.
Somatostatin has also been shown to inhibit
Ca2+ channels and open K+ channels.
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 Stimuli that cause GH release are-fasting,
hypoglycaemia, exercise, stress and i.v.
infusion of arginine.
GH secretion is inhibited by increase in
plasma free fatty acid levels and by high doses
of glucocorticoids.
Doparninergic agents cause a brief increase in
GH release in normal subjects but
paradoxically depress it in acromegalies.
IGF-1 causes feedback inhibition of GH
secretion. Short-loop feedback inhibition of
secretion by GH itself has also been described.

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 Pathological involvements

Excess production of GH is responsible for gigantism in

childhood and acromegaly in adults.
Hyposecretion of GH in children results in pituitary
dwarfism. GH deficiency in adults is rare.
Uses
The primary indication for GH is pituitary dwarfism
up to the age of 20-25 years.
Two forms of human GH produced by recombinant
DNA technique (rhGH) somatropin (191 AA) and
somatrem (192 AA) are available for clinical use.
Early diagnosis and institution of GH therapy
restores stature to near normal.
rhGH can also be used in Turner's syndrome and in
children with renal failure.
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 GH Contd
Adverse effects
Somatrem has an additional methionine
residue and is more immunogenic than
somatropin, but allergic reactions or resistance
to treatment are not a problem.
Pain at injection site and lipodystrophy can
occur.
Glucose intolerance, hypothyroidism (due to
unmasking of TSH deficiency), salt and water
retention, hand stiffness, myalgia, headache
are the possible adverse effects.
Rise in intracranial tension occurs in few cases.
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 Somatostatin

Is a 14 AA peptide inhibits the secretion of GH, TSH

and prolactin by pituitary; insulin and glucagon by
pancreas and of almost all gastrointestinal
secretions including that of gastrin and HCl.
The g.i. action produces steatorrhoea, diarrhoea,
hypochlorhydria, dyspepsia and nausea as side
effect.
It constricts splanchnic, hepatic and renal blood
vessels.
The decreased g.i. mucosal blood flow can be
utilized for controlling bleeding esophageal varices
and bleeding peptic ulcer, but octreotide is preffered
now due to longer duration of action.
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 Somatostatin Contd
Its antisecretory action is beneficial in pancreatic,
biliary or intestinal fistulae.
can also be used to reduce complications after
pancreatic surgery.
It also has adjuvant value in diabetic ketoacidosis
(by inhibiting glucagon and GH secretion).
Use of somatostatin in acromegaly is limited by its
short duration of action (t1/2 2-3 min)
lack of specificity for inhibiting only GH secretion
Causes GH rebound on discontinuation.

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Octreotide
Is a synthetic octapeptide surrogate of somatostatin is 40
times more potent in suppressing GH secretion and longer
acting (t1/2 ~ 90 min), but only a weak inhibitor of insulin
secretion.
It is being preferred over somatostatin for acromegaly and
secretory diarrhoeas associated with carcinoid, AIDS, cancer
chemotherapy or diabetes.
Control of diarrhoea is due to suppression of hormones
which enhance intestinal mucosal secretion.
Octreotide intravenous injection reduces hepatic blood flow
and helps stop esophageal variceal bleeding.
Adverse effects: are abdominal pain, nausea, steatorrhoea,
diarrhoea and gall stones (due to biliary stasis).

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 Growth hormone antagonist

Pegvisomant
Mechanism of action:
It blocks the action of growth hormone at the growth
hormone receptor to reduce the production of IGF-1.
IGF-1 is responsible for most of the symptoms of
acromegaly.
Normalising its levels may control the symptoms.
Uses:
Treating acromegaly in patients who have not responded
to surgery, radiation therapy, or other medical procedures,
or who are not candidates for those treatments.

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side effects
Back pain; diarrhea; dizziness; flu-like symptoms (eg,
mild fever or chills, headache, muscle aches, tiredness);
nausea; pain, redness, or itching at the injection site;
runny or stuffy nose; sinus pain.
Severe allergic reactions (rash; hives; itching; difficulty
breathing; fainting; tightness in the chest; swelling of the
mouth, face, lips, throat, or tongue; unusual hoarseness;
wheezing); burning, numbness, or tingling; chest pain;
fever, chills, or persistent cough or sore throat; severe or
persistent headache or dizziness; swelling of the hands,
ankles, or feet; symptoms of liver problems (eg,
yellowing of the skin or eyes, dark urine, pale stools,
unusual tiredness, severe or persistent nausea, vomiting,
or stomach pain, loss of appetite, bruising easily);
thickening of the skin or lumps at the injection site;
unusual weight gain.
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 PROLACTIN

It is a 199 AA, single chain peptide of MW 23000;

quite similar chemically to GH.
Physiological function
It is the primary stimulus which in conjunction
with estrogens, progesterone & several other
hormones, causes growth & development of
breast during pregnancy.
It promotes proliferation of ductal & acinar cells
in the breast & induces synthesis of milk
proteins and lactose.
After parturition it induces milk secretion, since
the inhibitory influence of high estrogen &
progesterone levels is withdrawn.
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 Prolactin Contd
Prolactin suppresses hypothalamopituitarygonadal axis by
inhibiting GnRH release.
Continued high level of prolactin during breastfeeding is
responsible for lactational amenorrhoea, inhibition of
ovulation and infertility for several months postpartum.
Prolactin may affect immune response through action on T
-lymphocytes.
A specific prolactin receptor is expressed on the surface of
target cells, which is structurally and functionally
analogous to GH receptor:
action is exerted by transmembrane activation of
cytoplasmic tyrosine protein kinases.
Placental lactogen and GH also bind to prolactin receptor
and exert similar effects.
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Regulation of secretion
Though TRH can stimulate prolactin secretion, no
specific prolactin releasing factor has been identified.
Endogenous opioid peptides may also be involved in
regulating prolactin secretion, but no feedback
regulation by any peripheral hormone is known.
Prolactin levels in blood are low in childhood, increase in
girls at puberty and are higher in adult females than in
males.
A progressive increase occurs during pregnancy,
peaking at term.
Subsequently, high prolactin secretion is maintained by
suckling.
Stress, exertion and hypoglycaemia also stimulate
prolactin release.
it falls if breast feeding is discontinued.
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 Prolactin Contd
Prolactin is under predominant inhibitory control of
hypothalamus through PRIH which is dopamine that
acts on pituitary lactotrope D2 receptor.
Dopaminergic agonists (DA, bromocriptine,
cabergoline) decrease plasma prolactin levels.
Dopaminergic antagonists (chlorpromazine,haloperidol,
metoclopramide)& DA depleters (reserpine, methyldopa) cause
hyperprolactinemia.
Physio-pathological involvement
Hyperprolactinaemia
In females it causes galactorrhoea amenorrhoea-
infertility syndrome.
In males it causes loss of libido & depressed fertility.
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 Prolactin Contd
causes of hyperprolactinaemia
I. Disorders of hypothalamus removing the
inhibitory control over pituitary.
II. Antidopaminergic and DA depleting drugs
these are a frequent cause now.
III. Prolactin secreting tumours-these may be
microprolactinomas or macroprolactinomas.
IV. Hypothyroidism with high TRH levels also
increases prolactin secretion.

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 Prolactin inhibitors

1. Bromocriptine
Is a synthetic ergot derivative 2-bromo-aergocryptine is
a potent dopamine agonist.
It has greater action on D2 receptors, while at certain
dopamine sites in the brain it acts as a partial agonist
or antagonist of D1 receptor.
It is also a weak a adrenergic blocker.
Actions
1.Decreases prolactin release from pituitary by activating
dopaminergic receptors on !actotrope cells-a strong
antigalactopoietic.
2. Increases GH release in normal individuals,
but it decreases GH release in pituitary tumours that
cause acromegaly.
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 Bromocriptine Contd

3. Has levodopa like actions in CNs-

antiparkinsonian and behavioral effects.
4. Produces nausea and vomiting by stimulating
dopaminergic receptors in the CTZ.
5. Hypotension-due to central suppression of
postural reflexes and weak peripheral
adrenergic blockade.
6. Decreases gastrointestinal motility.
Uses
1.Hyperprolactinemia due to microprolactinomas
causing galactorrhoea, amenorrhoea and
infertility in women; gynaecomastia, impotence
and sterility in men.
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 Bromocriptine Contd

2.Acromegaly due to small pituitary tumours and

inoperable cases.
3. Parkinsonism used alone or adjunct to levodopa in
patients not adequately benefited and in those showing
marked 'on-off' effect.
4. Hepatic coma: it may cause arousal.
5.It suppresses lactation & breast engorgement in case of
neonatal death.
Pharmacokinetics
Only 30 % of an oral dose of it is absorbed &
bioavailability is further lowered by high first pass
metabolism in liver.
lts plasma half life is 3 - 6 hours.
Metabolites are excreted mainly in bile.
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 Bromocriptine Contd

Side effects:
Early: Nausea, vomiting, constipation, nasal
blockage. Postural hypotension may be
marked at initiation of therapy-syncope may
occur if starting dose is high. Hypotension is
more likely in patients taking
antihypertensives.
Late: Behavioral alterations, mental confusion,
hallucinations, psychosis-are more prominent
than with levodopa.
Abnormal movements, livedo reticularis.
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PERGOLIDE
Pergolide an ergot derivative approved by the
FDA for treatment of PD, also is used off
label to treat hyperprolactinemia.
SE: same as bromocriptine.
CABERGOLINE
Cabergoline is an ergot derivative with a
longer t1/2 (~65 hours), higher affinity, and
greater selectivity for the D2 receptor than
bromocriptine.
lower tendency to induce nausea than
Bromocriptine.

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 GONADOTROPINS (Gns)

The anterior pituitary secretes two Gns(FSH

and LH).
Physiological functions FSH and LH act in
concert to promote gametogenesis and
secretion of gonadal hormones.
FSH In female induces follicular growth,
development of ovum and secretion of
estrogens.
In the male it supports spermatogenesis and
has a trophic influence on seminiferous
tubules.
Ovarian and testicular atrophy occurs in the
absence
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 FSH is a 35.5 kDa glycoprotein heterodimer,
consisting of two polypeptide units, alpha and
beta.
Its structure is similar to those of LH, TSH& hCG.
The alpha subunits of the glycoproteins LH, FSH,
TSH and hCG are identical and consist of about 96
amino acids, while the beta subunits vary.
Both subunits are required for biological activity.
FSH has a beta subunit of 111aas (FSH ), which
confers its specific biologic action & is responsible
for interaction with the FSH receptor.
The sugar portion of the hormone is covalently
bonded to asparagine and is composed of N-
acetylgalactosamine, mannose, N-
acetylglucosamine, galactose, and sialic acid.
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 Gonadotropins Contd
LH induces preovulatory swelling of the ripe
graafian follicle and triggers ovulation followed
by luteinization of the ruptured follicle and
sustains corpus luteum till the next menstrual
cycle.
LH is also probably responsible for atresia of the
remaining follicles.
Progesterone secretion occurs only under the
influence of LH.
In the male LH stimulates testosterone secretion
by the interstitial cells and is designated inter-
stitial cell stimulating hormone (ICSH).
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 Gonadotropins Contd
Distinct LH and FSH receptors are expressed on the
target cells.
Both are G protein coupled receptors which on
activation increase cAMP production.
This in turn stimulates gametogenesis and conversion of
cholesterol to pregnenolone-the first step in
progesterone, testosterone and estrogen synthesis.
In the testes FSH receptor is expressed on seminiferous
(Sertoli) cells & initiate spermatogenesis.
LH receptor is expressed on interstitial (Leydig) cells &
stimulate production of testosterone.
In the ovaries FSH receptors are present only on
granulosa cells.
LH receptors are widely distributed on interstitial cells,
theca cells, preovulatory granulosa cells and luteal cells.
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 Gonadotropins Contd
Regulation of secretion
A single releasing factor (GnRH or gonadorelin) is
produced by the hypothalamus which stimulates
synthesis and release of both FSH and LH from
pituitary.
Pathological involvement
Disturbances of Gn secretion from pituitary may be
responsible for delayed puberty or precocious
puberty both in girls and boys.
Inadequate Gn secretion results in amenorrhoea and
sterility in women; oligozoospermia, impotence and
infertility in men.
Excess production of Gn in adult women causes
polycystic ovaries.
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 Gonadotropins Contd
Uses
1.Amenorrhoea and infertility due to deficient
production of Gns by pituitary to induce ovulation
when non ovulation is due to polycystic ovaries.
2.Hypogonadotrophic hypogonadism in males
manifesting as delayed puberty or defective
spermatogenesis lead to oligozoospermia
3.Cryptorchism Since undescended testes can
cause infertility and predispose to testicular
cancer, medical/ surgical treatment is
imperative.
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4. To aid in vitro fertilization Menotropins
(FSH + LH or pure FSH) have been used
to induce simultaneous maturation of
several ova and to precisely time
ovulation so as to facilitate their
harvesting for in vitro fertilization
Praparations:
1. Menotropins (FSH + LH): obtained
from urine of menopausal women.
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2.Urofollitropin or Menotropin (pure FSH),
preferred over combined for induction of
ovulation in women with polycystic
ovarian disease:
these patients have elevated LH/FSH
ratio; use of FSH alone is considered
advantageous.
It is also claimed to improve chances of
obtaining good quality ova for in vitro
fertilization.
3.Human chorionic gonadotropin (HCG): is
derived from urine of pregnant women.
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 Gonadotropins Contd
Precautions
Precocious puberty is a risk when given to children.
Allergic reactions have occurred and skin tests are
advised.
Hormone dependent malignancies (prostate,
breast) must be excluded.
Adverse effects
Ovarian hyperstimulation-polycystic ovary, pain in
lower abdomen and even ovarian bleeding and
shock can occur in females.
Other side effects are edema, headache, mood
changes.
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 GnRH agonists
Many analogues of GnRH( Buserelin, Goserelin,
Leuprolide, Nafarelin & Triptorelin) have been
developed.
They are 15-150 times more potent than natural Gn RH
and longer acting (t1/2 2-6 hours) because of high
affinity for GnRH receptor and resistance to enzymatic
hydrolysis.
They acutely increase Gn secretion, but after 1-2 weeks
cause desensitization and down regulation of GnRH
receptors lead to inhibition of FSH and LH secretion lead
to suppression of gonadal function.
Spermatogenesis or ovulation cease and testosterone or
estradiol levels fall to castration levels.
Recovery occurs within 2 months of stopping treatment.
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 GnRH agonists Contd
uses
In precocious puberty, prostatic carcinoma,
endometriosis, premenopausal breast cancer,
uterine leiomyoma, polycystic ovarian disease and
to assist induced ovulation.
It also has potential to be used as contraceptive for
both males and females.
Nafarelin
long-acting GnRH agonist is 150 times more potent
than native GnRH with a plasma t1/2 of 2 3 hours.
Down regulation of pituitary GnRH receptors occurs
in 10 days but peak inhibition of Gn release occurs
at one month.
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Uses
1. Assisted reproduction: Endogenous LH surge
needs to be suppressed when controlled ovarian
hyperstimulation is attempted by exogenous
FSH and LH injection, so that precisely timed
mature oocytes can be harvested.
2. Uterine fibroids it can reduce the size of
leiomyoma and afford symptomatic relief.
3. Endometriosis
4. Central precocious puberty breast and
genital development is arrested in girls and
boys.
The effect is reversible; pubertal changes
resume when therapy is discontinued.
AEs: Hot flashes, loss of
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libido, vaginal dryness,
41
Triptorelin is a long-acting GnRH agonist
indications in carcinoma prostate,
endometriosis, precocious puberty and uterine
leiomyoma.
For prostate cancer, it is combined with an
androgen antagonist flutamide or bicalutamide
to prevent the initial flare up of the tumour that
occurs due to increase in Gn secretion for the
first 1-2 weeks.
GnRH antagonists
They inhibit Gn secretion without causing initial
stimulation.
The early GnRH antagonists had the limitation of
producing reactions due to histamine release.
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 GnRH antagonists Contd

Newer agents like ganirelix and cetrorelix have

low histamine releasing potential and are being
clinically used in specialized centres for inhibiting
LH surges during controlled ovarian stimulation in
women undergoing in vitro fertilization.
Advantages over long-acting GnRH agonists
They produce quick Gn suppression by
competitive antagonism.
Lower risk of ovarian hyperstimulation syndrome.
They achieve more complete suppression of
endogenous Gn secretion.

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 oxytocin Vasopressin
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(argipressin) 45
 Oxytocin Contd
Oxytocin is a cyclic nonapeptide that differs
from vasopressin by only 2 amino acids
It is synthesized in the hypothalamus &
transported to the post. Pit.
It also synthesis in the luteal cells of the
ovary, the endometrium, and the placenta.
Its secretion occurs by sensory stimulation
from cervix ,vagina , and from suckling at
breast.

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Mechanism of Action:
the interaction of endogenous or
administered oxytocin , with myometrial
cell membrane receptor promotes the
influx of ca++ from extra cellular fluid
and from S.R in to the cell ,
this increase in cytoplasmic calcium
,stimulates uterine contraction .
Stimulates both the frequency and force
of uterine contractility particularly of the
fundus segment of the uterus.

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 These contractions resemble the
normal physiological contractions of
uterus (contractions followed by
relaxation)
Immature uterus is resistant to
oxytocin.
Contract uterine smooth muscle only
at term.
Sensitivity increases to 8 fold in last
9 weeks and 30 times in early labor.
Clinically oxytocin is given only when
uterine cervix is soft and dilated.

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Therapeutic Uses of Oxytocin
1. Induction & augmentation of labor (slow I.V
infusion)
a. Mild preeclampsia d. Uterine inertia
b. Incomplete abortion e. Post maturity
c. Maternal diabetes
2. Post partum uterine hemorrhage(I.V drip)
(ergometrine is often used)
3. Impaired milk ejection One puff in each
nostril 2-3 min before nursing

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 Oxytocin receptor antagonist
Atosiban
Is an oxytocin receptor antagonist used in treatment of
patients in preterm labor resulted in prolongation of
pregnancy for up to 7 days for those at a gestational age
28 weeks.
This occurred with a low rate of maternal-fetal adverse
effects.
In addition, at a gestational age 28 weeks, the infant
morbidity and mortality of atosiban-initiated standard care
were similar to those with placebo-initiated standard care.
These observations support the use of this oxytocin
receptor antagonist in the treatment of patients in preterm
labor with intact membranes.

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 Vasopressin
It is derived from a preprohormone precursor that
is synthesized in the hypothalamus and stored in
vesicles at the posterior pituitary.
is a peptide hormone that increases water
permeability of the kidney's collecting duct and
distal convoluted tubule by inducing translocation
of aquaporin -CD water channels in the plasma
membrane of collecting duct cells.
It also increases peripheral vascular resistance,
which in turn increases arterial blood pressure.

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 It plays a key role in homeostasis, by the
regulation of water, glucose and salts in the
blood.
Most of vasopressin is stored in the posterior
pituitary to be released into the bloodstream.
Some AVP may also be released directly into the
brain, and accumulating evidence suggests it
plays an important role in social behavior,
sexual motivation and pair bonding, and
maternal responses to stress.
It has a very short half-life between 1624
minutes
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 Vasopressin Contd

Vasopressin possesses antidiuretic and vasopressor

properties.
Mechanism of action :activates two subtypes of
receptors
V 1 receptors are found on vascular smooth muscle cells
V 2 receptors are found on renal tubule cells and reduce
diuresis .
Clinical Pharmacology
Diabetes insipidus,
Nocturnal enuresis (by decreasing nocturnal urine
production)
Side effects Over dosage can result in hyponatremia and
seizures.
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