Download DRUG ACTING ON ENDOCRINE SYSTEM Pituitary Hormones in

DRUG ACTING ON ENDOCRINE
SYSTEM
Pituitary Hormones in clinical
practice
•
LEARNING OBJECTIVES
At the end of lecture, students must able to
know :
– Names of pituitary hormones.
– Clinical uses, side effects and toxic
effects of pituitary hormones.
– Pharmacokinetics and
pharmacodynamics of pituitary
hormones.
ENDOC
RINE
DRUGS
•
The
con
trol
of
met
abolism, growth
& reproduction is
mediated by a combination of neural &
endocrine
systems
located
in
the
hypothalamus & pituitary gland.
Pharmacologic applications Hypothalamic &
Pituitary Hormones



Hypothalamic
and
pituitary
hormones (and their synthetic analogs)
have pharmacologic applications in
three areas:
As replacement therapy for hormone
deficiency states
As drug therapy
As diagnostic tools for performing
stimulation tests
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Hypothalamic & Pituitary Hormones
The hypothalamus & pituitary gland
synthesize several hormones that regulate
other glands & tissues throughout the
body.
One group of hypothalamic hormones
regulates the release of anterior pituitary
hormones.
The other hypothalamic hormones are
transported to the posterior pituitary are
released from the pituitary into the
general circulation, and act directly on
distant tissues
1.
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The Hypothalamic Hormones
Hypothalamic releasing hormones e.g:
Growth hormone releasing hormone
GHRH (somatocrinin)
GHR-inhibiting hormone (somatostatin):
Thyrotropin releasing hormone (TRH)
Corticotropin releasing hormone (CRH)
Gonadotropin- releasing Hormone (Gn RH
or LHRH)
Prolactin inhibiting hormone (PIH)
2. Other hypothalamic hormones:

Oxytocin & vasopressin are transported to
the posterior pituitary.
NB: the above hormones are polypeptides and
should be used by i.m or inhalation
route.
Hypothalamic & Pituitary Hormones Receptors
•
Growth hormone & Prolactin – single
chain peptide hormone (JAK/STAT
family)
•
Thyroid stimulating hormone (TSH) &
follicle stimulating hormone (FSH) &
luteinizing hormone (LH) – dimeric
proteins (G protein coupled)
•
Adrenocorticotropic hormone (ACTH) single chain peptide hormone (G protein
coupled)
Growth Hormone (Somatotropin)
•
•
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Natural GH was obtained from the
pituitary glands of human cadavers.
Now GH is obtained by recombinant DNA
technology in E.coli.
GH stimulates growth via the production
of peptide insulin-like growth factor
IGF1 (somatomedin) in the liver and
other organs.
GH inhibits peripheral glucose uptake
producing hyperglycemia (anti-insulin).
It also causes lipolysis and positive
nitrogen & calcium balance.
Overproduction of GH produces gigantism
before closure of the epiphysis and
acromegaly after closure of the
epiphysis of the long bones.
Growth Hormone (Somatotropin)…
U s es
•
Children: short stature due to growth-
hormone deficiency, Turner's syndrome,
renal failure, small size for gestational
age & idiopathic short stature.
Treatment continued until closure of the
epiphyses.
•
Adults: in cases of GH deficiency to
increase lean body mass, and to improve
exercise performance and overall quality
of life
Adverse effects
increase weight, hypertension, diabetes
and hyperlipidemia.
Acromegaly
Excess GH  diabetes hypertension &
arthritis
Treatment
•
Surgery (hypophysectomy) is the
treatment of choice.
•
Irradiation of pituitary is alternative to
surgery
•
If surgery failed use octreotide or
bromocriptine to decrease GH release
especially in young patients male or
female who wish to retain fertility.
Growth Hormone Releasing Hormone GHRH
(somatocrinin)
•
•
It stimulates growth hormone (GH)
release from anterior pituitary.
It is used to treat a variety of GH
deficiency as that due to hypothalamic
disease, idiopathic and pituitary stalk
severance.
SERMORELIN
•
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Analogue used for diagnosis / treatment of
GH deficiency
Sermorelin is commercially available. It
and
other
GHRH
analogs,
given
subcutaneously, can also stimulate GH (and
therapy growth) in certain GH-deficient
children with short stature.
Sermorelin is given only to children have
had a positive growth hormone response to
the diagnostic test and who have a bone
age of less than 7.5 years (girls) or 8 years
(boys)
Adverse effects
-Flushing
-Pallor
-Chest tightness -Pain /
erythemas at injection site
-Nausea
-Headache
Metallic taste
MECASERMIN
•
Used for Rx of severe IGF-1 deficiency
not responsive to GH
•
Complex of recombinant human IGF-1 &
recombinant human IGF binding protein 3
•
SC adm BD
•
AEs
– Hypoglycemia
– IC hypertension
– Elevation of liver enzymes
Growth Hormone Release-inhibiting Hormone
(Somatostatin)
•
•
•
It is present in pancreas, gut & CNS.
It inhibits the release of GH, thyrotropin,
glucagon, insulin, serotonin and gastrin.
It is of no clinical value in treatment of
acromegaly because of its short duration
of action. Use Octreotide instead
GROWTH HORMONE RELEASE-INHIBITING
HORMONE (SOMATOSTATIN)…
•
•
Octreotide
Octreotide is a synthetic somatostatin
analogue with a longer duration of action
45 x more potent
U s ed :
•
Acromegaly, carcinoid tumor, gastrinoma
and glucagonoma
•
Variceal bleeding (decreases splanchnic
blood flow)
•
Radiolabelled somatostatin is used to
localize and in higher doses to treat
metastases from neuroendocrine tumors
(bear somatostatin receptors).
GROWTH HORMONE RELEASE-INHIBITING
HORMONE (SOMATOSTATIN)…
Pegvisomant
 GH Receptor Antagonist
 PEG der of mutant GH, B2036
 Less potent than B2036
 R
x
o
f
a
c
r
o
m
e
g
a
l
y
Gonadotropin-Releasing Hormone (GnRH /
LHRH)
•
•
Diagnostic uses
Agonists: Stimulation of gonadotropin
release
– Stimulation
–
• Female infertility
• Male infertility
• Diagnosis of LH responsiveness
Suppression of gonadotropin
production
• Controlled ovarian
hyperstimulation
• Endometriosis
• Uterine fibroids
• Prostate cancer
• Central precocious puberty
Gonadotropin-Releasing Hormone (GnRH /
LHRH)….
GnRH analogues
o Gonadorelin
o Leuprolide
o Nafarelin
Gonadotropin-Releasing Hormone (GnRH /
LHRH)….
GnRH antagonists
Four synthetic decapeptides
 Ganirex, Cetrorelix, abarelix, degarelix
–
–
Suppression of gonadotropin
production
Advanced Prostate cancer - abarelix
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PROLACTIN
198 AA peptide hormone produced in
anterior pituitary
Principal hormone responsible for lactation
Hypoprolactinemia – failure to lactate &
luteal phase defect
Hyperprolactinemia – syndrome of
amenorrhea & galactorrhea in women, loss
of libido & infertility in males
PROLACTIN INHIBITING HORMONE (PIH)
Dopamine
•
Dopamine is the physiological inhibitor of
prolactin release.
•
Dopamine is not used in hyperprolactinemia
because of its peripheral effects and
parenteral administration.
PROLACTIN INHIBITING HORMONE (PIH)…
Bromocriptine
•
It is an ergot derivative
•
Acts on dopamine receptors (D2).
•
It inhibits prolactin secretion
Uses:
•
Bromocriptine is used to induce ovulation in
amenorrhea-galactorrhea syndrome via
inhibition of prolactin secretion.
•
Bromocriptine also reduces secretion of
GH from the pituitary tumors
Prolactin inhibiting hormone (PIH)…
Pergolide is another ergot derivative with
similar effects.
•
Cabergoline & Quinagolide: non-ergot
derivative
Anterior Pituitary Hormones
Thyroid Stimulating Hormone (TSH)
This peptide stimulates adnylyl cyclase
in thyroid cells & increases iodine
uptake & production of thyroid
hormones. TSH has been used as a
diagnostic tool to distinguish primary
from secondary hypothyroidism. The
hormone is still used occasionally to
increase 131I uptake (and tumoricidal
effect)
in
metastatic
thyroid
carcinoma.
Anterior Pituitary Hormones
Adrenocorticotropin (ACTH)
This peptide is formed from a large
precursor
peptide,
proopiomelanocortin. Although it has been
used therapeutically to increase
corticosteroid levels, ACTH is now
used almost exclusively for diagnostic
purposes in patients with abnormal
corticosteroid production. Cosyntropin,
a synthetic analog consisting of the
first 24 amino acids of ACTH, is most
commonly used for this purpose rather
than ACTH itself.
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Posterior Pituitary Hormones
Oxytocin
Oxytocin is a peptide synthesized in
cell bodies in the paraventricular nuclei
of the hypothalamus.
Oxytocin is an effective stimulant of
uterine contraction and is sometimes
used intravenously to induce or
reinforce labor.
Because it causes contraction of
smooth muscle in the myoepithelia;
cells of the breast, oxytocin also can
be used by lactating women as a nasal
spray to stimulate milk letdown.
POSTERIOR PITUITARY HORMONES
Oxytocin…
function:
•
Contraction of the uterus.
•
Contraction of myoepithelial cells of the
mammary gland.
U s es :
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Induction of labor and abortion.
Uterine inertia.
Postpartum hemorrhage.
Breast engorgement by milk (stimulates
milk let down).
Preparations:
•
Natural oxytocin: i.m & i.v drip
•
Synthetic oxytocin: syntocinon i.m, i.v drip
and nasal spray.
A/E: rupture of uterus in cephalo-pelvic
disproportion or presence of old scar from
previous Caesarian section.
POSTERIOR PITUITARY HORMONES
Oxytocin antagonist – Atosiban
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Antagonist of oxytocin receptor
Rx or preterm labor (tocolysis)
POSTERIOR PITUITARY HORMONES
Vasopressin (Antidiuretic Hormone, ADH)
Vasopressin is synthesized in the
supraoptic nuclei of the hypothalamus.
Vasopressin acts on V2 receptors &
increases the synthesis or insertion of
water channels by a cAMP-dependent
mechanism, resulting in an increase in
water permeability in the collecting
tubules of the kidney.
The increased water permeability
permits water reabsorption into the
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hypertonic renal papilla, thus causing
the antidiuretic effect.
Vasopressin also causes smooth muscle
contraction (a V1 effect). The primary
use of vasopressin is in the treatment
of pituitary diabetes insipidus.
DESMOPRESSIN
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It is vasopressin synthetic analogue.
It binds preferentially to V2 > V1
receptors.
:It has the following advantages
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Insignificant vasoconstriction.
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Longer duration of action.
•
Availability of oral, sublingual, nasal spray
and injection preparations.
•
In hemophilia Desmopressin can enhance
blood concentration of factor VIII.
U s es :
•
Diabetes insipidus, enuresis, mild
hemophilia A, and some types of Von
Willebrand's disease
Diabetes Insipidus (DI)
Persistent production of excess dilute urine
se
rapy
Pituitary DI
Nephrogenic DI
deficiency of ADH
insensitive nephrone to ADH
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ADH
(desmopressin)
Chlorpropamide
Carbamazepine
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Salt-restriction
Thiazide diuretics
Loop diuretic
POSTERIOR PITUITARY HORMONES
Vasopressin Antagonist
Conivaptan & Tolvaptan
Group of nonpeptide antagonists of
Vasopressin receptors
Relieve symptoms in hyponatremia &
heart failure
Pharmacology of Hypothalamus &