PHARMACOLOGY OF PITUITARY HORMONES Flashcards
Define the endocrine system and define hormones
Endocrine system: All the glands of the body and the hormones produced by them.
Hormones: chemical substance of intense biological activity produced by specific cells in the body and transported through the circulation to act on its target cells.
List the sites of hormonal action
Sites of hormonal action:
1. cell membrane receptors- cAMP, IP3/DAG generation, direct transmembrane activation of tyrosine kinase;
2. cytoplasmic receptors;
3. nuclear receptors
How are Anterior pituitary hormones classified?
Anterior pituitary hormones classifiable into:
1. somatotropins consisting of GH & Prolactin.
2. glycoproteins consisting of TSH, FSH, LH.
3. Proopiomelanocortin (POMC) derivatives: Corticotropin (ACTH), α-MSH.
Examples of regulators
- hypothalamic releasing hormones.
2.somatotropin-negative regulator of GH & thyrotropin secretion. - dopamine: inhibits prolactin secretion
What are the hormones of the posterior pituitary gland?
Posterior pituitary:
1. arginine vasopressin
2. oxytocin.
Types of GH and What is the Physiological effects of GH?
Principal form is a 22,000D single polypeptide chain of 191 amino acids.
Smaller form of about 20,000D containing 176 aas.
Stimulation of longitudinal growth of bones.
Increase in bone mineral density after closure of epiphyses.
Stimulation of myoblast differentiation.
Increased muscle mass
Increased GFR
Stimulation of preadipocyte differentiation into adipocytes.
Anti-insulin actions in liver and peripheral tissues.
Development and function of the immune system.
Anabolic and growth-promoting effects mediated through IGF-1
IGF-1 is produced in the liver and other tissues.
IGF-1 receptors are cell surface receptors resembling insulin receptors and has intrinsic tyrosine kinase activity.
IGF-1 receptor can be activated by insulin.
Discuss Growth hormone
Peptide hormone
Principal form is a 22,000D single polypeptide chain of 191 amino acids.
Smaller form of about 20,000D containing 176 aas.
Both have equal bioavailability.
What is the Mechanism of action og GH?
Via GH receptors which are cell surface receptors.
The receptor belongs to the class 1 cytokine receptor superfamily.
It shares structural similarity with receptors for prolactin, erythroprotein, GM-CSF and other interleukins.
Activation of the receptor is triggered by binding of a single GH molecule to two GHR to form a receptor dimer.
This activates autophosphorylation of JAK2.
JAK2 then phosphorylates STAT resulting in modulation of gene expression.
Discuss the Regulation of GH secretion
Secretion is high in children and reaches maximal levels at puberty.
Secretion is highness at night.
Secretion is stimulated by GHRH.
Negative inhibition by GH and IGF-1 and somatostatin.
Secretory stimuli: fasting, hypoglycemia, stress, exercise.
Inhibitory stimuli: corticosteroids, ffa.
What are the uses of GH?
Cases of GH deficiency in children and adults.
Prader-Willi syndrome.
Turner’s syndrome.
CRF (Chronic renal failure) in children.
SGA (small for gestational age) children.
Idiopathic short stature.
Catabolic states: burns, renal failure, osteoporosis, bed-ridden patients.
AIDS wasting syndrome.
Performance enhancer by athletes.
Noonan syndrome
Imbalance of GH results in what?
GH deficiency in childhood results in dwarfism and adiposity.
deficiency in adulthood results in increased mortality from cvs diseases, decreased muscle mass, decreased bone density, impaired psychosocial function.
Excessive secretion results in gigantism and acromegaly.
What is Mecaserin
Mecaserin
Complex of rhIGF-1 and rhIGFBP-3.
Indicated for children with severe IGF-1 deficiency.
It is administered twice daily subcutaneously.
Main adverse effect is hypoglycemia.
Others are intracranial HT, elevated hepatic enzymes.
GH preparations include
Preparations :
Somatropin
Somatrem
Long acting somatropin suspension.
side effects
Injection site pain.
First 8 weeks: intracranial HT, papilledema, visual changes, headaches, nausea/vomiting.
Hypothyroidism, salt and water retention, myalgia, hand stiffness.
Increase incidence of type 2 DM
What are GH antagonists?
Antagonists of GH:
Somatostatin and its analogs.
Pegvisomant.
Dopamine receptor agonists.
These are used in the management of syndromes of GH excess.
Somatostatin analogs
These are ocreotide, lanreotide, vapreotide,seglitide, BIM23268, CH275.
What is Ocreotide (SANDOSTATIN)?
Synthetic derivative of somatostatin.
It is an octapeptide.
Administered s/c 3 times daily.
Binds to SSTR-2 and SSTR-5 receptors.
Peak effect within 30 minutes.
Half-life about 90 minutes.
Duration of action 90 minutes.
It reduces GH secretion and IGF-1 levels.
It also reduces tumor size
It also inhibits thyrotropin secretion and is used for treating thyrotrope adenoma.
Also used for managing GI disorders.
Side effects include nausea, diarrhea, abdominal pain, gallstones.
SANDOSTATIN LAR is a long-acting, slow-release form of ocreotide administered once every 4 weeks via the intramuscular route.
Other uses of ocreotide:
Secretory diarrhoeas associated with carcinoid, cancer chemotherapy, AIDS, diabetes.
Oesophageal bleeding.
For diagnostic imaging (when labelled with indium or technetium) of neuroendocrine tumors such as pituitary adenoma and carcinoids.
What is Lanreotide (SOMATULINE)?
Lanreotide (SOMATULINE)
Long acting octapeptide.
Shorter duration of action than SANDOSTATIN LAR.
Administered at a dose of 30mg i/m every 10-14 days.
SOMATULINE AUTOGEL is a longer acting form administered at a dose of 60mg 4 weekly.
What is Pegvisomant?
Competitive inhibitor of GH.
Binds to GH receptors without activating it.
Administered via the subcutaneous route.
Contraindicated in patients with elevated transaminases.
What is Prolactin?
Prolactin
Structurally related to GH and placental lactogen.
23,000D polypeptide with 199 aas.
Synthesized by lactotropes of the anterior pituitary.
Secretion is low in childhood, increases in girls at puberty, high in adult females, progressively increase in pregnancy peaking at term.
It induces growth and differentiation of the ductal and lobuloalveolar epithelium of the breast.
Essential for lactation.
Excessive secretion can cause galactorrhoea, amenorrhoea and infertility in females and loss of libido plus impotence in males.
It has no clinical value.
What are Prolactin inhibitors?
Hyperprolactinemia can result from hypothalamic or pituitary disease, from dopamine receptor antagonists or from pituitary adenomas.
Hyperprolactinemia is managed with dopamine receptor agonists.
What is Bromocriptine?
Action
Clinical use
Side effects
Semisynthetic ergot alkaloid.
Higher affinity for D2 than D1.
It normalizes serum prolactin levels in 70 to 80% of patients with prolactinoma.
Also reduces tumour size.
It is usually administered orally but can be administered intravaginally.
It is subjected to a high first pass metabolism, hence bioavailability is only about 7%.
Elimination half life is about 2-8 hours.
Agonist effect at D2 receptors to inhibit prolactin secretion.
Other uses include acromegaly, parkinsonism, suppression of breast engorgement, DM.
Side effects include nausea, vomiting, headache, postural hypotension, nasal congestion, psychosis (disconnection from reality), hallucinations, nightmares, insomnia.
What are other dopamine receptor agonists used in managing hyperprolactinemia?
Other dopamine receptor agonists used in managing hyperprolactinemia are pergolide, cabergoline, quinagolide.
Discuss GnRH and analogues (gonadorelin, goserelin, histrelin, leupolide, nafarelin)
It is a decapeptide produced in the hypothalamus.
Release is regulated by the GnRH pulse generator and estradiol.
Release is intermittent.
Administration by iv, im, sc or nasal spray or sc depot.
Mechanism of action is through Gq/11, PLC-IP3-Ca2+.
Uses:
Infertility:hypogonadotropic hypogonadism, controlled ovarian hyperstimulation, suppression of LH surge.
Treatment of HR breast or prostate cancer.
Endometriosis, myomas, acute intermittent porphyria.
Side effects:
Hot flashes, Vaginal dryness, Osteoporosis, headache, depression, reduced libido, breast atrophy.
GnRH antagonists
Ganirelix, cetrorelix, abarelix.
Both are adminstered subcutaneously with good absorption.
Used in ART to inhibit the LH surge.
Abarelix is used for treating prostate Ca.
Advantages over GnRH analogues include:
shorter onset of action with concomittant shorter duration of administration.
Lower risk of OHSS.
