Hypothalamic and Pituitary Pharmacology Flashcards
Control of anterior pituitary hormone release
Release of hypothalamic hormones (releasing factors) under CNS control via neurotransmitters (NE, DA, GABA, 5HT, ACh)
Release of anterior pituitary hormones (trophic hormones) is controlled by hypothalamic hormones (either releasing or inhibiting factors) that are synthesized in and released from peptidergic neurons.
They are then delivered via portal circulation to the pituitary gland for release into the systemic circulation where they act on endocrine glands to regulate production of hormones that perform ultimate regulatory functions
Control of posterior pituitary hormone release
Synthesized in peptidergic neurons in the hypothalamus and then transported to the neuronal terminal in the posterior lobe of pituitary
Neuronally released into the systemic circulation and act directly on target tissues to perform regulatory functions
Growth Hormone (kinds and when naturally increases and decreases)
GH, Somatropin, Somatrem
Release increased by GHRH, exercise, hypoglycemia, dopamine, l-DOPA, arginine
Decreased by somatostatin and paradoxically decreased by dopamine agonists in acromegaly
Describe GH replacement in children and how to treat if GH insensitive
Given daily at bedtime via SC injection (more effective, mimics natural release pattern) or 3 times a week IM - SR preparations for weekly SC injection are in development
If growth hormone insensitive (receptor mutation - Laron dwarf) can treat with recombinant IGF-1 (Mecasermin); concern with hypoglycemia, so carb intake prior to injection
Uses of Growth Hormone
Replacement therapy in children with deficiency
Treatment of poor growth due to Turner’s syndrome, Prader-Willi syndrome, and chronic renal insufficiency
Growth hormone deficiency in adults (most commonly due to pituitary tumor or consequences of its treatment - surgery and/or radiation)
Treatment of wasting or cachexia in AIDS patients
Patients with short bowel syndrome dependent on total parenteral nutrition
Illicit uses by athletes for muscle mass and by the elderly for “anti-aging”
Side effects of Growth hormone
Generally safe when used for replacement in children:
Insulin resistance and glucose intolerance may occur
Slight increased risk for idiopathic intracranial hypertension (pseudotumor cerebri)
Rarely pancreatitis, gynecomastia, nevus growth
Misuse in athletes: Acromegaly, arthropathy, visceromegaly, extremity enlargement
Growth Hormone Releasing Hormone (GHRH)
Rapidly stimulates GH synthesis and secretion via binding to GPCR coupled to Gs → increasing cAMP and Ca++ levels in somatotrophs - no receptor down-regulation with continuous stimulation
Dominant inhibitory regulator is somatostatin. Growth hormone also acts as own feedback inhibitor
Ghrelin
Also stimulates GH release via a different GPCR. It is secreted predominantly by endocrine cells in stomach and also stimulates appetite and increases food intake.
Acts in complex manner to integrate functions of GI tract, hypothalamus, and pituitary.
Uses of GHRH
Diagnostic evaluation of patients with idiopathic GH deficiency
Potential use in GH-deficient children (preserves feedback at pituitary level - smaller molecule than GH, less expensive); potentially fewer side effects. However, synthetic human growth hormone is now usually used for treatment of GH deficiency.
For approximately two-thirds of GH deficient children, the deficiency may be secondary to inadequate GHRH release
Tesamorelin (Egrifta®) is a GHRH analog available for use in HIV patients with lipodystrophy secondary to use of highly active retroviral therapy (HAART) - reduces excess abdominal fat
Somatostatin actions
(SST, Growth Hormone-Inhibiting Hormone, Somatotropin Release-Inhibiting Factor)
Present in hypothalamus, nervous system, gut, endocrine and exocrine glands - function varies
Inhibits GH release via GPCR coupled to Gi decreasing cAMP levels and activating K+ channels
Decreases secretion of gastric enzymes and acid - decreased GI motility - suppresses release of serotonin and gastroenteropancreatic peptides
Reduces insulin and glucagon release - complex effects on blood glucose
Interferes with TRH ability to release TSH
Pharmacokinetics of somastatin and its analogues
Somatostatin: T1/2 following exogenous administration only 3-4 min limiting therapeutic usefulness - kidney has significant role in clearance
Octreotide (Sandostatin®): plasma t1/2 ∼ 90 min (duration ∼ 12 hrs); given SC every 6-12 hours
Octreotide (Sandostatin LAR® depot) given intramuscularly every 4 weeks
Lanreotide (Somatuline® depot) given subcutaneously every 4 weeks
Uses of somatostatin analogues
Pituitary - excess of growth hormone (acromegaly, gigantism)
Surgical resection preferred unless adenoma does not appear fully resectable, patient has high surgery risk, or does not choose surgery
Long-acting somatostatin analog is preferred pharmacotherapy - utilized after response seen to SC octreotide
Control of bleeding from esophageal varices and GI hemorrhage - direct action on vascular smooth muscle to constrict splanchnic arterioles.
Treatments for Growth Hormone Excess - Acromegaly-Gigantism
Surgical removal of tumor
Somatostatin Analogs: Octreotide, Lanreotide
Dopamine Agonists: Cabergoline (oral), Bromocriptine
GH Receptor Antagonist: Pegvisomant (subcutaneous)
Side effects of somatostatin analogues
Transient deterioration in glucose tolerance (HYPERGLYCEMIA) then subsequent improvement
Abdominal cramps, loose stools
Cardiac effects include sinus bradycardia (25%) and conduction disturbances (10%)
Prolactin
Prolactin release is under inhibitory control by hypothalamic dopamine at D2 receptors
Main stimulus for release is suckling - causes 10-100-fold increase within 30 min
Stimulates milk production if appropriate levels of insulin, estrogens, progestins, and corticosteroids are present
Stimulates proliferation and differentiation of mammary tissue during pregnancy
Inhibits gonadotropin (FSH/LH) release and/or ovarian response to these hormones - related to lack of ovulation during breastfeeding
