Pituitary/Hypothalamic Drugs PDF

Pituitary/Hypothalamic Drugs Dr. Mary Law Department of Pharmacology and Therapeutics  Lecture Outline Review of Pituitary and Hypothalamic Hormones Treatment of GH deficiency and excess (acromegaly). Treatment of hyperprolactinemia. The gonadotropins and...

Pituitary/Hypothalamic Drugs Dr. Mary Law Department of Pharmacology and Therapeutics  Lecture Outline Review of Pituitary and Hypothalamic Hormones Treatment of GH deficiency and excess (acromegaly). Treatment of hyperprolactinemia. The gonadotropins and their uses. Gonadotropin-releasing hormones and analogs. Posterior pituitary hormones.  Links between hypothalamic, anterior pituitary, and target organ hormone or mediator Anterior Pituitary Hypothalamic Hormone Target Organ Hormone Growth hormone (GH, Growth hormone releasing Liver, bone, muscle, somatotropin) hormone (GHRH) (+) kidney, and others Somatostatin (-)/Dopamine (-) Thyroid stimulating Thyrotropin releasing hormone Thyroid hormone (TSH) (TRH) (+) Adrenocorticotropin Corticotropin releasing hormone Adrenal cortex (ACTH) (CRH) (+) Follicle stimulating Gonadotropin releasing hormone Gonads hormone (FSH) (GnRH) (+) Luteinizing hormone (LH) Prolactin (PRL) Dopamine (-) Breast Source: Katzung BG, Masters SB, Trevor AJ: Basic and Clinical Pharmacology, 12th edition  Growth Hormone (Somatotropin) A 191-amino acid protein Effects are mediated via IGF-1 Necessary to attain normal adult size Effects on lipid, protein, and carbohydrate metabolism and on lean body mass and bone density. Increases muscle mass and reduces adiposity.  Growth Hormone Deficiency Children present with short stature and mild adiposity. There is a tendency toward hypoglycemia. In adults, GH deficiency presents as generalized obesity, reduced muscle mass, and reduced cardiac output. Most cases are treated with replacement recombinant GH (rGH).  rGH Somatropin – 191-amino acid protein identical to hGH. Somatrem – 192-amino acid protein including an extra methionine at the N- terminal.  Clinical uses of GH Primary Therapeutic Objective Clinical Condition Growth Growth failure in pediatric patients associated with: Growth hormone deficiency Chronic renal insufficiency pre-transplant Noonan syndrome Prader-Willi syndrome Short stature homeobox-containing gene (SHOX) deficiency Turner syndrome Small for gestational age with failure to catch up by age 2 years Idiopathic short stature Improved metabolic state, increased lean Growth hormone deficiency in adults body mass, sense of well-being Increased lean body mass, weight, and Wasting in patients with HIV infection physical endurance Improved gastrointestinal function Short bowel syndrome in patients who are also receiving specialized nutritional support Source: Katzung BG, Masters SB, Trevor AJ: Basic and Clinical Pharmacology, 12th edition  Side Effects of rGH Rare In children, pseudotumor cerebri, slipped capital femoral epiphysis, progression of scoliosis, edema, hyperglycemia, increased risk of diabetes. In adults, peripheral edema, myalgias, arthralgias, carpal tunnel syndrome, increased risk of diabetes.  Growth Hormone Excess If excess GH is produced before closure of the epiphyses, gigantism occurs in children. In adults, excess GH causes acromegaly.  Acromegaly Symptoms include: Enlarged hands, feet, nose Protruding jaw and brow Deepened voice Enlarged tongue Thickened skin Source: mayoclinic.org Treatment includes somatostatin analogs, GH receptor antagonists, or dopamine receptor agonists. Somatostatin Analogs -- Octreotide Somatostatin – a 14-amino acid peptide that inhibits the release of GH, TSH, glucagon, insulin, and gastrin. Octreotide – a long-acting analog of somatostatin. Inhibits GH secretion and reduces GH levels. Side effects include gallstone formation, sinus bradycardia, and Vitamin B12 deficiency with long term use. Lanreotide was recently approved for the treatment of acromegaly in the U.S.  GH Receptor Antagonists -- Pegvisomant A polyethylene glycol (PEG) derivative of a mutated form of GH. Binds to the GH receptor, but does not activate downstream signaling. Normalizes IGF-1 levels. Used for the treatment of acromegaly. Side effects rarely include increased growth of GH-secreting pituitary tumors and increased liver enzymes.  Dopamine Receptor Agonists Bromocriptine and Cabergoline Used primary for the treatment of hyperprolactinemia, but reduces GH release in patients with acromegaly. Doses required for acromegaly are higher than doses required for the treatment of hyperprolactinemia.  Prolactin A 198-amino acid protein, similar in structure to GH. Stimulates milk production. Deficiency is rare and results in the failure to lactate.  Hyperprolactinemia Most commonly caused by a prolactin- secreting adenoma (prolactinoma). Causes amenorrhea and galactorrhea in women and loss of libido and infertility in men. Hypogonadism and infertility are the result of inhibition of GnRH release.  (-) Hypothalamus Prolactin Gonadotropin-Releasing (+) Hormone (GnRH) Pituitary Luteinizing Follicle-Stimulating Hormone (LH) Hormone (FSH) (+) (+) Ovary Estrogen + Progesterone Int. J. Mol. Sci. 2013, 14 (5), 9319-9337  Dopamine Agonists for the Treatment of Hyperprolactinemia Bromocriptine and Cabergoline are high affinity dopamine D2 receptor agonists. These drugs shrink prolactinomas, lower circulating prolactin levels, and restore ovulation in some women. Can be used for the treatment of acromegaly. Side effects include nausea, orthostatic hypotension, psychiatric manifestations, pulmonary infiltrates.  Review GH deficiency – rGH Acromegaly – somatostatin analogs, GH receptor antagonists, dopamine agonists Hyperprolactinemia – dopamine agonists  The Gonadotropins LH and FSH are produced by a single type of pituitary cell, the gonadotroph. hCG is produced by the placenta. Pulses of GnRH stimulate LH and FSH release.  FSH Directs ovarian follicle development in women. Needed for ovarian steroidogenesis. Stimulates the conversion of androgens to estrogens by granulosa cells Regulator of spermatogenesis in men.  LH Needed for ovarian steroidogenesis. Stimulates androgen production by theca cells in the follicular stage of the menstrual cycle. Controls estrogen and progesterone production in the luteal phase of the menstrual cycle. (hCG takes over function if pregnancy occurs). Main stimulus for testosterone synthesis by Leydig cells in men.  Gonadotropin Preparations Administered by subcutaneous or intramuscular injection, usually on a daily basis. Used in states of infertility to stimulate spermatogenesis in men and to induce ovulation in women. Their most common use is controlled ovarian hyperstimulation in assisted reproductive technology procedures.  Gonadotropin Preparations, summarized. Drug Hormone Mechanism of Indications Side Effects Action Menotopins FSH and LH Replacements for Ovarian induction, Ovarian (hMG) from urine endogenous FSH controlled ovarian hyperstimulation and LH hyperstimulation, syndrome, Purified FSH hypogonadotropic multiple Urofollitropin hypogonadism in pregnancies, (uFSH) from urine males ovarian cysts, gynecomastia in Follitropin alfa Recombinant males and beta FSH (rFSH) Lutropin alfa Recombinant LH hCG Recombinant hCG (rhCG)  Gonadotropin-Releasing Hormone (GnRH) Secreted by neurons in the hypothalamus. Travels through the hypothalamic-pituitary venous portal plexus to the anterior pituitary. Pulsatile GnRH stimulates gonadotroph cells to produce and release LH and FSH. Nonpulsatile GnRH inhibits the release of FSH and LH from the pituitary, resulting in hypogonadism. Used to produce gonadal suppression in men with prostate cancer. Used to women undergoing assisted reproductive technology procedures.  GnRH, cont. Pulsatile IV administration of GnRH and its analogs every 1 – 4 hrs stimulates FSH and LH secretion. Continuous administration produces a biphasic response. During the first 7-10 days of treatment, gonadal hormone concentrations increase. After this period, the continual presence of GnRH or its analogs results in a drop in the concentration of gonadotropins and gonadal steroids.  GnRH Receptor Agonists GnRH analogs include leuprolide, goserelin, histrelin, nafarelin, and triptorelin. These drugs are more potent and longer-lasting than GnRH. Given subcutaneously, intramuscularly, via nasal spray (nafarelin), or as a subcutaneous implant. Treatment lengths depend on clinical use. Used for a few days for ovulation induction to a number of years for the treatment of metastatic prostate cancer.  Uses of GnRH Receptor Agonists Diagnosis of hypogonadism. Suppression of endogenous LH surge that could prematurely trigger ovulation in assisted reproductive technologies. Treatment of endometriosis, uterine fibroids, central precocious puberty, and prostate cancer. Other uses – advanced breast and ovarian cancer, amenorrhea and infertility in polycystic ovary disease Side Effects of GnRH Receptor Agonists Menopausal symptoms – hot flashes, headaches Reduced bone density/osteoporosis Ovarian cysts Temporary exacerbation of precocious puberty  GnRH Receptor Antagonists Ganirelix, cetrorelix, degarelix Inhibit the secretion of FSH and LH with no “flare” effect. Given subcutaneously. Used to prevent the LH surge during controlled ovarian hyperstimulation. Degarelix is approved for the treatment of advanced prostate cancer.  Side Effects of GnRH Receptor Antagonists Nausea, headache, injection site reactions. Continuous treatment with Degarelix can cause symptoms of androgen deprivation, including hot flashes, muscle weakness, weight gain.  Drug Hormone Mechanism Indications Side Effects Agonist or of Action Antagonist Leuprolide GnRH Produces Suppress LH surge in Menopausal Receptor initial “flare” or controlled ovarian symptoms Goserelin Agonist agonist effect hyperstimulation Histrelin followed by a Osteoporosis Nafarelin long-lasting Treatment of Triptorelin endometriosis and suppression. Ovarian cysts uterine fibroids Temporary Prostate cancer exacerbation of precocious Central precocious puberty puberty Breast and ovarian cancer, polycystic ovary disease. Ganirelix GnRH Inhibition of Suppress LH surge in Nausea, Receptor LH and FSH controlled ovarian headache, Cetrorelix Antagonist secretion hyperstimulation injection site Degarelix Prostate cancer reactions, symptoms of androgen deprivation  Other Drugs Cosyntropin – A synthetic peptide consisting of amino acids 1 – 24 of ACTH. Used in the ACTH stimulation test to diagnose pituitary-adrenal disorders. Thyrotropin alfa – Recombinant human TSH. Used to test the ability of the thyroid, both normal and malignant, to take up radioactive iodine and release thyroglobulin.  Posterior Pituitary Two hormones, vasopressin and oxytocin, are synthesized by neuronal cell bodies in the hypothalamus and are stored in and released from the posterior pituitary.  Oxytocin Stimulates the uterine contraction during labor and facilitates milk ejection in lactating women. Used to induce labor. Usually given IV via an infusion pump with appropriate fetal and maternal monitoring. Used to control postpartum bleeding. Adverse side effects include uterine hypersensitivity which can lead to fetal distress, placental abruption, or uterine rupture. High concentrations of oxytocin can activate vasopressin receptors.  Vasopressin Also known as antidiuretic hormone, ADH. Possess antidiuretic and vasopressor properties. A deficiency in vasopressin leads to diabetes insipidus (polyuria, polydipsia, hypernatremia). V1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction. Extrarenal V2 receptors regulate the release of coagulation factor VIII and von Willebrand factor.  Desmopressin Desmopressin in a long-acting synthetic analog of vasopressin with minimal pressor activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin. Vasopressin and Desmopressin are used to treat diabetes insipidus, bedwetting in children, and for the treatment of coagulopathy in hemophilia A and von Willebrand’s disease. Adverse side effects include headache, nasuea, abdominal cramps, and agitation. An overdose can cause vasoconstriction (use cautiously in patients with coronary artery disease).  Review Oxytocin Vasopressin