Anterior Pituitary Pharmacology Lecture Notes PDF

Manish Issar, Ph.D 4 Page Department of Basic Medical Sciences, PHARMACOLOGY OF ANTERIOR PITUITARY Office: Rm# 1210 at HEC (1st flr.) Email: [email protected] LEARNING OBJECTIVES: At the end of this lecture the student should be able...

Manish Issar, Ph.D 4 Page Department of Basic Medical Sciences, PHARMACOLOGY OF ANTERIOR PITUITARY Office: Rm# 1210 at HEC (1st flr.) Email: [email protected] LEARNING OBJECTIVES: At the end of this lecture the student should be able to: 1. Identify and describe various hormones that are secreted by the anterior pituitary gland. 2. Identify and describe mechanism of action of agents used to treat GH deficiency and overproduction in adults and children. 3. Identify and describe the adverse effects of agents used to treat the deficiency and hypersecretion of GH and prolactin in adults and children 4. Identify and describe the indications for use of GH, mecasermin/mecasermin rinfibate. PHARMACOLOGY OF ANTERIOR PITUITARY BACKGROUND The anterior pituitary hormones can be classified into three different groups: 1. Pro-opiomelanocortin (POMC) derived: a) Corticotropin also known as adrenocorticotropin hormone (ACTH) (will be covered under pharmacology of adrenal gland) b) α-melanocyte-stimulating hormone (α-MSH) 1. Somatotropic Hormones a) Growth Hormone (GH) b) Prolactin (PRL) 2. Glycoprotein hormones  a) Luteinizing hormone (LH) (will be covered under reproductive system, FOM7) b) Follicle stimulating hormone (FSH) (will be covered under reproductive system, FOM7) c) Human chorionic gonadotropin (hCG) (will be covered under reproductive system, FOM7) d) Thyroid stimulating hormone (TSH) (will be covered under pharmacology of thyroid gland, FOM7) The synthesis and release of anterior pituitary hormones are influenced by the central nervous system (CNS). Their secretion is positively regulated by a group of peptides referred to as HYPOTHALAMIC RELEASING HORMONES, which are released from hypothalamic neurons in the region of the median eminence and reach the anterior pituitary through the hypothalamic-adenohypophyseal portal system. The HYPOTHALAMIC- RELEASING HORMONES include: a) Corticotropin-releasing hormone (CRH) b) Growth hormone–releasing hormone (GHRH), c) Gonadotropin-releasing hormone (GnRH), d) Thyrotropin-releasing hormone (TRH). Somatostatin (SST), another hypothalamic peptide, negatively regulates secretion of pituitary GH and TSH. The neurotransmitter dopamine inhibits the secretion of prolactin by lactotropes. Here we will discuss the following in detail: TREATMENTS FOR GH DEFICIENCY SOMATOTROPINS GROWTH HORMONE (GH) Decreased GH causes DWARFISM whereas excess causes ACROMEGALY (gigantism of pituitary origin. Not all forms gigantism involves GH). GH is the only ANT PIT hormone that exerts effects on almost all tissues of body. Others have specific target organs e.g. TSH on thyroid gland; ACTH acts on adrenal cortex; FSH acts on ovaries/testes. Product(s) available as: SOMATROPIN – used to stimulate growth, whether in patients with genetic deficiency of GH or wasting associated with AIDS. In any case, can lead to a proportional increase in size of most organs except brain & eyes encased in cranium which doesn't expand much. Although GH does have direct effects on lipid & carbohydrate metabolism, anabolic (nitrogen retaining) & growth-promoting effects thought mediated by the SOMATOMEDIN an INSULIN-LIKE GROWTH FACTOR-1 (IGF-1). IGF-1 is thought to be an important mediator of GH action. When GH binds to its receptor it will lead to an increase in synthesis of IGF-1 by liver & other tissues. IGF-1 would then act on the target tissue eliciting a response via IGF-1 receptors causing cell differentiation and proliferation. (see slide #7 from ppt to compliment mechanism of action of GH) IGF-1 receptor is a tyrosine kinase & when bound by IGF leads to phosphorylation of tyrosine residues on various proteins that further leads to an increase in uptake of amino acids required for protein synthesis & cell growth. INDICATIONS FOR USE OF GH: 1. GH deficiency 2. Tx pediatric patients with short stature Prader-Willi syndrome with growth failure Turner syndrome Idiopathic short stature 3. Tx of wasting in patients with AIDS 4. Tx of patients with short bowel syndrome. SIDE-EFFECTS OF GH: Children have shown to tolerate the GH therapy well. On the contrary, adults have shown greater side effects to GH therapy. Some of the side effects that have been reported with the use of GH are given below: Pancreatitis, gynecomastia, carpal tunnel syndrome, CYP450 induction, peripheral edema, myalgias and arthalgias. Care with diabetic pts on insulin therapy. Hyperglycemia, edema, increased risk of asphyxiation in severely obese pt’s with Prader-Willi syndrome and airway obstruction. MECASERMIN/MECASERMIN RINFABATE: Mecasermin is rhIGF-I alone, while mecasermin rinfabate is a complex of rhIGF-I and recombinant human insulin-like growth factor–binding protein-3 (rhIGFBP-3). The use of IGFBP-3 protein significantly increases the circulating half-life of rhIGF-I. INDICATIONS FOR USE: A small number of children with growth failure have severe IGF-I deficiency that is not responsive to exogenous GH. Causes include mutations in the GH receptor and in the GH receptor signaling pathway, neutralizing antibodies to GH, and IGF-I gene defects. SIDE-EFFECTS: most common side-effect from use of this drug is hypoglycemia. Therefore, it is recommended to administer this drug within 20 mins of consuming a carbohydrate rich snack or meal. Other side effects may include intracranial hypertension, adenotonsillar hypertrophy. ************************* Release of endogenous GH regulated in part by SOMATOSTATIN release from HYPOTHALAMUS. As "statin" implies, effect is to inhibit release of GH whereas GHRH stimulates release GH from ANT PITUITARY. It also inhibits release of TSH & PROLACTIN from ANTERIOR PITUITARY. ************************* TREATMENTS FOR GH EXCESS (ACROMEGALY) DOPAMINE AGONISTS: In normal healthy adults, dopamine agonists cause an increase in GH production. However, patients with acromegaly when given DA agonists paradoxically suppress GH production. Dopamine agonists can be given orally and are cheaper alternatives to somatostatin receptor ligands (SRLs) are often less effective compared to SRLs. BROMOCRIPTINE – short half-life CABERGOLINE – longer half-life (~65 hrs), high affinity for D2 receptors COMMON SIDE EFFECTS: CNS symptoms include dizziness, headache, lightheadedness, fatigue. Common GI effects include and nausea and vomiting (b/c of presence of D2 receptors in area postrema which when get stimulated induce nausea and vomiting) abdominal pain or diarrhea. WARNING: Use of Cabergoline is associated with valvular heart disease in as a result of an agonist effect at serotonin 5-HT2B receptor. However, the use of lower doses in pts w/ GH access has not been reported. Thus, cardiac assessment seems appropriate in pts w/ chronic cabergoline treatments. SOMATOSTATIN (SST) ANALOGS: B/c of the short t½ & lack off specificity, SOMATOSTATIN is not suitable for clinical use but semi-synthetic analogs are used instead. Two somatostatin analogs are available in US. Octreotide – long-acting parenteral formulation (IV/SubQ) ® Sandostatin LAR - depot form used IM, 1x monthly. Lanreotide – long-acting formulation Pasireotide – long acting: i.m; 1 x month COMMON MECHANISM: act as agonists at the somatostatin receptors. COMMON SIDE EFFECTS: Most common side effects from somatostatin analog therapy are GI disturbances like diarrhea, nausea, abdominal cramps, malabsorption of fat and flatulence. These GI side effects appear in ¾ of patients being treated with these agents which subside within 2 weeks of continued use. SST analogs also inhibit CCK release and gallbladder motility, predisposing pts to the development of cholelithiasis on long term use SST analogs. Most pts are asymptomatic. GH RECEPTOR ANTAGONISTS: PEGVISOMANT – given SubQ MECHANISM: a genetically engineered GH derivative that binds to the GH receptors but fails to activate it, thus leads to inhibition of IGF-1 production by the liver. Therefore, it blocks physiological effects of GH on target tissues. SIDE EFFECTS: injection site pain, GI complaints like nausea and diarrhea, significant elevations in hepatic aminotransferase concentrations (25%), flu-like symptoms, tumor growth in small fraction of pts. --------------------------------------------------------------------- TREATMENTS FOR HYPERPROLACTIN SECRETION HYPERPROLACTINEMIA is a state of persistent serum prolactin elevation. The most common causes for elevated prolactin levels are benign prolactin-secreting pituitary tumors known as prolactinomas and various medications like dopamine receptor antagonists (antispychotics like haloperidol), SSRIs and oral contraceptives (estrogens and progestins). Dopamine is the neurotransmitter (NT) that keeps check on prolactin release. Blockade of dopamine receptors in the tuberoinfundibular pathway would cause an increase in blood prolactin levels. Thus, drugs most commonly and effectively used to reduce elevated prolactin levels are BROMOCRIPTINE and CABERGOLINE. (See details listed under dopamine agonists) ---------------------------------------------------------------------