Endocrine Pharmacology Hypothalamic Pituitary Hormones Overview of Endocrine Pharmacology o Terminology endocrine hormones vs neurotransmitters secreted into circulation by endocrine glands act on target cells tissues by binding to specific receptors locally acting on cells that surround the cell that produced it paracrine hormones autocrine hormones prohormones neurohormones boundary between the nervous and endocrine releasing and inhibiting hormones that are released hypothathalmus and regulate the P pituitary o General Mechanisms of Hormone Action Membrane bound receptors increasing or decreasing intracellular second messengers like c AMP controlling membrane permeability ionic movements Nuclear receptors In nucleus or cytoplasm that is bound to a chaperone a chemical that perseveres it act as transcription factors usually promoting or reducing the biosynthesis of specific proteins that subserve hormone related functions chaperone have two binding sites 1 for the DBD and 1 for the hormone GI contraction secretion energy production ECF vol composition adaption growth development o normally effet protein synthesis all steroidal class of hormones and T3 o Hormones regulate vital functions reproduction lactation Endocrine Glands Hormones o Review your physiology know major hormones glands target tissues major actions review how hormone secretion levels is regulated Hormonal Drugs Have Many Uses by negative feedback by external stimuli o Physiological dose replacement therapy for hormone deficiencies only giving enough hormone to restore the normal function could be another hormone o Pharmacological dose i e anti inflammatory use of glucocorticoids careful can shut down adrenal glands severe side effects use NSAIDS before the use of glucocortiocoids o Diagnosis o Futuristic use life extension of endocrine disorders strategies anti aging agents o Drugs to treat over secretion syndromes Too much of one hormone suppressed its secretion negative feedback hormone receptor antagonists hormone biosynthesis enzyme inhibitors Physiology Pharmacology of Pituitary Gland o Anatomical organization hypothalamic hypophyseal portal circulation inhibiting hormones from the hypothalamus neurosecretory cells o Anterior pituitary hormones GH FSH LH TSH ACTH prolactin o Posterior pituitary hormones oxytocin vasopressin ADH o Regulation of pituitary gland Growth Hormone o A heterogenous mixture of peptides main form 191 amino acids 2 disulfide bridges o Normal secretion pattern high in children peaks in adolescence declines during adulthood pulsatile release maximal after onset of deep sleep many factors inhibit release GH IGF 1 adrenergic agonists free fatty acids many factors promote release Growth Hormone Replacement Drugs o GH extracted from cadavers historical o Somatropin recombinant rGH genetically engineered synthetic human GH can only use human growth hormone Somatrem GH analog with an added methionine group equieffective to somatropin but more antigenic DA 5 HT adrenergic agonists hypoglycemia exercise stress emotional states protein rich meals o administered SC self or IM patient parents need to learn sterile injection technique o used to get the GH from cadavers but this promoted the spread of slow growing viruses Growth Hormone Deficiency o Usually congenital idiopathic can also be acquired o GH deficiency in small children results in short stature dwarfism o GH deficiency in adults no obvious problems possibly reduced physical mobility socialization energy levels possibly greater risk of c v disease most often related to hypopituitarism from a pituitary tumor or following removal of the anterior pituitary Growth Hormone o Indications o Abuse Potential competitive athletes Growth Hormone Actions Growth failure due to inadequate GH secretion Anabolic agents to treat severe catabolic states o Direct Effects GH binds to GH receptor are potentiated by glucocorticoids stimulation of IGF 1 production in liver other tissues stimulation of triglyceride hydrolysis in adipose tissue stimulation of hepatic glucose output Note direct effects of GH are opposite the effects of insulin IGF 1 on fat CHO metabolism o Indirect Effects via IGF 1 binding to IGF receptor inhibited by glucocorticoids IGF 1 mediates anabolic growth promoting actions increases organ size by increasing number of cells blocks actions of receptor bound insulin to induce insulin resistance glucose intolerance Growth Hormone o Contraindications o Precaution o Adverse Effects Growth Hormone Excess o Children o Adults o Drug Treatments pts with closed epiphyses will have no effect neoplastic disease cancerous tumors accelerate cancerous disease risk of hyperglycemia secondary to insulin resistance in diabetic pts common joint muscle pain serious insulin resistance hypothyroidism GH antibodies acceleration of tumor growth gigantism accelerated linear bone growth before epiphyses close acromegaly over growth of the soft tissues face hands feet after epiphyses have closed DA agonists paradoxical action Somatostatin analogs Octreotide tid injections LA inject q 4 wks lanreotide GH antagonists Pegvisomant binds GH receptor but does not activate Jak signaling or increase IGF 1 Octreotide o Only approved analog of somatostatin GHIF Shorter molecule of somatostatin less inhibition of insulin release compared to somatostatin longer half life 1 7hrs vs 1 3min Somatostatin receptors wide distribution including CNS GI tract pancreas o Therapeutic uses treatment of acromegaly hyperinsulinemia due to insulinoma xs secretions associated GI endocrine tumors severe diarrhea due to carcinoid tumors or HIV unresponsive to other txs other off label control bleeding varices IBS dumping syndrome Hypothalamic Control of the Anterior Pituitary o Hypothalamic releasing factors hormones nuerohormones Nuerosecretory cells in the hypothalamus travel down the cells where they will be held in pituitary GHRH GHIH GnRH CRH TRH PIF all short polypeptides except PIF short half lives 3 18 min modify secretion of AP hormones mainly diagnostic use limited therapeutic use pulsatile release reach AP via hypothalamic hypophyseal portal circulation GnRH Receptor Agonists o Endogenous GnRH release is pulsatile frequency amplitude of release determine relative secretion of FSH LH release normally under negative feedback control high levels of FSH and or LH reduce release EXCEPTION just prior to FSH LH surge triggers ovulation estradiol stimulates GnRH release Becomes a