Chapter A9: Octreotide

INTRODUCTION

Octreotide is a long-acting, synthetic octapeptide analog of somatostatin, a hormone that inhibits the release of numerous anterior pituitary and gastrointestinal hormones, including pancreatic insulin. It is the essential complement to dextrose (Antidotes in Depth: A8) for the treatment of refractory hypoglycemia induced by overdoses of inhibitors of insulin secretagogues such as sulfonylureas (and rarely the meglitinides) and quinine (and rarely other quinolones).

HISTORY

Somatostatin is a collective term for shorter fragments (SRIF-28, SRIF-25, and SRIF-14) cleaved from preprosomatostatin (116 amino acids) and prosomatostatin (92 amino acids).¹⁷ In 1973 during the search for growth hormone–releasing factor, somatostatin was identified as a growth hormone inhibitor.¹⁵ Somatostatin has far-reaching effects as a central nervous system (CNS) neurotransmitter and as a modulator of hormonal release.^64,75 The importance of somatostatin on insulin secretion led to the need to create an analog as a therapeutic tool, as somatostatin use is limited by its short duration of action. Octreotide was synthesized in 1982 in an effort to develop a longer-acting somatostatin analog.⁷ Octreotide is currently approved by the FDA for the treatment of acromegaly, carcinoid tumors, and vasoactive intestinal peptide tumors. It is also used therapeutically for the treatment of pituitary adenomas, pancreatic islet cell tumors, portal hypertension, esophageal varices, and secretory diarrhea.⁶⁴

PHARMACOLOGY

Mechanism of Action on Insulin Secretion

The effects of somatostatin are mediated by high-affinity binding to membrane receptors on target tissues. The six different known somatostatin receptor subtypes belong to a superfamily of G-protein coupled receptors and are identified and assigned numbers (SSTR1–SSTR5) according to their order of discovery, with SSTR2 having 2 splice variants (SSTR2A and SSTR2B).^17,23,76,88 By sequence homology, SSTR2, SSTR3, and SSTR5 belong to one group, which bind the classic somatostatin receptor ligands (SRLs), whereas SSTR1 and SSTR4 do not.⁷⁶ Somatostatin receptor type 2 (SSTR2) is found in the brain, pituitary, stomach, liver, kidney, lung, intestine, spleen, thymus, uterus, prostate, and adrenal gland; SSTR5 is found in brain, pituitary, stomach, intestine, thyroid, and adrenal gland.^64,72,84,108 These varied SSTR targets underlie the use of SRLs in acromegaly; carcinoid, vasoactive intestinal peptide, and neuroendocrine tumors; portal hypertension; esophageal varices; and secretory diarrhea.⁶⁴ The pancreas contains all 5 subtypes, but SSTR5 is more prevalent in the β-cells and SSTR2 is more prevalent in the α-cells in mice.¹⁰⁸ In humans, SSTR2 is the functionally dominant somatostatin receptor in pancreatic β- and α-cells.^55,72

Experiments in both healthy human volunteers and an isolated perfused canine pancreas model demonstrate the ability of somatostatin to inhibit glucose-stimulated insulin release.^2,36 In pancreatic β-cells that hypersecrete insulin through targeted mutagenesis of the sulfonylurea receptor, octreotide suppresses C-peptide, and insulin release.⁴⁶ Somatostatin inhibits ...