2024-08 OLP RX411 Live session 1.pptx

2024 RX411 Live session 1 Anterior vs. posterior pituitary hormones Anterior pituitary Posterior pituitary Hypothalamic neurons release factors Hypothalamic neurons (stimulatory or inhibitory)...

2024 RX411 Live session 1 Anterior vs. posterior pituitary hormones Anterior pituitary Posterior pituitary Hypothalamic neurons release factors Hypothalamic neurons (stimulatory or inhibitory) synthesize hormones in the cell body Carried by hypothalamic-pituitary portal system to Axon transport to nerve anterior pituitary terminals in posterior pituitary. Release into Anterior pituitary neurons systemic circulation synthesize and release hormones to systemic circulation GH (growth hormone) TSH ACTH Oxytocin Gonadotropins (LH & FSH) ADH (vasopressin) PRL (prolactin) Figure 37-1, Katzung BG, Vanderah TW. eds. Basic & Clinical Pharmacology, 15th ed. McGraw-Hill; 2021 Hypothalamic-pituitary-growth hormone (GH) axis Hypothalamu Hypothalamic factors: s - GHRH ↑ GH release * Growth - SST ↓ GH release Somatosta hormone- tin releasing The gastric peptide ghrelin Anterior (SST) ↑ GH release hormone Ghrelin (GHRH) (from stomach) Pituitary Growth GH stimulates Hormone (GH) - directly target tissues Liver, bone, - indirectly to release of IGF- kidney, other 1 tissues autocrine, paracrine IGF-1 feedback inhibits Insulin-like - GH secretion growth - GHRH release factor-1 (IGF-1) Physiological effects of GH and IGF-1 GH stimulates the body to convert energy from sugar and fat to build up more muscle and bone mass. ↑glucose and lipid in blood Net effects: Anabolic IGF-1 (insulin-like growth factor 1) is the major hormone responsible for stature growth. Note GH and IGF-1 has similar effects on protein synthesis and Figure 18-6, Barrett KE, Barman SM, Brooks HL, Yuan bone growth, but opposite JJ. eds. Ganong's Review of Medical Physiology, 26e. McGraw Hill; 2019. effects on blood glucose and lipid levels. 4 Effect of Sex Steroids on Growth Stimulate IGF-1 production from cartilage Eventually cause epiphyseal closure and long bone growth cessation Prepubertal sex steroid excess (precocious puberty) causes premature - sexual maturation - growth acceleration - epiphyseal closure, resulting in adult short stature Prepubertal sex steroid deficiency causes abnormal body proportions (span>height, upper:lower segment ratio < 0.9) in adult Figures 24-8, 24-10, Barrett K, Brooks H, Boitano S, et al. eds. Ganong’s Review of Medical Physiology, 23rd ed. McGraw Hill; 2010 GH use in dairy production In 1993 FDA approved use of recombinant bovine GH (rBGH) in cows to increase milk production. Question: are you concerned about drinking milk from cows treated with recombinant bovine growth hormone (rBGH)? If residual rBGH gets into the human body, what will happen? Hypothalamic-pituitary–GH axis in health and disease Liver unresponsive to Pituitary Hypothalamus GH stimulation unresponsive to can’t secret GHRH Laron dwarfism GHRH stimulation Figure 27-3. Golan DE, Armstrong EJ, Armstrong AW. eds. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy, 4th ed. Wolters Kluwer Health; 2017 Treatment for 1°, 2°, 3° growth hormone deficiency Hypothalam Mechanism Rx indications us 3° Sermorelin Stimulates * Diagnostic evaluation no advantage – synthetic release of GH of decreased GH over GH in GHRH * HIV lipodystrophy GH- deficient GHRH children (44 aa) Tesamoreli (why?) n – GHRH analog Pituitary 2° Somatropi Acts through GH Replacement therapy in SC injection, n- receptors to GH deficiency. 6-7 GH (191 aa) recombinant increase times/weekly, production of or available human GH Liver, bone, IGF-1 as depot kidney, injection. others 1° Mecasermi Stimulate IGF-1 Replacement in IGF-1 SC injection – n receptors. deficiency that is not twice-daily or Laronrecombinant Improve growth dwarfism: autosomal responsive recessive disorder.to Insensitive once-daily. to GH stimulation, and exogenous GH. IGF-1 humanusually caused by GH receptor mutation. metabolism. Laron dwarfism (70 aa) IGF-1 Questions: 1) Can somatropin be used to treat Laron dwarfism? Why? Growth Hormone Therapy Somatropin (recombinant human GH, 191 amino-acid peptide) – Give SC once daily in evening (why?), or depot injection form Plasma t = 20 min; biological t = 9-17 hr (why?) 1/2 1/2 Measure IGF-1 to monitor initial response – Mainly used for GH deficiency in pediatric and adult patients. – Other uses include AIDS wasting and short bowel syndrome in adults Three weekly injection GH analogs have been approved by FDA since 2020 Question: think about why these structural modifications render them long- acting? Somapacitan-beco Lonapegsomatropin-tcgd Somatrogon-ghla (Sogroya®) (Skytrofa®) (Ngenla®) Approved 2020 2021 2023 in Structure Recombinant hGH Recombinant hGH Recombinant hGH conjugated with an conjugated with PEG fused with fragment of albumin-binding moiety hCG Therapeut Adults with GH deficiency Pediatric patients with growth failure due to low ic endogenous GH  Questions: Questions: 4) Which is listed as a banned 1)Why is GH given in substance by World Anti-Doping evening? Agency (WADA)? GHRH GH (somatropin, 2)Why GH has a longer somapacitan, somatrogon, lonapegsomatropin). biological half life? IGF-1 Ghrelin 3)How do determine if a patient respond well to GH 5) What adverse effects are induced by excessive use these treatment, use a quick substances without medical diagnostic test? supervision? 11 Treatment of acromegaly - summary Hypothalamu Somatostatin receptor agonists: s Octreotide, lanreotide – long acting Somatosta formulation available GHRH tin Surgery, radiation therapy – remove Pituitary pituitary tumor. GH Pegvisomant – GH receptor Liver, bone, antagonist kidney, other tissues Prevent GH receptor dimerization and activation. PEGylated – conjugated with polyethylene glycol to increase T1/2 Questions: If we want to design a novel drug to target the IGF-1 receptor to treat acromegaly, it should be receptor agonist of The hypothalamic-pituitary–gonadal axis Kisspepti n GnRH concentration is low in childhood. receptor Hypothalam At puberty GnRH secretion stimulated by us kisspeptin GnRH - Kisspeptin receptors are on GnRH neurons in hypothalamus Pituitary - Mutation of kisspeptin receptor causes failure of FSH GnRH recept puberty LH or GnRH in pulses every 60-90 min increases Gonads FSH & LH FSH/LH secretion affected by both GnRH Sex pulse amplitude and frequency steroids - Pulse frequency constant in males, variable in females Synthetic GnRH agonists and antagonists Synthetic Synthetic agonists antagonists T1/2 : ~ 3h T1/2 > 10 h Ganirelix, Leuprolide Cetrorelix, Goserelin Degarelix Histrelin (non-peptide, oral tablets) Nafarelin Elagolix Relugolix (Approved in Triptorelin 2020) GnRH Note difference in T1/2 T1/2 ~ 4 min GnRH vs. synthetic analogs – why? Millar, R. P. & Newton, C. L. (2013) Current and future applications of GnRH, kisspeptin and neurokinin B analogues Nat. Rev. Endocrinol. doi:10.1038/nrendo.2013.120 Long Acting GnRH Receptor Agonists Hypothala GnRH analogs: Leuprolide, Goserelin, Histrelin, mus Nafarelin, Triptorelin GnRH receptor agonists GnRH GnRH recept Anterioror Pulsatile administration ↑ FSH, LH Pituitary FSH Continuous administration LH ↓ FSH, LH Ovaries / Treatment for: testes ►Breast cancer, endometriosis Estrogen ►Prostate cancer, BPH Testosterone ►Precocious puberty ►Controlled ovarian hyperstimulation GnRH receptor antagonists – Clinical uses - SC injection (except elagolix and relugolix – oral use) ►Degarelix, Relugolix: approved for advanced prostate cancer ►Elagolix: approved for endometriosis ►Ganirelix, Cetrorelix: Prevent premature LH surge (which triggers ovulation) controlled infertilityovulation management Advantages over hyperstimulatio n GnRH agonists - Because of immediate effect (unlike GnRH agonists), they can be used in IVF for shorter period of time Adverse effects: Toxicity: Nausea, headache, injection-site reactions  From a clinical trial report Questions: 1) Why leuprolide induced an initial increase of testosterone level in patients? 2) What are possible advantage and disadvantage of relugolix? 18 Controlled ovarian hyperstimulation – time course 3. When oocyte is ready hCG to induce final (as assessed by medical oocyte maturation & imaging), an injection of ovulation hCG induces ovulation. hCG can activate LH receptors, and has a long 3 4. progesterone Time course of hormone Stimulate T1/2. is given daily to administration follicle maintain 1. Daily gonadotropin development pregnancy. injections to stimulate follicle 1 development 4 Long-acting GnRH 2. To prevent premature ovulation, a agonist OR antagonist 2 long-acting GnRH agonist or antagonist is given daily to Inhibit LH surge. Why to prevent premature ovulation an agonist is used longer? Figure 37-3, Katzung BG, Vanderah TW. eds. Basic & Clinical Pharmacology, 15th ed. McGraw-Hill; 2021