OXYTOCIN Is synthesized in the PVN (SON) Is synthesized in the PVN (SON) (luteal cells, endometrium, and the placental) Oxytocin-neurophysin complex Oxytocin-neurophysin complex Neurohypophysis, hypothalamus, brain stem, and spinal cord Neurohypophysis, hypothalamus, brain stem, and spinal cord

OXYTOCIN Stimuli for secretion: dilation of the cervix, vagina and from suckling at the breast Stimuli for secretion: dilation of the cervix, vagina and from suckling at the breast Estradiol and Relaxin Estradiol and Relaxin Ethanol, pain, dehydration, hemorrhage and hypovolemia Ethanol, pain, dehydration, hemorrhage and hypovolemia

Physiological Roles of Oxytocin Uterus (estrogen and progestrone) Uterus (estrogen and progestrone) Breast (milk ejection) Breast (milk ejection) Oxytocin receptors (PG production) Oxytocin receptors (PG production)

Clinical Use of Oxytocin Induction of labor Induction of labor Augmentation of labor Augmentation of labor Third stage of labor and puerperium Third stage of labor and puerperium Oxytocin challenge test Oxytocin challenge test Oxytocin-receptor antagonists (Atosiban) Oxytocin-receptor antagonists (Atosiban)

Vasopressin and Other Agents Affecting the Renal Conservation of Water

INTRODUCTION TO VASOPRESSIN ADH ADH Vasopressor Vasopressor Neurotransmitter Neurotransmitter Secretion of ACTH Secretion of ACTH Regulation of CVS Regulation of CVS Temperature Temperature Visceral functions Visceral functions Promotes the release of coagulation factors Promotes the release of coagulation factors Platelet aggregability Platelet aggregability

Physiology of Vasopressin Anatomy (hypothalamiconeurohypophyseal system, and renal collecting-duct system) Anatomy (hypothalamiconeurohypophyseal system, and renal collecting-duct system) Synthesis (SON, PVN) Synthesis (SON, PVN) Parvicellular neurons Parvicellular neurons Synthesis Synthesis Transport and storage Transport and storage Release Release

Vasopressin Synthesis Outside the CNS Heart (elevated wall stress) Heart (elevated wall stress) Adrenal Gland (catecholamine secretion) Adrenal Gland (catecholamine secretion)

Regulation of Vasopressin Secretion Hyperosmolality (osmoreceptive complex) Hyperosmolality (osmoreceptive complex) SFO, OVLT, MnPO (Aquaporin 4) SFO, OVLT, MnPO (Aquaporin 4) Hepatic Portal Osmoreceptors Hepatic Portal Osmoreceptors Hypovolemia and hypotension (baroreceptors in the left atrium, left ventricle, pulmonary veins, carotid sinus and aorta) Hypovolemia and hypotension (baroreceptors in the left atrium, left ventricle, pulmonary veins, carotid sinus and aorta) Pain, nausea, and hypoxia Pain, nausea, and hypoxia

Modulation of Vasopressin Secretion Stimulators ACh (nAChR) ACh (nAChR) Histamine (H1 receptors) Histamine (H1 receptors) Dopamine (D1 and D2 receptors) Dopamine (D1 and D2 receptors) Glutamine Glutamine Aspartate Aspartate CCK, NPY, SP, VIP, PGs, Ag ΙΙ, Ag III CCK, NPY, SP, VIP, PGs, Ag ΙΙ, Ag III Inhibitors ANP GABA Opioids

Pharmacological Agents of Vasopressin Secretion Vincristine Vincristine Cyclophosphamide Cyclophosphamide TCAs TCAs Nicotine Nicotine Epinephrine Epinephrine Morphine (HD) Morphine (HD) Lithium Lithium Ethanol Phenytoin Morphine (LD) Fluphenazine Haloperidol Promethazine Carbamazepine

Basic Pharmacology of Vasopressin Vasopressin receptors (V1a, V1b, and V2) Vasopressin receptors (V1a, V1b, and V2) V1 receptors: Gq-PLC pathway V1 receptors: Gq-PLC pathway V2 receptors: Gs-AC pathway V2 receptors: Gs-AC pathway

Mechanisms by which vasopressin increases the renal conservation of water

Pharmacological Modifications of Antidiuretic Response to Vasopressin NSAIDs (indomethacin) NSAIDs (indomethacin) Carbamazepine Carbamazepine Chlorpropamide Chlorpropamide Lithium (PTH) Demeclocycline

Nonrenal Actions of Vasopressin Cardiovascular System Cardiovascular System Central Nervous System Central Nervous System (learned behaviors, depression, antipyretic factors, modulation CNS autonomic systems, and secretion of ACTH) Blood coagulation (V2 receptors) Blood coagulation (V2 receptors) Contraction of uterus, GIT, platelet aggregation and glycogenolysis Contraction of uterus, GIT, platelet aggregation and glycogenolysis

Vasopressin Receptor Agonists and Antagonists Arginine vasopressin (AVP) Arginine vasopressin (AVP) Desmopressin (DDAVP) Desmopressin (DDAVP) Mozavaptan Mozavaptan Telipressin (Glypressin) Telipressin (Glypressin)

Vasopressin Receptor Agonists And Antagonists V 1 R agonistTerlipressin V 1 R antagonistRelcovaptan V 1 R /V 2 R antagonistConivaptan V 2 R antagonistMozavaptan V 2 R antagonistTolvaptan

Diseases Affecting the Vasopressin system Diabetes Insipidus (DI) Diabetes Insipidus (DI) Central DI Nephrogenic DI SIADH ( lethargy, anorexia, nausea, vomiting, muscle cramp, coma, convulsions, and death) SIADH ( lethargy, anorexia, nausea, vomiting, muscle cramp, coma, convulsions, and death)

Clinical Summary: Pharmacology of Vasopressin Peptides V1 receptor-mediated therapeutic applications Post operative ileus Post operative ileus Dispel intestinal gas Dispel intestinal gas Esophageal varices Esophageal varices Portal hypertension Portal hypertension Reduce bleeding during acute hemorrhagic gastritis Reduce bleeding during acute hemorrhagic gastritis Burn wound excision Burn wound excision cyclophosphade- induced hemorrhagic cystitis Liver transplantation Cesarean section Uterine myoma resection Vasodilatory shock Asystole

‍ Clinical Summary: Pharmacology of Vasopressin Peptides V2 receptor-mediated therapeutic applications V2 receptor-mediated therapeutic applications Water conservation Water conservation Release of blood coagulation factors (type I vWB, type IIn vWB, factor VIII, uremia and cirrhosis) Release of blood coagulation factors (type I vWB, type IIn vWB, factor VIII, uremia and cirrhosis) Primary nocturnal enuresis Primary nocturnal enuresis Relieve post-lumbar puncture headache Relieve post-lumbar puncture headache

Toxicity, Adverse Effects, Contraindications, and Drug Interactions Marked facial pallor Marked facial pallor Increased intestinal activity Increased intestinal activity Coronary circulation (CAD) Coronary circulation (CAD) Water intoxication Water intoxication Acute renal failure Acute renal failure Angina, hypertension, and heart failure Angina, hypertension, and heart failure Primary or psychogenic polydipsia Primary or psychogenic polydipsia Allergic reactions Allergic reactions Local adverse effects Local adverse effects

Future Directions in Vasopressin Analogues V1a selective antagonists Dysmenorrhea Dysmenorrhea Preterm Labor Preterm Labor Raynoud ’ s syndrome Raynoud ’ s syndrome

Future Directions in Vasopressin Analogues V1b selective antagonists Stress-related disorders Stress-related disorders Anxiety Anxiety Depression Depression ACTH-secreting tumors ACTH-secreting tumors Cushing ’ s syndrome Cushing ’ s syndrome

Future Directions in Vasopressin Analogues V2 selective antagonists Heart failure Heart failure SIADH SIADH Cirrhosis Cirrhosis Hyponatremia Hyponatremia Brain edema Nephrotic syndrome Diabetic nephropathy Glucoma

Future Directions in Vasopressin Analogues V2 selective agonists Central DI Central DI Nocturnal enuresis Nocturnal enuresis Nocturnal polyuria Nocturnal polyuria Urinary incontinence Urinary incontinence