OXYTOCINOXYTOCIN

Is synthesized in the PVN (SON)Is synthesized in the PVN (SON)(luteal cells, endometrium, and the (luteal cells, endometrium, and the

placental)placental)

Oxytocin-neurophysin complexOxytocin-neurophysin complex

Neurohypophysis, hypothalamus, Neurohypophysis, hypothalamus, brain stem, and spinal cordbrain stem, and spinal cord

OXYTOCINOXYTOCIN

Stimuli for secretion: dilation of Stimuli for secretion: dilation of the cervix, vagina and from the cervix, vagina and from suckling at the breastsuckling at the breast

Estradiol and RelaxinEstradiol and Relaxin

Ethanol, pain, dehydration, Ethanol, pain, dehydration, hemorrhage and hypovolemiahemorrhage and hypovolemia

Physiological Roles of Physiological Roles of OxytocinOxytocin

Uterus (estrogen and Uterus (estrogen and progestrone)progestrone)

Breast (milk ejection)Breast (milk ejection)

Oxytocin receptors (PG Oxytocin receptors (PG production)production)

Clinical Use of OxytocinClinical Use of Oxytocin Induction of laborInduction of labor

Augmentation of laborAugmentation of labor

Third stage of labor and puerperiumThird stage of labor and puerperium

Oxytocin challenge testOxytocin challenge test

Oxytocin-receptor antagonists Oxytocin-receptor antagonists (Atosiban)(Atosiban)

Vasopressin and Vasopressin and Other Agents Other Agents Affecting the Affecting the

Renal Renal Conservation of Conservation of

WaterWater

INTRODUCTION TO INTRODUCTION TO VASOPRESSINVASOPRESSIN

ADH ADH VasopressorVasopressor NeurotransmitterNeurotransmitter Secretion of ACTHSecretion of ACTH Regulation of CVSRegulation of CVS TemperatureTemperature Visceral functionsVisceral functions Promotes the release of Promotes the release of

coagulation factorscoagulation factors Platelet aggregabilityPlatelet aggregability

Physiology of Physiology of VasopressinVasopressin

Anatomy Anatomy (hypothalamiconeurohypophyseal (hypothalamiconeurohypophyseal system, and renal collecting-duct system, and renal collecting-duct system)system)

Synthesis (SON, PVN)Synthesis (SON, PVN) Parvicellular neuronsParvicellular neurons SynthesisSynthesis Transport and storageTransport and storage ReleaseRelease

Vasopressin Synthesis Vasopressin Synthesis Outside the CNSOutside the CNS

Heart (elevated wall stress)Heart (elevated wall stress)

Adrenal Gland Adrenal Gland (catecholamine secretion)(catecholamine secretion)

Regulation ofRegulation of Vasopressin Vasopressin SecretionSecretion

Hyperosmolality (osmoreceptive complex)Hyperosmolality (osmoreceptive complex) SFO, OVLT, MnPO (Aquaporin 4)SFO, OVLT, MnPO (Aquaporin 4) Hepatic Portal OsmoreceptorsHepatic Portal Osmoreceptors

Hypovolemia and hypotension Hypovolemia and hypotension (baroreceptors in the left atrium, left (baroreceptors in the left atrium, left ventricle, pulmonary veins, carotid sinus ventricle, pulmonary veins, carotid sinus and aorta)and aorta)

Pain, nausea, and hypoxiaPain, nausea, and hypoxia

Modulation of Vasopressin Modulation of Vasopressin SecretionSecretion

StimulatorsStimulators ACh (nAChR)ACh (nAChR) Histamine (H1 Histamine (H1

receptors)receptors) Dopamine (D1 and Dopamine (D1 and

D2 receptors)D2 receptors) GlutamineGlutamine AspartateAspartate CCK, NPY, SP, CCK, NPY, SP,

VIP, PGs, Ag VIP, PGs, Ag ΙΙΙΙ, Ag , Ag IIIIII

InhibitorsInhibitors ANPANP GABAGABA OpioidsOpioids

Pharmacological Agents of Pharmacological Agents of Vasopressin SecretionVasopressin Secretion

VincristineVincristine CyclophosphamiCyclophosphami

dede TCAsTCAs NicotineNicotine EpinephrineEpinephrine MorphineMorphine (HD) (HD) LithiumLithium

EthanolEthanol PhenytoinPhenytoin Morphine (LD) Morphine (LD) FluphenazineFluphenazine HaloperidolHaloperidol PromethazinePromethazine CarbamazepineCarbamazepine

Basic Pharmacology of Basic Pharmacology of VasopressinVasopressin

Vasopressin receptors (V1a, V1b, Vasopressin receptors (V1a, V1b, and V2)and V2)

V1 receptors: Gq-PLC pathwayV1 receptors: Gq-PLC pathway

V2 receptors:V2 receptors: Gs-AC pathwayGs-AC pathway

Mechanisms by which vasopressin Mechanisms by which vasopressin increases the renal conservation of increases the renal conservation of

waterwater

Pharmacological Pharmacological Modifications of Modifications of

Antidiuretic Response to Antidiuretic Response to VasopressinVasopressin

NSAIDs NSAIDs (indomethacin)(indomethacin)

CarbamazepineCarbamazepine

ChlorpropamideChlorpropamide

Lithium (PTH)Lithium (PTH)

DemeclocyclineDemeclocycline

Nonrenal Actions of Nonrenal Actions of VasopressinVasopressin

Cardiovascular SystemCardiovascular System Central Nervous SystemCentral Nervous System(learned behaviors, depression, antipyretic (learned behaviors, depression, antipyretic

factors, modulation CNS autonomic factors, modulation CNS autonomic systems, and secretion of ACTH)systems, and secretion of ACTH)

Blood coagulation (V2 receptors)Blood coagulation (V2 receptors) Contraction of uterus, GIT, platelet Contraction of uterus, GIT, platelet

aggregation and glycogenolysisaggregation and glycogenolysis

Vasopressin Receptor Vasopressin Receptor Agonists and AntagonistsAgonists and Antagonists

Arginine vasopressin (AVP)Arginine vasopressin (AVP)

Desmopressin (DDAVP)Desmopressin (DDAVP)

MozavaptanMozavaptan

Telipressin (Glypressin)Telipressin (Glypressin)

Vasopressin Receptor Agonists And Antagonists

TerlipressinV1R agonist

RelcovaptanV1R antagonist

ConivaptanV1R /V2R antagonist

MozavaptanV2R antagonist

TolvaptanV2R antagonist

Diseases Affecting the Diseases Affecting the Vasopressin systemVasopressin system

Diabetes Insipidus (DI)Diabetes Insipidus (DI)Central DICentral DI

Nephrogenic DINephrogenic DI

SIADH ( lethargy, anorexia, SIADH ( lethargy, anorexia, nausea, vomiting, muscle cramp, nausea, vomiting, muscle cramp, coma, convulsions, and death)coma, convulsions, and death)

Clinical Summary: Clinical Summary: Pharmacology of Pharmacology of

Vasopressin PeptidesVasopressin Peptides V1 receptor-mediated V1 receptor-mediated

therapeutic applicationstherapeutic applications Post operative ileusPost operative ileus Dispel intestinal Dispel intestinal

gasgas Esophageal varicesEsophageal varices Portal hypertensionPortal hypertension Reduce bleeding Reduce bleeding

during acute during acute hemorrhagic hemorrhagic gastritisgastritis

Burn wound Burn wound excisionexcision

cyclophosphade-cyclophosphade-induced induced hemorrhagic hemorrhagic cystitiscystitis

Liver Liver transplantationtransplantation

Cesarean sectionCesarean section Uterine myoma Uterine myoma

resectionresection Vasodilatory shockVasodilatory shock AsystoleAsystole

Clinical Summary: Clinical Summary: Pharmacology of Pharmacology of

Vasopressin PeptidesVasopressin Peptides V2 receptor-mediated V2 receptor-mediated

therapeutic applicationstherapeutic applications Water conservationWater conservation Release of blood coagulation Release of blood coagulation

factors (type I vWB, type IIn vWB, factors (type I vWB, type IIn vWB, factor VIII, uremia and cirrhosis)factor VIII, uremia and cirrhosis)

Primary nocturnal enuresisPrimary nocturnal enuresis Relieve post-lumbar puncture Relieve post-lumbar puncture

headacheheadache

Toxicity, Adverse Effects, Toxicity, Adverse Effects, Contraindications, and Contraindications, and

Drug InteractionsDrug Interactions Marked facial pallorMarked facial pallor Increased intestinal activityIncreased intestinal activity Coronary circulation (CAD)Coronary circulation (CAD) Water intoxicationWater intoxication Acute renal failureAcute renal failure Angina, hypertension, and heart Angina, hypertension, and heart

failurefailure Primary or psychogenic polydipsiaPrimary or psychogenic polydipsia Allergic reactionsAllergic reactions Local adverse effectsLocal adverse effects

Future Directions in Future Directions in Vasopressin AnaloguesVasopressin Analogues

V1a selective antagonistsV1a selective antagonists DysmenorrheaDysmenorrhea

Preterm LaborPreterm Labor

RaynoudRaynoud’’s syndromes syndrome

Future Directions in Future Directions in Vasopressin AnaloguesVasopressin Analogues

V1b selective antagonists V1b selective antagonists Stress-related disordersStress-related disorders

AnxietyAnxiety

DepressionDepression

ACTH-secreting tumorsACTH-secreting tumors

CushingCushing’’s syndrome s syndrome

Future Directions in Future Directions in Vasopressin AnaloguesVasopressin Analogues

V2 selective antagonistsV2 selective antagonists

Heart failureHeart failure

SIADHSIADH

CirrhosisCirrhosis

HyponatremiaHyponatremia

Brain edemaBrain edema

Nephrotic Nephrotic syndromesyndrome

Diabetic Diabetic nephropathynephropathy

GlucomaGlucoma

Future Directions in Future Directions in Vasopressin AnaloguesVasopressin Analogues V2 selective agonistsV2 selective agonists

Central DICentral DI

Nocturnal enuresisNocturnal enuresis

Nocturnal polyuriaNocturnal polyuria

Urinary incontinenceUrinary incontinence