Posterior Pituitary Posterior Pituitary HormonesHormones

ADH (Vasopressin) & OxytocinADH (Vasopressin) & OxytocinNonapeptides (9 a.a)Nonapeptides (9 a.a)Known as neurohormonesKnown as neurohormonesSynthesized in the hypothalamusSynthesized in the hypothalamusStored in the posterior pituitary → Stored in the posterior pituitary →

releaserelease? Role as neurotransmitters (V? Role as neurotransmitters (V11R’s in R’s in

CNS)CNS)Role of Oxytocin in man is unknownRole of Oxytocin in man is unknown

ADH ( Vasopressin)ADH ( Vasopressin)Physiological and pharmacological actions:Physiological and pharmacological actions:- Vasoconstriction (V- Vasoconstriction (V11 receptors) receptors)- ↑ reabsorption of H- ↑ reabsorption of H22O from collecting O from collecting

ducts (Vducts (V22 receptors) receptors)- ↑ synthesis of certain clotting factors - ↑ synthesis of certain clotting factors

(VIII, Von Willebrand) (V(VIII, Von Willebrand) (V22 receptors) receptors)- ↑ ACTH release (V- ↑ ACTH release (V33 receptors) receptors)- Oxytocin-like activity- Oxytocin-like activity

Factors/Drugs ↑ ADH release:Factors/Drugs ↑ ADH release:- Hypovolemia, hyperosmolarity, - Hypovolemia, hyperosmolarity,

pain, stress, nausea, fever, hypoxiapain, stress, nausea, fever, hypoxia- Angiotensin II- Angiotensin II- Certain prostaglandins- Certain prostaglandins- Nicotine, cholinergic agonists, - Nicotine, cholinergic agonists, ββ--

adrenergicsadrenergics- Tricyclic antidepressants- Tricyclic antidepressants- Insulin, morphine, vincristine… - Insulin, morphine, vincristine…

Factors/Drugs ↓ ADH release:Factors/Drugs ↓ ADH release:- Hypervolemia- Hypervolemia- Hypoosmlarity- Hypoosmlarity- Alcohol- Alcohol- Atrial natriuretic peptide- Atrial natriuretic peptide- Phenytoin- Phenytoin- Cortisol- Cortisol- Anticholinergics, - Anticholinergics, αα-adrenergics, -adrenergics,

GABA...GABA...

Disorders affecting ADH release:Disorders affecting ADH release:A. Excess production (inappropriate ADH A. Excess production (inappropriate ADH

secretion) → Dilutional hyponatremiasecretion) → Dilutional hyponatremiaCauses:Causes:- Head trauma, encephalitis- Head trauma, encephalitis- Meningitis, oat cell carcinoma- Meningitis, oat cell carcinomaRRxx::- Water restriction (R- Water restriction (Rx x of choice)of choice)- Hypertonic saline solution- Hypertonic saline solution- Fludrocortisone → ↑ Na- Fludrocortisone → ↑ Na++ blood level blood level- ? ADH antagonists- ? ADH antagonists

ADH antagonistsADH antagonists- Conivaptan, V- Conivaptan, V11 & V & V22 R antagonist R antagonist

given IVgiven IV- Tolvaptan; Lixivaptan & Satavaptan, - Tolvaptan; Lixivaptan & Satavaptan,

orally effective selective Vorally effective selective V22R R antagonistsantagonists

Clinical uses:Clinical uses:- Inappropriate ADH secretion- Inappropriate ADH secretion- CHF- CHF

B. Deficiency of ADH → Diabetes B. Deficiency of ADH → Diabetes insipidus (DI)→ polyureainsipidus (DI)→ polyurea

Causes:Causes:- Idiopathic DI- Idiopathic DI- Congenital, Familial DI- Congenital, Familial DI- Hypothalamic surgery, head trauma, - Hypothalamic surgery, head trauma,

malignanciesmalignancies- Gestational DI, overproduction or - Gestational DI, overproduction or

decreased clearance of vasopressinasedecreased clearance of vasopressinaseRRxx::ADH preparations (HRT)ADH preparations (HRT)

ADH preparations:ADH preparations:- Natural human ADH (Pitressin)- Natural human ADH (Pitressin)Given I.M, S.C, has short half-life (15 min)Given I.M, S.C, has short half-life (15 min)- Lypressin (synthetic, porcine source)- Lypressin (synthetic, porcine source)Given intranasally, I.V, I.M, has short DOA Given intranasally, I.V, I.M, has short DOA

(4hrs)(4hrs)- Desmopressin (synthetic ADH-like drug)- Desmopressin (synthetic ADH-like drug)Given intranasally, S.CGiven intranasally, S.CMost widely used preparation, has long DOA Most widely used preparation, has long DOA

(12 hrs)(12 hrs)

- Felypressin (synthetic ADH-like - Felypressin (synthetic ADH-like drug)drug)

Has strong vasoconstrictor activityHas strong vasoconstrictor activityMainly used in dentistryMainly used in dentistry Clinical uses to ADH:Clinical uses to ADH:- DI- DI- Nocturnal enuresis- Nocturnal enuresis- Hemophilia- Hemophilia- Bleeding esophageal varices- Bleeding esophageal varices

Side effects to ADH preparations:Side effects to ADH preparations:- Allergy- Allergy- Pallor- Pallor- Headache, nausea, abdominal pain in ♀’s - Headache, nausea, abdominal pain in ♀’s

(oxytocin-like activity) (oxytocin-like activity) - Anginal pain (coronary artery vasospasm)- Anginal pain (coronary artery vasospasm)- H- H22O intoxication (massive doses)O intoxication (massive doses)- Gangrene (rare particularly with - Gangrene (rare particularly with

desmopressin= has great affinity to Vdesmopressin= has great affinity to V22 receptors) receptors)

Drugs acting on the uterus

I. Uterine stimulantsI. Uterine stimulants1. Oxytocin:1. Oxytocin: (nonapeptide=9 a.a peptide) (nonapeptide=9 a.a peptide)- Contracts the myoepithelial cells of the - Contracts the myoepithelial cells of the

breast → milk letdown; milk ejectionbreast → milk letdown; milk ejectionMajor stimuli, baby cry and sucklingMajor stimuli, baby cry and suckling- Contracts the uterus → delivery- Contracts the uterus → deliveryThe uterus is insensitive to oxytocin in The uterus is insensitive to oxytocin in

early pregnancy but its sensitivity early pregnancy but its sensitivity increases with advanced pregnancy increases with advanced pregnancy reaching maximum at time of deliveryreaching maximum at time of delivery

- Has slight ADH-like activity- Has slight ADH-like activity

Oxytocin MOA:Oxytocin MOA:- Surface receptors → stimulation of - Surface receptors → stimulation of

voltage-sensitive Cavoltage-sensitive Ca++++ channels → channels → depolarization of uterine muscles → depolarization of uterine muscles → contractionscontractions

- ↑ intracellular Ca- ↑ intracellular Ca++++

- ↑ prostaglandin release - ↑ prostaglandin release

Clinical uses to oxytocin:Clinical uses to oxytocin:- Induction of labor- Induction of laborDrug of choice given in units in an I.V infusionDrug of choice given in units in an I.V infusion- Postpartum hemorrhage, I.M. Ergot alkaloids - Postpartum hemorrhage, I.M. Ergot alkaloids

arearebetter (ergonovine, methylergonovine, better (ergonovine, methylergonovine,

syntometrine=syntometrine=oxytocin+ ergometrine)oxytocin+ ergometrine)- Breast engorgement, intranasally- Breast engorgement, intranasally- Abortifacient, I.V infusion. ≥ 20 weeks of - Abortifacient, I.V infusion. ≥ 20 weeks of

gestation, ineffective in early pregnancygestation, ineffective in early pregnancy

Side effects to oxytocin:Side effects to oxytocin:- Rupture of the uterus- Rupture of the uterusMajor and most serious side effectMajor and most serious side effect- H- H22O intoxication and hypertensionO intoxication and hypertensionDue to its ADH-like activityDue to its ADH-like activity Specific oxytocin antagonistSpecific oxytocin antagonistAtosiban (inhibitor to uterine Atosiban (inhibitor to uterine

contraction=tocolytic), effective in the contraction=tocolytic), effective in the management of premature delivery, given management of premature delivery, given IVIV

2. Prostaglandins:2. Prostaglandins:* Dinoprostone (PGE* Dinoprostone (PGE22))Vaginal pessaries, inserts and gel, Vaginal pessaries, inserts and gel,

tabtabAbortifacient, induction of laborAbortifacient, induction of labor* Dinoprost (PGF* Dinoprost (PGF22αα))I.V infusion and intramniotic I.V infusion and intramniotic Same uses as dinoprostoneSame uses as dinoprostone

* Carboprost (PGF* Carboprost (PGF22αα))I.M and intramnioticI.M and intramnioticAbortifacient and postpartum hemorrhageAbortifacient and postpartum hemorrhage* Gemeprost (PGE* Gemeprost (PGE11))Vaginal pessariesVaginal pessariesUsed to prime the cervixUsed to prime the cervix3. Ergot alkaloids:3. Ergot alkaloids:Ergonovine, MethylergonovineErgonovine, MethylergonovineI.M, oralI.M, oral

Ergot alkaloids remain the drugs of choice Ergot alkaloids remain the drugs of choice to manage postpartum hemorrhage to manage postpartum hemorrhage

As compared to oxytocin, ergot alkaloids As compared to oxytocin, ergot alkaloids are more potent, they produce more are more potent, they produce more prolonged and sustained contractions of prolonged and sustained contractions of the uterus and they are less toxicthe uterus and they are less toxic

Ergot alkaloids are contraindicated to be Ergot alkaloids are contraindicated to be used as inducers to delivery (associated used as inducers to delivery (associated with high incidence of fetal distress and with high incidence of fetal distress and mortality) mortality)

II. Uterine relaxants (Tocolytics)II. Uterine relaxants (Tocolytics)Major clinical use: premature delivery Major clinical use: premature delivery

(weeks 20-36) → improve the survival (weeks 20-36) → improve the survival of the newbornof the newborn

1. 1. ββ-adrenergic agonists:-adrenergic agonists:↑ ↑ cAMP → ↓ cytoplasmic CacAMP → ↓ cytoplasmic Ca++++

* Ritodrine* RitodrineI.V infusionI.V infusionMost widely used Most widely used * Terbutaline, Oral, S.C, I.V* Terbutaline, Oral, S.C, I.V

Side Effects to Side Effects to ββ-adrenergics:-adrenergics:Sweating, tachycardia, chest pain…Sweating, tachycardia, chest pain…2. Magnesium sulfate2. Magnesium sulfateI.V infusionI.V infusionActivates adenylate cyclase and Activates adenylate cyclase and

stimulates Castimulates Ca++++ dependent ATPase dependent ATPaseUses: premature delivery and Uses: premature delivery and

convulsions of pre- eclampsiaconvulsions of pre- eclampsia

3. Progesterone3. ProgesteroneOral, I.MOral, I.MDydrogesteroneDydrogesterone4. Oxytocin competitive antagonists4. Oxytocin competitive antagonistsAtosibanAtosiban5. Prostaglandin synthesis inhibitors5. Prostaglandin synthesis inhibitorsIndomethacin, MeloxicamIndomethacin, Meloxicam6. Nifedipine6. Nifedipine** Major contraindication to tocolytics: ** Major contraindication to tocolytics:

fetal distressfetal distress