Transcript Pharmacology of Uterotonics

Oxytocin
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Oxytocin
Prostaglandin
Ergot alkaloid
Progesterone antagonist
Tocolytics
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-adrenergist agonist
Ca2+-channel blocker
PG-synthase inhibitors
Magnesium Sulfate
Ethanol
Biosynthesis
• a cyclic non peptic, structurally similar to
vasopressin
• synthesized as a larger precursor molecul
• rapidly broken down to the active hormone
• packaged into secretory granules as and oxytocinneurophysin complexs
• secreted from nerve ending primarily in the
posterior pituitary gland (neurohypophyses)
Uterus
Stimulates contraction : frequency and force
highly dependent on estrogen
immature uterus : resistance
Responsiveness : paralel to spontaneous activity
Exogenous oxytocin : enhance rythmic contraction
high dose for early pregnancy
Breast
milk ejection
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Oxytocin
1,4,5 triphosphate
• mobilization Ca2+ intracellular
• activation voltage-sensitive Ca2+ channels
Local prostaglandin production
• Induction of labor (selected)
risk of continued pregnancy
isoimmunization
intrauterine growth retardation
placental insufficiency
• Augmentation of labor
should not be used : progressing normally
hypotonic contraction in disfunctional labor
complication : trauma of the mother / fetoes
uterine rupture compromized
fetal oxygenation
very prolong latent phase of cervical dilation
arrest / descent of dilation
epidural anesthesia
• Third stage of labor and puerperium
after delivery or following therapeutic abortion
• Oxytocin challenge test
pregnancy hold increased risk for maternal or
fectal complication
• Oxytocin receptor antagonists
competitively inhibit the interaction of oxytocin
with its membran receptor
potential use in the treatment of preterm labor
HPETEs
Inhibitors of Eicosanoid Biosynthesis
• Calcium reducer
• Glucocorticoids
• NSAIDs
• Analogs of the natural fatty acid
precursores
Cardiovascular system
prostaglandin
tromboxan A2
leukotriens
Blood
Smooth muscle
bronchial and tracheal
uterus
continued
PGFs
contracted
TXA
PGEs : relaxes
Non pregnant : contractile > before menstruation
relaxation > midcycle
Pregnant :
PGFs
contracted
low concentration PGE2
high concentration PGE2
relaxed
PGI2
Tone, frequency & intensity of
iv PGE2
rhytmic contraction >
PGF2
continued
Gastric and intestinal secretion
Kidney and Urine Formation
Central Nervous System
Endocrine
Metabolic effects
 Therapeutic abortion
abortifacients when given early in pregnancy
dinoprostone (PGE2)
misoprostol (PGE1) + mifepristone or methotrexate
 Gastric Cytoprotection
 Impotence
 Maintenance of Patent Ductus Arteriosus
Pharmacokinetic
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Absorption : variably from GI tract
Oral dose of ergotamine 10x > im dose
speed of absorption and peak blood level can
be improved with caffeine
Also absorbed from buccal cavity, rectum and
after aerosol inhaler
• Metabolism : extensive
A MOA :
agonist
at -adrenoceptor &
partial agonist
serotonin receptor
antagonist
agonist at dopamine CNS receptor
uterus : agonist / partial agonist at 5-HT2R
B Organ system effects
CNS
Vascular smooth muscle
Uterine smooth muscle
Other smooth muscle
Clinical Uses :
A. Migraine
B. Hyperprolactinemia
C. Postpartum hemorrhage
D. Diagnosis of Variant Angina
E. Senile Cerebral Insufficiency
Toxicity :
- gastrointestinal
- medullary vomiting centre
- prolong vasospasm
* large doses of nitroprusside
- fibroblastic changes
* periodic drug holidays (methysergide)
Contraindication :
- obstructive vascular diseases
- collagen disease
- (pregnancy)
Mifepristone (RU486)
derivate of the 19-norprogestin norethindrone
competitive antagonist of glucocorticoid and
progesterone
Pharmacological actions :
- antagonist progesterone
- mifepristone - antagonist invivo
- agonist invitro
- onapristone - antagonist invivo & invitro
Early stage of pregnancy
Decidual breakdown
Detachment of the blastocyst
h CG <
Progesterone <
PG >
Contraction
 Pharmacokinetics :
- orally active
- good bioavailability
- peak plasma : several hours
- H.L.
: 20-40 hours
- Binding 1 – acid glycoprotein
- Liver metabolism & enterohepatic circulation
- Excretion : > faeces
Therapeutic Uses :
- Mifepristone
termination early pregnancy
+ misoprostol
- Mifepristone (48 hours)
medical abortion T 1
+ prostaglandin
- Postcoital contraceptive
treatment of Preterm Labor
* bedrest
* hydration
* sedation
(+ tocolytics)
Ritodrine
Terbutaline
Tachycardia
Hypotension
edema
Hypo kalemia
Hyperglycemia
Pulmonary
Palpitation, tremor,
angina
 iv. to arrest premature labor
 can prolong pregnancy
 Inhibit preterm labor
 Overt inebriation
 iv : impaired gag reflex
 Carbohydrate metabolism
more serious in diabetic
 Crosses placenta
 Inhibit labor
 Oral / rectal endomethacin
effective in the treatment of preterm labor
 Serious potential ADR in the fetoes
 Verapamil and nifedipine
 Inhibition of premature labor
 Nifedipine :
- decreasing uterine contraction
- severe dysmenorrhea
- PG – induced abortion
 Inhibiting premature labor
antagonizes Ca 2+
 Agent of choice in diabetic patients
 Crosses placenta // maternal level
 Respiratory depression in the mother :
10 ml of 10% calcium gluconate
Diazoxide
Aminophylline
Progesterone