Drugs acting on Uterus - drdhriti

Drugs acting on Uterus : 

Drugs acting on Uterus Department of Pharmacology NEIGRIHMS, Shillong

Uterine stimulants (oxytotics or abortifacients) : 

Uterine stimulants (oxytotics or abortifacients) Posterior Pituitary hormones: Oxytocin, Desamino oxytocin Ergot alkaloids: Ergometrine, methylergometrine Prostaglandins: PGE2, PGF2α, misoprostol Miscellaneous: ethacridine and quinine

Oxytocin : 

Oxytocin Hormone of Posterior pituitary. The other hormone is vasopressin

Biosynthesis : 

Biosynthesis Synthesized as cell bodies of praventricular nucleus and supraoptic nucleus of hypothalumus as prohormone Precursor broken down to active hormone and neurophysin complex Packaged into the secretory granules by oxytocin-neurophysin complex Secreted from nerve endings in posterior pituitary gland (neurohypophysis) Oxyticinergic nerves project to hypothalumus, brain stem and spinal chord Luteal cells of ovary, luteal cells and fetal membranes synthesize oxytocin

Oxytocin secretion : 

Oxytocin secretion Sensory stimuli from cervix, vagina and breast suckling Expulsive phase is triggered by sustained distension of uterine cervix and vagina Oestrogen increases its secretion Ovarian polypeptide relaxin inhibits its release Pain, haemorrhage and dehydration increases secretion

Physiological Role : 

Physiological Role Uterus Increase in force and frequency of contractions Full relaxation occurs between the contractions at low doses Very low level of motor activity in the first two trimesters 3rd trimester – spontaneous motor activity progressively increases and sharp rise initiates labor Exogenous oxytocin can initiate rhythmic contractions 8 fold increase in uterine sensitivity in last 9 weeks and 30 fold increase in number of oxytocin receptors between early pregnancy and early labor – estrogen Increase in contraction is restricted to fundus and the body Non pregnant uterus are resistant to its action Oxytocin antagonist ATOSIBAN suppresses preterm labor

… Physiological Role : 

… Physiological Role Breast Role in milk ejection Breast suckling and manipulation induces oxytocin release Contractions of myoepithelial surrounding alveolar channels in mammary gland forces milk into large collecting sinuses – milk ejection reflex

Oxytocin – other effects : 

Oxytocin – other effects CVS No effect in low dose but at higher doses fall in BP, reflex tachycardia and flushing Kidney ADH like effect in high doses – decreased urine output, pulmonary oedema etc.

Oxytocin – Mechanism of action : 

Oxytocin – Mechanism of action Specific G protein-coupled membrane receptors related V1 and V2 vasopressin receptors Human myometrium – receptors coupled to Gq and G11, activation leads to generation of IP3 Intracellular Ca++ mobilization from stores Activation of voltage sensitive calcium channels No. of receptors and myometrium sensitivity increases late in pregnancy – labor initiation and postpartum invilution Increase in local prostaglandin concentration – uterine contraction

Clinical uses of oxytocin : 

Clinical uses of oxytocin 1. Induction of labor To induce or augment labor in pregnant women Premature rupture of membranes Intra uterine growth retardation (IUGR) Placental insufficiency – diabetes, preeclampsia or eclampsia Before induction, rule out: Abnormal fetal position Cephalopelvic disproportion Evidence of fetal distress Placental abnormalities Previous uterine surgery Oxytocin is the drug of choice for induction of labor

Clinical uses of oxytocin – contd. : 

Clinical uses of oxytocin – contd. Oxytocin (Pitocin or syntocinon) 10 IU is diluted in 1 L of 5% glucose or 0.9% saline – 10 milli IU/ml Start at low dose of 1-20 mU/min and increase at 1 mU/min every 30-40 minutes Or, 6 mU/min and increase by 2 mU/min every 20 minutes Induces labor within 2 – 4 IU If no induction after giving upto 30 – 40 mU/min – higher doses are unsuccessful If labor – reduce the dose progressively

Oxytocin infusion Monitoring : 

Oxytocin infusion Monitoring Presence of Physician Mother and fetus monitoring – fetal and maternal heart rate, maternal BP and strength of contractions If uterine hyper stimulation – discontinue infusion Short half life – 3 to 6 minutes Higher dose (more than 20 mu/min) may reduce water clearance – leading to water intoxication, coma and death

Clinical uses of oxytocin – contd. : 

Clinical uses of oxytocin – contd. 2. Augmentation of labor In hypotonic contractions in dysfunctional labor (nulliparous) – administer as above But be careful, normal progression of labor should never be tried to hasten, because over stimulation may cause uterine rupture Trauma of mother Trauma of fetus Compromised fetal oxygenation Useful in prolong latent phase of cervical dilation or arrest of dilation

Clinical uses of oxytocin – contd : 

Clinical uses of oxytocin – contd 3. Post partum haemorrhage, cesarean section: 5 IU IM or slow IV for immediate response Especially useful in hypertensive women where ergometrine cannot be used Also to maintain normal tone of uterine muscle 4. Breast engorgement: Inefficient milk ejection reflex Intranasal spray before suckling Preparations: Being a peptide not effective orally Available as injections for IM and IV use – 0.5 ml, 1 ml and 5 ml etc.

Ergometrine : 

Ergometrine It is an ergot alkaloid also called ergonovine and methylergometrine is its derivative It is an amine alkaloid Amino acid alkaloids – ergotamine ergotoxin etc. Semisynthetic derivatives - DHE Claviceps purpurea

Pharmacological actions : 

Pharmacological actions Uterus Increases force, frequency and duration of contractions At low dose contraction is phasic in nature with normal relaxation in between But moderate increase in dose – sustained contraction occurs More sensitive - Gravid uterus and at puerperium Contractions involve lower segment also CVS Weaker vasoconstrictors than their amino acid counterparts Less chance of developing endothelial damage No significant rise in BP

Pharmacological actions – contd. : 

Pharmacological actions – contd. CNS Interacts partially with dopaminergic, adrenergic and serotonergic receptors No significant effect in usual doses GIT High doses cause increased peristalsis Methylergometrine is preferred over ergometrine due to its higher potency and less marked other effects

Ergometrine – contd. : 

Ergometrine – contd. Pharmacokinetics: Near complete absorption form GIT Immediate onset of action with IV route Metabolized in liver and excreted in urine Half life – 1 to 2 hrs Adverse effects: No complication in usual doses Nausea, vomiting and rise in BP may occur Decrease in milk secretion (dopaminergic)

Ergometrine - Uses : 

Ergometrine - Uses Postpartum haemorrhage: to prevent Used the dose of 0.2 to 0.3 mg IM immediately after delivery Continued for 4 - 7 days post partum If already PPH, use higher dose 0.5 mg IV Cesarean section and instrumental delivery – to prevent uterine atony Subinvolution: 0.125 mg orally tds for 4 – 7 days postpartum

Uterine relaxants : 

Uterine relaxants Tocolytics

Tocolytics - drugs : 

Tocolytics - drugs These are drugs that inhibit uterine contractions Beta-sympathomimetics (beta-2) Ritodrine, isoxsuprine, terbutalin and salbutamol Calcium channel blockers: Nifedepine Magnesium sulfate Prostaglandin inhibiting agents: Indomethacin Oxytocin antagonist: Atosiban Ethyl alcohol

Tocolytics : 

Tocolytics Therapeutic uses: Delay or postpone labor – to allow fetus to mature and transfer of mother to a healthcare centre Threatened abortion Dysmenorrhoea

Ritodrine : 

Ritodrine MOA: Relaxation of uterine smooth muscle by stimulation of beta-2 receptors Doses: 50 mg of ritodrine in 500 ml of 5% glucose solution. Start by 10 drops per minute and increase by 5 drops every 10 minutes until uterine contractions cease Infusion should be continued for 12-48 Hrs after cessation of contractions Oral therapy should be continued every 8 Hrs after food Monitor maternal pulse, BP and FHS Adverse effects: CVS effects like hypotension, tachycardia, arrhythmia etc and metabolic effects like hyperglycemia, hyperinsulinemia and hypokalaemia

Ritodrine – contd. : 

Ritodrine – contd. Contraindications: Heart disease - Hypertension or hypotension   Hyperthyroidism and diabetes Antepartum haemorrhage (dilatation of the uterine arteries may increase the bleeding) Rupture of membrane Preparations: available as Ritodie/yutopar Tablet 10 mg / tablet or injections 10 mg/ml – 1ml or 5 ml Isoxsuprine (duvadilan) is available as oral and injections (10, 20, 40 mg tablets)

Magnesium sulfate : 

Magnesium sulfate Action: The intracellular calcium is displaced by magnesium ion leading to inhibition of the uterine activity Dosage: The initial dose is 40 cc of 10% solution given slowly IV. The subsequent doses depend upon the response and the development of MgSO4 toxicity so reflexes and respiratory rate should be observed Uses: Used for prevention of seizures in eclampsia, not used for arrest of preterm labor for its toxicites

Summary – must know : 

Summary – must know Drugs used as uterine stimulants Oxytocin – Physiological Role and its therapeutic uses Ergometrine – Pharmacological actions in uterus and therapeutic uses Drugs used as Tocolytics – role of ritodrine (beta-2 agonists) in arrest of labor

Slide 27: 

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