Drugs Acting on Uterus

Uterus has endometrium & myometrium

Sensitivity of myometrium to drugs affected by hormonal &gestational status

Drugs Acting on uterus

Uterine Stimulants Or Oxytocic Uterine Relaxants

Drugs/ Ecbolics/Abortifacients Or
Tocolytics

They ↑uterine contraction

during delivery or at ↓uterine motility
various stages of labour Relax- uterus

USES:-
USES- To delay labour
Induce abortion Arrest threatened abortion
Minimize Postpartum hemorrhage (PPH) To treat Dysmenorrhoea
Augment abnormal labour
Preventing the early rupture of membrane
 Drugs Acting on uterus
Tocolytics
Uterine stimulants
Adrenergic Agonists-
Posterior pituitary hormones Ritodrine, Isoxsuprine,
Oxytocin, Salbutamol,Terbutaline
Desamino oxytocin
CCB’s - Nifedipine
Ergot alkaloids Oxytocin blockers- Atosiban
Ergometrine MgSo4
Methylergometrine Miscellaneous drugs

Prostaglandins
PGE2 ,
PGF2α
15-methyl PGF2α
Misoprostol

Miscellaneous agents
 Ethacridine, Quinine
 Introduction
Oxytocin
Oxys+ tokos="quick" + "birth

Oxytocin is a nonapeptide freely water soluble & acid stable –

posterior pituitary hormone (Para ventricular nuclei)

1911-used child birth contractions

 Chemistry
2 1 Both are 8-amino
acid peptide
Octapeptide.
phe Arg

But differ in 2
amino acids at
Position 3 & 8

Ile Leu
 Synthesis, storage and release of Oxytocin

Para-ventricular nucleus

Synthesis
Hypothalamus

•Oxytocinase –destroy oxytocin

•Due to pulsatile release –difficult to
hypothalohypophyseal measure Cp

Stored in secretory Posterior pituitary Storage

granules as
oxytocin-
neurophysin (Stimuli for release)
complex Persistent distension of cervix
,vagina.suckling,Etc.
Release of oxytocin inhibited by relaxin & alcohol
Causes contraction of
Causes contraction of myoepithelial cells of the female
Pregnant uterus breast
Mechanism of Action:-
Oxytocin binds to specific GPCR(Gq) on myometrium
oxy

Plasma membrane

α ßγ
Phospholipase c

Phosphatidyl inositol 4,5 bisphosphate(PIP2)

Inositol-1,4,5-triphisphate(IP3) Diacyl glyceral(DAG)

Sacroplasmic
reticulum ca

Myosin light
chain kinase

calmodulin
Pharmacokinetics
 Peptide in nature-so destroy by proteolytic enzyme (Gut)
 Inactive orally
 I.V(I.V.-infusion ), I.M, intranasal spray
 Metabolized in kidney and liver
 Plasma t ½ ~6min
 Destroyed- oxytocinase secreated by pregnant uterus & placenta

Dilution & rate of preparation:-

1IU of oxytocin = 2µg of pure hormone
 Pharmacodynamic Action-
On UTERUS:-
• ↑ in force and frequency of contractions in pragnancy
• Uterine sensitivity to oxytocin - ↑ by estrogen & ↓by progesterone
• Early pregnancy – high dose of oxytocin is necessary
• Contraction of upper segment & relaxation of lower segment of uterus
→ Expulsion of fetus
• Non-pregnant uterus → resistance to oxytocin
• In human –
Small dose-↑Tone & Amplitude
Large Dose- ↑ Frequency of contraction + Incomplete relaxation
Higher Dose- Sustained contraction without relaxation ↔ resulted in
↓Blood flow to fetal, fetal distress & death (Asphyxial injury)
• During parturition- ↑ Number of Oxytocin receptor (↑ sensitivity )
• Exogenous oxytocin- initiate rhythmic contraction
On breast:-
Suckling by infant
↓
Stimulate nipple mechanoreceptors
↓
Hypothalamus
↓
Posterior pituitary
↓
↑Oxytocin release
↓
Contraction of myoepithelial cells of mammary gland
Milk ejection
CVS
Normal therapeutic dose= No effect
High doses =vasodilatation
fall in BP ,
Reflex-tachycardia, and flushing

Kidney
-High doses- ADH like effect
In ↓urine output , pulmonary edema etc..
Clinical uses of oxytocin
Induction of labor:-(5IU+500 ml of 5% D)
• To induce or augment abnormal labor in pregnant women
• Premature rupture of membranes
• Isoimmunization
• Fetal growth Restriction
• Uteroplacental insufficiency diabetes, preeclampsia, or
eclampsia.
Oxytocin in preferred – IV infusion
Advantages-
1.Plasma t1/2 is short – intensity of action can be controlled
2.At low conc. There is period of complete relaxation between
uterine contraction which prevent fetal asphyxia
3.lower uterine segment is not contracted so, fetal descent is not
compromised
 Before induction ,rule out:-
 Abnormal fetal position
 Fetal distress
 Placental abnormalities
 Previous uterine surgery

 OXYTOCIN ( Pitocin or Syntocinon):-

 Administered by i.v. infusion
 5IU is diluted in 500ml of glucose or saline solution
 Uterine inertia
absence of effective uterine contractions during labor

Oxytocin can be infused i.v - augment satisfactory

contractions

Oxtocin is the DOC and is preferred over

ergometrine/PGs
• Its short duration of action
• Normal relaxation in b/w contraction
• lower segment is not contracted
• Uterine contractions are consistently augmented
 Post partum haemorrhage(PPH)-
 oxytocin –IV-infusion or IM
 Especially useful in hypertensive women where
ergometrine is contraindicated

 Action- It acts by forcefully contracting uterine muscle

which compresses the blood vessels passing through it to
arrest hemorrhage.
 Breast engorgement:-
• Insufficient milk ejection reflex
• Intranasal spray few minute before suckling
• dose not ↑ milk production

Oxytocin challenge test:-

• To assess fetal well-being/utero-placental adequacy
Purpose:- To assess the fetal heart rate response to contractions. The
results of the test may be used to aid the decision making process
regarding mode and timing of delivery

• I.v. infusion in low rate –cont. till uterus contracts about every 4 min
at the same time fetal heart rate is measured.

# if ↑HR=uteroplacental flow is insufficient (fetal hypoxia) need

immediate cesarean delivery
 Adverse effect -
Non judicious use can leads to serious reaction
i.e. Fetal distress, placental abruption or uterine rupture
High concentration –
excessive fluid retention, or water intoxication :
hyponatremia, heart failure,
seizures, and death.

Bolus injection - hypotension

Desamino-oxytocin:-
• Buccal formulation of oxytocin
• Action is similar to oxytocin
 Indications-
 Induction of labor:-50 IU buccal tabs , every 30 min ,max
10 tabs.
 uterine inertia:-25 IU , every 30mis , 25-50 IU 5times for
7days
 Breast engorgement:-25-50IU
 It is also preferred in hypertensive women in which
ergometrine in contraindicated
 Ergot Alkaloids
Source:-
Ergot alkaloids Source

Ergometrine Claviceps purpurea a fungus which infects grasses and

grains (Rey)
Methyl- Semi-synthetic derivative obtained from lysergic acid
ergometrine
 Methyl ergometrine is more potent & preferred than ergometrine

 They ↑ strength,duration,frequency of uterine contraction

Of both upper & lower segment

• Contraction involve- Fundus,Body,cervical segments

Pharmacokinetics
 Orally absorbed rapidly and completely
 Onset of action oral – 15mins
i.m. – 5mins
i.v. – 1 to 2mins
 t1/2: 1 – 2 Hrs
 Partially metabolized and excreted in urine
 Hepatic damage increases toxicity
Mechanism:-
They have agonistic activity on 5-HT2 & α1- adrenergic receptor present
on uterus myometrium
Pharmacological actions

Uterus:
 Highly sensitive
 Elicits immediate and powerful response
 Small dose – ↑FOC + Normal relaxation
 High dose – ↑↑ Contractions are powerful,
frequency, resting muscle tone is also
 Uterine atony
 Risk of fetal distress, compression, asphyxia and death
CVS:-
 No adrenergic blocking activity
 Increase in BP is not seen at doses used in obstetrics (2 mg)
CNS:-
 No effects are seen at obstetrics doses
 High dose – Interactions with adrenergic, serotonergic
and dopaminergic receptors
 Direct stimulating action on emetic center
GIT:
 Quite sensitive to ergot alkaloids, increases peristalsis
 GI side effects are seen at low doses as it acts on both
emetic center directly and on GI serotonin receptors
Uses
 In PPH:- Prophylaxis and treatment of PPH
(0.2 to 0.3mg I.M. or 0.2mg i.v.)
Mechanism- cause sustained tonic uterine contraction- uterine BV
are compressed by myometrial meshwork & bleeding stop
 Methyl-Ergometrine is preferred over ergometrine because
• Effective orally
• Small doses, less toxic and min adverse effects
• Devoid of adrenergic blocking, vasoconstriction and emetic activity

 Management of 3rd stage of labour- Ergometrine (0.2-0.5mg I.M.)

They also prevent uterine atony & control bleeding
 Adverse Effects

 Ergometrine and methyl ergometrine are less toxic than

ergotamine
 GI side effects and increase in BP rarely
 High doses – Decrease in milk secretion
 Over dose of ergometrine causes prolonged vasospasm, gangrene
of finger & toes due to vasoconstriction effect
Contraindications

 During pregnancy and before 3rd stage of labor

 Patients with hypertension, preeclampsia, eclampsia, porphyria,
vascular diseases and collagen diseases
 Threatened spontaneous abortions
 Liver and kidney diseases
 Presence of sepsis may cause gangrene
Bromoergocryptine

 Bromocryptine is synthetic ergot derivative

 Selective D2 receptor agonist
 Effective in decreasing the high levels of prolactin
(2.5mg × TDS)
 Oxytocic and cardiovascular actions are negligible
 Prostaglandins
 20 carbon containing fatty acids
 Lipid derived autacoid
 Human seminal fluid, ovary, myometrium and
menstrual fluid
 Many PG’s shows inhibitory effect
 PGF2 and PGE ↑tone & amplitude of uterine contractions
 Sensitize the uterus to oxytocin and also causes oxytocin release
 PGF2 helps in process of labor
 Pharmacological actions:-

 Uterine contractions by stimulant effect

 Cervical priming:- Cervical ripening at the time of
delivery and abortions
 Luteolytic agents :- structural and functional degradation of
the corpus luteum
 Inhibits the secretion of progesterone
 PG’s are effective in 2nd and 3rd trimesters
 Mifepristone is administered priorly as it sensitivity of uterus to
PG’s
 Adverse effects

 Head ache, fever and vasodilatation

 Cautiously IOP, hypertension, diabetes, angina and epilepsy
 PGF2α has more GI effects than PGE2
 Smoking and alcohol consumption is avoided during use and 48hrs
after use
 High incidence of adverse effects and delivery complications are
seen when PG’s alone is used
Contraindication:-
 Cardiac, renal, pulmonary and hepatic disorders
 Uses
 Therapeutic abortion:
o 2nd trimester pregnancy termination
o Gemeprost administered vaginally as pessaries
o Carboprost analogue of PGF2α given as i.m.
o Misoprostol is give orally or i.v. combined with
mifepristone (T-pill upto 49days)

 Cervical priming:
o Dinoprostone
o Endocervical gels, suppositories and oral tablets
 Post-partum Hemorrhage:
o PG analogue like carbopost is given i.m.

 Induction and augmentation of term labor:

o Dinoprostone is preferred - diuretic action
o 0.5mg orally at 30-60mins time interval
(max up to 4 tabs)
o PG’s causes hyperstimulation of uterus
 Uterine relaxants:-
Action-
Suppress myometrial smooth muscle contraction by
–
↓Intracellular Ca++ conc.& reduce the effect of Ca++
on smooth muscle
Inhibiting the synthesis & release of PG & oxytocin
1. β -agonist-
Mechanism- Bind to β2 receptor on myometrium
↓
Activate adenyle cyclase activity
↓
↑cAMP levels – activate cAMP dependent protein
kinase
↓
↓intracellular Ca++ conc..
(Muscle relaxation )
 β2 adrenergic agonists
Drugs:-
Ritodrine
Isoxsuprine
Salbutamol
Terbutaline
 RITODRINE:-
Selective β2 adrenergic agonist
Specifically developed as a uterine relaxant

Route:
i.v infusion,i.m

Side effects:
Pulmonary edema Q
Hypotension
Tachycardia
Hyperglycaemia
Hypokalaemia
 ISOXSUPRINE:
1.Indicated in premature labour
2.Habitual abortion- three or more consecutive pregnancy
losses
3.Threatened abortion- vaginal bleeding that occurs in the first 20 weeks of
pregnancy
4.Dysmenorrhoea

Route:-i.v, i.m.
SIDE EFFECTS:
Rashes
Nausea
Vomiting
Dizziness
Hypotension
 SALBUTAMOL:
Used as a primary drug to delay delivery 24-72 hours

Side effects:-
Palpitation
Restlessness
Nervousness
Throat irritation
Ankle edema
TERBUTALINE:
It delay births but only during the first 48 hours of
treatment

ADVERSE EFFECTS:
Tachycardia
Hypotension
Pulmonary edema
CALCIUM CHANNEL BLOCKERS:-

NIFEDIPINE:-
Used for uterine relaxation

Action- It acts via impairing the entry of Ca++ into

myometrial cells via voltage dependent channels & there by
inhibit contractility
It improve fetal outcomes and produce less side effects
Produce few maternal side effects than ritodrine

Side effect-
 Hypotension
 Tachycardia
 MAGNESIUM SULFATE
It suppress uterine contractions
Used to control convulsions
To reduce BP in toxemia of pregnancy
Drug of choice for prevention and treatment of seizures in
pre-elampsia
ROUTE: i.v
This is uesd when β adrenergics are contraindicated

Action- they directly uncoupled EC in myometrial cells &

inhibits cellular Action potential
 Toxicity-
Life threatening
 Lose patellar reflexs – Cp>8-10mEq/L with
 Respiratory depression- Cp>10-12mEq/L with
 Higher levels cause cardiac arrest

It is monitors by 3 parameter
1.Patellar reflex
2.Respiratory rate
3.Urinary output
 PROSTAGLANDIN SYNTHESIS INHIBITORS
INDOMETHACIN:
Used to delay preterm labour
Tocolytic effect- inhibiting the PG synthesis
It also can decrease amniotic fluid volume
USE OF INDOMETHACIN IS:
Its unpredictable efficacy-orally or rectally given
Premature closure of fetal ductus arteriosus
Chances of intraventricular hemorrhage in new
born
 OXYTOCIN RECEPTOR ANTAGONIST

ATOSIBAN :
Oxytocin receptor blocker
↑uterine relaxation by competitively blocks the oxytocin
receptor
Route-IV-infusion
SE-Nausea, vomiting, Hypotension, skin rashes
 MISCELLANEOUS DRUGS
NITRIC OXIDE DONARS:
Potent vasodilator
Smooth muscle relaxant
Nitroglycerine and other nitrates used to treat Myocardial
ischemia
Used for inhibition of preterm labour

SE-Maternal hypotension
C2H5OH- Not used because of CNS depression, fetal
hypoxia
Progesterone- treatment of threatened abortion