Uterine stimulants and relaxants

Definitions & Key takeaways

Uterine stimulants and relaxants are medications used to induce or inhibit contractions of the uterus. Uterine stimulants are also called uterotonics because they increase the tone of the muscles of the uterus. They're mainly used to induce or facilitate labor, reduce postpartum hemorrhage, and induce abortion. Examples of uterine stimulants include oxytocin, ergonovine, and prostaglandins.

Uterine relaxants, on the other hand, decrease the activity of the uterine muscles. They are also called tocolytics, where �toco-' refers to childbirth, and �-lytic' means to terminate. They're used to stop premature labor to give time for the fetal lungs to mature. Examples of uterine relaxants include elective β2-adrenoceptor agonists, calcium channel blockers, cyclooxygenase inhibitors, and oxytocin receptor antagonists.

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Introduction0:00–0:39

Uterine stimulants and relaxants, as their names suggest, are medications used to induce or inhibit contractions of the uterus.
Uterine stimulants are also called uterotonics, because they increase the tone of the muscles of the uterus. They’re mainly used to induce or facilitate labor, to reduce postpartum hemorrhage, and to induce abortion.
Uterine relaxants are also called tocolytics, where ‘toco-’ refers to childbirth, and ‘-lytic’ means to terminate. They’re used to stop premature labor inorder to give time for the fetal lungs to mature.

Physiology0:39–2:31

So, the uterus is a super important organ in the female body, because not only does it allow the development of the baby during pregnancy, but it also generates the force necessary to push out that tiny human during labor.
This force results from the muscle contractions that take place in the middle layer of the uterus, the myometrium. The regulation of these muscle contractions happens at the cellular level, and it all comes down to the activity of myosin light-chain kinase by calcium ions.
This enzyme phosphorylates myosin, inducing muscle contraction. On the other hand, this enzyme can be turned off via phosphorylation by protein kinase A, which causes the muscles to relax.
Now, during labor, uterine contractions become stronger and more frequent. Normally, this happens at some point when the fetus is considered full term, which means all their organs are functional and it’s able to live outside mommy’s womb.
This typically happens between 37 and 42 weeks’ gestation. Sometimes labor doesn’t start even though it’s been more than 42 weeks.
In these cases, it should be induced by the administration of uterine stimulants which include oxytocin, ergonovine, and prostaglandins.
In other situations the baby, the mother, or both, are at risk if the pregnancy continued. These include fetal growth restriction, isoimmunization, premature rupture of the membranes, pre-eclampsia, or eclampsia.
Uterotonics are also indicated to augment labor when the contractions aren’t strong enough, and they have the added benefit of preventing postpartum hemorrhage by compressing uterine blood vessels.
Finally they can be used for therapeutic abortion. Okay, let’s look at the uterotonics starting with oxytocin.

Oxytocin2:31–4:52

This medication activates Gq protein coupled receptors, which activates the enzyme phospholipase C - or PLC for short. PLC then cleaves a phospholipid called phosphatidylinositol 4,5-bisphosphate into inositol trisphosphate and diacylglycerol.
Inositol trisphosphate is soluble and diffuses freely through the cytoplasm and into the endoplasmic reticulum where it opens up calcium channels.
Since the calcium concentration is higher in the endoplasmic reticulum than in the cytoplasm, calcium flows out of the endoplasmic reticulum to the cytoplasm.
Calcium ions then bind to calmodulin and activate myosin light-chain kinase, inducing muscle contraction. Now, oxytocin is given via intravenous infusion and the main indication is for labor induction.
In fact, it’s the drug of choice for this purpose. But it’s also indicated in facilitation of labor, and to prevent or treat postpartum hemorrhage.
In the last case by intramuscular injection. But oxytocin not only exerts actions on the uterus, which causes some side effects.
On blood vessels, for example, it causes vasodilation, which ultimately leads to hypotension and reflex tachycardia. Also, oxytocin can activate antidiuretic hormone-receptors on the collecting ducts of the kidneys.
Therefore, stimulating water retention. For this reason, fluids should be carefully administered.
Otherwise, they can cause water intoxication, leading to coma, or even death. On the other hand, in patients who are suffering preeclampsia, or hypertension during pregnancy, and those with cardiac or renal disease, water retention can be an issue, and extra care must be taken.
Finally, a situation called uterine hyperstimulation can occur where uterine contractions are too long, lasting two minutes or more, or too frequent, with five or more in ten minutes.
Uterine hyperstimulation can cause uterine rupture or impaired oxygen delivery to the baby. Which are obviously serious complications.
So if this happens, oxytocin administration should be discontinued right away. Now, moving on to ergonovine, the exact mechanism of action isn’t completely understood, but it certainly stimulates uterine contraction.

Ergonovine4:52–5:42

Unlike oxytocin ergonovine is only used to prevent or treat postpartum hemorrhage because ergonovine can cause prolonged tetany of the myometrium, so it should not be used for induction or facilitation of labor.
It can be given by intramuscular or intravenous injection. Besides uterine contraction, ergonovine causes vasoconstriction, which increases blood pressure.
So, it should be avoided in patients with hypertension. Also, ergonovine can cause vasospasm of the arteries that perfuse the heart and trigger angina.
Other side effects include nausea, vomiting, blurred vision, and headache. Okay, so the last type of uterotonic agents are prostaglandins, which include dinoprostone and misoprostol.

Prostaglandins5:42–6:34

They exert their actions by stimulating Gq protein coupled receptors, just like oxytocin. They’re also used to facilitate labor and to prevent or treat postpartum hemorrhage.
But, dinoprostone and misoprostol are also indicated to induce abortion after the administration of mifepristone or methotrexate.
They can be administered orally, vaginally or intracervically. Some side effects include nausea, vomiting, and diarrhoea, as well as uterine pain, and uterine hyperstimulation.
Finally, dinoprostone causes bronchoconstriction, so it’s contraindicated in patients with asthma. Let’s switch gears and talk about uterine relaxants or tocolytics.

Tocolytics6:34–7:33

Sometimes labor begins too early. If this happens before the 37th week of gestation, the fetal organs, especially the lungs, might not be fully developed.
If the baby’s born in this condition, they may not be able to breath, or have other serious complications, like pulmonary hypertension, or intracranial hemorrhage.
So, in this case, labor can be suppressed with uterine relaxants, thus giving the fetus a few more days in the uterus. During this time, the mother can be given glucocorticoids to stimulate maturation of the fetal lungs.
Uterine relaxants include selective β2-adrenoceptor agonists, calcium channel blockers, cyclooxygenase inhibitors and oxytocin receptor antagonists; and the indication for all of them is the same: prevention or arrest of preterm labor.

Terbutaline7:33–8:38

Let’s start with the selective β2-adrenergic receptor agonists like terbutaline. As the name suggests, they stimulate β2-adrenergic receptor, which is a Gs protein coupled receptor.
Protein Gs stimulates the enzyme adenylate cyclase. Activated adenylate cyclase takes adenosine triphosphate or ATP, and removes two phosphate molecules transforming it into cyclic adenosine monophosphate or cAMP.
cAMP moves throughout the cytoplasm and activates protein kinase A - or PKA for short. PKA then phosphorylates and inactivates myosin light-chain kinase, which inhibits uterine contraction.
Terbutaline can be administered orally, subcutaneously, or intravenously. Since it’s a β2-adrenergic receptor agonist, it stimulates the sympathetic system, causing side effects like tachycardia, palpitations, tremor, and nervousness.

Calcium channel blockers8:38–9:15

Next up are the calcium channel blockers. These medications block the influx of calcium ions into the cell, so that they won’t be able to bind to calmodulin and activate myosin light-chain kinase.
The final result then, is inhibition of uterine contractions. The calcium channel blocker indicated as tocolytic is nifedipine, which is one of the drugs of choice for preterm labor and it can be given per orally or parenterally.
Nifedipine also causes vasodilation, which causes some side effects like flushing, and dizziness. Moving onto the cyclooxygenase inhibitors like indomethacin, which is one of the medications of choice to prevent preterm labor, just like nifedipine.

Indomethacin9:15–9:56

The mechanism of action of indomethacin is simply to inhibit the synthesis of prostaglandins, by inactivating a critical enzyme in charge: cyclooxygenase.
So, no prostaglandins, no uterine contractions. However, prostaglandins are also important for the baby since it delays the closure of the ductus arteriosus and promote platelet aggregation.
So the main side effects of indomethacin are premature closure of the ductus arteriosus and hemorrhages. Finally, the oxytocin receptor antagonist, atosiban, binds and inhibits oxytocin receptors, blocking the signalling pathway that leads to uterine contractions.

Atosiban9:56–10:18

However, although several studies have shown that it could be a first line medication, with no major risks, it’s not approved by the FDA in the United States.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharm facts! Let’s set the scene in a mattress shop.

Memory Palace10:18–13:31

We can put the uterine relaxants on the show floor where the customers can relax on the mattress samples. In the storage room at the back, we have the employee pushing hard to move the mattresses, and this is where we put the uterine stimulants that cause uterine contraction.
So let’s start by looking at the uterotonics in this back room. First, we have a minotaur with big feet and big toes for oxytocin.
For the main side effects, he worked too hard and fainted, representing hypotension. Someone is pouring water on him to wake him up, for water intoxication.
To represent uterine hyperstimulation which is increased contraction, we can compress his chest by putting a 50kg weight on it.
Next up we have ergonovine, which will be represented by an eagle who flew into the backroom and got entangled in thorny vines.
The thorns tore up the eagle pretty bad, and it’s bleeding a lot. This will help you remember ergonovine is only used to treat postpartum hemorrhage and not induction of labor like the other medications in the back room.
For other important side effects, we can put a blood pressure cuff on the wing of the eagle for hypertension, and a little knife in its chest for angina.
Okay the last group of drugs in this room are the prostaglandins like dinoprostone and misoprostol, so let’s have a stone dinosaur for dinoprostone.
He’s the manager and he’s drinking miso soup, for misoprostol. Since these medications also cause uterine hyperstimulation, let’s put the dino and his soup on a 50kg weight so he can watch over the entire room.
Now dinoprostone causes bronchoconstriction, so let’s give our manager a necktie that’s a little too tight. Now let’s move onto the showfloor where we have some customers testing out the mattresses and they will represent the uterine relaxants, or tocolytics.
So first we have the beta and calcium channel blockers so let’s use two knights with shields. One knight has a bee on his shield for the beta blockers.
He’s wearing a turban for terbutaline which is the main beta blocker used for this purpose. For the calcium channel blocker, let’s give the other knight a shield with a bottle of milk on it.
His weapon is a large butter knife with cheese dip on it for nifedipine. Okay, for indomethacin, someone left a big lump of dough on a mattress.
A rooster is pecking at it to help remind you this is a cyclooxygenase inhibitor. Also on the bed, there’s a duck pecking at a bleeding heart on a broken plate.
This will help remind you that indomethacin can cause the premature closure of the ductus arteriosus and it inhibits platelet aggregation.
The final drug is atosiban, an oxytocin receptor antagonist. So let’s have a big footed minotaur laying on the last mattress.
Toes are banned on this mattress to help you remember atosiban, so let’s give this minotaur a pair of gigantic socks. All right, as a quick recap… Uterine stimulants - or uterotonics - include oxytocin, ergonovine, and prostaglandins, which are medications used to induce contractions of the uterus, in order to induce or facilitate labor, to reduce postpartum hemorrhage, or to induce abortion.

Review13:31–14:13

Uterine relaxants - or tocolytics - include selective β2-adrenoceptor agonists, calcium channel blockers, cyclooxygenase inhibitors and oxytocin receptor antagonists, which are medications used to inhibit uterine contractions, in order to prevent premature labor.
But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.

Mind Map14:13–14:24

Stay tuned for the answers after the credits.