12- Pharmacology of the Uterus

Question 1

What is the myometrium?

Answer 1

A layer of smooth muscle that forms the wall of the uterus – located between the endometrium and the perimetrium

Question 2

How many layers of smooth muscle does the myometrium have + what are these layers?

Answer 2

3 smooth muscle layers
- Outer longitudinal muscle fibres
- Middle: figure-of-eight/mesh-like fibres
- Inner: circular fibre

Question 3

Why is the myometrium a highly muscular organ?

Answer 3

In order to provide contractions during the menstrual cycle and during delivery of the foetus

Question 4

What are the mechanical properties of the myometrium?

Answer 4

Rhythmic contractions
- Spontaneously active
- Vary during menstrual cycle and pregnancy – indicates that they are sensitive to different hormones
- Force content towards the cervix and out of the body

Contractions within the uterus originate in the muscle itself
- Doesn’t require neuronal or hormonal input – factors that regulate the contractions
- But highly sensitive to e.g. sex hormones

Question 5

What initiates contraction in the uterus?

Answer 5

• Mechanism is kind of like that of the heart
• Spontaneous depolarisation of ‘pacemaker’ cells - give rise to action potentials - APs spread to different cells
• Electrical communication between (smooth muscle) cells
• Gap junctions spread depolarisation
• Myometrium can function as a syncytium - entire organ functions as a single unit i.e. entire uterus contracts simultaneously when delivering a pregnancy
  Initiated by depolarisation of pacemaker cells

Question 6

Explain excitation-contraction coupling?

Answer 6

• Slow waves of pacemakers and smooth muscle responses are modulated by neurotransmitters and hormones
• Depolarisation initiates firing of APs and therefore contraction
• Depolarisation spreads to other smooth muscle cells throughout the uterus and enables contraction and the allows the uterus to function as a syncytium
• Depolarisation is conducted to other cells

Question 7

What facilitates smooth muscle contraction in the uterus?

Answer 7

• similar to other smooth muscle tissues
• increased intracellular [Ca2+]
• incremental increases in [Ca2+]i causes incremental increases in the forces of contraction
• the amount by which intracellular calcium levels increase by determines the force of contraction

Question 8

What is the effect of an influx of Ca2+?

Answer 8

Causes the opening of voltage gated calcium channels, Ca2+ floods into the cell and causes membrane depolarisation of smooth muscle

Question 9

What is a mechanism for lowering [Ca2+]i ?

Answer 9

Ca2+ extrusion

Question 10

How is contraction modulated by hormones and neurotransmitters?

Answer 10

Oxytocin acts on a G protein coupled receptor and activates the Phospholipase C chain of activity ( breakdown of PIP2 into IP3 and DAG , IP3 binds to a receptor to cause intracellular release of Ca2+ from internal calcium stores causing contraction

Ca2+ binds to calmodulin and activates myosin light chain kinase which interacts with actin to cause a contraction

Question 11

How is uterine contraction measured?

Answer 11

Isometric tension recording
- Measure tension generated with diameter of the muscle ring remains constant

Oxytocin induced contractions

Ion channel modulators
- K+ channel activator (Higher K+ concentrations inhibit depolarisation and therefore reduces the frequency and amplification of contractions)
- Ca2+ channel blocker (inhibit Ca2+ influx)

Question 12

How are smooth muscles of the uterus regulated by neurotransmitters?

Answer 12

Uterus has sympathetic innervation expression of alpha and beta adrenoreceptors

alpha adrenoreceptor agonist - contraction
- this is via the a1 pathway à breakdown of phospholipase C, production of IP3 and DAG from PIP3
- causes release of intracellular Ca2+ à smooth muscle contraction

beta2 adrenoreceptor agonist - relaxation
- Gs coupled GPCRs
- Activation of adenylate cyclase à causes breakdown of cyclic cAMP
- Causes relaxation within smooth muscle

Question 13

How are smooth muscles of the uterus regulated by sex hormones?

Answer 13

Progesterone - inhibits contraction
Oestrogen - increases contraction
Both act on both nuclear and membrane receptors

Question 14

Describe the regulation of a non pregnant uterus by sex hormones

Answer 14

Week contractions early in the cycle- oestrogen low
Strong contractions during menstruation - progesterone low

Question 15

Describe the regulation of a pregnant uterus by sex hormones

Answer 15

Weak and uncoordinated contractions in early pregnancy (high progesterone – inhibits contractions)

7 month till term – Oestrogen increases towards, progesterone stays constant
Progesterone: oestrogen ratio significant during pregnancy

Oestrogen / progesterone ratio increases throughout last trimester culminating with strong, coordinated contractions for delivery (low progesterone to oestrogen ratio)
Entire uterus functions as a syncytium for delivery as different parts of the uterus are co-ordinated via oestrogen

Question 16

What is oxytocin?

Answer 16

A non peptide hormone synthesised in the hypothalamus and released by the posterior pituitary gland
Its released in response to suckling and cervical dialation

Question 17

How is the uterus regulated by oxytocin?

Answer 17

Increased oestrogen production due to pregnancy progression causes oxytocin release, and increases expression of oxytocin receptors
Oxytocin also increases synthesis of prostaglandins

Question 18

How is the uterus regulated by prostaglandin?

Answer 18

Release and synthesis is stimulated by oxytocin

Prostaglandins induce myometrial contraction (PGE and PGF- activate receptors to induce a contractions)

Role in dysmenorrhoea (severe menstrual pain), menorrhagia (severe menstrual blood loss), pain after parturition (after childbirth)

NSAIDS- inhibit prostaglandin release and synthesis, reduce contraction and pain

Question 19

What is the role of contractile agents and give example of some?

Answer 19

They cause an increase in intracellular calcium concentration [Ca2+]
- ergots
- oxytocin
- prostaglandins

Question 20

What is ergot?

Answer 20

Fungus that grows on some cereals (e.g. rye) and grasses
- Contains ergometrine
- Can induce abortion within cows and humans
- Highly poisonous to animals and humans

Question 21

What is the action and mechanism of ergot?

Answer 21

Action:
- Powerful and prolonged uterine contraction

Mechanism:
- Stimulation of a-adrenoceptors, 5-HT receptors
- Cause contraction of blood vessels that surround the uterus hence why administered after child birth to stop bleeding

Question 22

What are the uses of ergot?

Answer 22

• post partum bleeding
• not used in induction( can be dangerous- cause foetal distress)

Question 23

What are the uses of oxytocin as a contractile agent?

Answer 23

Used to induce/augment labour at term
- Augment labour – i.e. to enhance labour when it has started but is not progressing enough

Can’t be used before term:
- Levels of OxyRs and oxytocin increase due to increase in oestrogen towards the end of the pregnancy
- Not enough oxytocin receptors before full term à will have no effect

Dose dependent increases in contraction – but too much can cause sustained contraction and foetal distress (can be very damaging)
- Dose-dependant to ensure rhythmic contractions

Also used in postpartum haemorrhage

Question 24

What are the uses of prostaglandins as a contractile agent?

Answer 24

Induction of labour – before term

Induce abortion

Postpartum bleeding

Question 25

What are the uses of myometrial relaxants?

Answer 25

Relaxants may be used in premature labour
-Delay delivery by 48 hrs, so Mother can be transferred to specialist unit, and given antenatal corticosteroids to aid foetal lung maturation and increase survival

Question 26

What are some examples of myometrial relaxants?

Answer 26

• beta2 adrenoreceptor stimulants (ritodrine)
• Ca 2+ channel antagonists (nifedipine)
• oxytocin receptor antagonist (retosiban)
• COX inhibitors (NSAIDS)

Question 27

What is the mechanism of beta2 adrenoreceptor stimulants as a myometrial relaxant?

Answer 27

• Relax uterine contractions by a direct action on the myometrium
• Used to reduce strength of contractions in premature labour
• May occur as a side effect of drugs used in asthma

Question 28

What is the mechanism of COX inhibitors like NSAIDs as a myometrial relaxant?

Answer 28

They decrease prostaglandin release

Question 29

What is the mechanism of Ca2+ channel antagonists as a myometrial relaxant?

Answer 29

Reduce influx of Ca2+ into smooth muscle cells of the uterine muscle and reduces strength of contraction

Question 30

What is the mechanism of oxytocin receptor antagonist as a myometrial relaxant?

Answer 30

Antagonise endogenous oxytocin and prevention of natural labour occurring prematurely
Block oxytocin receptors