Pharmacology of the Uterus

Question 1

Describe the structure of the myometrium

Answer 1

• Outer longitudinal fibres
• Middle figure-eight fibres
• Inner circular fibres

Question 2

What does contraction of the myometrium do?

Answer 2

Increase in uterine pressure, forcing content towards the cervix and acts as a natural ligature to prevent blood lost.

Question 3

What type of muscle is the myometrium?

Answer 3

Spontaneously active - myogenic

Produces regular contractions without neuronal or hormonal input

Question 4

What is the myometrium sensitive to?

Answer 4

It is highly sensitive to neurotransmitters and hormones

Question 5

Why does the myometrium contract rhythmically?

Answer 5

It contractions rhythmically for parturition

Question 6

How is synchronous contraction achieved?

Answer 6

By pacemaker cells in the myomterium - the interstitial cells of cajal (ICCs) that initiate and coordinate contractions
- Electrical communication via gap junctions made of connexion proteins

Question 7

Where are the gap junctions located and what do they do?

Answer 7

• Between ICCs
• Between ICCs and smooth muscle cells
• Between smooth muscle cells
• Function as a syncytium

Question 8

Describe the electrical activity of the myometrium

Answer 8

ICC periodic activation of inward currents which causes depolarisation. Calcium enters via VGCCs and increases intracellular calcium levels and causes contraction.

Question 9

What modulates the slow waves of ICCs and smooth muscle responses?

Answer 9

Neurotransmitters and hormones

Question 10

Briefly describe the mechanism of smooth muscle contractions

Answer 10

• Oxytocin or another substance binds to a GCPR q/11.
• IP3 binds to SR and causes release of Calcium and increases intracellular calcium
• DAG activates ion channels.
• Action of ion channels increases membrane excitability
• Causes depolarisation
• Activates VGCCs which induces Ca2+ influx
• Increase of intracellular calcium
• Activates calmodulin, activates myosin light chain kinase that cause the reaction between the myosin head and the actin.
• This causes contraction

Question 11

What is the graded response of calcium?

Answer 11

Incremental increases in calcium -> incremental increases in force of contraction

Question 12

What is excitation - contraction coupling?

Answer 12

• Increase in slow wave frequency producing high frequency of contractions
• Increase in frequency of action potentials on top of slow waves producing both high frequency and force of contractions
• Increase plateau of slow wave producing prolonged sustained contractions
• Hypertonus
• Ca2+ extrusion processes not effective

Question 13

What is hypertonus?

Answer 13

It is incomplete relaxation

Question 14

What type of innervation does the myometrium receive?

Answer 14

Sympathetic innervation

Question 15

What receptors does the myometrium express?

Answer 15

Express:

• Alpha-adrenoreceptors
• Beta adrenoreceptors

Question 16

What do alpha adrenoreceptor agonists cause?

Answer 16

Contraction

Question 17

What does beta adrenoreceptors cause?

Answer 17

Relaxation

Question 18

What does progesterone do on the myometrium?

Answer 18

It inhibits contraction

Question 19

What does oestrogen do on the myometrium?

Answer 19

It increases contraction

Question 20

Describe the regulation of the myometrium via sex hormones during non-pregnancy

Answer 20

Weak contractions early in the cycle

Strong contractions during menstruation (low progesterone, high prostaglandins)

Question 21

Describe the regulation of the myometrium via sex hormones during pregnancy

Answer 21

Weak and uncoordinated in early pregnancy (high progesterone)
Strong and co-ordinated at parturition (high oestrogen)

Question 22

What increases during parturition?

Answer 22

Oestrogen/Progesterone ratio increases
Oestrogen increases while progesterone decreases gap junction expression in myometrium
Oestrogen/Progesterone receptors are also found on ICCs

Question 23

What does the myometrium and endometrium synthesise?

Answer 23

They synthesise prostaglandins: PGE2 and PGF2a - promoted by oestrogens.

Question 24

What do the prostaglandins do?

Answer 24

They induce myometrial contraction

Question 25

What is dysmenorrhoea?

Answer 25

Severe menstrual pain

Question 26

What is menorrhagia?

Answer 26

Severe menstrual blood loss

Question 27

What drugs can reduce contraction and pain?

Answer 27

NSAIDs

Question 28

What do NSAIDs and Prostaglandins do?

Answer 28

They act together to: - Coordinate high frequency/force of contractions - High gap junctions - Soften cervix

Question 29

When are prostaglandins effective?

Answer 29

In early and middle pregnancy

Question 30

What are analogues?

Answer 30

Compounds with a molecular structure closely similar to that of another

Question 31

Give examples of prostaglandin analogues

Answer 31

- Dinoprostone (PGE2) - Carboprost (PGF2a) - Mistoprotol (PGE1)

Question 32

What are the uses of prostaglandin analogues?

Answer 32

- Induction of labour; before term - Induce abortion - Postpartum bleeding - Softening the cervix

Question 33

What are the concerns of the use of prostaglandin analogues?

Answer 33

- Dinoprostone can cause systemic vasodilatation - Potential for cardiovascular collapse - Cause hypertonus and foetal distress

Question 34

What is oxytocin?

Answer 34

It is a non-peptide hormone synthesised in the hypothalamus and released from the posterior pituitary gland

Question 35

What is oxytocin released in response to?

Answer 35

In response to suckling and cervical dilatation

Question 36

What does oestrogen do in parturition?

Answer 36

Increases oxytocin release Increases oxytocin receptors Increased gap junctions

Question 37

What does oxytocin increase?

Answer 37

It increases synthesis of prostaglandins

Question 38

What time is oxytocin only effective?

Answer 38

It is only effective at term - requires oestrogen-induced oxytocin receptor expression.

Question 39

Name 2 synthetic oxytocin drugs

Answer 39

Syntocinon | Pitocin

Question 40

What are the pharamcological actions of oxytocin analogues?

Answer 40

- Low concentrations increase frequency and force of contractions - High concentrations cause hypertonus and may cause fetal distress

Question 41

What are the uses of oxytocin analogues?

Answer 41

- Induce labour at term - does not soften cervix - Treat/prevent post-partum haemorrhage - Syntometrine - oxytocine (rapid) / ergot (prolonged) combination

Question 42

What is ergot?

Answer 42

Fungus that goes on some cereals (e.g. Rye) and grasses

Question 43

What does ergot contain?

Answer 43

It contains array of potent agents inc. ergot alkaloids (e.g. ergometrine, ergotamine; both based on LSD moiety), histamine, tyramine and acetylcholine

Question 44

What happens when ergot is ingested?

Answer 44

- Ergotism - Gangrene - Convulsions - Abortion

Question 45

What is the action of ergot?

Answer 45

- Powerful and prolonged uterine contraction, but only when the myometrium is relaxed

Question 46

What does ergot act on?

Answer 46

It stimulates alpha adrenoreceptors and 5-HT receptors

Question 47

What are the uses of ergot?

Answer 47

Post-partum bleeding - Not induction

Question 48

Why are relaxants used in premature labour?

Answer 48

They can delay delivery by 48 hours, so the mother can be transferred to specialist unit, and given antenatal corticosteroids to aid foetal lung maturation and increase survival.

Question 49

What are beta2 adrenoreceptor stimulants used for?

Answer 49

- 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 50

Give an example of beta 2 adrenoreceptors

Answer 50

salbutamol

Question 51

Give examples of calcium channel antagonists

Answer 51

Nifedipine (used in hypertension) | Mg Sulfate

Question 52

Give an example of oxytocin receptor antagonists

Answer 52

Retosiban

Question 53

Give an example of COX inhibitors

Answer 53

NSAIDs

Question 54

What does the stimulation of beta2 adrenoreceptors on smooth muscle do?

Answer 54

It causes the adenylyl cyclase to change ATP to cAMP activates PkA. This increases Ca2+ ATPase (SERCA) to increase uptake into SR/exculsion from the cell. It also increases K+ channel activity, causing hyperpolarisation decreasing in Ca2+ entry via VGCCs. PkA also dereases the action of MLCK. All of these produce relaxation

Question 55

What induces labour at term?

Answer 55

Oxytocin

Question 56

What induces labour/termination in early term?

Answer 56

Prostaglandins

Question 57

What causes post-partum bleeding?

Answer 57

Prostaglandins Oxytocin Ergots

Question 58

What prevents premature birth?

Answer 58

Beta2 adrenoreceptor agonists Ca2+ channel blockers, Mg Sulfate Oxytocin inhibitors

Question 59

How is uterine contraction measured?

Answer 59

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