Pharmacology of the Uterus

Question 1

What are the three layers making up the smooth muscle of the uterus?

Answer 1

→ Outer longitudinal fibres
→ Middle figure eight fibres
→ Inner circular fibres

Question 2

What are the three layers of the uterus?

Answer 2

→ endometrium
→ Myometrium
→ perimetrium

Question 3

What do uterine contractions do?

Answer 3

→ Increase uterine pressure
→ Forces content towards the cervix
→ acts as a natural ligature to prevent blood loss

Question 4

What is the activity of the myometrium like?

Answer 4

→ Spontaneously active basal electrical activity

Question 5

What kind of contractions are there in parturition?

Answer 5

→ Rhythmic

Question 6

What is the myometrium sensitive to?

Answer 6

→ Neurotransmitters

→ Hormones

Question 7

What type of cells are in the myometrium?

Answer 7

→ ICC pacemaker cells

Question 8

How is synchronous contraction achieved?

Answer 8

→ Electrical communication between gap junctions

→ electrical activity is transmitted to adjacent cells

Question 9

Where is electrical activity transmitted between in the myometrium?

Answer 9

→ Between ICCs
→ between ICC and smooth muscle
→ between smooth muscle cell

Question 10

How do the myometrium cells function as?

Answer 10

→ A syncytium

Question 11

Describe how contraction occurs?

Answer 11

→ ICC periodic activation of inward currents
→ depolarisations
→ Ca2+ entry through VGCC
→ Intracellular calcium leads to contraction

Question 12

What are the slow waves of ICCs and smooth muscle responses modulated by?

Answer 12

→ Neurotransmitters and hormones

Question 13

Describe how calcium is increased inside the cell?

Answer 13

Slow wave of depolarisation 
                      ↓
Ca2+ channels get activated
                       ↓
Ca2+ entry increases Ca2+ 
                     ↓
Ca2+ binds to calmodulin
                     ↓
This phosphorylates myosin light chain kinase 
                       ↓ 
actin interaction lead to contractions

Question 14

Describe how oxytocin leads to increased Ca2+?

Answer 14

Oxytocin is Gq couples 
                    ↓
Activation of phospholipase C 
                     ↓
PIP2 → DAG + IP3 
                    ↓
IP3 binds to IP3 receptors in the SR 
                     ↓ 
Causes Ca2+ from the store to be released into the cytosol 
                      ↓ 
Ca2+ increases

Question 15

What are smooth muscle cells joined by?

Answer 15

→ Gap junctions

Question 16

How can intracellular calcium be reduced?

Answer 16

→ Na+/Ca2+ exchanger
→ Ca2+ pump
→ some Ca2+ gets taken into the mitochondria

Question 17

What is the effect of low concentrations of stimulants on ICCs?

Answer 17

→ Increase in slow wave frequency producing

→ Increase in frequency of contractions

Question 18

How is the myometrium similar to other smooth muscle tissues?

Answer 18

→ There is a graded response - no threshold

→ increases in Ca2+ lead to increases in force of contraction

Question 19

What is the effect of higher concentrations of stimulants on ICCs?

Answer 19

→ Increased frequency of action potentials on top of slow waves
→ Increased frequency and force of contractions

Question 20

What is the effect of even higher concentrations of stimulants on ICCs?

Answer 20

→ plateau of slow wave producing prolonged sustained contractions

Question 21

What is the effect of large concentrations of stimulants on ICCs?

Answer 21

→ hypertonus (incomplete relaxation)
→Ca2+ extrusion process is not as effective
→ interferes with blood flow - fetal distress

Question 22

What innervation does the myometrium have?

Answer 22

→ Sympathetic

Question 23

What receptors does the myometrium express?

Answer 23

→ alpha and beta adrenoceptors

Question 24

What is the effect of alpha 1 adrenoceptor agonist?

Answer 24

→ contraction

Question 25

What is the effect of beta 2 adrenoceptor agonist?

Answer 25

→ relaxation

Question 26

What are alpha 1 adrenoceptors coupled with?

Answer 26

→ Gq

Question 27

What are beta 2 adrenoceptors coupled with?

Answer 27

→ Gs

Question 28

How does the Gs transduction mechanism work?

Answer 28

→ Stimulates the formation of cAMP → cAMP inhibits myosin light chain kinase → less contractile force

Question 29

What effects do progesterone and estrogen have on contraction?

Answer 29

→ Progesterone - inhibits contraction | → Estrogen - increases contraction

Question 30

What contractions does a non-pregnant uterus have?

Answer 30

→ Weak contractions early in the cycle | → Strong during menstruation (increased prostaglandins

Question 31

Why does the myometrium contract during menstruation?

Answer 31

→ Increased prostaglandins and decreased progesterone

Question 32

What contractions does a pregnant uterus have?

Answer 32

→ Weak and uncoordinated in early pregnancy ( high progesterone) → strong and coordinated at parturition ( increased estrogen)

Question 33

What increases and decreases gap junction expression in the myometrium?

Answer 33

→ Increases - estrogen | → Decreases - progesterone

Question 34

Where are estrogen and progesterone receptors also found?

Answer 34

→ ICCs

Question 35

What prostaglandins do the myometrium and endometrium synthesize?

Answer 35

→ synthesize PGE2 and PGF2alpha - promoted by estrogens

Question 36

What do prostaglandins induce?

Answer 36

→ Myometrial contractions → dysmenorrhoea → menorrhagia

Question 37

What helps with pain and contraction?

Answer 37

→ NSAIDs

Question 38

What is the function of prostaglandins?

Answer 38

→ Coordinate an increase and force of contractions → increase gap junctions → soften cervix

Question 39

What are 3 prostaglandin analogues?

Answer 39

→ Dinoprostone (PGE2) → Carboprost (PGF2a) → Misoprostol (PGE1)

Question 40

What is the function of PGE2?

Answer 40

→ Smooth muscle dilator around the body?

Question 41

What are the 4 uses of prostaglandin analogues?

Answer 41

→ Induction of labour - before term → induce abortion → postpartum bleeding → softening the cervix

Question 42

What is a side effect of dinoprostone?

Answer 42

→ Systemic vasodilation → cardiovascular collapse → hypertonus and fetal distress

Question 43

How is dinoprostone given to reduce side effects?

Answer 43

→ Gel

Question 44

What is oxytocin?

Answer 44

→ A non peptide hormone synthesised in the hypothalamus and released from the posterior pituitary gland

Question 45

When is oxytocin released?

Answer 45

→ In response to suckling | → cervical dilatation

Question 46

Why is oxytocin not effective in earlier stages?

Answer 46

→ Receptors are not expressed pre term so they are not effective

Question 47

What does estrogen produce in the later stages of parturition?

Answer 47

→ Increased oxytocin release → Increased oxytocin receptors → increased gap junctions

Question 48

What is the function of oxytocin?

Answer 48

→ Increases the synthesis of prostaglandins

Question 49

What is ergot?

Answer 49

→ Fungus that grows on some cereals

Question 50

What happens when you ingest ergot?

Answer 50

→ Ergotism → Gangrene → convulsions → abortion

Question 51

What is the action of ergot on the myometrium?

Answer 51

→ Powerful and prolonged uterine contraction when myometrium is relaxed

Question 52

What is the mechanism of action of ergot?

Answer 52

→Stimulation of alpha adrenoceptors | → 5-HT receptors

Question 53

What are the uses of ergot?

Answer 53

→ postpartum bleeding | → not induction

Question 54

Why are myometrial relaxants given?

Answer 54

→ Delay delivery by 48h | → mother can be given antenatal corticosteroids to help fetal lung maturation

Question 55

What is an example of a b2 adrenoceptor stimulant?

Answer 55

→ Salbutamol

Question 56

How does salbutamol work?

Answer 56

→ relaxes uterine contractions by direct action on the myometrium → increases Ca2+ uptake into SR - Ca2+ not available for contraction

Question 57

What is salbutamol used for?

Answer 57

→ Reduce strength of contractions in premature labour

Question 58

What is an example of a Ca2+ channel antagonist?

Answer 58

→ Nifedipine | → Mg sulfate

Question 59

What is an example of an oxytocin receptor antagonist?

Answer 59

→ Retosiban

Question 60

What is an example of a COX inhibitor?

Answer 60

→ NSAIDs

Question 61

How do NSAIDs work?

Answer 61

→ Decrease prostaglandins

Question 62

What is a side effect of NSAIDs?

Answer 62

→ Can cause fetal renal dysfunction

Question 63

What doest stimulation of beta 2 adrenoceptors cause?

Answer 63

→ Smooth muscle relaxation

Question 64

How does beta 2 adrenoceptor stimulation work?

Answer 64

→ PKA activity → Increased Ca2+ activity which increases uptake into SR → Increases K+ channel activity → hyperpolarisation and decreased Ca2+ entry via VGCC → Downregulates MLCK

Question 65

What is used for induction of labour?

Answer 65

→ Oxytocin

Question 66

What is used for induction of labour/termination in early term?

Answer 66

→ Prostaglandins ( because no oxytocin receptors)

Question 67

What is used for postpartum bleeding?

Answer 67

→ Prostaglandins → Oxytocin → Ergots

Question 68

What is used to prevent premature birth?

Answer 68

→ Beta 2 adrenoceptor agonists → Ca2+ channel blockers → oxytocin inhibitors

Question 69

What are the 2 ways to measure uterine contractions?

Answer 69

→ Isometric tension recording | → Measure tension generated with diameter of muscle ring remaining constant