10- Pharmacology of the Uterus

Question 1

Describe structural properties of the myometrium

Answer 1

outer longitudinal fibres, middle figure 8 fibres and inner circular fibres

Question 2

Describe mechanical properties of the myometrium

Answer 2

different layers of muscular fibres allow for strong contractions in all directions

rhythmic contractions originating from spontaneous depolarisation of uterus pacemaker cells - no neuronal or hormonal inputs, sensitive to sex hormones with increased contractions during menstruation

depolarisation communicated by gap junctions between cells = myometrium functions as syncytium

Question 3

what initiates uterus smooth muscle cell contractions?

Answer 3

spontaneous depolarisation of uterus pacemaker cells

Question 4

describe excitation-contraction coupling in smooth muscles

Answer 4

spontaneous depolarisations in pacemaker cells initiates a wave of depolarisation - transmitted through the syncytium of smooth muscle cells

smooth muscle cells exhibit spontaneous mechanical activity leading to an increase in muscle tone for contractions

wave of depolarisation leads to co-ordinated contractions across muscle cells

Question 5

describe the role of Ca2+ in muscle contraction

Answer 5

wave of depolarisation changes membrane potential

opening of v.g. Ca2+ channels – extent of opening depends on level of depol.

increase in intrac. Ca2+ = muscle contraction – this is a graded response where incremental Ca2+ increases = increase force of contraction

Question 6

how is contractile activity modulated?

Answer 6

can be modulated by hormones and neurotransmitters if they:
- increase intrac. Ca2+
- activate calmodulin and MLCK
- increase cross-bridge formation between actin and myosin

Question 7

how does oxytocin modulate contractile activity?

Answer 7

activates receptors = increases intrac. Ca2+ = increases contractions

Question 8

how do Ca2+ channel blockers modulate contractile activity?

Answer 8

block Ca2+ channels, prevemt Ca”+ influx

decrease intrac. Ca2+

prevent contractions

Question 9

how do K+ channel activators affect contractile activity of smooth muscle cells?

Answer 9

hyperpolarise membrane potential

decrease opening of voltage gated Ca2+ ICs

decrease channel activity and intrac. Ca2+

Question 10

how do neurotransmitters affect myometrial contractions?

Answer 10

through sympathetic innervation and neurotransmitters (adrenaline and noradrenaline)

A1 adrenoreceptor is Gq coupled - stimulates phospholipase activity, IP3 and DAG production = increase intrac. Ca2+ = induce smooth muscle contraction

B2 adrenoreceptor is Gs coupled - stimulates adenylyl cyclase, coverts ATP to cAMP = induces smooth muscle relaxation

Question 11

how do sex hormones affect myometrial contractions?

Answer 11

sex hormones - progesterone and oestrogen

in a non-pregnant state, progesterone inhibits contractions, causes weak contractions when high. oestrogen increases contractions, acting via nuclear and TK receptors

in early pregnancy, progesterone is high - induces weak, unco-ordinated contractions

in late pregnancy, oestrogen increases whilst progesterone remains constant. induces strong, co-ordinated contractions for childbirth

Question 12

how does oxytocin affect myometrial contractions?

Answer 12

oxytocin release stimulated by suckling and cervical dilation

synthesised in the hypothalamus, travels to posterior pituitary

acts on Gq coupled oxytocin receptors = activate phospholipase C = increase contraction by increasing intrac. Ca2+

oestrogen increases expression of oxytocin receptors

Question 13

how do prostaglandins affect myometrial contractions?

Answer 13

prostaglandin synthesis stimulated by oxytocin - induces pain

prostaglandin synthesised from arachidonic acid by COX enzymes

PGE and F increase myometrial contractions and induce pain

NSAIDS act as pain relief by inhibiting prostaglandin synthesis

Question 14

consequences of high prostaglandin levels?

Answer 14

dysmenrrhoea = painful cramping during periods

severe menstrual blood loss

post-childbirth pain

Question 15

name four factors that affect myometrial contractions

Answer 15

neurotransmitters (sympathetic NTs = adrenaline and noradrenaline)

sex hormones = oestrogen, progesterone

prostaglandins

oxytocin

Question 16

name the three types of myometrial (pharmacological) contractile agents

Answer 16

ergots
oxytocin
prostaglandins

Question 17

name the five types of myometrial (pharmacological) relaxant agents

Answer 17

oxytocin receptor antagonists
beta-2 adrenoreceptor agonist
anti-prostaglandins
Ca2+ channel blockers
nitric oxide donors

Question 18

mechanism of action & clinical use of ergots as myometrial contractile agents?

Answer 18

ergot is a type of fungus

mechanism of action:
- may act by 5-HT receptors
- acts by sympathetic stimulation of alpha adrenoreceptors = Gq coupled = phospholipase C = increase contractions

clinical use:
- post-partum bleeding
- not for inducing labour as it’s dangerous
- induces powerful, prolonged contractions

Question 19

mechanism of action & clinical use of oxytocin as a myometrial contractile agent?

Answer 19

mechanism of action:
- binds to Gq coupled receptor = phospholipase C = IP3 and DAG = increases intrac. Ca2+
- dose-dependent increase in myometrial contractions

clinical use:
- induce labour
- post-partum haemorrhage

Question 20

mechanism of action & clinical use of prostaglandins as myometrial contractile agents?

Answer 20

mechanism of action:
- induces smooth muscle contractions
- enhances oxytocin effects = synthesis stimulated by oxytocin

clinical use:
- induces labour and abortion
- post-partum bleeding prevention

Question 21

mechanism of action of Ca2+ channel blockers as myometrial relaxant agents?

Answer 21

blocks Ca2+ channel = prevents Ca2+ influx

decrease in intrac. Ca2+

leads to myometrial relaxation

Question 22

example of Ca2+ channel blocker?

Answer 22

nifedipine

Question 23

mechanism of action of beta-2 adrenoreceptor agonists as myometrial relaxant agents?

Answer 23

acts directly on myometrium – B2 adrenoreceptor is Gs coupled = adenylyl cyclase stimulated

reduces strength of contractions

Question 24

example of beta-2 adrenoreceptor agonist

Answer 24

terbutaline sulphate
ritodrine

Question 25

mechanism of action of nitric oxide donors as myometrial relaxant agents?

Answer 25

stimulates NO production = promotes relaxation

Question 26

example of nitric oxide donor

Answer 26

nitroglycerin

Question 27

mechanism of action of anti-prostaglandins as myometrial relaxant agents?

Answer 27

inhibit PG synthesis = reduces its contractile effects

Question 28

example of anti-prostaglandins

Answer 28

NSAIDS - e.g. aspirin

Question 29

mechanism of action of oxytocin receptor antagonists as myometrial relaxant agents?

Answer 29

blocks oxytocin receptor = prevents Gq coupled pathway that increases intrac. Ca2+

inhibits uterine contractions

Question 30

clinical use of myometrial relaxant agents

Answer 30

• delay premature labour by 48 hours = can administer antenatal corticosteroids for foetal lung maturation
• prevent miscarriage in women with a history of it