Pharmacology of the uterus Flashcards
What is the muscular structure of the uterus?
- outer longitudinal fibres
- middle figure-eight fibres
- inner circular fibres
What are some mechanical properties of the myometrium?
- contractions mean an increase in uterine pressure, forcing content towards the cervix and acts as a natural ligature to prevent blood loss
- it’s spontaneously active (myogenic): it produces regular contractions without neural or hormonal input
- highly sensitive to neurotransmitter and hormones
- rhythmic contractions for parturition
How is synchronous contraction achieved?
There are pacemaker cells in the myometrium called the interstitial cells of Cajal (ICCs), which initiate and coordinate contractions.
There is electrical communication via gap junctions made of connection proteins. These gap junctions are found:
- between ICCs
- between ICCs and smooth muscle cells
- between smooth muscle cells
They function as a syncytium.
What is the contractility mechanism of smooth muscle in the uterus?
We get:
- ICC periodic activation of inward currents
- depolarisations
- Ca2+ entry through VGCCs
- an increase in [Ca2+]i
- contraction
This works through the Gα q/11 subunit mechanism.
What effect does increasing calcium levels have on these SMCs?
An increase in [Ca2+]i will lead to contraction. This is a graded response; incremental increases in [Ca2+]i will lead to incremental increases in the force of contraction.
Describe the effect of gradually increasing calcium levels on these SMCs?
at low concentrations of stimulants on ICCs:
- there is an increased slow wave frequency, producing an increased frequency of contractions
at higher concentrations:
- there is an increased frequency of action potentials on top of those slow waves
- ie. increased peak of [Ca2+]i, producing both increased frequency and increased force of contractions
at higher concentrations still:
- there is an increased plateau of slow wave, producing prolonged sustained contractions
What will the effects of large concentrations of stimulants on ICCs indicate?
- the cells will be hypertonus (there is incomplete relaxation)
- the Ca2+ extrusion processes are not effective
- important: it interferes with blood flow, which can cause foetal distress
Describe the innervation and regulation of the uterus
The myometrium is sympathetically innervated. This means that there is the expression of α and β adrenoreceptors.
An α adrenoreceptor agonist will cause contraction.
A β adrenoreceptor agonist will cause relaxation.
How are contractions of the uterus regulated by sex hormones?
Progesterone inhibits contractions.
Oestrogen increases contractions.
Compare the contractions in a pregnant and a non-pregnant uterus
NON-PREGNANT UTERUS:
- weak contractions early on in the cycle
- strong contractions during menstruation (decreased progesterone, increased prostaglandins)
PREGNANT UTERUS:
- weak and uncoordinated contractions in early pregnancy (high progesterone)
- strong and coordinated contractions at parturition (increased oestrogen)
How do sex steroids affect ICCs?
Oestrogen/progesterone receptors are found on ICCs.
During parturition, the oestrogen:progesterone ratio increases. Oestrogen increases, while progesterone decreases the expression of gap junctions in the myometrium.
How is the uterus regulated by prostaglandins?
The myometrium and endometrium synthesise PGE2 and PGF2α - this is promoted by oestrogens. Both these prostaglandins induce myometrial contraction.
The prostaglandins act together to:
- coordinate an increased frequency/force of contractions
- increase the gap junctions
- soften the cervix
They play a role in dysmenorrhoea (severe menstrual pain), menorrhagia (severe menstrual blood loss) and pain after parturition. Thus, NSAIDS are effective, as they can reduce contractions and pain.
Prostaglandins are effective in early and mid-pregnancy.
What are some uses of prostaglandin analogues?
- induction of labour before term
- induction of abortion
- postpartum bleeding
- softening the cervix
What are some risks associated with prostaglandin analogues?
- dinoprostone can cause systemic vasodilation
- they have the potential for cardiovascular collapse (if given as cervical vaginal insert)
- PGs can make the uterus hypertonus and cause foetal distress
Describe the regulation of the uterus by oxytocins?
Oxytocin is a non-peptide hormone synthesised in the hypothalamus and released from the posterior pituitary gland. It is released in response to suckling and cervical dilation.
Oestrogen (released at later stages of parturition) produces:
- increased oxytocin release
- increased oxytocin receptors
- increased gap junctions
Oxytocin also increases the synthesis of prostaglandins.
