Pharmacology of the Uterus Flashcards
What is the structure of the myometrium?
-
3 layers of smooth muscle
- outer longitudinal fibres
- middle figure of eight-shaped fibres
- inner circular fibres
- organised so that contraction causes an inc in uterine pressure
- forcing any contents towards cervix
- acts as a natural ligature to prevent blood loss
The myometrium is myogenic (spontaneously active) - these spontaneous contractions are highly sensitive to NTs and hormones. What hormones have what impact on the myometrial contractions?
- progesterone - inhibits contactions
- oestrogen - increases contraction
- remember: increased oestrogen to progesterone ratio during partition (birth)
What are contractions like in a non-pregnant uterus?
- weak contractions early in cycle
- strong contractions during menstruation (decreased progesterone, increased prostaglandins)
What are contractions like in a pregnant uterus?
- weak + uncoordinated in early pregnancy (high progesterone)
- strong and co-ordinated at parturition (increased oestrogen)
What is the innervation of the myometrium?
- auotonomic nervous system
- innervated by sympathetic (not parasympathetic) nerves
- myometrium contains both alpha and beta receptors
- stimulation of alpha -> contraction
- stimulation of Beta2 -> relaxation
What is the myogenic mechanism of the myometrium?
- ‘pacemaker’ mechanism
- myometrium contains pacemaker cells - interstitial cells of Cajal
- initiate and coordinate contractions
- electrical activity generated in ICCs pass from smooth muscle cell to smooth muscle cell via gap junctions - made of connexin proteins
myometrium of uterus behaves as a ‘synctytium’ - electrical connected cells
The mechanisms for achieving synchronous contraction are affected by hormones. What effect does oestrogen have?
Oestrogen increases expression of gap junctions to promote contraction
What are slow waves and what follows them?
- the slow depolarisations produced by pacemaker cells (ICCs)
- electrical activity spreads via gap junctions to SMCs
- activates action potentials in SMcs: upstroke of APs are carried by Ca2+ ions through VGCCs which leads to increase in [Ca2+]i -> contraction
- slow waves/SMCs are modulated by NTs/hormones
What happens when you get stimulation of smooth muscle - eg. by oxytocin?
- stimulates Gq/11 pathway:
- PIP2 —–PLC—-> IP3 + DAG
- IP3 -> binds to IP3 receptor on sarcoplasmic reticulum -> opens ion channels -> calcium moves out into cytoplasm -> rise in [Ca2+]i
- DAG -> increases membrane excitability -> depolarisation -> activation of VGCCs -> induces Ca2+ influx -> rise in [Ca2+]i
- Ca2+-Calmodulin
- MLCK activated -> MLC phosphorylated -> cross-bridge formation -> contraction
as you have gap junctions, this depolarisation can move across cells - syncytium - wave of info moving through SMCs
What are some principles of excitation and inhibition - to do with contraction?
- contraction is caused by an increase in [Ca2+]i
- inceased force of contraction proportional to increase in [Ca2+]i
- each action potential will cause an incremental increase in [Ca2+]i
- but also there are mechanisms lowering [Ca2+]i - eg. Ca extrusion
- changes in [Ca2+]i will be the resultant effect of these processes
How will a low concentration of stimulants on ICCs impact on contractions?
- increased slow wave frequency producing
- increased frequency of smooth muscle cell contractions
How will a higher concentration of stimulant on ICC impact on contractions?
- increased frequency of action potentials on top of slow waves
- peak intracellular calcium conc
- producing both increased frequency and force of SMC contractions
How will higher concentrations still impact on contractions?
- increased plateau of slow wave
- producing prolonged sustained smooth muscle cell contractions
What will maximal stimulation (large concentrations) of ICCs result in terms of contraction?
- hypertonus - smooth muscle constantly contracting
- incomplete relaxation
- Ca extrusion process not effective
- interfere with blood flow - fetal distress!!!
Oxytocin
- what is it?
- where is it synthesised + released from?
- in response to?
- nonapeptide hormone
- synthesised in hypothalamus
- released from posterior pituitary gland
- released in response to suckling + cervical dilatation
- role in parturition?
What is a synthetic version of oxytocin?
Syntocinon/pitocin
What is action of oxytocin dependent on?
- dependent on oestrogen
- oestrogen, released at later stages of parturition, produces:
- increased oxytocin release
- increased oxytocin receptors
- increased gap junctions
- oxytocin is only effective at term
What are the pharmacological actions of oxytocin?
- low conc of oxytocin analogue
- increase frequency and force of contractions
- high concentrations cause hypertonus -> may cause fetal distress
What are uses of oxytocin?
- induction of labour at term - doesn’t soften cervix
- treat/prevent post-partum haemorrhage
- syntometrine - oxytocin (rapid) / ergot (prolonged) combo
What prostaglandins are produced in the uterus and where from exactly?
- PGE2 (vasodilator)
- PGF2a (vasoconstrictor)
- synthesised in myo and endometrium
- promoted by oestrogens
How are NSAIDs effective against prostaglandins?
PGs involved in
- dysmenorrhoea (severe menstrual pain)
- menorrhagia (severe menstrual blood loss)
- parturition (birth)
NSAIDs block production of COX
What effect do prostaglandins have in terms of contractions etc?
- act together to coordinate increased frequency + force of contractions
- increase gap junctions
- soften cervix
- increase synthesis of oxytocin
PGs are effective in early and middle pregnancy. What are examples of PG analogues?
- Dinoprostone (PGE2)
- Carboprost (PGF2a)
- Mistoprotol (PGE1)
What are uses of PG analogues?
- induction of labour - before term
- induce abortion, postpartum bleeding, softening of cervix
