Pharmacology of the uterus Flashcards
What is the general structure of the myometrium?
- Consists of 3 layers of smooth muscle
- Outer = longitudinal fibres
- Middle = figure of eight shaped fibres
- Inner = circular fibres
- Organised so that contraction causes an increase in uterine pressure forcing any contents towards the cervix - propels the baby out
- Also acts as a natural ligature to prevent blood loss
What are the general properties of myometrium?
- Spontaneously active - Myogenic
- Spontaneous contractions are highly sensitive to NTs, hormones (oestrogen and progesterone)
- Progesterone inhibits contraction, Oestrogen increases contraction
- Increase in O:P ratio during childbirth
What is the difference between pregnant vs non-pregnant uterus?
Non
- weak contractions early in the cycle, but strong contractions during menstruation (decreased P, increased PGs). Spontaneous activity increased
P
- Weak and uncoordinated in early pregnancy (high P), but strong and coordinated during parturition (high oestrogen)
What is the ANS innervation of the myometrium?
- Innervated by Sympathetic NS
- Contains both alpha and beta adrenoceptors
- Alpha produces contraction
- Beta 2 produces relaxation
How is synchronous contraction achieved?
- Has a myogenic ‘pacemaker’ mechanism
- Pacemaker cells are interstitial cells of Cajal (ICCs), which initiate and coordinate contractions
- Electrical activity generated in ICCs pass between smooth muscle cells through gap junctions made of connextin proteins
- Uterus behaves as a ‘syncytium’ - electrical connected cells
- Mechanisms are affected by hormones - oestrogen increases expression of gap junctions to promote contration
What is the relationship of electrical and mechanical activity?
- Slow wave - slow depolarisation produced by pacemaker cells (ICCs)
- Electrical activity spreads via gap junctions to neighbouring SMCs - activates APs in SMCs - upstroke of APs are carried by Ca2+ ions through VGCCs which leads to an increase in interstitial Calcium ions, causing contraction
- Slow waves/SMCs are modulated by NTs/Hormones
What are the cellular mechanisms of uterine smooth muscle contraction?
- Oxytocin acts on Gq to activate PLC, to form IP3 and DAG from PIP2
- IP3 acts on its receptor on the SR, allowing Calcium to move out into the cytoplasm
- DAG increases the excitability of the membrane, making it easier to depolarise and bring more Calcium in through VGCCs
- Together, they produce a rise in cytosolic calcium, producing calcium-calmodulin complexes, activating MLCK, phosphorylating MLC, which causes actin-myosin cross-bridge formation, causing contraction
What are the main principles of excitation and inhibition in uterine smooth muscle?
- Similar to other smooth muscle tissue
- Contraction is caused by an increase in [Ca2+]i
- Increase force production is proportional to increase in [Ca2+]i
- Each AP will cause an incremental increase in [Ca2+]i but also there are mechanisms lowering [Ca2+]i (calcium extrusion)
- Changes in [Ca2+]i will be the resultant effect of these processes
How do the principles of excitation and inhibition affect the uterus?
- Low concentrations of stimulants on ICCs, increase slow wave frequency, giving more frequent SMC contractions
- At higher concentrations, the frequency of APs on top of slow waves increases, increasing the frequency and force of SMC contraction
- Eventually there is a plateu of slow wave producing prolonged, sustained contractions
- Hypertonus caused when there is incomplete relaxation - the Ca extrusion process isnt effective
How will hypertonus affect the uterus?
- Interferes with blood flow to uterine tissue
- Leads to foetal distress
- Have to monitor drug dosage to avoid hypertonus
What is oxytocin?
- Nonapeptide hormone synthesised in hypothalamus and released from posterior pituitary
- released in response to suckling and cervical dilation
- Syntocinon is a synthetic version
- Its action is dependent on oestrogen
- Oestrogen increases oxytocin release, oxytocin receptors and gap junctions.
- Only effective at term because it needs oestrogen around to produce its receptors.
What are the pharmacological actions of oxytocin?
- Low concs of oxytocin/syntocinon increase frequency and force of contractions
- High concentrations cause hypertonus - may cause foetal distress
Why is oxytocin useful?
- Induction of labour at term - however doesnt soften the cervix
- Treat/ prevent post-partum haemorrhage - produce the ligature effect
- USEFUL ONLY AT TERM AS WE NEED OESTROGEN TO BE AROUND TO PROVIDE OXYTOCIN RECEPTORS
What are prostaglandins?
- PGE2 (vasodilator) and PGF2a (vasoconstrictor) synthesised in myo/endometrium, promoted by oestrogens
- May have a role in dysmenorrhoea (severe menstrual pain through uterine contraction), menorrhagia (severe menstrual blood loss through excess vasodilation) and parturition (birth)
- E2/F2a act together to coordinate increased frequency, force of contraction, gap junctions, synthesis of oxytocin and soften the cervix
- PGs are effctive in early and middle pregnancy
- Agonists: Dinoprostone (PGE2) and Carboprost (PGF2a)
What is effective at helping dysmenorrhea and menorrhagia?
NSAIDs
- decreases PGs to stop the increased contraction and reduce pain
