Pharmacology of the uterus Flashcards
What is the smooth muscle layer of the uterus called?
Myometrium
Describe the structure of the Myometrial layers.
- inner layer of circular fibres
- middle layer with figure of 8 spiral fibres
- outer layer of longitudinal fibres
How does the myometrium contract?
It is myogenic, providing rhythmic contractions
*doesn’t need activation of neuronal pathways or hormonal input, but still highly sensitive to neurotransmitters and hormones
How is the myometrium myogenic?
due to interstitial cells of Cajal (ICCs) which initiate and coordinate myometrial contractions by creating electrical signals via gap junctions
What are gap junctions made of?
connexion proteins
What do gap junctions allow for?
communication between cells via movement of molecules, ions and electrical impulses (electrical coupling)
the gap junctions therefore function as a syncytium to achieve synchronous contraction of the myometrium
Where are gap junctions located?
between ICCs
between ICCs and myometrial smooth muscle cells
between myometrial smooth muscle cells
Describe the process of Myometrium transduction.
1) ICC periodic activation of inward current
2) Causes depolarisation of smooth muscle cells (electrical coupling via gap junctions) which then opens VGCCs
3) Ca2+ influx through VGCCs
4) Increase in [Ca2+]i
5) Contraction of myometrial smooth muscles
What causes more sustained myometrial contractions?
slow waves of ICCs and smooth muscle responses mediated by neurotransmitters & hormones
Describe the Methods by which [Ca2+]i increases.
- Ca2+ entry via VGCCs
- Ca2+ release from sarcoplasmic reticulum after IP3 binds IP3 receptors on SR
How does an increase in [Ca2+]i cause contraction?
1) Calmodulin (calcium sensor) binds Ca2+
2) Calmodulin activates myosin light chain kinase
3) Myosin light chain kinase phosphorylates myosin, allowing for myosin to interact with actin and increases ATPase activity of myosin, altering myosin structure and increasing its affinity for ATP, allowing it to be primed for contraction
How is depolarisation transmitted to adjacent cells?
via gap junctions
What must happen for rhythmic contractions of the myometrium?
A subsequent decrease in Ca2+ after the initial increase so the myometrial smooth muscle cells don’t stay contracted all the time
Give some Methods by which [Ca2+]i decreases.
- Ca2+ pumped out of the cell via Ca2+ ATPase
- Ca2+ taken up by sarcoplasmic reticulum via SERCA pumps to be stored
- Ca2+ extruded via Na+/Ca2+ exchanger
- small amount of Ca2+ stored in mitochondria
What is the Effect of ICC stimulant concentration on contraction?
Low concentration of stimulants on ICCs
- increase in slow wave frequency
- increased frequency of contractions
High concentration of stimulants on ICCs
- increase in action potential frequency on top of slow waves
- increase in frequency & force of contraction
Higher concentrations
-increase in plateau of slow wave producing sustained contractions
Large concentrations
- hypertonus (incomplete relaxation) and Ca2+ extrusion processes not effective
- interferes with foetal blood flow and causes foetal distress
Describe the innervation of the uterine.
Mostly sympathetic innervation
- alpha adrenoceptor (aGq) causes contraction
- beta 2 adrenoceptor (aGs) causes relaxation
What is the Effect of progesterone on uterine contraction?
inhibits uterine contraction
What is the Effect of oestrogen on uterine contraction?
increases uterine contraction
Describe the differences between Contractions in non-pregnant and pregnant uterus.
Non-pregnant
- weak contractions in early cycle
- strong contractions during menstruation (high prostaglandins, low progesterone)
Pregnant
- weak and uncoordinated in early pregnancy (high progesterone)
- strong and coordinated and parturition (high oestrogen)
What is the Effect of oestrogen and progesterone on gap junctions?
Oestrogen increases expression of gap junctions
Progesterone decreases expression of gap junctions
*causes contraction/relaxation of myometrium at parturition
What is the Effect of prostaglandins on uterus contraction?
Prostaglandins (PGE2 & PGF2a) induce myometrial contraction
- coordinate increased frequency & force of contractions
- increase gap junctions
- soften cervix
What promotes the synthesis of uterine prostaglandins and where are they produced?
Oestrogen promotes the synthesis of PGE2 & PGF2a either in the:
- myometrium (autocrine)
- endometrium (paracrine)
*oxytocin also increases synthesis of PGs to induce contraction
What are the Side effects of uterine prostaglandins after parturition?
dysmenorrhoea (painful menstruation)
menorrhagia (prolonged bleeding)
pain
*treat using NSAIDs which reduce contractions and pain by inhibiting cyclo-oxygenase enzyme (which normally produces PGs)
Name the Prostaglandin Analogues.
Dinoprostone (PGE2)
Carboprost (PGF2a)
Mistoprotol (PGE1)
What are the Uses of prostaglandin analogues?
Induction of labour (pre term)
Induce abortion
Postpartum bleeding
Softening the cervix
What are the Concerns of prostaglandin analogues?
Dinoprostone (PGE2) cause cause systemic vasodilation, resulting in acute hypotension and cardiovascular collapse
PGs can cause hypertonus causing foetal distress, however this is not a problem is inducing abortion
Why do oxytocin levels increase during parturition?
Oestrogen released at later stages in parturition causes an increase in:
- oxytocin and oxytocin receptors
- gap junctions
Why is oxytocin only effective at term?
because it requires oestrogen-induced oxytocin receptor expression, which is only available at later stages of parturition due to high oestrogen levels
What are Oxytocin analogues?
Syntocinon & Pitocin
- need high oestrogen levels to express oxytocin receptors
- induce labour
- treat/prevent post-partum haemorrhage
Low concentrations of oxytocin analogue causes…
increased frequency & force of contractions
High concentrations of oxytocin analogue causes…
hypertonus which may cause foetal distress
What is Syntometrine?
combination of oxytocin (rapid) and ergot (prolonged) to cause contractions and prevent bleeding at the same time
What is Ergot?
exogenous fungus that grows on some cereal (e.g. rye) and grasses
- contains potent agents including ergot alkaloids (e.g. ergometrine, ergotamine), histamine, tyramine and ACh
- when ingested it can cause ergotism, gangrene, convulsions and abortion
What is Effect of ergot on uterine contractions?
causes prolonged uterine contractions- but only when myometrium is relaxed
-stimulates alpha adrenoceptors & 5-HT receptors
also used to treat post-partum bleeding (but not to induce abortion)
When are Myometrial relaxants used?
used in pre-term labour
Why are myometrial relaxants important in pre-term labour?
important to delay delivery by 48 hours so mother is transferred to specialist unit and given antenatal corticosteroids to aid foetal lung maturation and increase survival
Give some Types of myometrial relaxants.
Beta 2 (aGs) adrenoceptor agonists
Ca2+ Channel antagonists
Oxytocin receptor antagonists
COX-inhibitors
*all used to prevent premature birth
What is the use of Beta 2 (aGs) adrenoceptor agonists?
Salbutamol
- relax uterine contractions by a direct action on myometrium
- used to reduce strength of contractions in premature labour
What is the use of Ca2+ Channel antagonists?
Nifedipine- used in hypertension
Mg Sulphate- used for pre-eclampsia, eclampsia and foetal neuroprotection
Give a Oxytocin receptor antagonist.
Retosiban
What is the use of COX inhibitors?
NSAIDs
- decrease in PGs, decreasing contractions
- may cause foetal renal dysfunction
Name the Drugs to induce labour at term.
oxytocin (due to high oestrogen> oxytocin receptor expression)
Name the Drugs to induce labour/termination in early term.
prostaglandins (because no oxytocin receptor expression)
Name the Drugs used to treat/prevent post-partum bleeding.
prostaglandins, oxytocin, ergot
Name the Drugs to prevent premature birth.
Myometrial relaxants:
- B2 adrenoceptor agonists
- Ca2+ channel antagonists
- Oxytocin receptor antagonists
- COX inhibitors
What are the Methods of measuring uterine contraction?
Isometric Tension Reading
-measuring tension while diameter of muscle ring remains constant
Large Organ Baths
-e.g. aortic ring experiment
*these are widely used techniques to investigate the functional properties of uterine, vascular, airway and bladder smooth muscle segments
