Pharmacology of the uterus Flashcards
Lable the cross-section of the uterus
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Define contraction, in relation to the uterus
Contraction means an increase in uterine pressure, forcing content towards the cervix and acts as a natural ligature to prevent blood lost
Is the uterus an example of myogenic tissue?
Yes, it produces contractions without neuronal or hormonal input
Draw a graph of the size of contraction against time
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What is the uterus sensitive to and why are contractions needed?
- Highly sensitive to neurotransmitters and hormones
* Rhythmic contractions for parturition
How is synchronous contraction achieved?
• Pacemaker cells in myometrium (responsible for rhythmic contractions of the uterus) – interstitial Cells of Cajal (ICCs) Initiate and coordinate contractions • Electrical communication via gap junctions made of connexion proteins – ion channels, they align themselves forming a gap, forming a channel of communication. • They are found: Between ICCs Between ICCs and smooth muscle cells Between smooth muscle cells Function as a syncytium
What series of events lead to contraction?
Draw the graph as well
ICC periodic activation of inward currents -> depolarisations -> Ca2+ entry through VGCCs -> [Ca2+]i -> contraction
Describe the Cellular mechanisms of smooth muscle contraction
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Describe the cellular mechanisms for smooth muscle relaxation
- [Ca2+]i -> contraction
- Graded response: incremental increases in [Ca2+]i -> incremental increases in force of contraction
- Mechanisms for lowering [Ca2+]i: e.g. Ca2+ extrusion
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Describe the disinctive patterns of electrical activity
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What receptor causes contraction and what receptor causes relaxation?
- α-adrenoceptor agonist – contraction
* β2-adrenoceptor agonist – relaxation – Gs receptor coupled to cyclic amp and phosphokinase
How does oestrogen and progesterone influence contractions?
- Progesterone inhibits contraction
* Oestrogen increases contraction
Describe the contractions in a non-pregnant uterus and a pregnant uterus
• Non-pregnant uterus
o Weak contractions early in cycle
o Strong contractions during menstruation ( Low progesterone, High in prostaglandins)
• Pregnant uterus
o Weak and uncoordinated in early pregnancy (high progesterone)
o Strong and co-ordinated at parturition (High oestrogen)
Describe the changes to the levels of oestrogen and progesterone during parturition
• Oestrogen / progesterone ratio increases during parturition
o Oestrogen increases while progesterone decreases gap junction expression in myometrium
o Oestrogen / progesterone receptors are also found on ICCs
How are contractions regulated by prostaglandins?
• Myo- and endo-metrium synthesise PGE2 and PGF2α – promoted by oestrogens
o Both prostaglandins induce myometrial contraction
o Role in dysmenorrhoea (severe menstrual pain), menorrhagia (severe menstrual blood loss), pain after parturition
NSAIDs are effective – reduce contraction and pain
What do prostaglandins act to do?
o Coordinate Increase frequency/force of contractions
Increase gap junctions
o Soften cervix
• Prostaglandins are effective in early and middle pregnancy
What are the uses of prostaglandin analogues?
Dinoprostone (PGE2), Carboprost (PGF2α), Mistoprotol (PGE1) analogues
Uses:
- Induction of labour – before term
- Induce abortion
- Postpartum bleeding
- Softening the cervix
What are the concerns of prostaglandin analogues?
- Dinoprostone can cause systemic vasodilatation
- Potential for cardiovascular collapse (given as cervical gel/vaginal insert)
- PGs – hypertonus and foetal distress
Where is oxytocin released from and what is it released in response to?
- Non-peptide hormone synthesised in hypothalamus and released from the posterior pituitary gland
- Released in response to suckling and cervical dilatation
What role does oxytocin play in parturition?
• Oestrogen (released at later stages of parturition) produces:
o oxytocin release, High oxytocin receptors, High gap junctions
• Oxytocin also increases synthesis of prostaglandins
• Oxytocin is only effective at term (require oestrogen-induced oxytocin receptor expression)
Give some examples of synthetic versions of oxytocin and there uses
What do they induce?
What might hight conc cause?
What are there uses?
• Syntocinon and Pitocin are synthetic versions of oxytocin
• Pharmacological actions
o Low concentrations of oxytocin analogue - increase frequency and force of contractions
o High concentrations cause hypertonus – may cause fetal distress
Uses:
• Induction of labour at term – does not soften cervix
• Treat / prevent post-partum haemorrhage
• Syntometrine – oxytocin (rapid)/ergot (prolonged) combination
What is the function of ergometrine?
- Action
- Powerful and prolonged uterine contraction - but only when myometrium is relaxed
- Mechanism
- Stimulation of -adrenoceptors, 5-HT receptors?
- Uses
- Post-partum bleeding - NOT induction
Give some examples of myometrial relaxtants
• Relaxants may be used in premature labour
o Important: Delay delivery by 48 hrs, so Mother can be transferred to specialist unit, and given antenatal corticosteroids to aid foetal lung maturation and increase survival
• B2-adrenoceptor stimulants e.g. Salbutamol
o Relax uterine contractions by a direct action on the myometrium
o Used to reduce strength of contractions in premature labour
o May occur as a side effect of drugs used in asthma
• Ca2+ channel antagonists e.g. nifedipine (used in hypertension) or Mg Sulfate
• Oxytocin receptor antagonists e.g. Retosiban
• COX inhibitors e.g. NSAIDs - o (Increase prostaglandin) – why NSAIDS are useful to treat dysmenorrhoea and menorrhagia – but may cause fetal renal dysfunction
How does stimulation of B2-adrenoceptors on smooth muscle (vascular, airway, myometrial) produces relaxation
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B2-adrenoceptor stimulation PKA activity
• Ca2+ ATPase (SERCA) – increase uptake into SR/exclusion from cell
• K+ channel activity hyperpolarisation Ca2+ entry via VGCCs
• MLCK
