Pharmacology of the Uterus Flashcards
Structure of myometrium
Smooth muscle of the uterus
• Outer longitudinal fibres
• Middle figure-eight fibres
• Inner circular fibres
Mechanical properties of myometrium
- Contraction means increase in uterine pressure, forcing content towards the cervix and acts as a natural ligature to prevent blood lost
- Spontaneously active (myogenic)
- Produce regular contractions without neuronal or hormonal input
- Highly sensitive to neurotransmitters and hormones
- Rhythmic contractions for parturition
How is synchronous contraction achieved?
- Pacemaker cells in myometrium – interstitial Cells of Cajal (ICCs)
- Initiate and coordinate contractions
- Electrical communication via gap junctions made of connexion proteins
- Between ICCs
- Between ICCs and smooth muscle cells
- Between smooth muscle cells
- Function as a syncytium
Waves of electrical activity
ICC periodic activation of inward currents -> depolarisations -> Ca2+ entry through VGCCs ->[Ca2+]i -> contraction
Slow waves of ICCs and smooth muscle responses are modulated by neurotransmitters and hormones
Cellular mechanisms of smooth muscle contraction
- Depolarisation
- Activation of VGCCs - induces Ca 2+ influx
- Increase in intercellular calcium
- Ca 2+ calmodulin
- Myosin light chain kinase
- Myosin light chain/ actin interactions
- contraction
Basal and elevated [Ca2+] intracellular
Similar to other smooth muscle tissues
• [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
Excitation – contraction coupling
Distinctive pattern of electrical activity – Ca2+ changes – contraction
Low concentrations of stimulants on ICCs
• increase slow-wave frequency producing increase frequency of contractions
Higher concentrations
• increase frequency of action potentials on top of slow waves (i.e. increase peak [Ca2+]i) producing both increase frequency and force of contractions
Higher concentrations still
• increase plateau of slow-wave producing prolonged sustained contractions
Large concentrations
- Hypertonus (incomplete relaxation)
- Ca2+ extrusion processes not effective
- Important: Interfere with blood flow – foetal distress
Regulation by neurotransmitter
Myometrium • Sympathetic (not parasympathetic) innervation • Expression of α- and β- adrenoceptors • α-adrenoceptor agonist – contraction • β2-adrenoceptor agonist – relaxation • How? • G protein? • Signalling pathways?
Regulation by sex hormones
rogesterone inhibits contraction
• Oestrogen increases contraction
• Non-pregnant uterus
• Weak contractions early in cycle
• Strong contractions during menstruation (decrease progesterone,
increase prostaglandins)
• Pregnant uterus
• Weak and uncoordinated in early pregnancy (high progesterone)
• Strong and co-ordinated at parturition (increase oestrogen)
• Oestrogen / progesterone ratio increases during parturition
• Oestrogen increases while progesterone decreases gap junction expression in myometrium
• Oestrogen / progesterone receptors are also found on ICCs
Regulation by prostaglandins
• Myo- and endo-metrium synthesise PGE2 and PGF2α – promoted by oestrogens
• Both prostaglandins induce myometrial contraction
• Role in dysmenorrhoea (severe menstrual pain), menorrhagia (severe menstrual blood loss), pain after parturition
NSAIDs are effective – reduce contraction and pain
• Act together to,
• Coordinate frequency/force of contractions
• gap junctions
• Soften cervix
• Prostaglandins are effective in early and middle pregnancy
Uses of prodtaglandin analogues
- Induction of labour – before term
- Induce abortion
- Postpartum bleeding
- Softening the cervix
Concerns of prodtaglandin analogues
Dinoprostone can cause systemic vasodilatation
Potential for cardiovascular collapse (given as cervical gel/vaginal insert)
PGs – hypertonus and foetal distress
Prostaglandin analogues
Dinoprostone (PGE2), Carboprost (PGF2α), Mistoprotol (PGE1) analogues
Regulation by oxytocin
Non-peptide hormone synthesised in hypothalamus and released from the posterior pituitary gland
Released in response to suckling and cervical dilatation
Role of oxytocin in parturition
Oestrogen (released at later stages of parturition) produces:
increase oxytocin release, increase oxytocin receptors, Increase gap junctions
Oxytocin also increases synthesis of prostaglandins
Oxytocin is only effective at term (require oestrogen-induced oxytocin receptor expression)
Syntocinon and Pitocin are synthetic versions of oxytocin
Use of oxytocin
Induction of labour at term – does not soften cervix
Treat / prevent post-partum haemorrhage
Syntometrine – oxytocin (rapid)/ergot (prolonged) combination
Pharmacological actions
Low concentrations of oxytocin analogue - increase frequency and force of contractions
High concentrations cause hypertonus – may cause fetal distress
Ergot to ergomrtrine
- Ergot - fungus that grows on some cereals (e.g. rye) and grasses
- Contains array of potent agents inc. ergot alkaloids (e.g. ergometrine, ergotamine; both based on LSD moiety), histamine, tyramine and acetylcholine
- When ingested ergotism, gangrene, convulsions, abortion
Action of Ergot to ergomrtrine
Powerful and prolonged uterine contraction - but only when myometrium is relaxed
Mechanism of Ergot to ergomrtrine
Stimulation of Alpha-adrenoceptors, 5-HT receptors?
Uses of Ergot to ergomrtrine
Post-partum bleeding - NOT induction
Myometrial relaxants
- Relaxants may be used in premature labour
- 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
Beta adrenoceptor stimulants e.g. salbutamol
- Relax uterine contractions by a direct action on the myometrium
- Used to reduce strength of contractions in premature labour
- May occur as a side effect of drugs used in asthma
Other myometrial relaxants
- Ca2+ channel antagonists e.g. nifedipine (used in hypertension) or Mg Sulfate
- Oxytocin receptor antagonists e.g. Retosiban
- COX inhibitors e.g. NSAIDs
- ( prostaglandin) – why NSAIDS are useful to treat dysmenorrhoea and menorrhagia – but may cause fetal renal dysfunction
Beta 2-adrenoceptor stimulation -> PKA activity
- Increase Ca2+ ATPase (SERCA) – increase uptake into SR/exclusion from cell
- increase K+ channel activity -> hyperpolarisation -> decrease Ca2+ entry via VGCCs
- decrease MLCK
Overview of pharmacology on uterus
• Induction of labour at term - Oxytocin • Induction of labour/termination in early term - Prostaglandins (not oxytocin – no oxytocin receptors) • Post-partum bleeding - Prostaglandins, oxytocin, ergots • Prevent premature birth - 2-adrenoreceptor agonists - Ca2+ channel blockers, Mg Sulfate - Oxytocin inhibitors
Isometric tension recording
- Measure tension generated with diameter of the muscle ring remains constant
Y1 practicals: Large organ baths – aortic ring experiments
• Widely used techniques to investigate the functional properties of uterine, vascular, airway and bladder smooth muscle segments
