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Physiology 2 : Reproduction and bones > Pharmacology of the Uterus > Flashcards

Pharmacology of the Uterus Flashcards

1
Q

Structure of myometrium

A

Smooth muscle of the uterus
• Outer longitudinal fibres
• Middle figure-eight fibres
• Inner circular fibres

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2
Q

Mechanical properties of myometrium

A
  • 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
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3
Q

How is synchronous contraction achieved?

A
  • 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
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4
Q

Waves of electrical activity

A

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

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5
Q

Cellular mechanisms of smooth muscle contraction

A
  • 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
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6
Q

Basal and elevated [Ca2+] intracellular

A

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

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7
Q

Excitation – contraction coupling

A

Distinctive pattern of electrical activity – Ca2+ changes – contraction

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8
Q

Low concentrations of stimulants on ICCs

A

• increase slow-wave frequency producing increase frequency of contractions

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9
Q

Higher concentrations

A

• increase frequency of action potentials on top of slow waves (i.e. increase peak [Ca2+]i) producing both increase frequency and force of contractions

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10
Q

Higher concentrations still

A

• increase plateau of slow-wave producing prolonged sustained contractions

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11
Q

Large concentrations

A
  • Hypertonus (incomplete relaxation)
  • Ca2+ extrusion processes not effective
  • Important: Interfere with blood flow – foetal distress
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12
Q

Regulation by neurotransmitter

A 
Myometrium
•	Sympathetic (not parasympathetic) innervation
•	Expression of α- and β- adrenoceptors
•	α-adrenoceptor agonist – contraction
•	β2-adrenoceptor agonist – relaxation
•	How?
•	G protein?
•	Signalling pathways?
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13
Q

Regulation by sex hormones

A

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

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14
Q

Regulation by prostaglandins

A

• 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

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15
Q

Uses of prodtaglandin analogues

A
  • Induction of labour – before term
  • Induce abortion
  • Postpartum bleeding
  • Softening the cervix
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16
Q

Concerns of prodtaglandin analogues

A

Dinoprostone can cause systemic vasodilatation
Potential for cardiovascular collapse (given as cervical gel/vaginal insert)
PGs – hypertonus and foetal distress

17
Q

Prostaglandin analogues

A

Dinoprostone (PGE2), Carboprost (PGF2α), Mistoprotol (PGE1) analogues

18
Q

Regulation by oxytocin

A

Non-peptide hormone synthesised in hypothalamus and released from the posterior pituitary gland
Released in response to suckling and cervical dilatation

19
Q

Role of oxytocin in parturition

A

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

20
Q

Use of oxytocin

A

Induction of labour at term – does not soften cervix
Treat / prevent post-partum haemorrhage
Syntometrine – oxytocin (rapid)/ergot (prolonged) combination

21
Q

Pharmacological actions

A

Low concentrations of oxytocin analogue - increase frequency and force of contractions
High concentrations cause hypertonus – may cause fetal distress

22
Q

Ergot to ergomrtrine

A
  • 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
23
Q

Action of Ergot to ergomrtrine

A

Powerful and prolonged uterine contraction - but only when myometrium is relaxed

24
Q

Mechanism of Ergot to ergomrtrine

A

Stimulation of Alpha-adrenoceptors, 5-HT receptors?

25
Q

Uses of Ergot to ergomrtrine

A

Post-partum bleeding - NOT induction

26
Q

Myometrial relaxants

A
  • 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
27
Q

Beta adrenoceptor stimulants e.g. salbutamol

A
  • 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
28
Q

Other myometrial relaxants

A
  • 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
29
Q

Beta 2-adrenoceptor stimulation -> PKA activity

A
  • Increase Ca2+ ATPase (SERCA) – increase uptake into SR/exclusion from cell
  • increase K+ channel activity -> hyperpolarisation -> decrease Ca2+ entry via VGCCs
  • decrease MLCK
30
Q

Overview of pharmacology on uterus

A 
•	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
31
Q

Isometric tension recording

A
  • Measure tension generated with diameter of the muscle ring remains constant
32
Q

Y1 practicals: Large organ baths – aortic ring experiments

A

• Widely used techniques to investigate the functional properties of uterine, vascular, airway and bladder smooth muscle segments

Physiology 2 : Reproduction and bones (13 decks)

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