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Reproduction (Physiology 2) > Pharmacology of Uterus > Flashcards

Pharmacology of Uterus Flashcards

1
Q

Describe the different layers of myometrial smooth muscle

A

Outer longitudinal fibres
Middle figure-eight fibres
Inner circular fibres

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2
Q

Describe the vasculature of the uterus

A

Vasculature contains tube, blood vessels and smooth muscle cells wrapped around blood vessels in a spindle shape

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3
Q

Outline the different lining layers of the uterus

A

Lumen in middle
Endometrium has epithelial layer
Peritoneum has epithelial cells and connective tissue
Myometrial layer is the contractile agent causes uterine contractions

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4
Q

What is a contraction of the uterus?

A

An increase in uterine pressure, forcing content towards the cervix and acts as a natural ligature to prevent blood lost

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5
Q

Describe the mechanical properties of the myometrium

A

Spontaneously active (myogenic)
Regular contractions without neuronal/hormonal input
Highly sensitive to neurotransmitters and hormones
Rhythmic contractions for parturition

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6
Q

What causes a symchronous contraction?

A

Synchronised contractions are achieved via Pacemaker cells in myometrium – interstitial Cells of Cajal (ICCs)

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7
Q

What is the role of ICCs in uterine contractions?

A

Initiate and coordinate contractions

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8
Q

Describe the electrical communication that takes place in order for uterine contractions to occur

A

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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9
Q

Outline how ICCs cause waves of electrical activity for contraction

A
  1. ICC periodic activation of inward currents
  2. Depolarisations
  3. Ca2+ entry through VGCCs
  4. [Ca2+]i 🡪 contraction
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10
Q

How is smooth muscle contraction regulated?

A

Slow waves of ICCs and smooth muscle responses are modulated by neurotransmitters and hormones
most likely due to receptor mediated mechanisms e.g. oxytocin, 𝛼1 - these are coupled to the Gq pathway

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11
Q

What are the ways of increasing [Ca2+]ᵢ in smooth muscles?

A 
Calcium entry (VGCCs)
Calcium release via SR
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12
Q

How do SR stores of Ca2+ increase [Ca2+]ᵢ?

A

Can sequester Ca2+ from SR store causing IP to bind to its receptor allowing Ca2+ release

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13
Q

What is the significance of increasing [Ca2+]ᵢ?

A

Allows myosin light chain kinase to crosslink with actin increasing contraction of smooth muscle

This can occur spontaneously depending on cell type

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14
Q

How do ICCs initiate spontaneous MLCK activity?

A

ICCs do this via the basic activity of ion channels causing a small degree of depolarisation

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15
Q

Briefly outline the Gq subunit pathway

A

Gq excitation would activate phospholipase C → IP3 + DAG, IP3 binds to its receptor releasing Ca2+ from its stores
DAG can activate phosphokinase C or ketone channels and activate ion channels to cause depolarisation causing VGCCs depolarisation eventually

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16
Q

What is the significance of electrical coupling of cells?

A

Adjacent cells can also be depolarised via transmission from the Gq pathway if they’re coupled electrically via gap junctions

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17
Q

What is the result of Basal and Elevated [Ca2+]i?

A

↑ [Ca2+]i 🡪 contraction

Graded response: incremental increases in [Ca2+]i 🡪 incremental increases in force of contraction

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18
Q

What mechanisms are in place to lower [Ca2+]i?

A

Smooth muscles don’t remain in a contracted state due to Ca2+ extrusion via:
Ca2+ pumped out using Ca2+ pumps or taken back into intracellular stores in SR
If Ca2+ levels are v. high, mitochondria take up Ca2+
Na/Ca2+ exchanger helps remove Ca2+ from cytosol passively

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19
Q

what is the effect of Ca2+ extrusion?

A

Cause the extrusion of ca2+ to relax the cell : occurs rhythmically

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20
Q

How do low concentrations of stimulants on ICCs effect contraction?

A

Low concentrations of stimulants on ICCs

↑ slow wave frequency producing ↑ frequency of contractions

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21
Q

What is the effect of higher concentration stimulants on ICCs?

A

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

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22
Q

What is the effect of continued exposure to high concentrations of stimulants on ICCs?

A

↑ plateau of slow wave producing prolonged sustained contractions

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23
Q

What is the effect of large concentrations on ICCs?

A

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

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24
Q

How do neurotransmitters regulate myometrial contraction?

A

Sympathetic (not parasympathetic) innervation
Expression of α- and β- adrenoceptors
α-adrenoceptor agonist – contraction (Gq)
β2-adrenoceptor agonist – relaxation (Gs)

25
Q

How do gonadotrophins regulate myometrial contraction?

A

Progesterone inhibits contraction

Oestrogen increases contraction

26
Q

Describe how the myometrium contracts in a non-pregnant uterus?

A

Weak contractions early in cycle

Strong contractions during menstruation (↓progesterone,↑prostaglandins)

27
Q

Describe the contractions that occur in a pregnant uterus

A

Weak and uncoordinated in early pregnancy (high progesterone)
Strong and co-ordinated at parturition (↑ oestrogen)

28
Q

How do oestrogen/progesterone levels change during birth?

A

Oestrogen / progesterone ratio increases during parturition
- Oestrogen increases while progesterone decreases gap
junction expression in myometrium
- Oestrogen / progesterone receptors are also found on
ICCs

29
Q

What prostaglandins are secreted by the uterus linings?

A

Myo- and endo-metrium synthesise PGE2 and PGF2α – promoted by oestrogens

Both prostaglandins induce myometrial contraction

30
Q

What role d prostaglandins play in dysmenorrhoea?

A

Role in dysmenorrhoea (severe menstrual pain), menorrhagia (severe menstrual blood loss), pain after parturition
Higher levels of prostaglandins are associated with more-severe menstrual cramps

31
Q

How is dysmenorrhoea treated?

A

🡪 NSAIDs are effective – reduce contraction and pain
Act together to:
- Coordinate ↑ frequency/force of contractions
- ↑ gap junctions
- Soften cervix

32
Q

When are prostaglandins most effective?

A

Prostaglandins are effective in early and middle pregnancy

33
Q

Name some prostaglandin analogues

A

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

34
Q

What are the uses of prostaglandin analogues?

A

Induction of labour – before term
Induce abortion
Postpartum bleeding
Softening the cervix

35
Q

What are some of the concerns associated with prostaglandin analogues?

A

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

36
Q

What is oxytocin?

A

Non-peptide hormone synthesised in hypothalamus and released from the posterior pituitary gland

37
Q

What induces the release of oxytocin?

A

Released in response to suckling and cervical dilatation

38
Q

What is the relationship between oestrogen and oxytocin?

A

Oestrogen (released at later stages of parturition) produces:
↑ oxytocin release, ↑ oxytocin receptors, ↑ gap junctions
Oxytocin is only effective at term (require oestrogen-induced oxytocin receptor expression)

39
Q

What effect does oxytocin have on prostaglandins?

A

Oxytocin also ↑ synthesis of prostaglandins

40
Q

Name synthetic versions of oxytocin

A

Syntocinon and Pitocin are synthetic versions of oxytocin

41
Q

What are the pharmacological actions of oxytocin analogues?

A

Low concentrations of oxytocin analogue - increase frequency and force of contractions

High concentrations cause hypertonus – may cause fetal distress

42
Q

What are the pharmacological uses of oxytocin analogues?

A

Induction of labour at term – does not soften cervix
Treat / prevent post-partum haemorrhage

Syntometrine – oxytocin (rapid)/ergot (prolonged) combination

43
Q

What is ergot?

A

fungus that grows on some cereals (e.g. rye) and grasses

44
Q

What is the isgnificance of ergot?

A

Contains array of potent agents inc. ergot alkaloids (e.g. ergometrine, ergotamine; both based on LSD moiety), histamine, tyramine and acetylcholine

45
Q

What are the effects of ergot ingestion?

A

When ingested → ergotism, gangrene, convulsions, abortion

46
Q

What is the pharmacological action of ergot?

A

Action: Powerful and prolonged uterine contraction - but only when myometrium is relaxed
Mechanism: Stimulation of α-adrenoceptors, 5-HT receptors

Uses - Post-partum bleeding - NOT induction

47
Q

When may myometrial relaxants be used?

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

48
Q

What are myometrial relaxants used?

A

β2-adrenoceptor stimulants e.g. Salbutamol
COX inhibitors e.g. NSAIDs
Oxytocin receptor antagonists e.g. Retosiban
Ca2+ channel antagonists e.g. nifedipine (used in hypertension) or Mg Sulfate

49
Q

What are the effects of the relaxants?

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

50
Q

Outline the stimulation of β2-Adrenoceptors on smooth muscle cells

A

β2-adrenoceptor stimulation → PKA activity
↑ Ca2+ ATPase (SERCA) – increase uptake into SR/exclusion from cell
↑ K+ channel activity → hyperpolarisation → ↓ Ca2+ entry via VGCCs
↓ MLCK

51
Q

What hormone causes the induction of labour at term?

A

oxytocin

52
Q

What causes the induction of labour/termination in early term?

A

Prostaglandins (not oxytocin – no oxytocin receptors)

53
Q

What hormones cause postpartum bleeding?

A

Prostaglandins, oxytocin, ergots

54
Q

What mechanisms prevent premature birth?

A

β2-adrenoreceptor agonists
Ca2+ channel blockers, Mg Sulfate
Oxytocin inhibitors

55
Q

How can we measure uterine contractions?

A

Isometric tension recording
Measure tension generated with diameter of the muscle ring remains constant
E.g. Large organ baths – aortic ring experiments (Y1 practicals)

56
Q

What are the uses of aortic ring experiments?

A

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

57
Q

What causes myogenic myometrium contraction?

A

Slow waves electrical activity of ICC drive myogenic contractions of myometrium

58
Q

What factors affect myometrial contractility?

A

Myometrial contractility is sensitive to sex hormones, oxytocin and prostaglandins

Reproduction (Physiology 2) (12 decks)

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