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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What causes a symchronous contraction?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is the role of ICCs in uterine contractions?

A

Initiate and coordinate contractions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

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

A
Calcium entry (VGCCs)
Calcium release via SR
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

what is the effect of Ca2+ extrusion?

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
How do gonadotrophins regulate myometrial contraction?
Progesterone inhibits contraction | Oestrogen increases contraction
26
Describe how the myometrium contracts in a non-pregnant uterus?
Weak contractions early in cycle | Strong contractions during menstruation (↓progesterone,↑prostaglandins)
27
Describe the contractions that occur in a pregnant uterus
Weak and uncoordinated in early pregnancy (high progesterone) Strong and co-ordinated at parturition (↑ oestrogen)
28
How do oestrogen/progesterone levels change during birth?
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
What prostaglandins are secreted by the uterus linings?
Myo- and endo-metrium synthesise PGE2 and PGF2α – promoted by oestrogens Both prostaglandins induce myometrial contraction
30
What role d prostaglandins play in dysmenorrhoea?
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
How is dysmenorrhoea treated?
🡪 NSAIDs are effective – reduce contraction and pain Act together to: - Coordinate ↑ frequency/force of contractions - ↑ gap junctions - Soften cervix
32
When are prostaglandins most effective?
Prostaglandins are effective in early and middle pregnancy
33
Name some prostaglandin analogues
Dinoprostone (PGE2), Carboprost (PGF2α), Mistoprotol (PGE1) analogues
34
What are the uses of prostaglandin analogues?
Induction of labour – before term Induce abortion Postpartum bleeding Softening the cervix
35
What are some of the concerns associated with prostaglandin analogues?
Dinoprostone can cause systemic vasodilatation Potential for cardiovascular collapse (given as cervical gel/vaginal insert) PGs – hypertonus and foetal distress
36
What is oxytocin?
Non-peptide hormone synthesised in hypothalamus and released from the posterior pituitary gland
37
What induces the release of oxytocin?
Released in response to suckling and cervical dilatation
38
What is the relationship between oestrogen and oxytocin?
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
What effect does oxytocin have on prostaglandins?
Oxytocin also ↑ synthesis of prostaglandins
40
Name synthetic versions of oxytocin
Syntocinon and Pitocin are synthetic versions of oxytocin
41
What are the pharmacological actions of oxytocin analogues?
Low concentrations of oxytocin analogue - increase frequency and force of contractions High concentrations cause hypertonus – may cause fetal distress
42
What are the pharmacological uses of oxytocin analogues?
Induction of labour at term – does not soften cervix Treat / prevent post-partum haemorrhage Syntometrine – oxytocin (rapid)/ergot (prolonged) combination
43
What is ergot?
fungus that grows on some cereals (e.g. rye) and grasses
44
What is the isgnificance of ergot?
Contains array of potent agents inc. ergot alkaloids (e.g. ergometrine, ergotamine; both based on LSD moiety), histamine, tyramine and acetylcholine
45
What are the effects of ergot ingestion?
When ingested → ergotism, gangrene, convulsions, abortion
46
What is the pharmacological action of ergot?
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
When may myometrial relaxants be used?
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
What are myometrial relaxants used?
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
What are the effects of the relaxants?
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
Outline the stimulation of β2-Adrenoceptors on smooth muscle cells
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
What hormone causes the induction of labour at term?
oxytocin
52
What causes the induction of labour/termination in early term?
Prostaglandins (not oxytocin – no oxytocin receptors)
53
What hormones cause postpartum bleeding?
Prostaglandins, oxytocin, ergots
54
What mechanisms prevent premature birth?
β2-adrenoreceptor agonists Ca2+ channel blockers, Mg Sulfate Oxytocin inhibitors
55
How can we measure uterine contractions?
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
What are the uses of aortic ring experiments?
Widely used techniques to investigate the functional properties of uterine, vascular, airway and bladder smooth muscle segments
57
What causes myogenic myometrium contraction?
Slow waves electrical activity of ICC drive myogenic contractions of myometrium
58
What factors affect myometrial contractility?
Myometrial contractility is sensitive to sex hormones, oxytocin and prostaglandins