Pharmacology of the uterus

Question 1

Lable the cross-section of the uterus

Answer 1

On image

Question 2

Define contraction, in relation to the uterus

Answer 2

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

Question 3

Is the uterus an example of myogenic tissue?

Answer 3

Yes, it produces contractions without neuronal or hormonal input

Question 4

Draw a graph of the size of contraction against time

Answer 4

On image

Question 5

What is the uterus sensitive to and why are contractions needed?

Answer 5

• Highly sensitive to neurotransmitters and hormones

* Rhythmic contractions for parturition

Question 6

How is synchronous contraction achieved?

Answer 6

•	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

Question 7

What series of events lead to contraction?

Draw the graph as well

Answer 7

ICC periodic activation of inward currents -> depolarisations -> Ca2+ entry through VGCCs -> [Ca2+]i -> contraction

Question 8

Describe the Cellular mechanisms of smooth muscle contraction

Answer 8

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Question 9

Describe the cellular mechanisms for smooth muscle relaxation

Answer 9

• [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

On image

Question 10

Describe the disinctive patterns of electrical activity

Answer 10

On document

Question 11

What receptor causes contraction and what receptor causes relaxation?

Answer 11

• α-adrenoceptor agonist – contraction

* β2-adrenoceptor agonist – relaxation – Gs receptor coupled to cyclic amp and phosphokinase

Question 12

How does oestrogen and progesterone influence contractions?

Answer 12

• Progesterone inhibits contraction

* Oestrogen increases contraction

Question 13

Describe the contractions in a non-pregnant uterus and a pregnant uterus

Answer 13

• 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)

Question 14

Describe the changes to the levels of oestrogen and progesterone during parturition

Answer 14

• 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

Question 15

How are contractions regulated by prostaglandins?

Answer 15

• 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

Question 16

What do prostaglandins act to do?

Answer 16

o Coordinate Increase frequency/force of contractions
Increase gap junctions
o Soften cervix
• Prostaglandins are effective in early and middle pregnancy

Question 17

What are the uses of prostaglandin analogues?

Answer 17

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

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

Question 18

What are the concerns of prostaglandin analogues?

Answer 18

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

Question 19

Where is oxytocin released from and what is it released in response to?

Answer 19

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

Question 20

What role does oxytocin play in parturition?

Answer 20

• 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)

Question 21

Give some examples of synthetic versions of oxytocin and there uses

What do they induce?

What might hight conc cause?

What are there uses?

Answer 21

• 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

Question 22

What is the function of ergometrine?

Answer 22

• 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

Question 23

Give some examples of myometrial relaxtants

Answer 23

• 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

Question 24

How does stimulation of B2-adrenoceptors on smooth muscle (vascular, airway, myometrial) produces relaxation

Answer 24

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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