Pharmacology of the Uterus Flashcards

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1
Q

What is the structure of the myometrium?

A
  • 3 layers of smooth muscle
    • outer longitudinal fibres
    • middle figure of eight-shaped fibres
    • inner circular fibres
  • organised so that contraction causes an inc in uterine pressure
  • forcing any contents towards cervix
  • acts as a natural ligature to prevent blood loss
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2
Q

The myometrium is myogenic (spontaneously active) - these spontaneous contractions are highly sensitive to NTs and hormones. What hormones have what impact on the myometrial contractions?

A
  • progesterone - inhibits contactions
  • oestrogen - increases contraction
  • remember: increased oestrogen to progesterone ratio during partition (birth)
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3
Q

What are contractions like in a non-pregnant uterus?

A
  • weak contractions early in cycle
  • strong contractions during menstruation (decreased progesterone, increased prostaglandins)
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4
Q

What are contractions like in a pregnant uterus?

A
  • weak + uncoordinated in early pregnancy (high progesterone)
  • strong and co-ordinated at parturition (increased oestrogen)
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5
Q

What is the innervation of the myometrium?

A
  • auotonomic nervous system
  • innervated by sympathetic (not parasympathetic) nerves
  • myometrium contains both alpha and beta receptors
  • stimulation of alpha -> contraction
  • stimulation of Beta2 -> relaxation
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6
Q

What is the myogenic mechanism of the myometrium?

A
  • ‘pacemaker’ mechanism
  • myometrium contains pacemaker cells - interstitial cells of Cajal
  • initiate and coordinate contractions
  • electrical activity generated in ICCs pass from smooth muscle cell to smooth muscle cell via gap junctions - made of connexin proteins

myometrium of uterus behaves as a ‘synctytium’ - electrical connected cells

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7
Q

The mechanisms for achieving synchronous contraction are affected by hormones. What effect does oestrogen have?

A

Oestrogen increases expression of gap junctions to promote contraction

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8
Q

What are slow waves and what follows them?

A
  • the slow depolarisations produced by pacemaker cells (ICCs)
  • electrical activity spreads via gap junctions to SMCs
  • activates action potentials in SMcs: upstroke of APs are carried by Ca2+ ions through VGCCs which leads to increase in [Ca2+]i -> contraction
  • slow waves/SMCs are modulated by NTs/hormones
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9
Q

What happens when you get stimulation of smooth muscle - eg. by oxytocin?

A
  • stimulates Gq/11 pathway:
  • PIP2 —–PLC—-> IP3 + DAG
  • IP3 -> binds to IP3 receptor on sarcoplasmic reticulum -> opens ion channels -> calcium moves out into cytoplasm -> rise in [Ca2+]i
  • DAG -> increases membrane excitability -> depolarisation -> activation of VGCCs -> induces Ca2+ influx -> rise in [Ca2+]i
  • Ca2+-Calmodulin
  • MLCK activated -> MLC phosphorylated -> cross-bridge formation -> contraction

as you have gap junctions, this depolarisation can move across cells - syncytium - wave of info moving through SMCs

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10
Q

What are some principles of excitation and inhibition - to do with contraction?

A
  • contraction is caused by an increase in [Ca2+]i
  • inceased force of contraction proportional to increase in [Ca2+]i
  • each action potential will cause an incremental increase in [Ca2+]i
  • but also there are mechanisms lowering [Ca2+]i - eg. Ca extrusion
  • changes in [Ca2+]i will be the resultant effect of these processes
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11
Q

How will a low concentration of stimulants on ICCs impact on contractions?

A
  • increased slow wave frequency producing
  • increased frequency of smooth muscle cell contractions
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12
Q

How will a higher concentration of stimulant on ICC impact on contractions?

A
  • increased frequency of action potentials on top of slow waves
  • peak intracellular calcium conc
  • producing both increased frequency and force of SMC contractions
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13
Q

How will higher concentrations still impact on contractions?

A
  • increased plateau of slow wave
  • producing prolonged sustained smooth muscle cell contractions
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14
Q

What will maximal stimulation (large concentrations) of ICCs result in terms of contraction?

A
  • hypertonus - smooth muscle constantly contracting
  • incomplete relaxation
  • Ca extrusion process not effective
  • interfere with blood flow - fetal distress!!!
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15
Q

Oxytocin

  • what is it?
  • where is it synthesised + released from?
  • in response to?
A
  • nonapeptide hormone
  • synthesised in hypothalamus
  • released from posterior pituitary gland
  • released in response to suckling + cervical dilatation
  • role in parturition?
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16
Q

What is a synthetic version of oxytocin?

A

Syntocinon/pitocin

17
Q

What is action of oxytocin dependent on?

A
  • dependent on oestrogen
  • oestrogen, released at later stages of parturition, produces:
    • increased oxytocin release
    • increased oxytocin receptors
    • increased gap junctions
  • oxytocin is only effective at term
18
Q

What are the pharmacological actions of oxytocin?

A
  • low conc of oxytocin analogue
  • increase frequency and force of contractions
  • high concentrations cause hypertonus -> may cause fetal distress
19
Q

What are uses of oxytocin?

A
  • induction of labour at term - doesn’t soften cervix
  • treat/prevent post-partum haemorrhage
  • syntometrine - oxytocin (rapid) / ergot (prolonged) combo
20
Q

What prostaglandins are produced in the uterus and where from exactly?

A
  • PGE2 (vasodilator)
  • PGF2a (vasoconstrictor)
  • synthesised in myo and endometrium
  • promoted by oestrogens
21
Q

How are NSAIDs effective against prostaglandins?

A

PGs involved in

  • dysmenorrhoea (severe menstrual pain)
  • menorrhagia (severe menstrual blood loss)
  • parturition (birth)

NSAIDs block production of COX

22
Q

What effect do prostaglandins have in terms of contractions etc?

A
  • act together to coordinate increased frequency + force of contractions
  • increase gap junctions
  • soften cervix
  • increase synthesis of oxytocin
23
Q

PGs are effective in early and middle pregnancy. What are examples of PG analogues?

A
  • Dinoprostone (PGE2)
  • Carboprost (PGF2a)
  • Mistoprotol (PGE1)
24
Q

What are uses of PG analogues?

A
  • induction of labour - before term
  • induce abortion, postpartum bleeding, softening of cervix
25
Q

What are concerns regarding use of PGs?

A
  • Dinoprostone (PGE2) can cause systemic vasodilatation
  • potential for cardiovascular collapse (given as cervical gel/vaginal insert)
  • PGs - hypertonus + foetal distress
26
Q

What is ergot? What do they cause when ingested?

A
  • Ergot - fungus that grows on some cereals (eg rye) + grasses
  • contains array of potent agents eg. ergometrine, ergotamine (both based on LSD moiety), histamine, tyramine + ACh
  • when ingested -> ergotism, gangrene, convulsions + abortion
27
Q

What is the action of ergometrine on the myometrium?

A
  • powerful and prolonged uterine contraction
  • but only when myometrium is relaxed
28
Q

What is the mechanism of action of ergometrine?

A
  • stimulation of alpha-adrenoreceptors
  • 5-HT receptors (?)
29
Q

What is the use of ergometrine?

A
  • for post-partum bleeding
  • need a very powerful contraction - ergots potentially used
  • not used for induction - only for post-partum bleeding
30
Q

What are examples of myometrial relaxants?

A
  • B2 stimulants - eg. salbutamol - relax uterine contractions by a direct action on myometrium, used to reduce strength of contractions in premature labour - may occur as a side-effect of drugs used in asthma
  • Ca channel antagonists eg. Nifedipine (used in hypertension) or magnesium sulfate
  • Oxytocin receptor antagonists - eg. Retosiban
  • COX inhibitors - eg NSAIDs, decrease PG - may cause fetal renal dysfunction though
31
Q

Why are myometrial relaxants important?

A
  • these drugs may be used in premature labour
  • delay delivery by 48 hours, so mother can be transferred to specialist unit + given antenatal corticosteroids to aid foetal lung maturation + increase survival
32
Q

How does stimulation of B2-adrenoreceptors on smooth muscle (vascular, airway, myometrial) produce relaxation?

A
  • adrenaline binds / stimulation
  • Gs pathway
  • Adenlyl cyclase -> increase in cAMP
  • PKA activation…
    • inc Ca ATPase (SERCA) -> inc uptake into SR/exclusion from cell
    • inc K channel activity -> hyperpolarisation -> decrease VGCCs
    • decrease MLCK

all prod relaxation of smooth muscle

33
Q

What drug induces labour AT term?

A

Oxytocin

34
Q

What drug induces labour/termination in EARLY term?

A

prostaglandins (not oxytocin as there are no oxy receptors)

35
Q

What drugs stop post-partum bleeding?

A
  • prostaglandins
  • oxytocin
  • ergots
36
Q

What drugs prevent premature birth?

A
  • B2-adrenoreceptor agonists
  • Ca channel blockers
  • MgSulfate
  • Oxytocin inhibitors