Pharmacology of the Uterus Flashcards by V M

What is the structure of the myometrium?

Outer longitudinal fibres
Middle figure of 8 fibres
Inner circular fibres

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What does contraction of the myometrium cause?

Increases uterine content towards the cervix and acts as a natural ligature to prevent blood loss

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What type of muscle is in the myometrium?

Spontaneously active (myogenic)
Produces regular contractions without neuronal or hormonal input

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What is the myometrium sensitive to?

Highly sensitive to neurotransmitters and hormones

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Why does the myometrium need to contract rhythmically?

For parturition (childbirth)

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How is synchronous activity achieved?

Pacemaker cells called interstitial cells of Cajal (ICCs)
- Initiate and coordinate contractions
- Electrical communication via gap junctions made of connexion proteins

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Where are gap junctions located?

What do they function as?

Between ICCs
Between ICCs and smooth muscle cells
Between smooth muscle cells

Function as a syncytium

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Describe the electrical activity of the myometrium

ICC periodic activation of inward current = depolarisation

Ca2+ enters via VGCCs = increase of intracellular calcium = contraction

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What modulates slow waves of ICCs and smooth muscle responses?

Slow waves of ICCs and smooth muscle responses are modulated by neurotransmitters and hormones

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Describe the mechanism of smooth muscle contractions

Oxytocin or another substance binds to GCPR q/11
IP3 binds to SR and causes release of Ca2+ increasing intracellular Ca2+
DAG activates ion channels
Action of ion channels increase membrane excitabillity
= depolarisation
Activates VGCC’s induce Ca2+ influx
Increase intracellular calcium
Ca2+/calmodulin complex will activate MLCK
This phosphorylates myosin at a regulatory area caled myosin light chain at ser 19
Increases ATPase activity of myosin head x1000 fld
Allows myosin II to interact with actin forming actomyosin
A molecule of ATP will come along and cause contraction of smooth muscle

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What does a graded response of calcium mean?

Incremental increases in calcium = incremental increases in force of contraction

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What is a mechanism for lowering Ca2+?

This accounts for the relaxing phase of the wave of contraction
Removing calcium removes the contractile tone

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Describe excitation contraction coupling

Distinctive pattern of electrical activity - Ca2+ changes - contraction

Low concentrations of stimulants on ICCs
- slow wave frequency producing frequency of contractions
Higher concentrations
- frequency of action potentials on top of slow waves (i.e. peak [Ca2+]i) producing both frequency and force of contractions
Higher concentrations still
- plateau of slow wave producing prolonged sustained contractions
Large concentrations
- Hypertonus (incomplete relaxation)
- Ca2+ extrusion processes not effective
- Important: Interfere with blood flow – foetal distress

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What is hypertonus?

Incomplete relaxation

(Ca2+ processes are not effective - this is important as it interferes with blood flow = foetal distress)

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What type of innervation does the myometrium recieve?

Sympathetic innervation

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What receptors does the myometrium express?

α-adrenoceptor agonist – CONTRACTION coupled to Gq/11

β2-adrenoceptor agonist – RELAXATION coupled to Gas

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What do alpha adrenoreceptor agonists cause?

Contraction - coupled to Gq/11

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What do beta adrenoreceptor agonists cause?

Relaxation coupled to Gas

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What does progesterone do on to the myometrium?

Inhibits contraction

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What does oestrogen do on the myometrium?

Increases contraction

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Describe the regulation of the myometrium via sex hormones during non-pregnancy?

Weak contractions early in cycle
Strong contractions during menstruation - low progesterone, high prostaglandins

Describe the regulation of the myometrium via sex hormones during pregnancy

Weak + uncoordinated in early pregnancy = high progesteronoe
Strong and co-ordinated at parturition = high oestrogen

How doe the sex hormones increase during parturition?

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

What does the myometrium and endoemetrium synthesise?

They synthesise prostaglandins: PGE2 and PGF2a - promoted by oestrogens

What do prostaglandins do?

induce myometrial contraction

What do prostaglandins play a role in?

* Dysmenorrhoea (severe menstrual pain) * Menorrhagia (severe menstrual blood loss) * Pain after parturition

What drugs can reduce contraction and pain?

NSAIDs are effective reduce contracion and pain, inhibit the COX enzyme = reducing prostaglandin levels

When are prostaglandins effective?

In early and middle pregnancy

Give examples of prostaglandin analogues?

* Dinoprostone (PGE2) * Carboprost (PGF2a) * Mistoprotol (PGE1)

What are the uses of prostaglandin analogues?

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

What are the concerns of using prostaglandin analogues?

* Dinoprostone can cause **_systemic vasodilatation_** * Potential for cardiovascular collapse (given as cervical gel/vaginal insert) * PGs – hypertonus and foetal distress (if used to induce labour however okay to induce abortion)

What is the role of the hormone oxytocin?

Peptide hormone synthesised by the **posterior pituitary gland** *

What is oxytocin released in response to?

Suckling and cervical dilation

What does oestrogen do in parturition?

* Increases oxytocin release * Increases oxytocin receptors * Increased gap junctions * Oxytocin also ***increases synthesis of prostaglandins***

What time is oxytocin effective?

Only effective at term - requires **_oestrogen induced oxytocin expression_**

What are two synthetic versions of oxytocin?

Syntocinon and pitocin

What are the pharmacological actions of oxytocin analogues?

* Low concentrations increase frequency and force of contractions * High concentrations cause **hypertonus** and may cause fetal distress

Uses of oxytocin analogues?

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

What is ergot? how it it used for uterine contractions?

ERGOT = fungus which grows on some cereals Contains array of potent agents inc. ergot alkaloids, histamine, tyramine and acetylcholine When ingested can cause gangrene, convulsions and abortion **_ACTION_** = **powerful and prolonged uterine contraction - however only when myometrium is relaxed**

What does ergot act on?

Alpha adrenoreceptors and 5-HT receptors

What are the uses of ergot?

Post-partum bleeding - not induction (as myometrium also acts as a natural ligature for bleeding)

Why are relaxants used in premature labour?

* They will delay the delivery by 48 hours, this allows the mother to be transferred to a specialist unit and given antenatal corticosteroids to air foetal lung maturation and increase survival

Give examples of myometrial relaxants

* b2-adrenoceptor stimulants e.g. Salbutamol * Ca2+ channel antagonists e.g. nifedipine (used in hypertension) or Mg Sulfate * Oxytocin receptor antagonists e.g. Retosiban * COX inhibitors e.g. NSAIDs (decrease PG levels can treat dysmenorrhea and menorrhagia)

What is the action of beta-2 adrenoceptor stimulants?

* 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

What does stimulation of beta2 adrenoreceptors on smooth muscle do?

* Causes adenylyl cyclase to change ATP to cAMP activating PkA * Increases Ca2+ ATPase to increase uptake into SR from the cell * Also increased K+ channel activity = hyperpolarisation decreasing in Ca2+ entry via VGCC's * PkA also decreases the action of MLCK * All of these produce relaxation

What induces labour at term?

Oxytocin

What induces labour in early term and at term?

Early term: Prostaglandins (not oxytocin - no oxytocin receptors) Induction of labour at term: Oxytocin

What causes post-partum bleeding?

Prostaglandins, oxytocin, ergots

What prevents premature birth?

* b2-adrenoreceptor agonists * Ca2+ channel blockers, Mg Sulfate * Oxytocin inhibitors

How is uterine contraction measured?

Using **Isometric tension recording** = measure tension generated with diameter of the muscle ring remains constant