Pharmacology of the Uterus Flashcards
What are the general properties of myometrium?
compare pregnant vs non pregnant uterus?
Myometrium is spontaneously active = ?
Non-pregnant uterus:
- ? contractions early in cycle,
- ? contractions during menstruation (due to decreased ? levels and increased ? levels)
Pregnant uterus:
- ? contractions in early pregnancy (high ?)
- ? and ? at labour (high ?)
Myometrium is spontaneously active – myogenic
Progesterone inhibits, oestrogen increases contraction.
Non-pregnant uterus:
- Weak contractions early in cycle
- Strong contractions in menstruation (due to decreased pg levels and increased prostaglandin levels)
Pregnant uterus:
- Weak, uncoordinated contractions in early pregnancy (high pg), Strong and co-ordinated at labour (high oestrogen)
Describe the innervation of the myometrium
The myometrium is innervated by the ? NS!
It contains both ? and ? receptors
Alpha receptor stimulation produces ?, via the ? pathway
B2 receptor stimulation produces ?, via ? pathway
The myometrium is innervated by the sympathetic NS!
It contains both alpha and beta receptors
Alpha receptor stimulation produces contraction, via the Gq pathway
B2 receptor stimulation produces relaxation, via Gs pathway
How does the myometrium achieve synchronous contraction?
Myometrium= ?; it contracts in response to ?
ICCs ? + ? contractions
ICC impulses pass from ?, via ?
These mechanisms are affected by ?, eg ?
Myometrium=myogenic; it contracts in response to pacemaker cells, called interstitial cells of Cajal (ICCs). ICCs initiate + coordinate contractions
ICC impulses pass between smcs via connexin gap junctions
These mechanisms are affected by hormones, eg oestrogen increases connexin expression, increasing electrical conduction and promoting contraction
Describe the relationship of electrical and mechanical activity in the uterus
ICCs produce ? waves= ? depolarisations
The electrical activity spreads via ? to ?, where it stimulates ?
The upstroke of ? is carried by…
ICCs produce slow waves= slow depolarisations
Eelectrical activity spreads via gap junctions to smooth muscle cells, where it stimulates APs
The upstroke of AP’s is carried by Ca ions through VGCCs, increasing intracellular [Ca] –> activates calmodulin + MLCK –> actin-myosin cross bridge formation–> contraction.
How can oxytocin induce contraction?
oxytocin binds to…
Oxytocin can also cause uterine smc contraction in parturition:
oxytocin binds to Gq/11, causing Gq to dissociate + activate PLC - causes PIP2 -> IP3 & DAG
IP3 binds to IP3 receptors on SR–> Ca release–> activate calmodulin etc
DAG increases membrane excitability + VGCC activity
compare low Vs high stimulant concentrations on myometrial contractions?
Lower stimulant levels increase…
Higher stimulant levels increase ? This leads to…
Afterwards, Mechanisms lower ? for ?
Lower stimulant concentrations increase ICC slow wave frequency–> increased contraction frequency
Higher stimulant concentrations increase both ICC slow wave Hz and APs. This leads to greater intracellular [Ca] peak–> increases contraction frequency AND force
afterwards, Mechanisms lower [Ca] for relaxation (Ca reuptake into SR by SERCA + Ca-ATPase)
What happens if you have excessive stimulant concentrations acting on the myometrium?
Excessive stimulant concs–> incomplete myometrium relaxation.
This= hypertonus, Ca extrusion is ineffective here.
Hypertonus can cause fetal distress, but can help prevent bleeds (postpartum haemorrhage)
What is the function of oxytocin?
? hormone synthesised in ?, released from the ? in response to ?
Also stimulates ?
Oxytocin action depends on ?, which is released in the later stages of ?
? increases oxytocin ?, ? the oxytocin ? and increases ? expression
Nonapeptide hormone synthesised in hypothalamus, released from the posterior pituitary in response to suckling and cervical dilatation
Also stimulates contractions during parturition
Oxytocin action depends on oestrogen, which is released in the later stages of parturition – this means oxytocin is only effective at term
Oestrogen increases oxytocin release, upregulates the oxytocin receptor and increases gap junction expression
When do we give synthetic oxytocin?
Give 2 synthetic oxytocin forms
Low doses cause ?
High doses cause ?
Oxytocin can be combined w ? in the form of ? to give ?
Syntocinon + Pitocin=synthetic oxytocin forms, used to induce labour at term (though doesn’t soften the cervix). Prevents PPH
Low oxytocin analogue doses increase contraction Hz and force (useful for inducing labour)
High doses cause hypertonus–> fetal distress, but stops PPH
Oxytocin can be combined w ergometrine (prolongs uterine contractions) in the form of syntometrine to give extra help to control PPH.
What else is synthesised by the myometrium and what can it cause?
? = synthesised by ?, in response to ?
? and ? cause myometrial ?
Can cause ?
PGs= synthesised by endo/myometrium, in response to oestrogen
PGE2 (vasodilator) and PGF2a (vasoconstrictor) cause myometrial contractions
Can cause dysmenorrhoea (due to excess contraction) and menorrhagia (severe blood loss due to excess vasodilatation)
What is the effect of prostaglandins in preg?
Why are they used in early/middle pregnancy?
Examples?
Concerns?
PGE2 and PGF2 increase: contraction Hz and force, gap junction expression, cervical softening, oxytocin synthesis
Used in early/middle pregnancy to induce preterm labour, therapeutic abortions, soften cervix, control PP bleeding
Examples: Dinoprostone (PGE2), Carboprost (PGF2α)
Concerns: Dinoprostone can cause systemic vasodilatation- potential for CVS collapse (so given as a vaginal gel/insert)
Cause hypertonus and subsequent fetal distress
What is ergo and when is it used?
Ergot = a ? that contains array of potent agents:
? + ? (both based on LSD moiety)
When ingested, it causes ?
Produces ? but only when ?
Mechanism: stimulates ?
Major clinical use is to control ? – NOT ?
Ergot = a fungus that contains array of potent agents:
Ergometrine + ergotamine (both based on LSD)
Histamine, Tyramine, ACh
When ingested, it causes ergotism: gangrene, convulsions and spontaneous abortion
Produces powerful, prolonged uterine contraction, but only when myometrium is relaxed to begin w
Mechanism: stimulates α-adrenoceptors, and potentially 5-HT receptors
Major clinical use is to control PPH – NOT induction of labour
When do we use myometrial relaxants?
Important to delay ?
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
compare 4 myometrial relaxants?
What is an adverse effect of NSAIDs in pregnancy?
ß2-stimulants: Salbutamol relaxes myometrium. Reduces contraction strength in premature labour. May occur as a drug side effect in asthma
Ca2+ channel antagonists (nifedipine for hypertension), or Mg sulphate: Prevent intracellular [Ca2+]i rise, and Ca2+-C-MLCK
Oxytocin receptor antagonists e.g. Retosiban
COX inhibitors: NSAIDs (mefenamic acid): Decrease PG-mediated myometrial contractility - May cause foetal renal dysfunction if used in pregnancy
Beta-2 Mediated Smooth Muscle Relaxation?
Activation of the beta-2 receptor causes Gs to activate AC, which converts ATP into cAMP–> increases PKA–> causes sm relaxation via 3 mechanisms:
Increases SERCA activity–> increased Ca reuptake into the SR
Increases K channel activity–> hyperpolarisation, which reduces VGCC activity
It directly decreases MLCK activity
Summarise the different drugs used in maternal pharmacology
Induction of labour at term? - ?
Induction of labour/termination in early term? - ? : Not ? – as ? receptors not present in ?
Post-partum bleeding? - ?, ?, ?
Prevent premature birth? - ? agonists, ? channel blockers, ?, ? inhibitors
