Pharmacology of the Uterus Flashcards
What are the mechanical properties of the myometrium?
Rhythmic contractions:
- Spontaneously active
- Vary during menstrual cycle and pregnancy
- Force content towards the cervix
Contractions originate in the muscle itself:
- Doesn’t require neuronal or hormonal input
- BUT highly sensitive to e.g. sex hormones
What initiates the contraction of the myometrium?
Spontaneous depolarisation of ‘pacemaker’ cells
Give rise to action potentials
Electrical communication between cells
Gap junctions spread depolarisation
Myometrium can function as a syncytium, all parts of the uterus working together as one
What is excitation-contraction coupling?
ICC periodic activation of inward currents -> depolarisations -> Ca2+ entry through VGCCs -> [Ca2+]i -> contraction
Electrical activity is conducted by syncytium to SMCs
Slow waves of pacemakers and smooth muscle responses are modulated by neurotransmitters and hormones
What happens to the myometrium muscle when there is an increase in Ca2+?
Basal and elevated [Ca2+]i
Similar to other smooth muscle tissues
↑ [Ca2+]i contraction
Graded response: incremental increases in [Ca2+]I leads to incremental increases in force of contraction
We have mechanisms for lowering [Ca2+]i: e.g. Ca2+ extrusion
How can contraction be modulated by hormones and neurotransmitters?
Revise contraction mechanism from last year
But briefly its calcium activating myosin light chain kinase which interacts with actin and that’s what initiates contraction
Spread through gap junctions between cells
E.g.
Oxytocin-induced contractions
Both the force is greater and there is a greater number of contractions
How do you measure uterine contractions (an example)?
E.g. Isometric tension recording
Measure tension generated with diameter of the muscle ring remains constant
Y1 practicals: Large organ baths – aortic ring experiments
Widely used techniques to investigate the functional properties of uterine, vascular, airway and bladder smooth muscle segments
What are 2 different ion channel modulators and what effect do they have on contractions?
K+ channel activator
Less contractions the higher the concentration as we are preventing membrane depolarisation
Ca2+ channel blocker
Less contractions as calcium levels cannot increase
How can you regulate myometrial contractility via neurotransmitters? Give two examples with opposing effects.
Sympathetic (not parasympathetic) innervation
So we have adrenaline and noradrenaline being released
Expression of α- and β- adrenoceptors
α-adrenoceptor agonist – contraction
Through activation of the alpha1 pathway, a GQ coupled pathway resulting in the breakdown of Phospholipase C, the formation of IP3 and DAG
We end up with this release of calcium
β2-adrenoceptor agonist – relaxation
Beta adrenoreceptors are Gs-coupled so that causes activation of adenylate cyclase causing the breakdown of ATP to cAMP which results in relaxation in smooth muscle
How can myometrial contractility be regulated via sex hormones?
Progesterone inhibits contraction
Oestrogen increases contraction
Both act at nuclear and membrane receptors
What’s the difference in sex hormone effects on myometrial contractility between pregnant and non-pregnant uteri?
Pregnant uterus
Weak and uncoordinated contractions in early pregnancy (high progesterone)
7 month till term – Oestrogen increases, progesterone stays constant
Oestrogen / progesterone ratio increases throughout last trimester culminating with strong, coordinated contractions for delivery
Non-pregnant uterus:
Weak contractions early in cycle when we don’t have as much oestrogen
Strong contractions during menstruation (progesterone low)
What is oxytocin?
Non-peptide hormone synthesised in hypothalamus and released from the posterior pituitary gland
Released in response to suckling and cervical dilatation
Oestrogen (released at later stages of pregnancy) causes:
- oxytocin release, increase expression of oxytocin receptors
Oxytocin also increases synthesis of prostaglandins
What effect do prostaglandins have on myometrial contraction?
Prostaglandins induce myometrial contraction (PGE and PGF)
Role in dysmenorrhoea (severe menstrual pain), menorrhagia (severe menstrual blood loss), pain after parturition
NSAIDs are effective – reduce contraction and pain
Oxytocin stimulates release of prostaglandins
What is Ergot? what are its actions, mechanism, and uses?
Ergot to ergometrine
Ergot - fungus that grows on some cereals (e.g. rye) and grasses
Contains ergometrine
Action:
- Powerful and prolonged uterine contraction
Mechanism:
- Stimulation of α-adrenoceptors, 5-HT receptors meaning they can cause contraction of the blood vessels as well around the uterus
Uses:
- Post-partum bleeding - NOT induction
How are oxytocin and prostaglandins used pharmacologically?
Oxytocin: - Used to induce/augment labour at term - Dose dependent increases in contraction – but too much can cause sustained contraction and foetal distress - Also used in postpartum haemorrhage Prostaglandins: - Induction of labour – before term - To induce abortion - Or for postpartum bleeding
When would 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
So we have things like oxytocin receptor antagonists, anti prostaglandins
Some things such as calcium channel blockers and beta-adrenergic receptor agonists are things prescribed for other conditions so you have to take those into account during a pregnancy
