Lecture 8 - Nov 11

Question 1

Smooth muscle contraction:

Answer 1

-at term the myometrium is one large smooth muscle
-smooth muscle contracts when myosin light chain kinase MLCK phosphorylates the myosin head
-allows the myosin head to attach to actin filament
-myosin pulls past the actin (power stroke)
-mlck is activated when it binds with a calcium-calmodulin complex

-due to need for calcium to activate mlck the force of smooth muscle contraction is regulated by the amount of ca in the cytoplasm
-increases in intracellular Ca are due to release from either the sarcoplasmic reticulum or extracellular sources
-can inhibit smooth muscle contraction by either having low intracellular calcium or by stimulating the phospho kinase a PKA
-pka modifies mlck so that it can’t bind to the calcium-calmodulin complex

Question 2

Increasing cellular Ca:

Answer 2

-an increase in the 2nd messengers inositol triphosphate IP3 and diacylglycerol DAG
-IP3 binds into the sarcoplasmic reticulum, allowing the release of Ca
-DAG opens the Ca channels on the cell membrane
-IP3 can also activate voltage gated CA channels on the cell surface
-letting more extracellular Ca into cell

Question 3

Induction/Augmentation of Labour:

Answer 3

-agents that cause uterine contractions are called oxytocics (from greek - oxy = sift, tokos = childbirth)
-includes both prostaglandins and oxytocin
-should not be offered in the context of an unripe crevice (bishop score less than 7)
-perform cervical ripening first = the use of mechanical or pharmacologic means to soften, efface, and dilate the cervix prior to the induction of labour
-cervical ripening may be time consuming and may require more than 1 method
-ballon catheter, membrane sweeping, prostaglandinE (misoprostol), prostandlindE2 (dinoprostone)

Question 4

Prostaglandins for Cervical Ripening:

Answer 4

-mostly given per vagina:
-misoprostol PGE1 - various doses and routes (SL, PV, most effective)
-dinoprostone PGE2 supplied at pristine E2, vaginal gel, 1mg or 2mg place in posterior vaginal fornix and may be repeated 6 hrs later
-prepidil (0.5mg dinoprostone) gel form used for intracervical use
-cervidil (control-released dinoprostone vaginal insert): polymer base with 10mg dinoprostone attached to retrieval string; releases 0.3mg PGE2 per hours in vagina for 12hr
-due to longer t1/2 of prostaglandins should be used with caution if there is an increased likelihood of uterine tachysystole, foetal compromise or uterine rupture

Question 5

slide 9

Question 6

Oxytocin: iol or augmentation

Answer 6

-nonapeptide produced by the hypothalamus and released by posterior pituitary
-synthetic oxytocin sold as a clear aqueous solution for IM injection or IV infusion (pitocin)
-receptors for oxytocin exist in the myometrium, myoepithelial cells of breast ducts, glandular cells of breast alveoli, brain
-oxytocin receptors in the myometrium increase greatly in number in 2rd trimester (partially because of effects of oestrogen)
-contractions of the uterus are largely the result of prostaglandins and oxytocin produced during a posterior feedback loop
-doses of oxytocin can be given to induce or augment labour - stimulates positive feedback loop, associated with the cervical stretch induced by the initial uterine contractions
-oxytocin also has an affinity for the antidiuretic hormone receptor
-uterus may also be hypersensitive to oxytocin, leading to tachysystole

Question 7

slide 13

Question 8

Prostaglandins

Answer 8

-PGE1, PGE2, PGF2a and their analogues (ex misoprostol) may stimulate uterine contractions
-main receptors in the uterus for the PAGE fault are EP1 and EP3, misoprostol is synthetic PGE1, dinoprostone is PGE2
-FP receptors for PGF2a ex carboprost HEMABATE)

Question 9

Misoprostol:

Answer 9

-used for treatments for ulcers since it reduces gastric acid secretion (binds to prostaglandin receptors on surface of gastric cells; trade name cytotec)
-misoprostol PO or PR for labour induction has not been in Canada because of risks associated with uterine rupture and hypertonic (can lead to foetal distress)
-becoming more common in some centres
-added to last SOGC CPG in 2023
-prostanoids are tend not used for cervical ripening or IOL in people with previous caesarean delivery, uterine surgery or ruptured membranes
-absolute contraindications: previous full thickness uterine surgery and known foetal compromise
-common off-label uses include medical abortion, cervical ripening before surgical abortion, induction after intrauterine foetal death (its use for PPH will be discussed later in this lecture)

Question 10

slide 15

Question 11

Herbal Oxytocin - Castor Bean:

Answer 11

-castor oil is made from cold pressing the seeds (beans) of the ripe fruit of ricinus communis
-active oxytocin component appears to be ricinoleic acid
-taken PO, ricinoleic acid acts as a uterine stimulant but the mechanism is unclear
-shown to bind to EP3 receptor in uterus and bowel
-effects in part thought to be due to increased stimulation of the bowel therefore the uterus is stimulated by an irritant effect
-adverse effects: nausea, vomiting and subsequent dehydration

Question 12

Tocolytics for labour:

Answer 12

-greek, tokos = childbirth, lysis = loosening
-used in attempts to prevent preterm labour or relieve uterine tachysystole (sometimes used for ECV)
-none of the clinically used tocolytic agents will be able to suppress myometrial contractions in the presence of strong stimulation of myometrium

Question 13

Nifedipine (ADALAT):

Answer 13

• a Ca channel blocker
  -works by blocking entry of extracellular Ca into myometrial cells (slow/stop uterine contractions)
  -sometimes used in hypertensive disorders of pregnancy as well as it dilates blood vessels
  -few undesirable side-effects (commonly reported = headache and hypotension 10-20% of cases)

Question 14

Nitroglycerin:

Answer 14

-glyceryl trinitrate, NITROL
-primarily a heart medication for treatment of angina
-used off-label for tocolysis in cases of uterine tachysystole (either as a skin patch or a sublingual spray)
-mechanism = production of nitric oxide from nitroglycerine
-NO travels to smooth muscle cells, activates guanylyl cyclase
-GS converts GTP to cGMP
-cGMP causes a sequestration of CA
-smooth muscle cells relax
-relaxes smooth muscle both in in blood vessels and the myometrium

Question 15

Postpartum haemorrhage PPH:

Answer 15

-defined as blood loss of more than 500ml following a vaginal delivery or more than 1000 ml after a caesarean delivery
-clinically, any amount of blood loss that results in S Sx of hypovolemic shock or hemodynamic instability should be considered a PPH
-primary PPH occurs in 2-6% of births worldwide, secondary or delayed PPH in 1-3%

Question 16

slide 22 - the 4 t’s of pph

Question 17

Uterine contraction:

Answer 17

-usually normal uterine contractions after delivery prevent PPH
-special helical arrangement of myosin and actin in the uterus allow for contraction of the entire organ
-uterine contraction compresses the spiral arteries enough to slow blood flow and allow clot formation
-active management of the 3rd stage is thought to reduce the likelihood of PPH

Question 18

Oxytocics for the treatment of PPH:

Answer 18

-first line treatment = oxytocin
-2nd/3rd line = ergonovine maleate, carboprost tromethamine, misoprostol
-3rd line = carbetocin

Question 19

slide 24

Question 20

slide 25

Question 21

Oxytocin side effects:

Answer 21

-very common:
-vascular effects: feeling of warmth, flushing, hypotension
-gastrointestinal: nausea, abdominal pain
-common:
-nervous system disorders: headache, dizziness, tremor
-GI: vomiting, metallic taste
-rare:
-cardiac disorders: tachycardia

-structurally related to ADH, theoretical potential for water retention and water intoxication (hyponatremia)
-oxytocin and carbetocin can get into milk but its a tiny amount and will be degraded by peptidases in infant GI tract
-may cause milk let-down
-allergic reactions are highly unlikely

Question 22

slide 27

Question 23

slide 28

Question 24

ergonovine side effects

Answer 24

-nausea vomiting
-stimulates alpha 1 adrenoceptors found in blood vessels which leads to an increase in blood pressure
-headache
-contraindications - pregnancy and hypertension

Question 25

slide 30, 31, 32

Question 26

Misoprostol adverse effects:

Answer 26

-shivering
-fever
-diarrhoea
-uterine hypertonus
-asthma exacerbation is commonly seen as a possibility particularly if there is a known sensitivity to one of the other E family of prostaglandins but the EP1 receptor us not on bronchioles
-drug interactions: misoprostol will interact with other uterotnci agents but that is the idea

Question 27

slide 34, 35

Question 28

Tranexamic acid (cyklokapron):

Answer 28

-an inhibitor of fibrinolysis used to treat bleeding
-an adjunct treatment fir PPH
-even if the PPH us though to be due to none
-this is because some of the bleeding may also be due to trauma and becaue the increases in clotting may by time to manage hemorahe die to tone whule minimzineg blood loss
-becoming increasinly common to add to the mamanemt algorithm (even fairly upstream in the proces)
-side effects incdlue nasure/vommitning and visual distrubacnes or dizziness (non-severe)

Question 29

Hemostasis

Answer 29

1. injury
2. vascular spasm
3. platelet plug formation (activated platelets become spiked and stick to each other and the wond site, release mediators to activate and attract other platelets)
4. coagulation (fibrinogen is converted to fibrin which forms a mesh to produce/stabilize the clot

Question 30

slide 39

Question 31

tranexamic acid (cyklokapron)

Answer 31

-shown to reduce maternal death but not hysterectomy
-reduces the need for laparotomy to control bleeding
-dose is 1g IV (rate of 1ml/min given over 10 min)
-can be repeated if bleeding persists after 30min, or bleeding re-starts within 24 hours