Maternal-fetal Flashcards
Pregnancy + PK/PD changes
Absorption
- Absorption + bioavailability not usually effect (net effect equal)
- Gastric emptying delayed in labour + with opioids
- ↑transdermal + mucosal uptake (↑CO)
- Pulm uptake ↑ (↑MV 20-40%, ↓FRC, ↑CO)
- ↓epidural space due to venous engorgement ↓required dose of LAs
Distribution
- Intravascular volume ↑40%, extravascular volume ↑, average gain of 8L TBW
- ↑VD (↑TBW -> ↑VD for hydrophilic drugs, need ↑NDMR dose)
- ↑Body fat 4kg (relatively minor given large VD of lipophilic drugs)
- Fetus/ placenta forms additional compartment for distribution
- ↑CO -> ↑regional distribution of IV/inhaled drugs. May have faster onset/ offset. For volatiles - may not have faster onset as ↑CO ↑tissue distribution. IV - ↑CO -> ↑central compartment volume -> ↑induction dose
- Plasma protein - albumin ↓70% due to dilution
Metabolism
- Progesterone induces enzymes
- Oestrogen competes for metabolic enzymes
- ↓BChE activity (nil clinically significant prolongation of sux due to incr VD)
- Hepatic flow unchanged
Elimination
- ↑RBF (60-80%) + ↑GFR (50%)
- ↑tubular reasbsorption (counters effects of ↑GFR)
- ↑MV (↑inhalation elimination)
- Hepatobiliary clearance of drugs reduced by cholestatic effects of oestrogen
GA
- ↑sensitivity to volatiles (↓MAC)
- ↑sensitivity to IV anaesthetics
LAs
- ↑sensitivity (due to progesteron)
- Epidural engorgement and smaller CSF reduces dose needed for neuraxial
Analgesia
- ↑circulating endogenous endorphins, ↓effect of painful stimuli
- Higher pain threshold
- Main pathways involved are spinal cord KOP and DOP systems
- Interaction with descending a2-noradrenegic pathways also important
- Changed therapeutic indices due to concerns regarding fetal damage and teratogenicity
Anaesthetic drugs
Vasoactive
- Ephedrine crosses placenta and may stimulate fetal metabolism -> lactic acidosis
- Metaraminol does not sufficiently ↓uterine blood flow (preferred agent)
IV anaesthetics
- Propofol may ↓APGAR
- No incr risk of uterine bleeding
- Rapidly cleared from foetus + mother
- Propofol for maintenance has incr neonatal depression vs volatiles
Inhalational
- Despite crossing placenta, rapidly eliminated
- High MV and low FRC
Analgesics
- Remi safest due to fast offset and CL
- Otherwise withhold opioids until after delivery
Oxytocin
- Endogenous - similar to ADH, synthesised in hypothalamus
- Exogenous - synthetic, nonapeptide
- Uses - augment labour, uterine contraction post delivery, aid in lactation
- Dose 40IU/L IV slow infusion over 4hrs, 2-3IU bolus up to 10IU. 1IU = 2mcg
MoA
- Acts on oxytocin GqPCR on SM cells -> ↑IP3/ DAG -> opening of Ca channels -> ↑Ca influx -> further release of Ca from SR -> SM contraction
- Myometrial oxytocin receptors are upregulated during pregnancy, reaching a peak during labour + delivery
PK
- Poor PO absorption (inactivation by chymotrypsin)
- No plasma protein binding
- Metabolised by oxytocinase (liver, kidney, placenta)
- T1/2 B 5-12mins
Effects
- Uterine contraction
=> Myometrial oxytocin receptors upregulation important for cervical dilation and labour
=> Low dose IV infusion -> rhythmic uterine contractions
=> High dose IV infusion -> Sustained titanic uterine contractions
- Stimulates lactation
- Direct relaxant effect on vasc SM -> hypotension -> reflex tachycardia, N+V
- Arrhythmia
- transient pulm HTN
- Slight ADH-like activity -> water retention
- Anaphylaxis
- Fetal distress (over stimulated uterus)
- Uterine spasm + rupture
- Tachyphylaxis with prolonged infusions due to internalisation of oxytocin receptors (higher incidence of uterine atony in protracted augmented labour)
Ergometrine
- Naturally occurring alkloid
- Dose 500mcg IM, 250mcg IV
MoA
- Acts on alpha and 5HT2 receptors on uterine and vascular SM
- Highly potent for uterine contraction - cannot be used to augment labour
PK
- Onset 40s, duration 2-3hrs
Effects
- ↑force and frequency of uterine contractions
- ↑uterine tone
- ↑contraction of cervix
- Vasoconstriction -> ↑BP, coronary vasoconstriction
- Pulmonary oedema
- Bradycardia (↑vagal tone)
- N+V
- Relatively contraindicated with preeclampsia, pulmHTN, or IHS
Syntometrine = Ergometrine + oxytocin
Prostaglandins
PGF2a (carboprost)
MoA
- Binds GqPCR -> ↑IP3 + DAG -> ↑Ca intracellular -> uterine contraction
Dose
- 250mcg IM
- Can be given as intra-myometrial injection
Adverse effects
- Bronchospasm
- HTN
- N+V
- Diarrhoea
- Pulm vasoconstriction
- Risk of uterine rupture
PGE1 analogue (misoprostol)
- Binds PGE2 receptor
- Multiple GPCR subtypes -> uterine contraction
- Up to 1000 mcg PR
- Effects - induction of labour (ripening of cervix, uterine contraction), medical termination of pregnancy, bronchodilator so safer in airway disease or pulmHTN.
- Adverse - maternal fever, shivering, diarrhoea
Tocolytic agents
Tocolytic
- Drugs that decrease uterine tone
- Used to manage pre-term labour
- May be used in anaesthetic to facilitate LSCS or fetal surgery
B2 agonists
- Terbutaline (250mcg IV) or salbutamol (100mcg)
- Bind B2 receptors on outer membrane of myometrial cells
- Gs receptors ↑adenyl cyclase -> ↑cAMP -> ↑PKA phosphorylating MLCK -> inhibition of contraction -> myometrial relaxation
- Adverse effects - maternal + fetal tachycardia, pulm oedema, hypokalaemia, lactic acidosis, tremour
CCB
- E.g nifedipine
- ↓intracellular Ca inhibiting MLCK -> ↓uterine contraction
- Adverse - ↓BP, flushing/ headache, peripheral oedema, reflex tachycardia
MgSO4
- Ca + Ca channel antagonist
Nitrates
- E.g GTN - prodrug
- NO donors that increase activity of guanylate cyclase -> cGMP -> inactivates MLCK -> ↓uterine contractility
- 100-200mcg GTN IV for rapid relaxation at delivery
- Adverse - ↓BP, reflex tachycardia, flushing, headache, MetHb
- Tachyphylaxis (depletion of sulfhydryl groups)
NSAIDs (e.ng indomethacin)
- ↓formation of PGE2 and PGF2a
- Fetal complications- premature closure of DA, oliguria -> oligohydramnios, necrotising enterocolitis, intracranial have,orrhage, bronchopulmonary dysplasia
Volatiles (MAC >1)
Pre-eclampsia
Pre-eclampsia
- Complicates 2-7% of pregnancies
- Tx = delivery of placenta + fetus
- Before delivery, mx aimed to prevent seizures, control of BP and maintenance of placental perfusion
- Anticonvulsant - Mg is the drug of choice
Drugs used
- Mg
- Labetalol
- Hydralazine
- Nifedipine
Magnesium
- Uses - anticonvulsant in eclampsia, anti-HTN, arrhythmias, fetal neuroprotection in preterm neonates
- Dose 4-6g (10-20mmol) IV loading over 20mins followed by 1-2g/hr infusion. Aim 2-3.5 mmol/L
MoA
- Cofactor for enzymatic reactions involving ATP
- Regulates movement of Ca, K, Na
- Inhibits Ca channels and prevents influx of Ca (opposes action of Ca and can inhibit contraction and release of Ca dependent neurotransmitters)
Adverse
- Toxicity - muscle weakness + areflexia (4-5mmol/L), resp paralysis (>7.5mmol/K), ↑conduction (↑PR, QT + QRS -> SA + AV block, cardiac arrest)
=> Tx with small doses Ca, crosses the placenta and can cause neonatal flaccidity and resp depression, prolongs NMD
Other effects in obstetrics
- Cerebral vasodilation
- Attenuates vasopressors
- 20% decrease in MAC
Placental drug transfer
Types of transfer
- Complete (type I drugs) - rapidly cross placenta and reach equilibrium between maternal + fetal blood. Pharmacologically significant fetal concentrations
- Exceeding transfer (type II drugs) - cross placenta to reach a greater fetal concentration compared to maternal blood
- Incomplete (type III drugs) - unable to cross placenta completely - higher maternal conc than fetal
Mechanism
- Placenta is phospholipid in nature
- Transcellular through trophoblast layers
- Paracellular through water channels between layers
- Rate-limiting barrier for placental drug transfer is the layer of syncytiotrophoblast cells covering the vili
- Factors affecting placental drug transfer
=> Drugs factors - Fick’s law, pka
=> Maternal factors - ↑protein binding -> ↓drug transfer, material plasma pH, placental blood flow, placental metabolism, duration of exposure
=> Fetal factors - ↑fetal protein binding -> ↑drug transfer, fatal plasma pH (acidic cf mother -> ion trapping), metabolism of some drugs
Factors determining transfer
- Uterine blood flow = 700ml/min (10% CO)
- Umbilical blood flow = 350ml/min (50% fetal CO)
- Placental drug metabolism (not significant for drugs)
Fetal/ maternal ratio (F/M ratio)
- Ratio between the drug concentration in blood samples taken from umbilical cord and maternal veins
- Based on single measurement of blood samples obtained at delivery
- Greater the ratio the greater the drug transfer
- E.g lignocaine 0.6, bupiv 0.3
Neonate PK
Absorption
- ↑uptake of inhalational agents (very high MV, small FRC)
- ↑transdermal absorption (thinner stratum corneum, ↑cutaneous perfusion, larger skin SA)
- PO - slower (delayed gastric emptying, ↑gastric pH)
- IM unchanged - smaller muscle with reduced blood flow, but ↑density of capillaries
Distribution
- ↑TBW - ↑VD for hydrophilic drugs, ↑ECF
- ↓fat content, redistribution T1/2 of lipophilic drugs increased -> ↑duration
- ↓lean mass
- Protein binding (↓albumin, ↓AAG in neonates, ↓plasma protein binding)
- ↓Transport proteins = ↑crossing of BBB
- BBB - immature BBB allows crossing
- CBF↑ in infancy and early childhood
Metabolism
- ↓metabolism/ clearance until first year of life
- Plasma esterases at 100%
- Kidney function reduced 30% at birth
- Liver function reduce 20-50% at birth
Elimination
- Renal - GFR 30% of adults in neonates, 90% at 1yr
