Pharmacology of the Placenta

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Uterine Blood Flow

The uterine arteries provide the uterus with ~ 700 cc/min of maternal blood. The placenta is supplied by two umbilical arteries from the fetus. The fetus receives oxygenated blood from the placenta through a single umbilical vein.

Effect of Common Vasoactive Drugs: Phenylephrine vs. Ephedrine

There is minimal autoregulation in the uterine vascular system, but vasoconstriction secondary to sympathetically active agents is possible. Data from pregnant ewe suggest that methoxamine (a long-acting α-agonist) reduces uterine blood flow [Ralston DH et al. Anesthesiology 40: 354, 1974], thus practitioners have traditionally favored ephedrine for the treatment of hypotension

The preference of ephedrine has recently come into question. First, a review of randomized controls comparing phenylephrine with ephedrine showed no difference in maternal hypotension, neonatal acidosis (defined as pH < 7.2), or APGAR scores, but slightly lower neonatal pH values in women who received ephedrine (mean difference 0.03) [Lee A et al. Anesth Analg 94: 920, 2002; FREE Full-text at Anesthesia & Analgesia]. A randomized, double-blind trial of phenylephrine vs. ephedrine in 125 parturients undergoing spinal anesthesia showed that increasing amounts of ephedrine led to decreases in fetal pH, base excess, and umbilical arterial oxygen content [Kee N et al. Anesth Analg 107: 1295, 2008; FREE Full-text at Anesthesia & Analgesia]. A possible explanation for these changes in neonatal pH is that ephedrine crosses the placenta and may stimulate the neonate, thus increasing its metabolic requirements [Khaw KS et al. Fetal and Maternal Med Rev 17: 157, 2006]. Some authors have suggested that ephedrine, which causes NE release and can produce tachyphylaxis, may need to be avoided in spinal patients as it is theoretically possible for ephedrine to reduce the potency of epinephrine if used prior to EPI administration in an emergency situation

Data from pregnant sheep suggest that maternal stress can lead to increased native NE production and subsequently reduced uterine blood flow [Shnider SM et al. Anesthesiology 50: 524, 1979], suggesting that a regional technique may help preserve oxygen delivery to the fetus

Placental Exchange

Size

Most drugs with MW < 500 Da cross the placenta, and most drugs with MW > 1000 Da do not cross the placenta (ex. heparin, protamine, insulin). Neither succinylcholine (highly ionized) or non-depolarizing NMBDs (high molecular weights) cross the placenta.

Charge

Non-ionized drugs tend to cross the placenta more easily than ionized drugs, however the fetus usually has a lower pH than the mother, leading to “ion trapping.”

Protein Binding

Traditionally it was taught that protein-bound drugs did not cross the placenta, however as these medications exist in equilibrium with non-bound versions, it appears that this is not true [Pacifici GM and Nottoli R. Clin Phamacokin 28: 235, 1995]

Lipophilicity

While liphophilicity is generally advantageous with regards to placental transfer, extreme lipophilicity (ex. sufentanil) may impede transfer as highly lipophilic substances can accumulate in the placenta

Specific Anesthetic Agents

All inhalational agents and most intravenous agents used by anesthesiologists will cross the placenta – inhalational agents cause very little fetal depression if used at < 1 MAC and delivery occurs within 10 mins of induction. Thiopental, propofol, benzodiazepines, and ketamine all cross the placenta, although only benzodiazepines are noted to produce significant fetal effects. Opiates all cross the placenta to some extent (amount is variable) – from a respiratory standpoint, newborns are most sensitive to maternal morphine.Fentanyl appears to be safe if given at < 1 ucg/kg. Epidural opiates produce minimal effects. Ephedrine, B-blockers, vasodilators, metoclopramide, and atropine cross the placenta, although glycopyrrolate (which also does not pass the blood-brain barrier) does not

Summary of Placental Transfer of Anesthetic Drugs

DRUGS WHICH DO NOT CROSS THE PLACENTA

• All paralytics
• Glycopyrrolate
• Insulin
• Heparin

DRUGS WHICH CROSS THE PLACENTA Potentially Dangerous

• Opiates (morphine, fentanyl if > 1 ucg/kg)
• Benzodiazepines
• Ephedrine (increased metabolism)
• Local anesthetics
• Atropine
• B-blockers

Safe

• Propofol
• Thiopental
• Ketamine
• Fentanyl at < 1 ucg/kg
• Epidural opiates (fentanyl, sufentanil)

Factors that Affect Placental Pharmacology

Location

paracervical > epidural (caudal > lumbar) > IM > subarachnoid

Vasoconstrictors

Epinephrine can prolong the effect of certain local anesthetics, primarily by slowing absorption. Epinephrine has a differential effect on various anesthetics, substantially prolonging both lidocaine and mepivacaine and having a relatively minor effect (if any) on bupivacaine and ropivacaine

Volume of Distribution

Vd = total drug / [drug]plasma. In pregnant women, who have increased plasma volume (and body fat), Vd increases

Drug Clearance

Varies depending on the agent. SCh, 2-chlorprocaine, and remifentanyl, all of which are metabolized by plasma esterases, are relatively unaffected. Normeperidine is clearly slowly by the fetus, and thus meperidine should be avoided in the mother

Protein Binding

While pregnant women are hypoosmotic due to decreased plasma protein concentrations, the fetus still has 50% less protein than its mother. The implications of this in terms of placental transfer are unclear, however it is certain that highly protein-bound drugs (ex. bupivacaine) are found in higher maternal (as opposed to fetal) concentrations

pH and pKa

Drugs with a pKa near 7.4 will exist in a partially non-ionized state, and are associated with high placental transfer. Drugs with a pKa > 7.4 are associated with less placental transfer.

Fetal Uptake

While fetuses have less protein, the plasma concentration of drugs is nearly equal to that of their mothers. Fetal pH is slightly lower than maternal (7.32 to 7.38), thus most unionized drugs are “ion trapped” to a degree, even in a healthy fetus. Of note, chloroprocaine (pKa 8.7) is the drug of choice for epidural analgesia and a decompensating fetus, because it does not participate in ion trapping (is this because it already exists in ionized form in maternal blood stream and thus does not cross the placenta readily?). Note also that due to fetal circulation, 57% of fetal blood bypasses its tissues prior to uptake in the placenta.