Pharmacology and toxicology in pregnancy

Toxicology of pregnancy comes up against three main issues: altered pharmacokinetics, teratogenicity and the toxicity to the foetus. There is only a handful of drugs (valproate, salicylates, carbon monoxide) which are more harmful to the foetus than to the mother. Othwerise, management of the mother's toxicology takes priority- what's good for the host organism is good for the parasite.

Question 28 from the first paper of 2016 asked about the toxicological differences between management of the poisoned child, pregnant woman and renally impaired elder. The main source for my answer was Goldfranks Manual of Toxicologic Emergencies: 2007 Edition, Ch. 30: "Reproductive and Perinatal Principles". Most of the summary below comes from this chapter. Its greatest flaw is the failure of the authors to reference many of the statements they make.  Another good source was the Toxicology Handbook by Murray et al  (2015), as according to previous exam experiences this is the favourite college source for SAQs. Around page 127 one finds a brief entry on the toxicology of pregnancy. Oh's Manual was useless. Additional references and summaries on the pharmacokinetic and pharmacodynamic changes of pregnancy may be found in the Part One required reading chapter which addresses this topic in greater detail.

Changes to pharmacokinetics

• Delayed absorption: gastric emptying is delayed in pregnancy, and virtually abolished by labour.
• More complete absorption because of slower gut transit
• Increased volume of distribution: at the third trimester, blood volume is increased by 50%
• Decreased protein binding due to diluted serum proteins
• Altered hepatic clearance: circulating hormones can induce or inhibit metabolic enzymes
• Increased renal clearance: due to increased blood flow to the kidneys
• Delayed release of toxins from fat stores: xenobiotics are laid down together with increasing fat stores in early pregnancy, and then mobilised during later stages and the postpartum period
• Increased fatty acid levels: they will compete with drugs for binding sites on albumin
• The placenta has liver-like biotransformarive enzymes, although these are not equivalent to the liver in their metabolic capacity, and probably not an effective protection for the foetus.

Issues to consider with regard to foetal exposure:

• What's good for the mother is good for the foetus. Keeping the mother from becoming hypoxic or having poor cardiac output contributes to the survival of the foetus.
• Foetal exposure is determined by maternal blood levels. Most drugs cross the placenta according to the boring rules of passive diffusion. There are only a few examples of the opposite effect; for instance valproate and diazepam are for some reason concentrated in the foetus.
• Characteristics which favour rapid penetration of the placenta:
  • Low molecular weight (anything over 1000Da does not cross)
  • Lipid solubility
  • Neutral polarity
  • Low protein binding
• Foetal pH causes "ion trapping". The intracellular pH of the foetus is more alkaline when compared to the mother's cells, and foetal blood pH is more acidic (by about 0.10-0.15 pH points).  The upshot of this is the tendency for weak acids and bases to become trapped in the foetus. The foetus therefore tends to concentrate certain drugs, eg.sodium valproate.
• There are a few drugs which pose a greater threat to the foetus than the mother:  of these, the following list is of greatest importance
  • Carbon monoxide
  • Methaemoglobin-inducing agents
  • Lead
  • Salicylates
  • Valproate
• Teratogenicity of drugs must be considered, as the damage to the foetus may not become obvious until later (however, this risk is no longer an issue after the first trimester: organogenesis takes place between days 18 and 60).
• Breastfeeding during acute poisoning may be surprisingly safe, particularly with drugs which have very poor oral bioavailability (eg. morphine).

Cardinal differences in managing a maternal overdose

• On a practical level, the management is the same as managing any other sort of overdose in a non-pregnant patient. for example, oral charcoal and bowel irrigation do not pose any special risks.
• According to Goldfranks, "Analgesics, vitamins, iron, antibiotics, and psychotropic medications account for 50–79% of the reported ingestions by pregnant women".
• Almost all of the antidotes to the various toxins are FDA pregnancy-risk category C, i.e. "maybe harmful: we don't know". The exceptions are N-acetylcysteine, glucagon and naloxone (category B).