Outline the changes to drug pharmacokinetics and pharmacodynamics that occur at term in pregnancy.

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College Answer

Answers framed around absorption, distribution, metabolism and excretion performed better. Some brief comments on physiology are required as the basis for pharmacokinetic change, but discussion of physiology that was not then specifically related to pharmacology did not score marks. Specific ‘real life’ examples necessitating change in practice or prescribing were well regarded e.g. reduction in spinal/epidural local anaesthetic dosing. Vague statements about possible or theoretical changes were less well regarded.

Discussion

Pharmacokinetics:

  • Absorption:
    • Some factors decrease intestinal absorption:
      • Gastric emptying is delayed
      • Gastric pH is higher
    • Some factors increase intestinal absorption:
      • More complete absorption because of slower gut transit
      • Increased gastrointestinal blood flow
    • Net effect is stable oral bioavailability for most drugs over the course of pregnancy.
    • Increased cardiac output affects changes in skin and muscle blood flow, supposedly increasing the absorption of drugs via subcutaneous and intramuscular routes
    • Increased blood flow speeds up the rate of onset of IV drugs, eg. muscle relaxants and anaesthetic agents
    • Increased pulmonary blood flow and increased respiratory rate allow an increased rate of volatile anaesthetic uptake and therefore decreased time until onset of effect
    • Decreased peridural space due to venous engorgement decreases the required dose of local anaesthetics
  • Distribution:
    • Increased volume of distribution: at the third trimester, blood volume is increased by 50%
    • Decreased protein binding due to diluted serum proteins
    • 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
    • Increased sensitivity to local anaesthetics (due to decreased α1-glycoprotein levels)
  • Metabolism:
    • Altered hepatic clearance:
      • circulating hormones can induce or inhibit metabolic enzymes.
      • Progesterone induces enzymes
      • Oestrogen competes for metabolic enzymes (eg. with vecuronium and rocuronium)
    • Decreased plasma cholinesterase activity (though this does not result in increased duration of action for suxamethonium)
    • The placenta has liver-like biotransformative enzymes, although these are not equivalent to the liver in their metabolic capacity, and probably not an effective protection for the foetus.
  • Elimination:
    • Renal clearance of drugs increases mainly due to increased glomerular filtration rate. Drugs cleared solely by glomerular filtration are most affected (eg. cephazolin, clindamycin)
    • Tubular resorption of substances also increases, counteracting the increased GFR
    • Thus, renal clearance for any specific drug is difficult to predict - eg. clearance doubles for lithium, increases 30% for digoxin, and only increases 12% for atenolol  (Feghali et al, 2015)
    • Hepatobiliary clearance of drugs is reduced by the cholestatic effects of oestrogen

Pharmacodynamics

  • Increased sensitivity to volatile anaesthetics (decreased MAC)
  • Increased sensitivity to IV anaesthetics
  • Increased sensitivity to local anaesthetics
  • Changed therapeutic indices due to concerns regarding foetal damage and teratogenicity

References

References

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