The Pharmacokinetics of Antiarrhythmic Agents in Pregnancy and Lactation

The pharmacokinetics of various drugs may be profoundly altered during different stages of pregnancy, parturition, and lactation. Gastrointestinal absorption or bioavailability of drugs may vary due to changes in gastric secretion and motility. Various haemodynamic changes such as an increase in cardiac output, blood volume, and renal plasma flow may affect drug disposition and elimination. The increase in blood volume and total body water which occurs during pregnancy can alter the volume of distribution for various drugs. Although exact quantifications are not easy, these changes in pharmacokinetic parameters should be considered when dosing antiarrhythmic agents in pregnant women. Plasma protein concentrations and drug binding capacity are altered in the mother and fetus as pregnancy advances. With highly protein bound drugs, these changes may be clinically significant, as the pharmacological efficacy and toxicity are presumed to be related to the concentration of free drug in both the mother and fetus. In some instances, the fetus may be susceptible to greater drug toxicity as free drug concentrations may be underestimated by measurement of total drug concentrations. Changes in maternal drug metabolism and metabolism by the fetoplacental unit also contribute to alterations in the pharmacokinetics of drugs. As the placenta contains many metabolising enzymes, biotransformation of drugs at this site could potentially convert a drug into an active metabolite, or prevent fetal exposure to a toxic drug. Placental transfer of drugs, leading to toxicity in the fetus, is a major concern in the pharmacological management of the pregnant patient. The passage of individual drugs will vary depending on their apparent volumes of distribution, degree of protein binding, the rates of metabolic conversion and excretion within the placenta and fetus, the pH difference between the maternal and fetal fluids, and maternal haemodynamic changes. Drug properties such as lipid solubility, protein binding characteristics, and ionisation constant (pKa) also influence the placental passage of drugs. For weakly basic antiarrhythmic agents, the fetal drug concentration may potentially exceed the maternal plasma concentration when the fetal pH is lowered as in the case of fetal acidosis; this is due to ‘ion trapping’. Additionally, higher free drug concentrations of these basic drugs may exist, due to decreased α1acid glycoprotein concentration and binding affinity in the fetus. Lignocaine(lidocaine) has been shown to enter fetal plasma rapidly with fetal-maternal concentration ratios in the range of 0.52 to 0.66. The metabolites, monoethylglycinexylidide and glycinexylidide have been detected in the maternal plasma within 10 minutes and 40 minutes, respectively, after epidural administration. Fetal-maternal concentration ratios for these metabolites range between 0.55 to 1.0. Alterations in protein binding and pH differences between the mother and fetus may thus be clinically important considerations with lignocaine. Increased dose requirements and reduced plasma phenytoin (diphenylhydantoin) concentrations have been reported during the administration of phenytoin. Impaired drug absorption has also been reported, although the data are conflicting. Phenytoin appears to readily cross the placenta, with fetal cord concentrations ranging from 65 to 100% of the maternal concentrations. Decreases in the maternal albumin concentration with advancing pregnancy have been correlated with a progressive increase in the phenytoin free fraction. However, both total and free drug concentrations were found to be lower during late pregnancy than in the non-pregnant state. Increases in phenytoin plasma clearance have also been reported. Quinidine appears to readily cross the placenta with fetal cord-maternal concentration ratios ranging from 0.24 to 1.4. High concentrations of quinidine have also been detected in the amniotic fluid. Procainamide appears to be transferred across the placenta with fetal-maternal concentration ratios reported as high as 1.32. The N-acetyl procainamide metabolite has been detected in the fetal cord with fetal-maternal concentration ratio of 123. Reports of isolated experiences with disopyramide and mexiletine reveal fetal-maternal concentration ratios of 0.39 and 1.0, respectively. Both digitoxin and digoxin appear to be rapidly transferred into the fetus after maternal administration, with fetal-maternal concentration ratios ranging from 0.38 to 1.0. Both amiodarone and desethylamiodarone have been detected in fetal cord blood. Fetal-maternal drug concentration ratios for amiodarone range from 0.095 to 0.145, while one neonatal-maternal concentration ratio was 0.26. The fetal-maternal concentration ratios for desethylamiodarone ranged from 0.17 to 0.285. Both amiodarone and desethylamiodarone were detected in the amniotic fluid, and high concentrations of desethylamiodarone were detected in the amniotic fluid, and high concentrations of desethylamiodarone were found in the placental tissue. Experience with verapamil in pregnancy is quite limited, but the drug appears to cross the placental membrane with fetal-maternal concentration ratios of 0.17 and 0.26 at 49 minutes and 109 minutes, respectively, after a single oral dose. The β-adrenoceptor blockers reviewed, propranolol, metoprolol, atenolol, and acebutolol all appear to transfer across the placenta, showing fetal-maternal concentration ratios in the range of 0.88 to 1.27. The protein binding of propranolol and alprenolol, but not metoprolol, were reduced during pregnancy. Increased plasma clearance, decreased bioavailability, and an increase in total urinary metabolites are reported with metoprolol during pregnancy. Protein binding, lipid solubility, and ionisation characteristics of the antiarrhythmic agents similarly influence partitioning of these drugs into breast milk during lactation. The pH difference between the maternal plasma and milk may also allow for accumulation of weakly basic agents into breast milk. Although data are limited, attempts have been made to estimate breast milk-maternal plasma concentration ratios with equations that include these physiochemical properties. However, better clinical data supporting the use of the equations to predict milk-maternal concentration ratios are still needed. Several of the antiarrhythmic agents reviewed show that many of these agents show wide variation in the milk-plasma concentration ratios. The clinical impact of antiarrhythmic drug partitioning to the fetus and into breast milk remains to be established. More rigorous studies with appropriate body fluid sampling and pharmacokinetic modelling would provide necessary data to help clinicians establish safe and effective antiarrhythmic dosage regimens in the pregnant and lactating patient.