2. Pharmacokinetics in Pregnancy
Pharmacological effects of drugs are related to the drug’s concentration at the site of action. Low (subtherapeutical) levels may lead to therapeutic failures; on the contrary, high (supratherapeutical) levels may produce toxic effects. Changes in any of the physiological processes occurring after the administration of a drug are the reasons of the concerns in the pharmacological management of medical conditions in pregnant females [23-25]. Therapeutic dosage regimens of drugs, that is, dose and dosage interval, are generally calculated according to major pharmacokinetic parameters, primarily total body clearance and volume of distribution, obtained from studies conducted in healthy non pregnant individuals. The physiological changes during pregnancy may modify the absorption, distribution, and rate of elimination of a drug to an extent that dose adjustment would be required for its safe and clinically effective use.
The high progesterone concentration during pregnancy induces a reduction in the gastrointestinal motility and increases the intestinal blood flow. These modifications may affect (increase, decrease, or neither) the oral absorption of a drug and hence its bioavailability [23, 24].
Extensive maternal cardiovascular adaptation takes place in order to sustain the development of the fetus. Blood volume and cardiac output increase, and there is a redistribution of blood flow to the different organs [25-28].
Distribution of polar drugs is limited mostly to the extracellular fluids, as the low lipid solubility impairs their diffusion through biological membranes and precludes their entrance into the intracellular space. During pregnancy, total body water increases as a result of intravascular and extravascular expansion, leading to modifications in the volume of distribution of the polar drugs [25]. Pregnancy modifies plasma proteins profile. Acute phase proteins, which include C-reactive protein, serum amyloid A, fibrinogen, and ceruloplasmine, are significantly increased [29, 30] whereas the increase in plasma volume results in a dilutional hypoalbuminaemia, as the synthesis of this protein is not modified. Changes in the concentration of plasma proteins, particularly albumin, may affect drug protein binding, modifying the free fraction of drugs. This fraction is the one that distributes extravascularly and reaches the site of action, thus is the pharmacologically active drug. If maternal albumin serum concentration is decreased, correspondingly, free fraction of drug may be increased. For highly bound drugs, such as AINEs, furosemide and digoxin, this may have clinical implications. However, if protein binding of the drug is maximal even at the low albumin concentrations that may be found during pregnancy, no pharmacokinetic modifications may be expected [31].
Opposite and unpredictable modifications due to pregnancy changes may be observed in the clearance of lipid-soluble drugs that are primarily eliminated by metabolism. Pregnancy may enhance drugs biotransformation by two mechanisms: increasing the access of the drug to the site of metabolism, particularly the liver and increasing the activity of the enzymatic system, particularly the hepatic cytochrome P-450 (CYP) family. Decreased binding to plasma proteins due to the pregnancy-related hypoalbuminaemia may increase liver metabolization of low hepatic extraction drugs, while increased hepatic blood flow may increase liver biotransformation of high hepatic extraction drugs. The activity of some drug metabolizing enzymes may be affected, either enhanced or decreased, by the action of the sexual steroids progesterone and oestradiol. During pregnancy, the expression of genes encoding hepatic CYP450 superfamily of microsomal enzymes may be decreased [16, 17, 32].
Increases in plasma volume and cardiac output and consequent redistribution of blood flow to the kidney produce marked increases in the glomerular filtration rate [26]. In consequence, plasma concentrations of hydrophilic, polar drugs may be lower, and half-life may be shorter when water-soluble drugs are given during pregnancy.
Different pharmacokinetic behavior of antimicrobial agents in pregnant females of different species has been described [33-43]. For betalactams, kinetics may be greatly influenced by changes in the extracellular fluid and glomerular filtration rate. Increased volume of distribution and clearance leading to a decrease in the maternal serum concentrations has been described for piperacillin [33] and imipenem [34] in pregnant women and penicillin [35] in ewes. Cefatrizine’s oral bioavailability was decreased in women during pregnancy [36]. In contrast, no changes related to pregnancy were found in the pharmacokinetics of amoxicillin [37], ceftriaxone [38], and the aminoglycoside tobramycin [39] in pregnant women. Opposite results were described for gentamicin, as its pharmacokinetic disposition did not change in mares [40] whereas increased clearance and decreased half-life was found in pregnant women [41, 42] and in ewes at the end of pregnancy [43].