PK and PD in aging and pregnancy

• Pharmacokinetics in pregnancy involves understanding the physiological changes in pregnancy that are relevant to pharmacokinetics.
• Pregnancy may affect the absorption, distribution and metabolism of drugs.
• The hepatic extraction ratio is a key concept in pharmacokinetics.
• The hepatic clearance is a significant factor contributing to hepatic clearance.
• Altered protein binding can significantly affect drug exposure.
• Drugs with altered pharmacokinetics in pregnancy include some that are teratogenic.
• Therapeutic drug monitoring is important to know whether an assay measures total or free drug concentration.
• Pharmacodynamics in pregnancy involves understanding the impact of pregnancy on drug pharmacodynamics and the physiology of the placenta.
• Placental physiology and the passage of drugs across the placenta are important aspects of pharmacology.
• Pharmacokinetics changes in early life and late life are important to understand.
• Drugs with teratogenic effects have pharmacology-physiology leading to these effects.
• Learning outcomes for this module include outlining the physiological changes in pregnancy that are relevant to pharmacokinetics, explaining how pregnancy may affect the absorption, distribution and metabolism of drugs, defining the hepatic extraction ratio and hepatic clearance, explaining the significant factors contributing to hepatic clearance, explaining the effect of altered protein binding on drug exposure, and giving examples of drugs with altered pharmacokinetics in pregnancy.
• The physiological changes in pregnancy that are relevant to pharmacodynamics include outlining the impact of pregnancy on drug pharmacodynamics and giving examples of drugs with altered pharmacodynamics in pregnancy.
• Therapeutic drug monitoring is important to know whether an assay measures total or free drug concentration.
• Drugs with altered pharmacodynamics in pregnancy include some that are teratogenic.
• Placental physiology and the passage of drugs across the placenta are key concepts in pharmacodynamics.
• Drugs with teratogenic effects have pharmacology-physiology leading to these effects.
• Pharmacokinetics changes in early life and late life are important to understand.
• Teratogenic effect is defined as persistent structural or functional adverse effects due to the influence of the drug on foetal development.
• Teratogenic effects can alter chromosomes, prevent implantation, cause foetal death or abortion, growth retardation, or functional impairment such as hearing, neurological development or behaviour.
• The developing blood brain barrier in the foetus results in relative scarcity of metabolizing enzymes, and CYP2c (diazepam) and 1A2 (caffeine) are absent from foetal liver.
• There seems to be increased sensitivity to volatile, intravenous, and local anaesthetics in pregnancy.
• P-glycoprotein expression is upregulated in pregnancy, enhancing both renal filtration and intrinsic clearance of the organ.
• Early pregnancy is when the foetus is most vulnerable to teratogenic effects, and some effects may not be apparent until later in pregnancy or even after birth.
• Synergistic effects of teratogenicity can occur with the number of anticonvulsants taken by the mother, increasing risk of teratogenicity from 4% to 23%.
• Most drugs will enter the foetal circulation to some degree, with placental transfer being the most important route.
• Some effects appear to be dose dependent, for example, dose of valproate and neural tube defects, but response is variable, for example, foetal alcohol syndrome with minimal alcohol intake.
• The placenta provides a barrier between maternal and foetal circulations, and there are metabolic functions such as CYP450 enzymes present.
• LMWH concentrations are reduced in pregnancy due to increased blood flow to kidneys, which increases GFR.
• Other CYP enzymes are present from first trimester, but adult levels are not reached until after first year of life.
• LMWH (low molecular weight heparin) are anti-thrombotic drugs.
• Other drugs with enhanced clearance in pregnancy include penicillins, digoxin, metformin and lithium.
• Metabolic processes are immature at birth, with some cytochrome p450 enzymes undetectable at birth and others already at 30% of adult levels.
• Acetylation and sulfation processes are underdeveloped at birth, but are well established in the old-old.
• The Food and Drug Administration (FDA) summarizes the situation as follows: From a scientific and ethical standpoint, the population of pregnant women is complex, based on the risks and benefits of a drug to both the woman and the foetus.
• In 2014, only 1.3% of pharmacokinetic studies included pregnant women.
• Historically, safety data for medications is obtained retrospectively.
• Phase 2 reactions have a variable rate of maturation, with some glucuronyl transferase enzymes achieving adult levels at 6-months and others taking a decade to develop.
• Women are typically young and healthy, so it is not a problem to prescribe medication during pregnancy.
• Undertreatment may contribute to maternal and fetal morbidity and mortality.