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DRUG THERAPY IN PREGNANCY During pregnancy most drugs can cross the placenta and expose the baby to their effects Factors affecting placental drug transfer and drug effects on the fetus include Drug physiochemical properties Rate at which drug crosses placenta and amount reaching the fetus Duration of drug exposure Distribution in different fetal tissues Stage of placental and fetal development Effects of drugs used in combination
PREGNANCY INDUCED MATERNAL PHYSIOLOGIC CHANGES Gastrointestinal absorption Decreased GI motility Secondary to progesterone levels Reduction in gastric acid secretion Increase in gastric mucus secretion Increase in gastric pH, therefore negatively affects drugs that require acidic pH for absorption Nausea and vomiting Lung absorption Cardiac and tidal volumes increase by approximately by 50% in pregnancy. Hyperventilation and increased pulmonary blood flow Transdermal absorption Increase in peripheral vasodilation and increase in blood flow to the skin. Enhanced transdermal absorption
PHYSIOLOGIC CHANGES IN PREGNANCYOrgan System Dynamic Change during pregnancy CardiovascularBlood volume Increased by 30-50%Cardiac output Increased by 30-50%Systemic vascular resistance DecreasedOrgan System Dynamic Change during pregnancy GastrointestinalpH of intestinal secretions IncreasedGastric emptying time IncreasedGastric acid secretions DecreasedIntestinal motility Decreased
PHYSIOLOGIC CHANGES IN PREGNANCYOrgan System Dynamic Change During Pregnancy KidneyRenal Blood Flow rate IncreasedGlomerular Filtration rate IncreasedOrgan System Dynamic Change during Pregnancy GynecologicUterine Blood Flow Increased
LIPID SOLUBILITY Drug passage through the placenta is depended on lipid solubility and degree of ionization Example: Salicylate Lipophilic drugs tend to diffuse readily across the placenta and enter the fetal circulation Example: Thiopental use during cesarean sections may cause apnea in the newborn Impermeability to polar compounds is relative rather an absolute Achieved during high enough maternal-fetal concentration gradient
MOLECULAR WEIGHT (MW) Influences the rate and amount of drug transferred across the placenta Depending on lipid solubility and degree of ionization the following rule for MW apply 250-500: Cross the placenta easily 500-1000: Cross with more difficulty > 1000: cross very poorly Clinical application Heparin is large and polar, thus unable to cross the placenta Provides alternative to coumadin, which is teratogenic
PLACENTAL TRANSPORTERS Several drug transporters have been identified in the placenta There is increasing recognition of their effects on drug transfer to the fetus P-glycoprotein transporter Pumps back into maternal circulation a variety of drugs and other agents Example: cancer drugs and viral protease inhibitors Clinical benefit Prevention of toxic effects to the fetus
PHARMACODYNAMIC FACTORS INFLUENCING DRUG THERAPY Maternal drug actions Physiology of some organs (heart, lungs, kidneys, CNS) may be altered by pregnancy May require the use of drugs not needed by the same woman when she is not pregnant Example: Diuretics in pregnancy induced HF Fetal therapeutics Involves drug administration to the pregnant woman with the fetus as the drug target Example: Corticosteroids to stimulate lung maturation when pre -term birth is expected
PHARMACODYNAMIC FACTORS INFLUENCING DRUG THERAPY Predictable toxic drug actions in the fetus Neonatal withdrawal syndrome Caused by chronic use of opioids by the mother Use of teratogenic drugs during pregnancy ACEI causing renal damage to the fetus Teratogenic mechanisms (multifactorial) Direct drug effects on maternal tissues with indirect effects on fetal tissue Direct effects on processes for tissue differentiation Deficiency in a critical substance folic acid prevents spina bifida
PHARMACODYNAMIC FACTORS INFLUENCING DRUG THERAPY To be considered teratogenic a substance should Result in a characteristic set of malformations Exert its effects at a particular stage of fetal development Show a dose dependent incidence FDA teratogenic risk categories Attempt to quantify teratogenic risk Range from A (safe) to X (definite human teratogenic risk)
SELECTED DRUGS WITH SIGNIFICANT ADVERSE EFFECTS ON THE FETUS Drug Trimester EffectACEI All, Renal damageTCAs Third Neonatal withdrawal syndromeBarbiturates All Chronic use: Neonatal dependenceCarbamazepine First Neural tube defectsCocaine, tamoxifen All Risk of spontaneous abortionEthanol All Fetal alcohol syndromeIodine All Congenital goiter, hypothyroidismLithium First Icreased ICPTobacco All Intrauterine growth retardationTetracycline All Discoloration of teeth and altered bone growthThalidomide & DES First Limb malformation (DES Cancer Risk Icreased)Warfarin First Alters respiratory tract formation Second CNS malformation Third Risk of bleeding – IC hemorrhage
DRUG ABSORPTION Absorption after IM or SC injections in neonates depends on Blood flow to the area and gastrointestinal function Blood flow is reduced by Cardiovascular shock, vasoconstriction, HF, very little muscle mass and diminished perfusion of area GI function in the neonate changes significantly after birth Full-term: GI secretions begin soon after birth Pre-term: GI secretions begin more slowly Gastric emptying time is by 6-8hrs Peristalsis is irregular and may be slow Gastrointestinal enzymes tend to be lower
DRUG USE DURING PREGNANCY AND LACTATION Most drugs given to lactating women are detectable in breast milk Concentrations are usually low, preventing infants form receiving therapeutic amounts Some drugs carry serious toxicities and must be avoided Example: Radioactive iodine, cancer chemotherapy Recommendations for feeding mothers Safe drug: Take it 30-60 minutes after nursing and 3-4 hours before the next feeding No safety data: Avoid drug use or discontinue breast feeding
POSSIBLE EFFECTS ON INFANT OF SELECTED DRUGS USED DURING LACTATION Drug CommentsTetracycline Risk of permanent tooth staining in infantIsoniazid Risk of pyridoxine deficiency in the infantBarbiturates Lethargy, sedation and poor suck reflexesChloral hydrate Drowsiness if infant fed at peakDiazepam Drug accumulation and sedationMethadone Risk of withdrawal if breast feeding stopsIodine Thyroid suppression and risk of cancerPropylthiouracil Can suppress thyroid function in infant