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Special Aspects Of

Special Aspects Of

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Special Aspects of Perinatal Pharmacology

(Drug Therapy in Pregnancy and Lactation)
Gideon Koren, MD & Martin S.Cohen, MD Dept. of Pediatric Pharmacology Faculty of Medicine, University of Toronto, Canada (Teks dari Katzung BG, Basic & Clinical Pharmacology, 6thed, 1995) Kuliah sebelumnya Pengantar Perinatologi Kuliah berikutnya Congenital Malformations Menu / Daftar Isi CAKUL ADA KOREKSI / TAMBAHAN !?!? EMAIL ABUD !!!! Homepage Abud

The effects of drugs on the fetus and newborn infant are based on the general principles. However, the physiologic context in which these pharmacologic laws operate, are DIFFERENT in pregnant women and in rapidly maturing infants. At present, the special pharmacokinetic factors operative in these patients are beginning to be understood, whereas information regarding pharmacodynamic differences (eg, receptor characteristics and response) is still quite preliminary. This chapter presents basic principles of pharmacology in the special context of perinatal and pediatric therapeutics.

DRUG THERAPY IN PREGNANCY
Pharmacokinetics Most drugs taken by pregnant women CAN cross the placenta and expose the developing embryo and fetus to their pharmocologic and teratogenic effects. Critical factors affecting placental drug transfer and drug effects on the fetus include the following : 1. The physiochemical properties of the drug 2. The rate at which the drug crosses the placenta and the amount sure to the drug 3. The duration of exposure to the drug 4. Distribution characteristics in different fetal tissues 5. The stage of placental and fetal development at the time of exposure to the drug 6. The effects of drugs used in combination A. Lipid Solubility

crosses the placenta almost immediately and can produce sedation or apnea in the newborn infant. which is almost completely ionized at physiologic pH. About 40-60% of umbilical venous blood flow enters the fetal liver. For example. hydroxylation. Transfer of these more lipid-soluble drugs and their overall rates of equilibration are more dependent on (and proportionate to) placental blood flow. and those with molecular weights greater than 1000 cross very poorly. thiopental. Ethanol and phenobarbital are oxidized in this way. (2) Drugs that have crossed the placenta enter the fetal circulation via the umbilical vein. cross the placenta slowly and achieve very low concentrations in the fetus. if a compound is very lipid-soluble (eg. drug passage across the placenta is dependent on lipid solubility and the degree of drug ionization. Because it is a very large (and polar) molecule. and the placenta may therefore augment toxicity (eg. . some anesthetic gases). It should be noted that metabolites of some drugs may be more active than the parent compound and may affect the fetus adversely. heparin may be safely given to pregnant women who need anticoagulation. This occurs because the small amount of salicylate that is not ionized is highly lipid-soluble. Differential protein binding is also important. Unlike warfarin. Molecular Size The molecular weight of the drug also influences the rate of transfer and the amount of drug transferred across the placenta. its transfer is slow and will probably be impeded by its binding to maternal plasma proteins. Drugs with molecular weights of 250-500 can cross the placenta easily. B. Several different types of aromatic oxidation reactions (eg. and local anesthetic agents. phenytoin. Placental and Fetal Drug Metabolism Two mechanisms help to protect the fetus from drugs in the maternal circulation : (1) The placenta itself plays a role both as a semipermeable barrier and as a site of metabolism of some drugs passing through it. Conversely. since some drugs exhibit greater protein binding in maternal plasma than in fetal plasma because of a lowered binding affinity of fetal proteins. Protein Binding The degree to which a drug is bound to plasma proteins (particularly albumin) may also affect the rate of transfer and the amount of drugs transferred. those with molecular weights of 500-1000 cross the placenta with more difficulty. Apparent exceptions to the "size rule" are maternal antibody globulins and certain polypeptides that cross the placenta by some selective mechanisms that has not yet been identified. If a drug is poorly lipid-soluble and is ionized. it is possible that the metabolic capacity of the placenta may lead to creation of toxic metabolites. N-dealkylation. it will not be affected greatly by protein binding. Impermeability of the placenta to polar compounds is relative rather than absolute. also used for cesarean section. Lipophilic drugs tend to diffuse readily across the placenta and enter the fetal circulation. Salicylate. A drug that enters the liver may be partly metabolized there before it enters the fetal circulation. crosses the placenta rapidly. D. a large proportion of drug present in the umbilical artery (returning to the placenta) may be shunted through the placenta back to the umbilical vein and into the liver again. If high enough maternal-fetal concentration gradients are achieved. depending upon their lipid solubility and degree of ionization. ethanol. This is because very lipid-soluble drugs diffuse across placental membranes so rapidly that their overall rates of equilibration do not depend on the free drug concentrations becoming equal on both sides. C. polar compounds cross the placenta in measurable amounts. which is teratogenic and should be avoided during the first trimester. heparin is unable to cross the placenta. An important clinical application of this property is the choice of heparin as an anticoagulant in pregnant women. In addition. the remaiinder bypasses the liver and enters the general fetal circulation. Highly ionized drugs such as succinylcholine and tubocurarine. a drug commonly used for cesarean sections. However.As is true also of other biologic membranes. This has been shown for sulfonamides. barbiturates. benzypyrenes). demethylation) have been shown to occur in placental tissue.

This involves drug administration to the pregnant woman with the fetus as the target of the drug. cardiac glycosides and diuretics may be needed for congestive heart failure precipitated by the increased cardiac workload of pregnancy. A less well understood fetal drug toxicity is caused by the use of angiotensin-converting enzyme inhibitors during pregnancy. administration of phenobarbital to the mother has been shown to decrease the risk of intracranial bleeding in preterm infants. etc) of the pregnant woman are sometimes altered by the endocrine environment appropriate for the stages of pregnancy. etc) may be altered and may require the use of drugs that are not needed in the same woman when she is not pregnant. etc). lungs. when given to pregnant women near term. At present. Recently. B. central nervous system. uterus. kidneys. Predictable Toxic Drug Actions in the Fetus Chronic use of opioids by the mother may produce dependence in the fetus and newborn. Drug effects on other maternal tissues (heart. For example. C. can induce fetal hepatic enzymes responsible for the glucoronidation of bilirubin. corticosteroids are used to stimulate fetal lung maturation when premature birth is expected. or insulin may be required for control of blood glucose in pregnancy-induced diabetes. This dependence may be manifested after delivery as a neonatal withdrawal syndrome. These drugs can result in significant and irreversible renal damage in the fetus and are therefore contraindicated in . are NOT changed significantly by pregnancy. renal blood flow.Pharmacodynamics A. and the incidence of jaundice is lower in newborns when mothers are given phenobarbital than when phenobarbital is not used. Maternal Drug Actions The effects of drug on the reproductive tissues (breast. Therapeutic Drug Actions in the Fetus Fetal therapeutics is an emerging area in perinatal pharmacology. though the physiological context (cardiac output. Antiarrythmic drugs have also been given to mothers for treatment of fetal cardiac arrhytmias. Phenobarbital.

must be at a critical time in the development of the limbs. . the central nervous system. drugs may have important direct actions on the processes of diferentiation in developing tissues. For example. Chronic consumption of high doses of ethanol during pregnancy. Drugs may interfere with the passage of oxygen or nutrients through the placenta and therefore have effects on the most rapidly metabolizing tissues of the fetus. vitamin A (retinol) has been shown to have important differentiation-directing actions in normal tissues. Continued exposure to a teratogen may produce cumulative effects or may affect several organs going through varying stages of development. suggesting that they alter the normal processes of differentiation. however. Adverse effects may also be delayed. Finally. Several vitamin A analogues (isotretinoin. In this syndrome. The thalidomide phocomelia riskk occurs during the fourth through the seventh weeks of gestation because it is during this time that the arms and legs develop. The mechanisms by which different drugs produce teratogenic effects are poorly understood and are probably multifactorial. For example. growth. as in the case of female fetuses exposed to diethylstilbestrol (DES). may result in the fetal alcohol syndrome. who may be at increased risk for adenocarcinoma of the vagina after puberty. (3) show a dose-dependent incidence. D. folic acid supplementation during pregnancy appears to reduce the incidence of neural tube defects. This exposure. To be considered as teratogenic.pregnant women. spina bifida. (2) exert its effects at a particular stage of fetal development. ie. Thalidomide is an example of a drug that may profoundly affect the development of the limbs after only brief exposure. eg. particularly during the first and second trimesters. drugs may have a direct effect on maternal tissues with secondary or indirect effects on fetal tissues. Teratogenic Drug Actions A single intrauterine exposure to a drug can affect the fetal structures undergoing rapid development at the time of exposure. deficiency of a critical substance appears to play a role in some types of abnormalities. etretinate) are powerful teratogens. Some drugs with known teratogenic or other adverse effects in pregnancy are listed in the table. indicating a selectivity for certain target organs. a candidate substance or process should : (1) result in a characteristic set of malformations. For example. Finally. during the limited time period of organogenesis of the target organs. and facial development may be affected.

she should optimally take it 30-60 minutes after nursing and 3-4 hours before the next feeding. If conditions are well controlled and there is a good relationship between the mother and the . Isoniazid reaches a rapid equilibrium between breast milk and maternal blood. Most sedatives and hypnotics achieve concentrations in breast milk sufficient to produce a pharmacologic effect in some infants. but most importantly. and the concentrations in breast milk will be relatively low. Chloramphenicol concentrations in breast milk are not sufficient to cause the gray baby syndrome. This allows time for many drugs to be cleared from the mother’s blood. If the nursing mother must take medications and the drug is a relatively safe one. and morphine enter breast milk in quantities potentially sufficient to prolong the state of neonatal narcotic dependence if the drug was taken chronically by the mother duriing pregnancy. methadone. Therefore. Drugs for which no data are available on safety during lactation should be avoided. Most drugs administered to lactating women ARE detectable in breast milk. the concentration of drugs achieved in breast milk is usually low. the total amount the infant would receive in a day is substantially less than what would be considered a "therapeutic dose". Most antibiotics taken by nursing mothers can be detected in breast milk. and the physician must know which drugs are potentially dangerous to nursing infants (see table). The concentrations achieved in breast milk are high enough so that pyridoxine deficiency may occur in the infant if the mother is not given pyridoxine supplements. and chloramphenicol should be avoided during lactation. and poor sucking reflexes in the infant. Diazepam can have a sedative effect on the nursing infant.DRUG USE DURING LACTATION Drugs should be used conservatively during lactation. Barbiturates taken in hypnotic doses by the mother can produce lethargy. Chloralhydrate can produce sedation if the infant is fed at peak milk concentration. Opioids such as heroin. sedation. or the breastfeeding discontinued while they are being given. Tetracycline concentrations in breast milk are approximately 70% of maternal serum concentrations and present a risk of permanent tooth staining in the infant. but there is a remote possibility of causing bone marrow suppresion. Fortunately. its long half life can result in significant drug accumulation.

Similarly. the infant can be tapered off the methadone as the mother’s dose is tapered. Mohon koreksi / tambahan juga dari teman2/dokter2/guru2/pembaca yang baik. breastfeeding should be avoided in mothers receiving cancer chemotherapy or being treated with similar agents for collagen diseases such as lupus erythematosus or post-transplant. diketik ulang hanya untuk kepentingan belajar ko-as. Very small amounts of caffeine are excreted in the breast milk of coffee-drinking mothers. London: Prentice-Hall International Ltd. and women who are receiving lithium may expose the baby to relatively large amounts of the drug. Breastfeeding is contraindicated after large doses and should be withheld for days to weeks after small doses. They should be avoided if possible or breastfeeding discontinued.. Basic & Clinical Pharmacology. Lithium enters breast milk in concentrations equal to those in maternal serum. 1995. Segala kekurangan / kesalahan yang mungkin ada.Kitaro) . Drugs such as propylthiouracil and tolbutamide enter breast milk in quantities sufficient to affect endocrine function in the infant. Minimal use of alcohol by the mother has not been reported to harm nursing infants. berasal HANYA dari kelalaian penyusun. Teks asli dari Katzung BG (ed). Radioactive substances such as iodinated I-125 albumin and radioiodine can cause thyroid suppression in infants and may increase the risk of subsequent thyroid cancer as moch as tenfold. FKUI 1992 (npm 0192000012). stop taking the drug abruptly. 6th ed. Excessive amounts of alcohol. drPLD 1999 Disusun dengan sumbangan catatan cukup banyak juga dari teman2 lain.physician. (musik latar : "Island of Life" . Nicotine concentrations in the breast milk of smoking mothers are low and do not produce effects in the infant. however. however. Kuliah sebelumnya Pengantar Perinatologi Kuliah berikutnya Congenital Malformations Menu / Daftar Isi CAKUL ADA KOREKSI / TAMBAHAN !?!? EMAIL ABUD !!!! Homepage Abud Anthonius Budi Marjono. The infant should be watched for signs of narcotic withdrawal. Clearance of this drug is almost completely dependent upon renal elimination. can produce alcohol effects in the infant. She should not. terimakasih. an infant could be breast-fed while the mother is taking methadone.

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