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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.

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

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

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

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

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

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

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