Aznan Lelo- Datten Bangun Departemen Farmakologi & Terapeutik FK USU 2012

Points to ponder:

Awareness of physiology of pregnancy How pregnancy alters pharmacokinetics Placental transfer Teratology Drugs utilised in pregnancy

Pregnancy poses important problems. Most drugs will diffuse passively across placenta, and some are transported actively, so the potential benefit of a drug to mother has to be considered in relation to the potential risk to the fetus. As a general rule, all drugs should be avoided in pregnancy unless theres a compelling reason for their use. Some drugs have been definitely linked to fetal abnormalities .
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Only half of all pregnancies are planned Many women need medications for pregnancy induced conditions (e.g. = Morning Sickness), = chronic conditions (e.g. Epilepsy), intercurrent conditions (Allergies) Women work with chemicals, exposed to radiation and use illicit drugs During embryogenesis-drugs &chemicals may adversely affect development

A) Anxiety of birth defects: Leads women not to take medications during pregnancy& lactation. Leads pharmaceutical companies not to develop drugs for pregnant &lactating women. B) Women are not treated appropriately even after first trimester, or for life threatening conditions

Sebagian besar dari obat-obat yang diminum oleh ibu hamil dapat melewati plasenta dan dapat masuk ke tubuh janin

Efek farmakologi Efek teratogenik

Critical factors affecting placental drug transfer and drug effects on fetus : 1. 2. 3. 4. 5. Physicochemical properties of the drug The rate at which the drug cross the placenta The amount of drug reaching the fetus The duration of the exposure to the drug Distribution characteristic in different fetal tissues 6. The stage of placental and fetal development at the time of exposure 7. The effects of drugs used in combination

in plasma volume in cardiac output in renal blood flow and GFR Induction of liver enzyme pathways in plasma protein content Delayed gastric emptying

volume of distribution plasma concentration excretion renal excretion hepatic metabolism

Golden rule is that every drug crosses the placenta and under normal circumstances most drugs equilibrate between maternal and fetal compartments. The only exception is heparin, which because of its large molecular weight and polarity, does not cross

1.

Liphophilic drugs : - tends to diffuse readily across the placenta - enter the fetal circulation

Thiopental (used during caesarean section) : cross the placenta immediately can produce sedation or apnea in the new born infant

2. Highly ionized drugs : - cross the placenta slowly achieve low concentration in the fetus

Succinylcholine or tubocurarine

3. Polar compound, but high-maternal-fetal concentration gradient cross the placenta

Salicylate

Drugs with mol. weight :

- 250-500 cross the placenta easily - 500-1000 : more difficulty - > 1000 : poorly

Heparin : - very large and polar unable to cross the placenta - safe to the fetus - used the placental transporter
Warfarin : - smaller than heparin - teratogenic - should be avoided

Ex. P-glycoprotein transporter pumps drugs back to the maternal circulation Including : - anti-cancer drugs (vinblastin, doxorubicin) - digoxin

Some drugs like sulfonamides, barbiturates, phenytoin, local anaesthetics exhibit greater protein binding in maternal plasma than in fetal plasma because of lower binding affinity of fetal proteins

1. Placenta : - semipermeable barrier - site of metabolism - baru sempurna setelah 4 bulan kehamilan 2. Drugs enter the fetal circulation enter the liver metabolism

A. Maternal Drug Actions - The effects of drugs on reproductive tissues of the pregnant woman sometimes are altered by endocrine environment appropriate for the stage of the pregnancy. - Drug effects on other system tissue (heart, lungs, kidneys, CNS) are not changed significantly, though sometimes cardiac output or renal blood flow maybe altered Ex. diuretics insulin for pregnancy induced diabetic

B. Therapeutic Drug Actions in The Fetus - Drugs are given to the mother with the fetus as the target of the drug Examples: corticosteroids to stimulate fetal lung maturation when preterm birth is expected. phenobarbital to reduce the incidence of jaundice

C. Predictable Toxic Drug Actions in The Fetus - chronic used of opioid by mothers drug dependence in the fetus and new born - ACE-I used by the mothers renal damage in the fetus - diethylstilbesterol adenocarcinoma

Pharmacodynamics

Teratos = monster Teratogen : substance that leads to the birth of malformed baby Teratogen : * result in a characteristic set of malformation * exerts its effect at a particular stage of fetal development (organogenesis) * show a dose-dependence incidence

Dose Frequency Length of exposure Stage of pregnancy upon exposure The properties of the drugs

Note: The Thalidomide babies (phocomelias) in early 1960.

Early development

Main embryonic period (weeks)

Fetal period (weeks)

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Neural tube defects TA, ASD, and VSD

Mental retardation HEART LIMBS UPPER LIP EARS EYES TEETH PALATE

CNS

Amelia/Meromeli
a

Cleft lip

Low-set malformed ears and deafness Microphthalmia, cataracts,glaucoma Enamel hypoplasia Cleft palate Masculinsation Embryo Death Common site(s) of action Major congenital anomalies Highly sensitive period

GENITALIA

Functional & minor anomalies Less sensitive period

Drugs in Pregnancy
FIRST TRIMESTER : congenital malformations (teratogenesis) SECOND & THIRD TRIMESTER : affect growth & fetal development or toxic effects on fetal tissues NEAR TERM :

adverse effects on Labour or

neonate after delivery

Thalidomide is a tranquiliser, sedative & immunosuppressant Critical exposure window 24 to 36 days post fertilisation Defects :

amelia - no limbs micromelia - short limbs cardiac defects haemangiomas defects of urinary tract defects of digestive tract

The intra-uterine period between 2 weeks 3 months is when the most serious abnormalities of fetal development can be caused by drugs. Its during this period that the major organs are being formed. In animal studies, even one dose of a drug administered at the critical time has been shown to have a major effect. The mechanisms of damage are not yet known, but the molecular basis of differentiation of embryonic cells is an intense area of basic research and is likely to provide new insights in the near future. Ampicillin and Cephalosporins are considered one of the safest drugs which can be used during pregnancy.

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During T2 & T3 of pregnancy, adverse effects on fetus of drugs administered to the mother are generally an exaggeration of the effects seen in the adult. Exceptions to this rule are the damage to tissues which are still developing e.g. teeth & bones by Tetracycline, and the impairment of brain development by Coumarin anticoagulant. Particular care must be taken with drugs given shortly before delivery. Analgesics, e.g. Meperidine (Pethidine), and tranquillizers e.g. (Benzodiazepines) may severely impair neonatal respiration. In addition, the newborn lacks many enzymes necessary for the efficient metabolism of drugs.
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Besok