SPECIAL CONCERNS OF PRENATAL PHARMACOLOGY

Dr. Sowmya B. P. G. Student

Dept. of Pharmacology
KVGMC, Sullia

INTRODUCTION
Pregnancy is a special physiological condition where drug treatment presents a special concern because 1. The physiological changes of pregnancy affects the pharmacokinetics of medications used

2. Drugs are given to treat the mother but the fetus is always a recipient
Avoiding medications when pregnant may be desirable, it is often not possible and may be dangerous

PHARMACOKINETIC VARIATIONS Understanding the pharmacokinetic changes that take place during pregnancy provides practitioners insight into the treatment of these women. Absorption Distribution Metabolism

Excretion

Absorption:
Progesterone - Gastric emptying time - especially in 3rd trimester. Eg. Digitoxin, salicylates, and phenytoin C.O and tidal volume - absorption of drugs administered by inhalation route. Eg. Volatile anesthetic (halothane) dose requirement Concurrent use of vitamins, calcium , iron- binds/inactivates drugs

Distribution:
in the plasma volume by 30-50% Plasma albumin level and binding capacity of plasma protein

free, unbound drug

available for metabolism & excretion Clinical importance: While monitoring plasma concentrations of phenytoin

Body fat- se in volume of distribution fat soluble drugs

Metabolism

Clearance of drugs like rifampicin is decreased due to the cholestatic property of oestrogen.

 Elimination
C.O - renal blood flow and GFR- elimination
of drugs- Subtherapeutic drug levels Example, penicillin and digoxin

Modify the dose while treating the pregnant women

PLACENTAL TRANSFER OF DRUGS

o Placenta as a barrier

o The rate of transfer depends on the chemical properties of the drug,

o Protein binding

o Lipid solubility
o Molecular weight of the drug. Eg. Heparin

PLACENTAL TRANSPORTERS
o Placental transporters syncytiotrophoblast

o It may be preferable to treat pregnant women with anti cancer drugs that are substrates for P- glycoprotein such as Paclitaxel, doxorubicin o Viral protease inhibitors- substrate for P- glycoprotein- low concentration in the fetal blood- increases risk of vertical transmission

FETAL DISTRIBUTION

Fetal albumin
Fetal fat tissue 15% of the body weight at term - limits the distribution of fat soluble drugs like - barbiturates, GA

FETAL METABOLISM OF XENOBIOTICS/DRUGS

CYP3A7 is mostly expressed in the fetal liver and is replaced at birth by CYP3A4. CYP2C are absent in the fetal liver. Hydroxylation of tolbutamide and demethylation of diazepam CYP1A2 and CYP2D6 are not expressed in the fetus. The N-demethylation of caffeine and theophylline is deficient

FETAL EXCRETION
The placenta is a major excretory organ. A trapping effect of drugs in the amniotic fluid - equilibrium between fetal or maternal compartments occurs slowly. Fetal swallowing may allow certain drugs to be recirculated Eg. Accumulation of Ampicillin, penicillin, kanamycin, gentamycin, sulfonamides and some of the cephalosporins.

PHARMACODYNAMIC ASPECTS OF DRUG ACTION ON THE FETUS

Maternal drug action Therapeutic action on the fetus Toxic action on the fetus

Teratogenic action

MATERNAL DRUG ACTION

Mother may need to take drugs for conditions that arise during pregnancy. These drugs may affect the fetus or fetal drug metabolism Example- Pregnancy induced heart failure ( digitalis and diuretics) pregnancy induced diabetes ( insulin)

THERAPEUTIC ACTION ON THE FETUS

Fetus as a target of drug action Eg. Corticosteroids-used to stimulate fetal lung maturation in expected premature birth

TOXIC ACTION ON THE FETUS

Opiates can cause dependency in newborn leading to neonatal withdrawal syndrome ACE inhibitors produce renal toxicity in the developing kidney

TERATOGENIC ACTION
Teratogenic mechanisms produced by different drugs are poorly understood and are probably multifactorial. Defining a teratogen: Teratogens result in characteristic malformation indicating selectivity of action of the drug Act predominantly at a defined stage of fetal development

Dose dependant

ACTUAL PERIOD OF DEVELOPMENT OF TERATOGENICITY

Critical period of organogenesis- 2nd & 3rd month of gestational period Critical period of some Congenital anomalies exceeds the end of 3rd month, eg. Posterior cleft palate & hypospadias covers the 12th- 14th weeks of gestation & undescended testis in 7-9 & PDA in 9-10 months Critical period of each congenital Anomaly is separate

SUMMARY
Avoid Unnecessary medication (OTC) during pregnancy

Proportion of free drug to protein-bound drug is altered; this has important implications for therapeutic drug monitoring
Knowledge of pharmacokinetic changes is important for drugs with a narrow therapeutic window The periconceptional folic acid can prevent the major proportion of neural-tube defects.