Paediatric Pharmacology

·        Drug therapy in pregnancy.

·        Teratogenic drug actions.

·        Drugs with adverse effects on the fetus.

·        Drug therapy in infants and children.

·        Drug use during lactation.

Drug therapy in Pregnancy

1.    Most drugs taken by pregnant women can cross the placenta and expose the developing embryo and fetus to their effects.

2.       Factors affecting placental drug transfer and drug effects on fetus:

a.       physicochemical properties of the drug.

b.    rate at which the drug crosses the placenta and the amount of drug reaching the fetus.

c.       duration of exposure to the drug.

d.       distribution characteristics in different fetal tissues.

e.       stage of placental and fetal development at the time of exposure to the drug.

f.     the effects of drugs used in combination.

3.       Lipophilic drugs tend to diffuse readily across the placenta and enter the fetal circulation.

4.       Drugs with molecular weights of 250-500 can cross the placenta easily, depending upon their lipid solubility and degree of ionization: the choice of heparin as an anticoagulant in pregnant women.

5.       Protein binding:

a.    if a compound is very lipid-soluble, it will not be affected greatly by protein binding: transfer of these more lipid-soluble drugs and overall rates of equilibration are more dependent on placental blood flow.

b.    if a drug is poorly lipid-soluble and is ionized, its transfer is slow and will probably be impeded by its binding to maternal plasma proteins.

c.       differential protein binding is also important, since some drugs exhibit greater protein binding in maternal plasma than in fetal plasma because of a lowered binding affinity of fetal proteins.

d.    this has been shown for sulfonamides, barbiturates, phenytoin, and local anesthetic agents.

6.    Two mechanisms help to protect the fetus from drugs in the maternal circulation:

a.    the placenta itself plays a role both as a semipermeable barrier and as a site of metabolism of some drugs passing through it.

b.       drugs that have crossed the placenta enter the fetal circulation via the umbilical vein, about 40-60% of which enters fetal liver where it may be partly metabolized.

7.       Toxic drug actions in the fetus:

a.       chronic use of opioids by the mother may produce dependence in the fetus and newborn: may be manifested after delivery as a neonatal withdrawal syndrome.

b.    use of ACE inhibitors during pregnancy can result in irreversible renal damage in the fetus.

Teratogenic drug actions

1.    A single intrauterine exposure to a drug can affect the fetal structures undergoing rapid development at the time of exposure.

2.       Mechanisms:

a.       direct effect on maternal tissues with secondary or indirect effects on fetal tissues.

b.       interfere with the passage of oxygen or nutrients through the placenta.

c.       direction actions on differentiation in developing tissues: retinol in normal tissues.

d.       deficiency of a critical substance may play a role in some types of abnormalities: folic acid supplements during pregnancy reduce incidence of spina bifida.

3.       Continued exposure to a teratogen may produce cumulative effects or may affect several organs going through varying stages of development.

4.       Chronic consumption of high doses of ethanol during pregnancy, particularly during the first and second trimesters, may result in the fetal alcohol syndrome.

5.       Criteria for a teratogen:

a.       result in a characteristic set of malformations, indicating a selectivity for certain target organs.

b.    exert its effects at a particular stage of fetal development.

c.       show a dose-dependent incidence.

4.       Drugs with adverse effects on the fetus

Drug therapy in infants and children

1.       Blood flow at site of administration:

a.    sick premature infants requiring intramuscular injections may have very little muscle mass.

b.    this is further complicated by diminished peripheral perfusion to these areas, in such cases, absorption becomes irregular and difficult to predict.

c.       example of drugs especially hazardous in such situations are cardiac glycosides, aminoglycosides and anticonvulsants.

2.       Gastrointestinal function:

a.    in full-term infants, gastric acid secretion begins soon after birth and increases gradually over several hours: drugs that are partially or totally inactivated by the low pH of gastric contents should not be administered orally.

b.       gastric emptying time is prolonged in the first day or so of life: drugs that are absorbed primarily in the stomach may be absorbed more completely than anticipated.

c.       neonates also have low concentrations of bile acids and lipase, which may decrease the absorption of lipid-soluble drugs.

3.    Drug distribution:

a.    most neonates will experience diuresis in the first 24 – 48 hours of life.

b.       since many drugs are distributed throughout the extracellular water space, the size of the extracellular water compartment may be important in determining the concentration of drug at the receptors site: important for water-soluble drugs.

c.       premature infants have less fat than full-term infants: organs that accumulate high concentrations of lipid-soluble drugs in adults and older children may accumulate smaller amounts of these agents in more immature infants.

d.       protein binding of drugs is reduced in the neonate: local anesthetics, diazepam, phenytoin, ampicillin and phenobarbitone.

e.       drugs given to a neonate with jaundice can displace bilirubin from albumin causing kernicterus.

4.    Drug metabolism and excretion:

a.       because of the neonate’s decreased ability to metabolize drugs, many drugs have slow clearance rates and prolonged elimination half-lives which predisposes the neonate to adverse effects from drugs that are metabolized by the liver.

b.    the glomerular filtration rate is much lower in newborns than in older infants, children or adults.

c.       drugs that depend on renal function for elimination are cleared from the body very slowly in the first weeks of life.

5.       Paediatric dosage forms and compliance:

a.       many drugs prepared for children are in the form of elixirs or suspensions.

b.       elixirs are alcoholic solutions in which the drug molecules are dissolved and evenly distributed; no shaking is required.

c.       suspensions contain undissolved particles of drug that must be distributed throughout the vehicle by shaking.

d.       compliance may be more difficult to achieve in children.

Drug use during Lactation

1.    Most drugs administered to lactating women are detectable in breast milk though the concentration is usually low.

2.    If the nursing mother must take medications and the drug is relatively safe, she should optimally take 30 – 60 minutes after nursing and 3 – 4 hours before the next feeding: this allows time for many drugs to be cleared from the mother’s blood.

3.    Most antibiotics taken by nursing mothers can be detected in breast milk.

4.    Most sedatives and hypnotics achieve concentrations in breast milk sufficient to produce a pharmacologic effect in some infants.

5.       Opioids such as heroin, methadone and morphine enter breast milk in quantities sufficient to prolong the state of neonatal narcotic dependence.

6.       Lithium enters breast milk in concentrations given to those in maternal serum.

7.       Drugs such as propylthiouracil and tolbutamide enter breast milk in quantities sufficient to affect endocrine function in the infant.

8.       Radioactive substances such as radioiodine can cause thyroid suppression in infants and may increase the risk of subsequent thyroid cancer.

Drugs used during lactation and possible effects on fetus