PREGNANCY AND LACTATION

ALTERED PHARMACOKINETICS:

ALTERED PHARMACOKINETICS -IN PREGNANCY AND LACTATION-

INTRODUCTION :

INTRODUCTION Two compartment model is the simplest model in pregnant ladies. (Mother & Fetus) But in practice, many compartments in mother & fetus may present. (eg. Placenta, amniotic fluid)

Alterations That Happens In ADME:

Alterations That Happens In ADME Absorption In Stomach: Acidic drugs in ionised form, so reaching of intestine is delayed. Therefore, no change in extent of absorption but kinetic of absorption is changed. Generally, 30% ↓ in peristaltic movement 40% ↓ in gastric acid secretion 40% ↓ in enzymes 40% ↑ in pH of the stomach.

In intestine:

In intestine Though peristaltic movement is decreased, blood flow is more which increase the rate of transport from mucosal side to seroal side. Therefore, no problem in absorption.

Distribution :

Distribution Decrease in albumin concentration due to haemo dilution. In pregnancy, though there is increased production on proteins, decrease in amount of proteins occur. This resembles hypo albuminimea. Due to decrease in protein binding, increase in free drug concentration leads to increased therapeutic effect. Also, increase in elimination or metabolism and increase in volume of distribution.

Slide 6:

Deviation-1: In any inflammatory condition α -1 acid glyco protein increases. Body mimics this during pregnancy. Therefore, increase in protein binding of basic drugs and so concentration of these drugs decreases in mother an increases in fetus. Deviation-2: Concentrations of lipoproteins and fat increase in pregnancy which leads to increased binding of fat with protein. Therefore, availability of protein further decreases for the drugs to get binding. Serum albumin become normal after 5-7 wks after parturition.

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Renal blood flow increases by 50% at first trimester but decreases slowly then approaching normal. Uterine blood flow gradually increases to 600-700 ml/min. Blood pH increases to 7.42 in mother while blood pH of the fetus remains same. Therefore, transfer of basic drugs more to the fetus. Eg: Diazepam. And it is vice-versa for acidic drugs.

Clearance:

Clearance Increase in renal plasma flow by 50-100% Increase in GFR up to 70% Increased levels of unbound drug in plasma All these factors lead to rapid elimination of drugs (which mainly depend on kidney for elimination) in pregnancy. Examples of such drugs include digoxin, gentamycin & cephalexin Hepatic clearance is however variable . Progesterone increases intrinsic hepatic clearance. This leads to rapid metabolic degradation , especially of the more lipid soluble drugs.

Pulmonary system:

Pulmonary system Respiratory rate is same. But the tidal volume differs Therefore, increased demand of oxygen. When more oxygen is taken in, more co 2 is sent out This lead to increase in pH of blood up to 7.4-7.42 Consequently, urine pH is also increased and so faster elimination of alkaline drugs and decreased elimination of acidic drugs. Because of increased perfusion of blood into capillaries around the alveoli more drug is sent to systemic circulation. The drugs which are to be present in pulmonary tract it becomes problem.

Plasma drug monitoring during pregnancy:

Plasma drug monitoring during pregnancy The physiological changes during pregnancy is longer (1day to 10 months) but return is very quick (5-7 wks after parturition) Monitoring is not useful in drugs used during childbirth. (I – stage:10 months, II – stage: few hrs, III – stage: few wks). Therefore II stage is not very important. Plasma levels of anticonvulsants may fall during I stage & III stage because of increased intrinsic clearance and increased fluid volume. Therefore, dosage adjustment based on the free fraction of the drug should be made.

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Monitoring every 4 wks from onset of pregnancy till parturition & weekly after birth for 2-3 wks & then every 2 wks until drug level stabilize is recommended. Plasma lithium levels should be monitored every 2 wks during 3 trimesters & every day after parturition until levels stabilize Digoxin is also needed monitoring Serum concentrations on antibiotics also need monitoring.

Points to be considered in teratogenic drug selection:

Points to be considered in teratogenic drug selection Teratogenicity: Birth defects in 2-4% of total birth. Of these, 65-70% with unknown cause, 25% due to genetic defects, 3% due to chromosomal aberrations and only 3% due to infections, drugs. Pre-implantation (1-16 days): Complete damage of replacement of cell possible. Organogenesis (17-56 days): Possibility of congenital malformations. Second and third trimesters: physical and brain growth retardation, behavioral changes, premature labour, neonatal toxicity.

Points to remember while prescribing drugs to a woman of reproductive age:

Points to remember while prescribing drugs to a woman of reproductive age Enquire whether she is pregnant or is likely to become pregnant in near future. Advice her if she is having unprotected sex, that if she has an unplanned pregnant she runs the risk of exposing her fetus to a drug or drugs she may be taking.