The Safety Pharmacotherapy During Pregnancy
THE SAFETY PHARMACOTHERAPY DURING PREGNANCY
ABSORPTION DURING PREGNANCY
GASTRO-INTESTINAL ABSORPTION
delayed gastric emptying ( with about 30-50% )
decreased intestinal motility
An increase in plasma progesterone level during pregnancy is responsible for the reduction in intestinal motility.
reduction in gastric acid secretions
( with about 40% during the first two semester of pregnancy )
increase in mucus secretion
The consequence of the changes is increase in gastric pH.
pH increase influences the drugs ionization and their gastro-intestinal absorption.
CUTANEOUS AND VAGINAL ABSORPTION
the increase of regional blood flows facilitates drugs’ penetrations at cutaneous level
at vaginal mucosa level drugs absorption is higher
DISTRIBUTION DURING PREGNANCY
maternal plasma volume expands from 30 to 50% during the first trimester
as a result of haemodilution plasma albumin declines
the concentration of 1-glycoproteins (which bind basic drugs) also decreases during pregnancy
HEMODYNAMICS CHANGES
total blood flow increase with about 30%, reaching the maximum between weeks 30 and 34 of pregnancy
cardiac flow increases with 50%
renal and pulmonary flow are increased in parallel with the cardiac flow
hepatic flow remains unmodified
uterine blood flow also increase
BODY HYDRIC COMPARTMENT
plasma volume increases with about 50%, reaching its maximum between weeks 30 and 34 of pregnancy
total body water increase very much;
60% of this amount is for the fetus, placenta and amnion, and the remaining 40%
refers to the body of the mother
BODY COMPOSITION
adipose tissue content might grow from 3-4 kg to about 19 kg at the end of pregnancy
this fat tissue accumulation during pregnancy explains the raise of distribution volume for liposoluble substances
(e.g. diazepam, petidine, thiopental ) and the persistence of a high drug concentration
after anesthesia ( thiopental, bupivacaine )
drug distribution in pregnant body is also influenced by the presence of fetus and placenta ( new distribution compartments ) which might play a very important role concerning drugs’ quantity and transport speed, from mother to fetus
placenta can not be considered a barrier that protects the fetus against any drugs used by mother
METABOLISM DURING PREGNANCY
MOTHER’S METABOLISM
hepatic metabolism depends on: drug binding of plasma proteins, blood hepatic flow
furthermore, progesterone stimulates the activity of hepatic microsomal enzymes (P450 cytochrome) and therefore accelerates the metabolism of some drugs
( e.g., fenytoine, valproic acid, carbamazepine )
induction of: CYP3A4, CYP2D6, CYP2C9
inhibition of: CYP1A2, CYP2C19
RENAL EXCRETION DURING PREGNANCY
MOTHER’S EXCRETION
As a result, the renal excretion of drugs during pregnancy is much accelerated, due especially to the weak bindings between drugs and plasma proteins, as a result of hypoalbuminemia caused by hemodilution
PREGNANCY - RISK CATEGORIES
The Food and Drug Administration (FDA) currently divides medications into 5 different pregnancy-risk categories
A - Controlled studies show no risk to the fetus in the first trimester ( and there is no evidence
of a risk in later trimesters ), and the possibility of fetal harm appears remote.
Example: vitaminum E
B- Either animal-reproduction studies have not demonstrated a fetal risk but there are no
controlled studies in pregnant women or animal-reproduction studies have shown
an adverse effect (other than a decrease in fertility) that was not confirmed in controlled
studies in women in the first trimester (and there is no evidence of a risk in later
trimesters).
Example: penicillins
C- Either studies in animals have revealed adverse effects on the fetus ( teratogenic or
embryocidal, or other ) and there are no controlled studies in women or studies in
women and animals are not available.
Drugs should be given only if the potential benefit justifies the potential risk to the fetus.
Example: gentamicin
D - There is positive evidence of human fetal risk, but the benefits from use in pregnant
women may be acceptable despite the risk (e.g., if the drug is needed in a life-
threatening situation or for a serious disease for which safer drugs cannot be used or are
ineffective).
Example: chloramphenicol
X - Studies in animals or human beings have demonstrated fetal abnormalities, or there is
evidence of fetal risk based on human experience, or both, and the risk of the use of the
drug in pregnant women clearly outweighs any possible benefit.
The drug is contraindicated in women who are or may become pregnant.
Example: etretinate