Download Drugs prescription during pregnancy

Drugs in Pregnancy and
Lactation
Dr Safaeian
DRUG THERAPY IN PREGNANCY
Most drugs taken by pregnant
women can cross the placenta and
expose the developing embryo and
fetus to their pharmacologic and
teratogenic effects.
Pharmacokinetics
Factors affecting placental drug transfer
and drug effects on the fetus :
(1) Physicochemical properties of drug
(2) The rate at which drug crosses placenta and
the amount of drug reaching fetus
(3) Duration of exposure to drug
(4) Distribution characteristics in different
fetal tissues
(5) Stage of placental and fetal development at
time of exposure to drug
(6) Effects of drugs used in combination
LIPID SOLUBILITY
Lipophilic drugs → diffuse readily across placenta.
Thiopental used for cesarean sections, crosses
placenta almost immediately → sedation or apnea in
newborn
Highly ionized Succinylcholine and Tubocurarine cross
placenta slowly → very low concentrations in fetus.
Impermeability of placenta to polar compounds is
relative rather than absolute.
In high enough maternal-fetal concentration
gradients → polar compounds cross placenta.
MOLECULAR SIZE
Molecular weight influences rate and amount of
drug transferred.
MW of 250-500 → cross placenta easily, depending
upon their lipid solubility and degree of ionization.
MW of 500-1000 cross more difficulty.
MW ˃1000 cross very poorly (Heparin is safe unlike
warfarin).
Yet placental transporters can carry larger molecules
to fetus (maternal antibodies as in Rh
incompatibility).
PLACENTAL TRANSPORTERS
Many drug transporters have been identified in
placenta.
P-glycoprotein transporter: pumps back into maternal
circulation a variety of drugs, including cancer drugs
(Vinblastine, Doxorubicin) and viral protease inhibitors
(↑risk of vertical HIV infection from mother to fetus).
Glyburide is effluxed from the fetal circulation by
specific transporters.
PROTEIN BINDING (PB)
PB may affect rate and amount transferred.
Very lipid-soluble (some anesthetic gases) diffuse so rapidly
will not be affected greatly by PB → more dependent on
placental blood flow
Transfer of poorly lipid-soluble and ionized drug is slow
and will probably be impeded by its binding to maternal
plasma proteins.
Differential protein binding is also important: some drugs
(sulfonamides, barbiturates, phenytoin, local anesthetic
agents) exhibit greater PB in maternal plasma than in fetal
plasma because of a lower binding affinity of fetal proteins.
PLACENTAL DRUG METABOLISM
Placenta plays role both as:
A semipermeable barrier
A site of metabolism of some drugs:
hydroxylation, N-dealkylation, demethylation
(Pentobarbital is oxidized).
Conversely, some metabolites may be toxic →
augment toxicity (Ethanol, Benzpyrenes).
FETAL DRUG METABOLISM
Drugs enter fetal circulation via umbilical vein.
About 40-60% of umbilical
venous blood flow enters fetal
liver and may be partially
metabolized drugs.
FETAL DRUG METABOLISM
In addition, a large proportion of drug present in umbilical
artery (returning to placenta) may be shunted through
placenta back to umbilical vein and into the liver again.
It should be noted: metabolites of some drugs may be
more active than parent compound and may affect fetus
adversely.
Pharmacodynamics:
MATERNAL DRUG ACTIONS
Alteration of drugs effects on reproductive tissues (breast,
uterus, …) in pregnancy
No significantly changes in drug effects on other maternal
tissues (heart, lungs, kidneys, CNS, …)
Alteration of physiologic context (cardiac output, renal blood
flow,…) → requiring the use of new drugs.
Cardiac glycosides and diuretics may be needed for heart
failure precipitated by ↑cardiac workload of pregnancy
Insulin may be required for control of blood glucose in
pregnancy-induced diabetes.
Pharmacodynamics:
THERAPEUTIC DRUG ACTIONS IN FETUS
Fetal therapeutics: drug administration to pregnant woman
with the fetus as the target of drug
Corticosteroids → stimulate fetal lung maturation when
preterm birth is expected.
Phenobarbital → near term, can induce fetal hepatic
enzymes responsible for glucuronidation of bilirubin →
↓incidence of jaundice in newborn
Antiarrhythmic drugs → treatment of fetal cardiac
arrhythmias
Zidovudine →↓transmission of HIV from mother to fetus
Pharmacodynamics:
PREDICTABLE TOXIC DRUG ACTIONS IN FETUS
Chronic use of opioids → dependence in fetus and
neonatal withdrawal syndrome after delivery
ACEIs during pregnancy → irreversible renal damage in
fetus → contraindicated in pregnant women.
Delayed Adverse effects: female fetuses exposed to
diethylstilbestrol → ↑risk for adenocarcinoma of
vagina after puberty.
Pharmacodynamics:
TERATOGENIC DRUG ACTIONS
Teratogen:
Thalidomide Tragedy
A substance:
• 1957 until 1961
1)Results in a malformation, indicating
• 10,000 birth defects
selectivity for certain target organs;
2) Exerts its effects at a particular
stage of fetal development, ie, during
limited time period of organogenesis
of target organs (thalidomide
phocomelia risk occurs during 4-7th
weeks of gestation);
3)Show a dose-dependent incidence.
Teratogenic mechanisms:
1. Direct effect on maternal tissues with secondary or indirect
effects on fetal tissues.
2. Interfere with passage of oxygen or nutrients through
placenta and effects on the most rapidly metabolizing tissues
of fetus.
3. Important direct actions on processes of differentiation in
developing tissues (vitamin A, isotretinoin, etretinate as
potent teratogens).
Teratogenic mechanisms:
4. Deficiency of a critical substance plays role in some
abnormalities (spina bifida in folic acid deficiency).
5. Continued exposure to a teratogen → cumulative
effects or affect several organs through varying stages of
development.
Counselling women about
teratogenic risk
Ability of appropriate counselling to prevent unnecessary
abortions.
Up-to-date and evidence-based information should be
provided.
Woman should understand that baseline teratogenic risk in
pregnancy (a neonatal abnormality in the absence of any
known teratogenic exposure) is about 3%.
It is critical to address maternal-fetal risks of untreated
condition if a medication is avoided → serious morbidity in
women who discontinued SSRIs for depression in pregnancy.
Schematic diagram of critical periods of human development
FDA Teratogenic Risk Categories
Category
Description
A
No evidence of a risk in the first and late trimesters from
controlled studies.
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 that was not confirmed in controlled studies
in women in the first and late trimester.
C
Studies in animals have revealed adverse effects on fetus
(teratogenic or embryocidal,….) and there are no
controlled studies in women. Drugs should be given only if
the potential benefit justifies the potential risk to fetus.
FDA Teratogenic Risk Categories
Category
Description
D
There is positive evidence of human fetal risk, but the
benefits from use in pregnant women may be acceptable
despite the risk (if drug is needed in a life-threatening
situation or for a serious disease for which safer drugs
cannot be used or are ineffective).
X
Studies in animals or human beings have demonstrated
fetal abnormalities or there is evidence of fetal risk based
on human experience or both. The drug is
contraindicated in women who are or may become
pregnant.
Drugs with significant adverse effects on fetus
Drug
ACE inhibitors
(D)
Antidepressants
tricyclic (C)
Anti-neoplastics
(B) (D) (X)
Barbiturates,
Diazepam (C)
Trimester
Effect
All, especially
Renal damage
second and third
Third
Neonatal withdrawal
symptoms with clomipramine,
desipramine, and imipramine
All
Various congenital
malformations; low birth
weight
All
Chronic use can lead to
neonatal dependence.
Drugs with significant adverse effects on fetus
Drug
Trimester
Effect
Carbamazepine(D) First
Neural tube defects
Ethanol
All
Risk of fetal alcohol syndrome
and alcohol-related neurodevelopmental defects
Heroin,
Methadone(C)
All
Chronic use leads to neonatal
dependence
Iodide
All
Congenital goiter, hypothyroidism
Isotretinoin,
Etretinate (X)
All
Extremely high risk of CNS, face,
ear, other malformations
Lithium (D)
First
Ebstein's anomaly
Drugs with significant adverse effects on fetus
Drug
Trimester
Effect
Propylthiouracil(C) All
Hypothyroidism, Congenital goiter
Organic solvents First
Phenytoin (D)
All
Streptomycin(D) All
Multiple malformations
Valproic acid(D)
All
Neural tube defects, cardiac and limb
malformations
Warfarin (D)
First,
Second
Third
Fetal hydantoin syndrome
Eighth nerve toxicity
Hypoplastic nasal bridge, CNS
malformations
Risk of bleeding. Discontinue use 1
month before delivery.
Teratogenic Effects
Ebstein's anomaly: congenital heart defect in
tricuspid valve — the valve between
chambers on the right side of heart — and
possibly shunt between right and left atria.
Teratogenic Effects
Fetal alcohol syndrome: a pattern of
mental and physical defects
Teratogenic Effects
Fetal hydantoin syndrome: intrauterine
growth restriction with microcephaly and
develop minor dysmorphic craniofacial
features and limb defects including
hypoplastic nails.
DRUG USE DURING LACTATION
Most drugs are excreted into breast milk in amounts too small
(1% of drug) to adversely affect neonatal health.
More lipid soluble and more basic drugs →more excreted into
milk (milk has lower pH than serum; pH 7)
Examples of basic drugs: Antihistamines, Opioids alkaloids,
Isoniazid, Imipramine
Higher maternal plasma levels (renal insufficiency) → higher
breast milk concentrations
DRUG USE DURING LACTATION
Nursing mother should optimally take relatively safe drug
30-60 minutes after nursing and 3-4 hours before next
feeding.
Newborn is more susceptible to drugs effects during first
weeks.
Breast-feeding is contraindicated in cancer chemotherapy,
treating with cytotoxic or immune-modulating agents and
after large doses radioactive substances.
Drugs often used during lactation and possible
effects on nursing infant
Drug
Effect on
Infant
Comments
Possibility of bone marrow suppression;
Chloramphenicol Significant recommend not taking in breast-feeding.
Diazepam
Significant Accumulation and sedation
Iodine (radioactive)
Significant Thyroid suppression,↑risk of thyroid cancer
Milk concentrations equal maternal
concentrations. Possibility of pyridoxine
deficiency
Isoniazid (INH)
Minimal
Lithium
Mother should avoid breast-feeding unless
Significant
levels can be measured.
Propylthiouracil
Significant Suppress thyroid function in infant.
Drugs often used during lactation and possible
effects on nursing infant
Drug
Effect on
Infant
Comments
Breast-feeding under close physician
supervision. Signs of opioid withdrawal in
Significant
Methadone
infant if mother stops taking methadone or
stops breast-feeding abruptly.
Hypnotic doses cause lethargy, sedation, poor
Moderate
Phenobarbital
suck reflexes in infant.
Low maternal doses (5 mg/d) probably safe.
Moderate Doses 2 or more times physiologic amounts
Prednisone
(> 15 mg/d) should probably be avoided.
Possibility of permanent staining of
Tetracycline Moderate developing teeth in the infant. Should be
avoided during lactation.