Dr shameem R.

ALaasam
Pregnancy – What is different?

1) The need to study drugs during pregnancy relates to the physiologic changes

that occur with gestation.

2) To accommodate fetal growth and development, and perhaps provide a measure

of safety for the woman, pregnancy alters a woman’s underlying physiology.

3) This altered physiology can affect the pharmacokinetics of drugs.

PREGNANCY PHYSIOLOGY AND ITS EFFECTS ON
PHARMACOKINETICS

1. Gastrointestinal motility is decreased but there appears to be no

major affect in drug absorption except that reduced gastric
emptying delays the appearance in the plasma of orally
administered drugs, especially during labor.

2. Absorption from an intramuscular site is likely to be efficient

because tissue perfusion is increased due to vasodilatation.
Distribution:
1. Total body water increases by up to 8 Litres, creating a larger space within
which water soluble drugs may distribute.
2. As a result of haemodilution, plasma albumin (normal 33-55 g/1) declines by
some 10 g/1. Thus there is scope for increased free concentration of drugs that
bind to albumin.
3. Unbound drug, is free to distribute, metabolized and excreted; e.g. the free
(and pharmacologically active) concentration of phenytoin is unaltered,
although the total plasma concentration is reduced.
metabolism

Hepatic metabolism increases, but not the blood flow to liver.

So, increased clearance of drugs such as phenytoin and theophylline (elimination

rate depends on liver enzyme activity)

Drugs that are so rapidly metabolized that their elimination rate depends on their

delivery to the liver, i.e. on hepatic blood flow, have unaltered clearance, e.g.

pethidine.
Elimination:

Renal plasma flow almost doubles ,So there is rapid loss of drugs that

are excreted by kidney e.g. amoxycillin, dose of which should be

doubled for systemic infections (but not for urinary tract infections as

penicillins are highly concentrated in urine).

PLACENTAL TRANSFER OF DRUGS

1. The placenta is not a perfect barrier to drugs and chemicals administered

to mother.

2. Thalidomide tragedy, showed that placenta was capable of transferring

drugs ingested by mother to fetus, with potential for great harm.

3. On other hand, placental transfer of drugs administered to mother has

been used to treat fetal arrhythmias, congestive heart failure, & other
conditions.
factors affecting placental drug transfer &
Fetal tissue
(1) Physicochemical properties of drug

(2) Rate at which drug crosses placenta & amount of drug reaching the fetus

(3) Duration of exposure to drug

(4) Distribution characteristics in different fetal tissues

(5) Stage of placental & fetal development at time of exposure to the drug

(6) Effects of drugs used in combination

TERATOGENESIS

A is a chemical substance that can

induce a malformation during development.
Principles of teratology
▪ Teratogens act with specificity. A teratogen produces a specific
abnormality or constellation of abnormalities. Eg. thalidomide produces
phocomelia, and valproic acid produces neural tube defects.
▪ Teratogens demonstrate a dose-effect relationship.
▪ Teratogens must reach the developing conceptus in sufficient amounts to
cause their effects.
▪ The effect that a teratogenic agent has on a developing fetus depends
upon the stage during development when the fetus is exposed.
Mechanisms of Teratogenesis

▪ Genetic interference, gene mutation, chromosomal breakage,

interference with cellular function, enzyme inhibition, and altered
membrane characteristics.

▪ The response of the developing embryo to these insults is failure of

cell–cell interaction crucial for development, interference with cell
migration, or mechanical cellular disruption.
 Antibiotics
Antibiotics
Drug Adverse Effect
1. Chloramphenicol 1. Gray baby syndrome (peripheral
vascular collapses)
2. Sulphonamides 2. Kernicterus, methamoglobinemia

3. Tetracyclines 3. Dental discoloration (yellow) and

deformity, inhibition of bony growth,
cataract
4. Aminoglycosides 4. Fetal ototoxicity due to eighth CN
damage
5. Anti-malarials 5. Intrauterine death
Quinine & Chloroquine: Retinopathy,
Congenital deafness, corneal opacities
if used at dose higher than therapeutic
Chloramphenicol:
Gray Baby Syndrome
 Anticonvulsants
Anticonvulsants
Drug Adverse Effects
1. Phenytoin 1. Fetal Hydantoin
Syndrome (microcephaly,
cleft palate, hypoplastic
changes, IUGR)
2. Carbamazepine 2. Spina bifida
3. Phenobarbitone 3. Relatively safe
4. Sodium valproate 4. Neural Tube Defect
(NTD), hypospadias,
microstomia,
developmental delay
Phenytoin: Fetal Hydantoin
Sydrome

Carbamazepine: Spina
bifida
 Hormonal Agents
Hormonal Agents
Drug Adverse Effects
1. Corticosteroids 1. Growth retardation, cleft palate, and
lip
2. Diethyl stilbestrol 2. (used as “morning-after” pill)
-Vaginal adenosis in female offspring of
teenagers
-Risk of testicular cancer in later life in
male offspring
3. Anti-thyroid drugs 3. Neonatal hypothyroidism and goitre

4. Clomiphene 4. NTD, multiple gestation, Down’s

Syndrome
5. Synthetic progestins 5. Masculinization in female fetus,
hypospadias in male
 Drugs Drugs
Used Usedin Perinatal
in Perinatal Period Period

Drugs Adverse Effects

1. Oxytocin (used for 1. Hyperbilirubinemia in girl

induction of labour) babies
2. Prolonged cortisone 2. Adrenal crisis in infants

3. NSAIDs 3. Premature closure of the

ductus arteriosus
4. Dexamethasone 4. Periventricular
leukomalacia
Lithium: Ebstein’s Anomaly
 Vitamin D: William
Misoprostol: Mobius Syndrome Syndrome

Thalidomide:
Phocomelia
note
• All live viral vaccines are potentially dangerous to the
fetus
• Use of narcotics by the mother can cause depression
of CNS in the baby. apnea, bradycardia,
hypothermia
PRESCRIBING IN PREGNANCY
Prescribing in pregnancy is a balance between the risk
of adverse drug effects on the fetus and the risk of
leaving maternal disease untreated.
minimize prescribing;

• use ‘tried and tested’ drugs whenever possible in preference to new agents;
• use the smallest effective dose;
• remember that the fetus is most sensitive in the first trimester;
• consider pregnancy in all women of childbearing potential;
• discuss the potential risks of taking or withholding therapy with the patient;
• seek guidance on the use of drugs in pregnancy in the British National Formulary, Drug
Information Services, National Teratology Information Service (NTIS);
• warn the patient about the risks of smoking, alcohol, over-the-counter drugs and drugs of
abuse.
DRUG USE DURING
LACTATION
DRUG USE DURING LACTATION
▪ Non-ionized, low molecular weight, lipid soluble compounds are
usually excreted though the breast milk
▪ Most drugs administered to lactating women are detectable in breast
milk. Fortunately, the concentration of drugs achieved in breast milk
is usually low.
▪ Infant would receive in a day is substantially less than what would be
considered a “therapeutic dose.”
▪ If the nursing mother must take medications and the drug is a
relatively safe one, she should optimally take it 30–60 minutes after
nursing and 3–4 hours before the next feeding.
• Guidelines for medication during lactation:
• Benefits > Risk
• Select drugs that are most widely tested with short half life
• Monitor infant during course of therapy
• • Common side effects:
• Antibiotics …… Diarrhea
• Antihistaminics …….. Irritability
• Sedatives, Antidepressants, Antiepileptics ……… Drowsiness
 Some Maternal Medications and Effect
Some Maternal Medications and Effect on Lactation
on Lactation
Drug Effects on Lactation and
Neonate
1. Heparin 1. Does not cross into milk

2. Corticosteroids 2. No significant effect up to maternal dose

of 40mg daily

3. Acyclovir 3. Not known to be harmful

4. Tetracycline 4. Tooth staining, delayed bone growth

5. Narcotics, sedatives, and 5. Sedation with poor sucking reflex
anticonvulsants

6. Lithium 6. Lethargy, hypotonia, lithium toxicity

7. Combined Oral Pill 7. Suppression of lactation

 on Lactation
Drug Effect on Lactation and Neonate

8. Cytotoxic Agents 8. Risk of immune suppression. Risk may

9. Warfarin
10. Antithyroid drugs, radioactive iodine
outweigh benefits in some drugs
9. Safe in therapeutic doses. Risks may
outweigh the benefits depending on
individual drugs
10. Hypothyroidism, goiter, agranulocytosis

11. Metronidazole (single dose regimen) 11. Not significant but temporary cessation
of lactation for 12-24 hrs is advised
12. Bromocriptine 12. Avoid during lactation

13. Antihypertensives 13. Safe: Methyldopa, Propanolol,

Hydralazine, labetolol (small amounts
excreted)