Drug therapy in specific patient groups
By: Tsegaye Melaku
[B.Pharm, MSc, Clinical Pharmacist]
November, 2016
tsegayemlk@yahoo.com or tsegaye.melaku@ju.edu.et +251913765609
Chapter 2
Pregnancy & Lactation

Introduction

PK Changes During Pregnancy
Normal physiologic changes that occur during pregnancy may alter
medication effects  resulting in the need to more closely monitor
and, sometimes, adjust therapy.
Physiologic changes begin in the first trimester and peak during the
second trimester.
Maternal plasma volume, CO, and GFR increase by 30% to 50% or
higher potentially lowering the concentration of renally cleared
drugs.
20-Nov-16 3

Body fat increases  VD of fat-soluble drugs may increase.
Albumin concentration decreasesVD of highly protein bound
drugs increases,,,,,, fetal albumin increases!!!
However, rapid clearance unbound drugs
Hepatic perfusion increases increase the hepatic extraction of drugs.
Cont’d…
20-Nov-16 4

Transplacental Drug Transfer
Though act as barrier to drug transfer
Placenta is the organ of exchange for a number of substances,
Including drugs
Drug factors affecting placental transfer
Lipid solubility Lipophilic > hydrophilic drugs (Opioids and
antibiotics)
Molecular weight
Degree of protein binding higher concentrations of certain
protein-bound drugs in the fetus.
<500 Da readily cross the placenta
 600 to 1,000 Da  cross more slowly
>1,000 Da  do not cross the placenta in
significant amounts.
20-Nov-16 5

Fetal pH is slightly more acidic than maternal pH  permitting weak bases
to more easily cross the placenta.
Once in the fetal circulation, the molecule becomes more ionized 
 less likely to diffuse back into the maternal circulation.
Cont’d…
20-Nov-16 6

,,,,, So what??
Clinicians often must weigh the risks and benefits of drug therapy
during pregnancy or lactation.
Owing to fear of adverse effects on the developing fetus or
newborn infant, a common solution is avoidance of therapy.
However, pregnancy- and lactation-related disorders necessitate
therapy to preserve the health of the mother or the baby.

Epidemiology [1]
Studies conducted in the US have estimated that at least 2/3 of
pregnant women take medications during pregnancy.
Moreover, since approximately ½ of pregnancies are unplanned 
many women are exposed to medications before being aware of
their pregnancy.

Epidemiology [2]
The most popular medications:
Vitamins and minerals, analgesics, antacids, antibiotics, anti-
emetics,
Laxatives, asthma medication, cold and flu medications, and
Medications for topical administration(e.g., antifungals, antibiotics,
corticosteroids).

Causes of Congenital Anomalies
Although the risk of drug-induced teratogenicity is of concern, the
actual risk of birth defects from most drug exposures is small.
Medications are associated with fewer than 1% of all congenital
anomalies.
Other causes of anomalies include monogenetic conditions (8% to
18%), chromosomal disorders (7% to 10%), maternal infections (1%),
and unknown causes (34% to 43%).

Principles of Embryology
Pregnancy is usually divided into three trimesters of 13 weeks.
However, it can be divided more precisely into three phases:
I. Implantation and pre-differentiation,
II. organogenesis (or embryogenesis), and
III. Fetogenesis.
The risk of birth defects is most often higher during organogenesis.

Embryonic and fetal development

Teratogens
A teratogen is an exogenous agent that can modify normal
embryonic or fetal development.
Teratogenicity can manifest as:
Structural anomalies,
Functional deficit, cancer, growth retardation, and
Death (spontaneous abortion, stillbirth).

The probability of finding an association between a medication and a
malformation increases with the number of criteria present:
 Strength of the association
 Same effects observed in animal studies
 Biological plausibility based on pharmacologic effect
 Higher incidence of the anomaly in the population with the use of the
medication followed by a decreased incidence once the medication is
no longer available (e.g., thalidomide and limb anomalies)
 Dose–response relationship

Risk Evaluation:
To effectively treat maternal or fetal conditions when necessary
while minimizing risk to the developing embryo/fetus or the neonate.
Desired Outcomes

Medication and Pregnancy
Classical RCTs are usually not available to evaluate the safety of
medications during pregnancy and lactation.
Most available data come from post-marketing reports.
Animal studies are now mandatory before marketing a medication.
Very important to identify high risk medications and prevent
congenital anomalies.
I. Data Published on Medication Safety During
Pregnancy

Communication of data on medication use during pregnancy can be
challenging:
I. Data may be limited or contradictory.
II. Taking medications during pregnancy is a source of anxiety for
many women and for their healthcare providers.
III. Pregnant women tend to overestimate their risk of an anomaly
associated with medication use and to lower their risk associated
with the under treatment of their disease.
IV. Many people, including healthcare providers, cannot properly
understand numbers and probability.
II. Communication of the Information

Preconception Care/ Planning
Pregnancy outcomes are influenced by
Maternal health status, lifestyle, and
History prior to conception.
 Adverse pregnancy outcomes (prematurity, low birth weight, and birth
defects)  major health concerns.
 One contributing factor late start in prenatal care
The goal of preconception care:
Health promotion
Evidence-based screening
Intervention
Improve pregnancy outcomes

Preconception Risk Factors for Adverse Pregnancy
Outcomes
20-Nov-16 22

Taking folic acid,
Avoiding alcohol, smoking cessation,
Optimizing the treatment and management of chronic illnesses
(e.g., diabetes, epilepsy, hypertension),
Screening for infections (e.g., HIV, other STDs),
Appropriate vaccination, and
Reaching a healthy weight.
Strategies to improve pregnancy outcomes

Plays an important role in the prevention of neural tube defects (NTD).
One in every 1000 pregnancies is affected by an NTD
May also be involved in the reduction of other congenital anomalies,
including cardiovascular, oral clefts, limb deformities, and urinary
malformations.
All women of childbearing age should be counseled on the appropriate
dose of folic acid to prevent congenital anomalies.

Every woman of childbearing age take 0.4 to 0.8 mg of folic acid
daily,
Beginning 1 month before pregnancy and through the first 2 to
3 months, because nutritional sources alone are not sufficient.
 Women at higher risk of NTD:
 Those who have had a previous child or a 1st , 2nd , 3rd-degree
relative with a NTD, those with pre-pregnancy diabetes, those
with epilepsy taking carbamazepine or valproic acid) are
counseled to take 4 mg of folic acid per day.
Cont’d…

Anemia is a common problem during pregnancy;
It is defined as a Hg <11 g/dL during the 1st and 3rd trimesters
and < 10.5 g/dL during the 2nd trimester.
Maternal symptoms of anemia include fatigue, palpitations, and
decreased resistance to exercise and infections.
Fetal risks are prematurity, low birth weight, and perinatal death.
Iron supplementation decreases the prevalence of maternal
anemia at delivery.

Pregnancy-influenced Issues

When possible, treat conditions occurring during pregnancy with
non-pharmacologic treatments instead of drug therapy.
Evaluate the need for treatment, including benefits and risks.
Avoid treatments that do not show evidence of benefit or that can
be delayed until after pregnancy or breast-feeding.

GI Tract
Nausea and Vomiting (NVP)
As many as 85% of pregnant women suffer from N, V.
NVP usually begins during the fifth week of gestation and lasts through
week 20; peak symptoms occur between weeks 10 and 16.
Hyperemesis gravidarum (HG)
Unrelenting vomiting
Occurs in 0.3% to 2.3% of women
Causing wt loss of more than 5% pre-pregnancy wt,
dehydration, electrolyte imbalance, and ketonuria

 Non-pharmacologic measures for NVP:
Lifestyle (rest, avoidance of nausea triggers)
Dietary changes (small and frequent meals)
Fluid restriction during meals
Avoiding spicy or fatty foods
Ginger!!
 Pharmacologic measures
Pyridoxine (vitamin B6) + doxylamine=1st line
Metoclopramide/diphenhydramine/ondansetron=alternative
Corticosteroids are effective for HG
 Small increase in the risk of oral clefts in 1st trimester.
Cont’d…
20-Nov-16 30

Constipation
Up to 40% of pregnant women will suffer from constipation.
Non-pharmacologic treatment is the mainstay of treatment.
Pregnant women should be counseled to:
Eat a high-fiber diet, drink plenty of fluids,
Exercise regularly, and avoid prolonged time on the toilet,,, hemorrhoids?
Bulk-forming laxatives (psyllium and calcium polycarbophil)=1st-line agents
Cont’d…

If these methods fail, emollients or osmotic agents can be tried.
Stimulant laxatives(bisacodyl & senna)=2nd-line agents for short-
term or intermittent use.
During lactation, bulk-forming, emollient, osmotic laxatives, and the
stimulant laxatives are safe for use.
Castor oil** and mineral oil* should be avoided!
**Cause stimulation of uterine contractions
*Impairment of maternal fat-soluble vitamin absorption
Cont’d…

Heartburn/GERD
Heartburn affects a majority of pregnant women.
Non-pharmacologic recommendations include:
Small and frequent meals,
Remaining upright after eating,
Elevating the head of the bed,
Avoiding factors known to decrease lower esophageal
sphincter tone (e.g., smoking, chocolate, coffee, fatty foods,
and peppermint).

Calcium- or magnesium-containing antacids  1st line
If antacids fail to improve symptoms, ranitidine can be
recommended (best safety data among the H2 blockers).
Omeprazole, sucralfate, and metoclopramide =safe in pregnancy.
Use of PPIs should be reserved for women who do not respond to
H2 antagonists.
All the drugs used for heartburn during pregnancy are acceptable
during lactation.
Cont’d…

Nasal Congestion and rhinitis
Main-stays of therapy for the common cold:
Rest, fluids, humidified air, nasal saline, and acetaminophen.
Recommend avoiding irritants and known allergens and
Raising the head of the bed at 30 to 45 degrees.
 Treat nasal congestion as in the non-pregnant population, being mindful
to do the following:
1. Avoid oral decongestants during the 1st trimester owing to the risk of
fetal gastroschisis (incidence 4 to 6 per 10,000 treated women).

 After the 1st trimester, pseudoephedrine is the preferred agent for short-
term use if a topical decongestant or nasal saline solution is not effective.
2. Stop topical decongestants after 3 to 7 days in order to minimize the
incidence of rebound congestion.
3. Most 1st and 2nd-generation anti-histamines are safe in pregnancy at
recommended dosages.
4. Nasal corticosteroids are the best drugs for chronic rhinitis.
 During lactation, all the drugs previously used during pregnancy can be
continued.
Cont’d…

Urinary Tract Infections
 Asymptomatic bacteriuria and cystitis cause acute pyelonephritis.
 Acute pyelonephritis may lead to septic shock and adult respiratory
distress syndrome.
 Antimicrobial therapy should target E.coli infection.
 Safe agents=penicillins, cephalosporins, and nitrofurantoin.
 Nitrofurantoin must not be used for the treatment of pyelonephritis.
 Sulfonamides, ampicillin, and amoxicillin =2nd -line

 Avoid trimethoprim-sulfamethoxazole:
During organogenesis (congenital malformations) and
Near term (theoretical risk of neonatal jaundice) unless
there are no other suitable choices.
 Quinolones should be reserved for resistant infections due to
theoretical concerns of arthropathy.
Cont’d…

Bacterial Vaginosis
 Bacterial Vaginosis is associated with adverse pregnancy outcomes
such as:
Premature rupture of the membranes,
Chorio-amnionitis, preterm birth, and
Post-partum endometritis.
 Rx recommended in all symptomatic women and in asymptomatic
women at high risk for preterm delivery.
 CDC recommendation=oral metronidazole or clindamycin

 Metronidazole is deemed safe for use during all stages of
pregnancy.
 Oral antimicrobials are preferred to intra-vaginal antimicrobials,
 Clindamycin vaginal cream should be avoided due to association
with low birth weight and neonatal infection.
 During lactation, clindamycin or metronidazole vaginal formulations
are the preferred therapies for bacterial vaginosis.
Cont’d…

Vulvo-vaginal Candidiasis
 Only symptomatic vulvo-vaginal candidiasis should be treated in
pregnant or lactating women.
 1st-line treatment is topical azole therapy for 7 days in pregnant
women; shorter courses can be used during lactation.
 Oral fluconazole is not a 1st-line treatment during pregnancy; it
can be used during breast-feeding

GBS Infection
 Maternal transmission of GBS during the intra-partum period is a
cause of neonatal sepsis and death.
 Antibiotic therapy is effective in reducing the incidence of early-
onset neonatal GBS infection when administered to high-risk groups
of women.
 Empirical treatment should be started for GBS at the time of
membrane rupture and continued until delivery.
 Antibiotics of choice: penicillin G, ampicillin or clindamycin

Hypertension
 Hypertensive disorders in pregnancy:
Pre-existing (chronic) hypertension and
Pregnancy-induced hypertension (gestational hypertension or
preeclampsia).
 Preeclampsia (hypertension and proteinuria) is a syndrome produced by
endothelial dysfunction.
 Women may present with seizures (eclampsia), neurologic, hepatic, and
renal and/or coagulation complications, as well as fetal death and
intrauterine growth restriction.
HELLP (hemolysis, elevated liver enzymes, low platelets)

 Delivery is the only treatment for preeclampsia.
 Intravenous magnesium sulfate* may be used to prevent eclampsia.
 Severe hypertension in pregnancy (systolic blood pressure ≥160 mm Hg
or diastolic blood pressure ≥110 mm Hg) is an emergency and should be
treated aggressively.
 1st line= methyldopa, labetalol, and nifedipine.
 Avoid = ACEI, ARBs or renin inhibitors (fetopathy).
 Caution is advised with atenolol, as it has been associated with
intrauterine growth restriction.
Cont’d…
*4 to 6 g IV over 15 to 20 minutes followed by a 2 g/h continuous infusion

 Low-dose aspirin (75 to 160 mg) is useful in high-risk women in
preventing preeclampsia, preterm birth, and fetal/ neonatal death.
 Calcium supplements (1 g/day) are also helpful in preventing
preeclampsia.
Cont’d…

Diabetes
 Diabetes in pregnancy includes pre-gestational diabetes and
gestational diabetes.
 Women with T2DM may be started on insulin before pregnancy if
they do not achieve optimal control with oral agents.
 Insulin= 1st line treatment during pregnancy.
 In gestational DM, glyburide and metformin =alternatives
 Intravenous drip insulin should be used during labor.
 Metformin may be used during lactation

Anticoagulation
 Heparins are used for various purposes during and after
pregnancy:
Treatment or prevention of thromboembolism,
Prevention of prosthetic heart valve thrombosis, and
Prevention of pregnancy complications.
 Low-molecular-weight heparins are preferred to unfractionated
heparin.
Both are safe during pregnancy and lactation.

 Warfarin may be used in the 2nd trimester and early 3rd trimester.
 Warfarin is associated with bleeding at delivery and a risk of
teratogenesis during the 1st trimester after 6 weeks of gestational
age.
 Warfarin and heparins are safe for use during lactation.
Cont’d…

Mastitis
 Bacterial mastitis is seen typically within the first 6 weeks of breast-
feeding.
 Characterized by localized signs of inflammation (redness, swelling,
heat, or pain), and engorgement.
 Fever, shivering, and malaise can also occur.
 The most commonly bacteria=S. aureus (including methicillin-
resistant), followed by Streptococcus, Staphylococcus epidermidis, and
E. coli.

 Non-pharmacologic measures, such as cold or warm compresses
and more frequent breast-feeding or breast pumping, should be
encouraged.
 Analgesics (e.g., acetaminophen, ibuprofen, or naproxen) can be
used to relieve pain.
Cont’d…

Breast Candidiasis
 Candidiasis presents with severe and persistent nipple pain, which
can be throbbing and radiating to the breasts and back.
 The pain is usually more intense during and immediately after
breast-feeding.
 Candida albicans is the most common.
 Antifungal treatment must be given to the mother and the baby
simultaneously
 Analgesics (e.g., acetaminophen, ibuprofen, or naproxen) can be
used to relieve pain

Summary

Outcome Evaluation
 Report birth defects that are believed to be teratogenic effects.
 Report both positive and negative outcomes of drug exposure
during pregnancy.
 Monitor the mother for efficacy and adverse effects of drug
therapy used during pregnancy or lactation.
 Monitor all parameters that would be followed in a non-pregnant or
lactating population.

Galatoomaa!
20-Nov-16 63

Reading Assignment
 Enhancement of Lactation
 Preterm Labor management
 Drug therapy in geriatrics and patient with organ failure (renal &
hepatic)

 Preterm birth, especially before 32 weeks of pregnancy, is the
major cause of short- and long-term neonatal mortality and
morbidity.
 The underlying pathophysiologic conditions are diverse, and most
are unknown.
 There is a wide variation in management, diagnosis, and treatment
of preterm labor across the world:
Preterm Labor management

I. Antenatal Corticosteroids
 The most beneficial intervention in preterm labor is the administration of
antepartum corticosteroids.
 A single course of antenatal corticosteroids should be administered
between 24 and 34 weeks’ gestation to women at risk of preterm
delivery within 7 days.
 This approach decreases the incidence and severity of neonatal
respiratory distress syndrome, intra-ventricular hemorrhage,
necrotizing enterocolitis, and death.
 A single rescue course may be used.
Cont’d…

II. Tocolytic Agents
 Used to:
Buy time to complete a course of corticosteroids.
Delay delivery to allow transfer of the patient to a center with
neonatal intensive care unit facilities.
 Includes:
Magnesium sulfate, indomethacin, and nifedipine.
Nifedipine offers the best benefit-to-risk ratio.
Combined tocolytics and prolonged or repeated tocolytic therapy
should not be used  increased fetal risk
Cont’d…

 Magnesium sulfate administered to women at risk of imminent preterm
birth may prevent neonatal cerebral palsy.
 Indomethacin also prolongs pregnancy, but it has not been independently
associated with decreased neonatal morbidity.
50 to 100 mg LD (may be given per rectum), followed by 25 mg
orally every four to six hours.
It may be of particular benefit in women with hydramnios.
Do not use after 32 weeks of pregnancy???
Cont’d…

Nifedipine
 LD of 20 mg orally, followed by an additional 20 mg orally in 90
minutes.
 If contractions persist, 20 mg can be given orally every 3 to 8
hours for up to 72 hours, with a maximum dose of 180 mg/day.
 The American College of Obstetricians and Gynecologists (ACOG)
suggests a 30 mg LD and then 10 to 20 mg every four to six hours
20-Nov-16 69
Cont’d…

III. Antibiotics
 The administration of a 7-day course of parenteral (2 days) and
oral therapy (5 days) with ampicillin or amoxicillin and
erythromycin in the presence of premature rupture of the
membranes (before 34 weeks’ gestation);
Associated with a delay in delivery and a reduction in
maternal and neonatal morbidity.
Cont’d…

IV. Progesterone
 Progesterone is recommended to prevent preterm birth in women
with previous preterm delivery.
 This medication may also be useful in women with a sonographic
short cervix.
 Mechanism???
Cont’d…