DRUG THERPY IN SPECIFIC

PATIENT GROUPS

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DRUG THERPY IN SPECIFIC PATIENT GROUPS

• Pregnancy and lactation

• Geriatrics
• Pediatrics

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 PREGNANCY AND
LACTATION
Therapeutic Considerations

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 Objectives
Upon completion of the session, you will be able to:
1. Explain the principles of embryology and teratology.
2. Identify known teratogens and drugs of concerns
during lactation.
3. Evaluate the risks of a drug when taken during
pregnancy or lactation.
4. Counsel patients on the use of drugs during
pregnancy and lactation.
5. Describe physiologic changes during pregnancy and
their impact on pharmacokinetics.
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 Introduction
• Medication use during pregnancy and lactation is a challenge for
health professionals, as pregnant and breast-feeding women are
usually excluded from clinical trials.
• Since approximately one-half of pregnancies are unplanned,
many women are exposed to medications before being aware of
their pregnancy
• The most popular medications are:
Vitamins and minerals,
Analgesics, antibiotics
Antacids, antiemetics, laxatives,
Asthma medication, cold and flu medications, and
Medications for topical administration (e.g., antifungals,
antibiotics, corticosteroids) 5
 Introduction
• It is the clinician’s responsibility to ensure safe and
effective therapy
Before conception,
During pregnancy, and
After delivery.

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 PHYSIOLOGY OF PREGNANCY

• Fertilization occurs when a sperm attaches to a receptor

on the outer protein layer of the egg, the zona pellucida.
• Immediately, the egg becomes unresponsive to other
sperm.
• The attached sperm releases enzymes that cause the
egg’s chromosomes to mature
The sperm penetrate the zona pellucida and contact
the egg’s cell membrane.
• The membranes of the sperm and egg then are fused to
create a new, single cell.
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 PHYSIOLOGY OF PREGNANCY

• Fertilization usually occurs in the fallopian tube.

• Cell division continues for the first 2 days while
the fertilized egg travels down the fallopian tube,
reaching the uterine cavity on the third day.
• Cell division continues for another 2 to 3 days in
the uterine cavity before implantation begins.

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 PHYSIOLOGY OF PREGNANCY

• Approximately 6 days after fertilization, the cell mass is termed

a blastocyst.
• Human chorionic gonadotropin now is produced in amounts
that may be detected by commercial laboratories.
• A positive human chorionic gonadotropin (hCG+) lab result
confirms pregnancy.
• After 6 days of this growth, the blastocyst lies implanted under
the surface of the endometrium and begins to receive nutrition
from maternal blood.
Now it is called an embryo 9
 PHYSIOLOGY OF PREGNANCY

• The embryonic period lasts from approximately 2 weeks

after fertilization until 8 weeks after fertilization, when
the conceptus is renamed a fetus

• Most body structures are formed during the embryonic

period, and they continue to grow and mature during the
fetal period

• The fetal period continues until the pregnancy reaches

term, approximately 40 weeks after the last menstrual
period. 10
 Parity and Gravida
• Parity and gravida are terms used to describe a
pregnant woman.
• Parity is the number of deliveries after 20 weeks'
gestation.
• A delivery before the completion of 20 weeks'
gestation is considered an abortion and can be either
elective or spontaneous.
• Parity is independent of the number of fetuses
delivered (live or stillborn, single fetus, or twins) or
the method of delivery.
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 Parity and Gravida
• Gravida refers to the number of pregnancies a
woman has had regardless of the outcome.
• A multiple birth is counted as a single pregnancy.
• Example: a woman who is currently pregnant and
has previously delivered one set of twins and had
two spontaneous abortions is described as a
gravida 4 para 1 (G4P1).

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 Pregnancy Dating

• Approximately 280 days (about 40 weeks or 9

months) constitute the duration of a pregnancy;
this time period extends from the first day of the
last menstrual period (LMP) to birth.
• Pregnancy is typically divided into three
trimesters, approximately 13 to 14 weeks each.

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 Date of Confinement (Due Date)

• The assessment of gestational age is important to

determine the
Expected date of confinement (EDC),
Schedule a cesarean section, or
Determine when it is safe to end a pregnancy prematurely
• Gestational age can be determined by several methods,
including
The 1st day of the LMP,
Pelvic examination,
Uterine size, and
Measurement of fetal parameters by ultrasound. 14
 Date of Confinement (Due Date)

First day of the LMP

• The EDC is generally determined by adding 7 days
to the first day of the LMP, counting back 3
months, and adding 1 year (Nagele rule).
• Limitation:
 For a woman who doesn’t know her first day of LMP
 Women with irregular or prolonged menstrual cycles
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 Case: Due Date
• S.S., a 29-year-old, G1P1 woman, who has not started her
menstrual period since she had unprotected intercourse
about a month ago, come to your pharmacy today, on
November 27, 2015. She is worried that she may be
pregnant. S.S.'s first day of her LMP was estimated to be
on September 06, 2015. She asks her pharmacist for help
selecting an over-the-counter commercially available
home pregnancy test. When will be her due date?

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 Delivery
• Depending on the gestational age at the time of delivery,
the result can be an abortion, preterm, term, or post-term
birth.
• An abortion (spontaneous or terminal) is a delivery before
20 weeks' gestation.
• A term infant is a fetus delivered between 37 and 42
weeks gestation.
• A preterm birth is one occurring between 20 and 37
weeks' gestation, and a post-term (postmaturity) birth
occurs after the beginning of 43 weeks' gestation.
• Parturition refers to labor, and the puerperium is the 6 to
8 weeks after delivery. 17
 Pregnancy Signs and Symptoms

• Early symptoms: fatigue and increased frequency of

urination.
• At 6 weeks’ gestation: nausea and vomiting (morning
sickness) but can occur at any time of the day.
Nausea and vomiting usually resolve at 12 to 18 weeks’
gestation.
• Fetal movement is detected in the woman’s lower
abdomen at 16 to 20 weeks of gestation.
• Signs of pregnancy: sudden cessation of menses, changes
in consistency of the cervical mucus, bluish discoloration
of the vaginal mucosa, increased skin pigmentation, and
anatomic breast changes 18
 Transplacental Drug Transfer
• Most drugs move from the maternal circulation to
the fetal circulation by diffusion.
• Certain chemical properties influence the rate of
transfer across the placenta, such as:
Lipid solubility,
Electrical charge,
Molecular weight, and
Degree of protein binding of medications.

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 Transplacental Drug Transfer

• Drugs with molecular weights less than 500 Da

readily cross the placenta, whereas larger
molecules (600–1,000 Da) cross more slowly.
• Drugs with molecular weights greater than 1,000
Da, such as insulin and heparin, do not cross the
placenta in significant amounts.

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 Transplacental Drug Transfer
• Lipophilic drugs, such as opiates and antibiotics,
cross the placenta more easily than do water-
soluble drugs.
• Maternal plasma albumin progressively decreases
while fetal albumin increases during the course of
pregnancy, which may result in higher
concentrations of certain protein-bound drugs in
the fetus.

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 Transplacental Drug Transfer

• Fetal pH is slightly more acidic than maternal pH,

permitting weak bases to more easily cross the
placenta.
• Once in the fetal circulation, however, the
molecule becomes more ionized and less likely to
diffuse back into the maternal circulation.
Ion trapping

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

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• For a drug to be teratogenic, the drug has to cross the
placenta into the fetal circulation.
• Teratogenic drugs should be discontinued prior to
pregnancy, if possible.
• Pharmacokinetic changes during pregnancy may
require dose and regimen changes.
• For example, in women being treated for
hypothyroidism, an increased dose of levothyroxine
will be required in order to keep thyroid hormones
within normal ranges
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Phase of Development and Potential Teratogenic
Effect
• Pregnancy is usually divided into three trimesters of 13
weeks.
• However, it can be divided more precisely into three
phases:
Implantation and pre-differentiation,
Organogenesis (or embryogenesis), and
Fetogenesis
• The risk of birth defects is most often higher during
organogenesis

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 Phase of Development and Potential
Teratogenic Effect
• Organogenesis (embryogenesis)
Organs are formed; most critical period for structural
anomalies
Organs are formed at different times; period of
sensitivity for a potential teratogen could be different
for each organ
Stage of Pregnancy
• From day 14 until the 9th week after conception
(From day 28 until the 11th week after LMP)
Potential Teratogenic Effect
• Major or minor structural anomalies 26
 Phase of Development and Potential
Teratogenic Effect
• Fetogenesis
The fetus grows and organs begin to function (e.g.,
kidneys are formed during organogenesis, but glomerular
filtration begins during fetogenesis)
Active cell growth, proliferation, and migration (eg., CNS)
Stage of Pregnancy
• After the organogenesis and until birth
Potential Teratogenic Effect
• Fetal growth retardation
• Functional deficit (e.g., renal insufficiency, pulmonary
hypertension, neurologic impairment)
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 Embryonic and fetal development. The horizontal bars represent potential
sensitivity to teratogens. The colored areas represent the more critical times

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 Drug Ratings in Pregnancy (US FDA)

Category Interpretation

Controlled human studies show no risk

A Controlled studies in pregnant women fail to demonstrate a risk to the

fetus in the first trimester with no evidence of risk in later trimesters. The
possibility of fetal harm appears remote.

No evidence of risk in studies

Either animal-reproduction studies have not demonstrated a fetal risk but

B 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.

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 Drug Ratings in Pregnancy (US FDA)
Risk cannot be ruled out
Either studies in animals have revealed adverse effects on the fetus (teratogenic or
C embryocidal effects 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
benefits justify the potential risk to the fetus.
Positive evidence of risk
There is positive evidence of human fetal risk, but the benefits from use in pregnant
D women may be acceptable despite the risk (eg, 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).
Contraindicated in pregnancy
Studies in animals or human beings have demonstrated fetal abnormalities or there is
X 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.

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 Causes of teratogen
• Over 90% of pregnant women take OTC alone,
not including Rx drugs, while pregnant.
• The use of Rx drugs increased more than 60%
over the last 30 years,
• The good news is that birth defects due
medications, account for only 2% to 3% of all
birth defects.
• The vast majority of birth defects (60-70%) are
due to unknown causes.
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 Medications with Proven Teratogenic Effects in Humans

Drug/Drug Teratogenic Effects Critical Period

Class
Alkylating Malformations of many different Organogenesis
agents organs
Amiodarone Transitory hypothyroidism (17%, From 10th week after
goiter in 18% of these cases) or conception
hyperthyroidism (3%)
Androgens Masculinization of genital organs in Danazol: from 6th week
(danazol, female fetus after conception
Testosterone Testosterone: not
) defined
ACEI, ARBs Renal failure, anuria, After the first trimester
oligohydramnios, pulmonary
hypoplasia, intrauterine growth
restriction, limbs contracture, skull
hypoplasia
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 Medications with Proven Teratogenic Effects Cont’d
Drug or Drug Class Teratogenic Effects Critical Period
Anticonvulsants NTDs (for carbamazepine and valproic
• Carbamazepine acid); oral cleft, skeletal, urogenital, 7–14 weeks (gestational
• Phenytoin craniofacial, digital, and cardiac age); higher risk between 8
• Phenobarbital malformations; microcephalia and 11 weeks.
• Valproic acid Risk of major malformations estimated at Neurologic development:
5–10% depending on the agent used not established
(about 5% for carbamazepine, 10–14%
for valproic acid). Valproic acid: abnormal
neurologic development

Systemic Oral cleft (risk of 3–4/1,000 versus Organogenesis

corticosteroids 1/1,000 in general population)
Diethylstilbestrol Girls: Cervical or vaginal First and second trimesters
adenocarcinoma, incidence of less than
1.4/1,000 exposures. Structural genital
anomalies (e.g., of cervix, vagina) in 25%
of cases
Boys: Genital anomalies,
spermatogenesis anomalies
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 Medications with Proven Teratogenic Effects Cont’d
Drug Teratogenic Effects Critical Period
Fluconazole high Skeletal and craniofacial malformations, Not defined, but cases are
doses cleft palate (with chronic dose more reported where exposure was
than 400 mg/day; not reported with 150 for most parts of pregnancy
mg single dose)

Radioactive iodine Thyroid suppression (goiter) From 10th week after

(I131) conception (consider the
dosage and time to eliminate
the product on a
case-by-case basis)

Isotretinoin, CNS, skull, eyes and ears malformations, Organogenesis (risk of

acitretin, oral cleft, cardiac malformations, thymus teratogenic effect after
etretinate, and anomalies, mental retardation: organogenesis not
vitamin A (more estimated at 25–30% (may be higher for excluded)
than 10,000 IU/day) neurologic development impairment)
Contraindicated throughout pregnancy
Isotretinoin: discontinue 1 month before
pregnancy,

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 Medications with Proven Teratogenic Effects Cont’d
Drug Teratogenic Effects Critical Period
Lithium Cardiac malformations: risk of 0.9–6.8% Cardiac
(higher risks from small studies that included organogenesis
also minor cardiac anomalies) (general
population risk: approximately 1% )

Methimazole/ Methimazole: aplasia cutis, syndrome Organogenesis

propylthiouracil including choanal atresia, esophageal
atresia, facial anomalies, developmental
delay; risk probably low
Methimazole/propylthiouracil: fetal Second and third
hypothyroidism in 2–10% of infants trimesters
whose mothers were treated for Graves
disease or goiter
Methotrexate CNS and cranial malformations, oral cleft, Organogenesis
skeletal and limb malformations
It is recommended to stop the medication 3
months before pregnancy
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 Medications with Proven Teratogenic Effects Cont’d

Misoprostol Moebius syndrome± limb anomalies ± CNS anomalies Organogenesis

NSAIDs In utero closure of ductus arteriosus (constriction is rare Third trimester
before 25 weeks, 50–70% at 30 weeks and 100% at 32
weeks (gestational age) and pulmonary hypertension
Tetracyclines Teeth discoloration 14 weeks
postconceptional
Thalidomide Limb anomalies 20–36 days after
Cardiac, urogenital, GI, and ear malformations conception
Trimethoprim Cardiac and urogenital malformations, neural tube Organogenesis
defects, oral cleft
Warfarin Warfarin embryopathy including nasal hypoplasia, Between 4th and 7th
epiphysis dysplasia, vertebral malformations week postconception

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 Pharmacokinetic Changes During Pregnancy

Absorption
• Decreased gastrointestinal transit can result in a
delay in drug peak effect, prolonging the time of
contact of drugs with the intestinal mucosa, and
possibly enhancing absorption of certain drugs.
• The higher gastric pH may affect the absorption of
weak bases or acids.
• Skin, tissue, and lung absorption might also be
increased by physiologic changes during pregnancy
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 Pharmacokinetic Changes During Pregnancy

Distribution
• The volume of distribution increases for most
drugs during pregnancy due to plasma volume
expansion and the presence of amniotic fluid,
the placenta, and the fetus.
This results in a decrease in maximal concentrations of
drugs and in their half-life.
• In addition, hypoalbuminemia and decreased
protein binding of drugs increases free fraction of
some medication
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 Pharmacokinetic Changes During Pregnancy

Metabolism
• During pregnancy the activity of some isoenzymes is ed
(e.g., CYP3A4, CYP2A6, CYP2D6, CYP2C9), and the activity of
others is ed (e.g., CYP1A2, CYP2C19).
• It is difficult to predict the net impact on drug effect since
there is a wide inter-individual variability and since some
drugs are metabolized by several isoenzymes.
Renal Elimination
• Renal blood flow and glomerular filtration are increased
significantly during pregnancy.
• The impact of this increase is more important for drugs that
are eliminated in the urine 39
 Medication and Lactation
• Mothers should breastfeed exclusively for 6 months.
• Most drugs are safe during breast-feeding
• Health professionals should know which medications are of
concern during breast-feeding.
• One should also consider the additive side effects of medication for
the baby when the mother is taking a combination of medications.
• If clinical data are not available on drug transfer into breast milk,
choose drugs that:
Are highly protein bound,
Have a high molecular weight,
Have a short half-life,
Have no active metabolites, and
Are well tolerated by children
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 Drugs of Concern During Breast-Feeding
Drugs that can decrease the breast milk production
Clomiphene Has been used to suppress lactation
Ergot derivatives Have been used to suppress lactation
• Bromocriptine,
• Cabergoline,
• Ergotamine

Estrogens Hormonal contraceptives with ethinylestradiol

should be delayed for 4–6 weeks following delivery.
Pseudoephedrine Do not use in women with low milk production; a
few doses will probably not have significant clinical
effect

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 Drugs of Concern During Breast-Feeding
Drugs which may expose the neonate to a significant quantity and may necessitate
a strict follow-up
β-blocking agents Neonatal β-blockade reported
• Acebutolol, Concern for acebutolol, atenolol and sotalol, but some other β-
• Atenolol, blocking agents are safe to use
• Sotalol

Amiodarone May accumulate because of long hal-flife; possible neonatal

thyroid and cardiovascular toxicity
Antineoplastics Neonatal myelosuppression possible
Chloramphenicol Severe side effects reported when used to treat babies (blood
dyscrasia, grey baby syndrome)
Ergotamine Symptoms of ergotism (vomiting and diarrhea) reported
Illicit drugs Unknown contents and effects
Lamotrigine A breast-fed infant could have blood concentrations between 10%
and 50% of the maternal blood concentrations. 42
 Drugs of Concern During Breast-Feeding
Drugs which may expose the neonate to a significant quantity and
may necessitate a strict follow-up
Lithium Up to 50% of maternal serum levels have been
measured in infants; cases of infant toxicity have
been reported
Phenobarbital Drowsiness and reduced weight gain reported. Up to
25 % of a pediatric dose can be ingested via breast
milk
Radioactive Long radioactive half-life (21–42 days)
iodine-131
Tetracyclines Chronic use may lead to dental staining or decreased
epiphyseal bone growth

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 QUIZES(T/F)
1.Most drug related damages occur in the
second trimester of pregnancy.
2.Gestational age is counted starting from the
first day of conception.
3.The vast majority of birth defects are due to
medications use.

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PEDIATRICS 
Therapeutic Considerations

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 Objectives
Upon completion of the session, you will be able to:
1. Define different age groups within the pediatric
population.
2. Explain general pk and pd differences in pediatric versus
adult patients.
3. Identify factors that affect selection of safe and effective
drug therapy in pediatric patients.
4. Identify strategies for appropriate medication
administration to infants and young children.
5. Apply pediatric pharmacotherapy concepts to make drug
therapy recommendations, assess outcomes, and
effectively communicate with patients and caregivers. 46
 Introduction
• Children under age 15 account for nearly half (47
percent) of the total population

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 Introduction
• Pediatric clinical practice involves the care of infants,
children, and adolescents with the goal of optimizing their
health, growth, and development toward adulthood
• Despite the common misconception of pediatric patients as
“smaller adults” where doses are scaled only for their
smaller size, there are multiple factors to consider when
selecting and providing drug therapy for patients in this
specific population.
• Pediatric patients significantly differ within their age groups
and from adults regarding drug administration, psychosocial
development, and organ function development, which affect
the efficacy and safety of pharmacotherapy. 48
 Classification of Pediatric Patients
Pediatric Age Groups
Age Group Age
Neonate ≤28 days (4 weeks) of life
Infant 29 days to <12 months
Child 1–12 years
Adolescent 13–17 years

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 Classification of Pediatric Patients
Age Terminology Definition
Gestational age Age from date of mother’s first day of last menstrual
(GA) period to date of birth
Full term Describes infants born at ≥ 37-weeks gestation
Premature Describes infants born before 37-week gestation
Chronological Age from birth to present, measured in days, weeks,
or postnatal age months, or years
Corrected or Used to describe the age of a premature child up to 3
adjusted age years of age: Corrected age = Chronological age in
months – [(40 – GA at birth in weeks) ÷ 4 weeks].
For example, if a former 29-week GA child is now 10
months old chronologically, his corrected age is 7.25
months: 10 months – [(40–29 weeks) ÷ 4 weeks] =
7.25 months
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 Classification of Pediatric Patients
Weight Classification
Classification Definition
LBW infant Premature infant with birth weight between 1,500
and 2,500 g
VLBW infant Premature infant with birth weight 1,000 g to less
than 1,500 g
ELBW infant Premature infant with birth weight less than 1,000 g

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 Differences in Vital Signs
• Normal values for heart rate and respiratory rate
vary based on their age.
• Normal values for blood pressure vary based on
gender and age for all pediatric patients, and also
height percentile for patients older than 1 year
• In general, blood pressure increases with age,
With average blood pressures of 70/50 in neonates,
increasing throughout childhood to 110/65 in
adolescents

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 Differences in Vital Signs
• Heart rates are highest in neonates and infants,
ranging from 85 to 205 beats per minute (bpm)
and decrease with age, reaching adult rates (60 to
100 bpm) around 10 years of age.
• Respiratory rates are also higher in neonates and
infants (30 to 60 breaths/minute), decreasing with
age to adult rates around 15 years of age (12 to 16
breaths/minute).

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 Differences in Vital Signs
• Another vital sign commonly monitored in
children by their caregivers is body temperature,
especially when they seem “warm to the touch.”
• The American Academy of Pediatrics (AAP)
recommends rectal temperature measurement in
children less than 4 years of age, using a digital
thermometer.
• Generally, rectal temperature is greater than oral
temperature by 0.6°C (1°F), and oral temperature
is 0.6°C (1°F) higher than axillary temperatures
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 Differences in Vital Signs
• Low-grade fevers are considered those ranging
from 37.8° to 39°C (100° to 102°F),
• Antipyretic treatment (e.g., acetaminophen)
considered in cases of temperature greater than
38.3°C (101°F, any measurement route)
accompanied by patient discomfort.

55
 Differences in Vital Signs
• Considered as the fifth vital sign, pain assessment
is more challenging in neonates, infants, and
young children due to their inability to
communicate symptoms.
• Indicators of possible pain include physiological
changes such as
Increased heart rate, respiratory rate, and BP,
Decreased oxygen saturation,
Behavior changes such as prolonged, higher pitch
crying and facial expressions.
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 Fluid Requirements
• Fluid requirement and balance are important to
monitor in pediatric patients, especially in
premature neonates and infants.
• Maintenance fluid requirement can be calculated
based on body surface area for patients greater
than 10 kg with a range of 1,500 to 2,000 mL/m2 per
day.
• However, a weight-based method of determining
normal maintenance fluid requirement for children
is often used
57
 Fluid Requirements

Patient Body Weight Maintenance Fluid Requirement

Less than10 kg 100 mL/kg/day
11–20 kg 1,000 mL + 50 mL/kg over 10 kg
More than 20 kg 1,500 mL + 20 mL/kg over 20 kg

58
 Case study, MM
• MM is a 36-week GA premature baby boy weighing
2,250 g, length 47 cm, born to a 21-year-old
woman this morning. He requires maintenance IV
fluids until his further assessment for total
parenteral nutrition is complete
a) What is MM’s weight classification as a neonate?
b) Calculate MM’s corrected age for MM 6 months
from today.
c) How much maintenance fluid would you
recommend for MM at birth?
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 PHARMACOKINETIC AND
PHARMACODYNAMIC DIFFERENCES

Pediatric dose = Adult dose × [BSA (in m2)÷ 1.73 m2]

60
 PD: Efficacy and Toxicity
• The maintenance dose of digoxin is
substantially higher in infants than in adults.
– This is explained by
I. a lower binding affinity of receptors in the
myocardium for digoxin and
II. increased digoxin-binding sites on neonatal
erythrocytes compared with adult erythrocytes.
• Insulin requirements are highest during
adolescence
– Because of the individual’s rapid growth
62
 PD: Efficacy and Toxicity
• Certain adverse effects of drugs are most commonly
seen in the newborn period
– Promethazine now is contraindicated for use in children
younger than 2 years because of the risk of severe
respiratory depression. 
– Chloramphenicol toxicity is increased in newborns because
of immature metabolism and enhanced bioavailability.
– Similarly, propylene glycol, which is added to many
injectable drugs, including phenytoin, phenobarbital,
digoxin, lorazepam, vitamin D, and hydralazine, to increase
their stability, can cause hyperosmolality in infants
63
 PD: Efficacy and Toxicity
• Tetracyclines are contraindicated for use in
pregnant women, nursing mothers, and children
younger than 8 years because
– these drugs can cause dental staining and defects in
enamelization of deciduous and permanent teeth, as
well as a decrease in bone growth

64
 PD: Efficacy and Toxicity
• Some drugs may be less toxic in pediatric patients
than in adults.
• Aminoglycosides appear to be less toxic in infants
than in adults.
• In adults, aminoglycoside toxicity is related to both
peripheral compartment accumulation and the
individual patient’s inherent sensitivity to these
tissue concentrations
Newborn infants have less inherent tissue sensitivity
for toxicity than do adults.
65
 PK: Absorption
• Oral absorption may be different in premature infants and
neonates due to differences in gastric acid secretion and
pancreatic and biliary function.
• Full-term neonates have a gastric pH of 6 to 8 at birth and pH 1 to
3 by 48 hours of age.
• Gastric pH remains elevated in premature infants because of
immature acid secretion.
• Low gastric acid secretion can result in
Increased serum concentrations of acid-labile medications, such as
penicillin, ampicillin and naficillin
Decreased serum concentrations of weak acid medications, such as
phenobarbital, due to increased ionization 66
 PK: Absorption
• Gastric emptying time and intestinal transit time
are delayed in premature infants, increasing drug
contact time with the GI mucosa and drug
absorption.
• Deficiency in pancreatic secretions and bile salts in
newborns can result in decreased bioavailability
of prodrug esters, such as erythromycin, which
requires solubilization or intraluminal hydrolysis

67
 PK: Absorption
• Topical or percutaneous absorption in neonates
and infants is increased due to:
 A thinner stratum corneum,
 Increased cutaneous perfusion, and
 Greater body surface-to-weight ratio.
Hence, application of topical medications should be
limited to the smallest amount possible.

68
 PK: Absorption
• Intramuscular absorption in premature and full-
term infants can be erratic due to
Variable perfusion,
Poor muscle contraction, and
Decreased muscle mass compared with older patients.
• Use of IM route of administration can be painful
and is usually reserved when other routes are not
accessible,
– e.g., for initial IV doses of ampicillin and gentamicin for
neonatal sepsis.
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 PK: Volume of Distribution
• Total body water, as a percentage of total body
weight, has been estimated to be 94% in fetuses, 85%
in premature infants, 78% in full-term infants, and
60% in adults
• Extracellular fluid and total body water per kilogram
of body weight are increased in neonates and infants,
resulting in higher Vd for water-soluble drugs such as
aminoglycosides and decreases with age.
• This conforms to the
observed gentamicin distribution volumes of 0.48
L/kg in neonates and 0.20 L/kg in adults 70
 PK: Volume of Distribution
• Binding of drugs to plasma proteins is decreased in newborn
infants because of:
Decreased plasma protein concentration,
Lower binding capacity of protein,
Decreased affinity of proteins for drug binding, and
Competition for certain binding sites by endogenous
compounds such as bilirubin
• Neonates and infants have a lower normal range for serum
albumin (2 to 4 g/dL), reaching adult levels after 1 year of age.
• This affects highly protein-bound drugs such as phenobarbital,
salicylates and phenytoin, resulting in lower total serum
concentrations needed to achieve therapeutic unbound
71
serum concentrations
 PK: Volume of Distribution
• Pharmacologic and toxic effects are related directly
to the concentration of free drug in the body.
• Increases in free drug concentrations may result
directly from decreases in plasma protein binding
or indirectly from, for example, drug displacement
from binding sites.
• Increased mortality from the development of
kernicterus secondary to displacement of bilirubin
from albumin and other serum proteins by
sulfisoxazole in neonates is well documented
72
 PK: Volume of Distribution
• The amount of body fat is substantially lower in
neonates than in adults, which may affect drug
therapy.
• Certain highly lipid-soluble drugs are distributed
less widely in infants than in adults.
• The apparent volume of distribution of diazepam
has ranged from 1.4 to 1.8 L/kg in neonates and
from 2.2 to 2.6 L/kg in adults

73
 PK: Metabolism
• Drug metabolism is slower at birth in full-term infants
compared with adolescents and adults, with further delay in
premature neonates.
• Phase 1reactions and enzymes, such as oxidation and alcohol
dehydrogenase, are impaired in premature neonates and infants
and do not fully develop until later childhood or adolescence.
The use of products containing ethanol or propylene glycol can result in
increased toxicities, including respiratory depression, hyperosmolarity,
metabolic acidosis, and seizures, and they should be avoided in
neonates and infants.
• Cytochrome P450 isoenzymes (e.g., CYP2C9, CYP1A2) develop
at various ages, ranging from a few months to 3 years of age,
with delayed development in premature infants
74
 PK: Metabolism
• Among phase 2 reactions, sulfate conjugation by
sulfotransferases is well developed at birth in term
infants.
• Glucuronidation by the uridine diphosphate
glucuronosyltransferases, in contrast, is immature in
neonates and infants, requiring at least several months
to develop to adult values at approximately 4 years
of age.
– In neonates, this deficiency results in adverse effects
including cyanosis, ash gray color of the skin, limp body
tone, and hypotension, also known as “gray baby
syndrome” with use of chloramphenicol 75
 PK: Metabolism
• Interestingly, higher serum concentrations of
morphine are required to achieve efficacy in
premature infants than in adults,
Because infants are not able to metabolize morphine
adequately to its 6-glucuronide metabolite (20 times
more active than morphine).
This is balanced to some degree by the fact that the
clearance of morphine quadruples between 27 and 40
weeks of postconceptional age

76
 PK: Excretion
• Renal drug clearance is reduced in infants and slowest in
premature neonates, due to immature renal function, resulting
in the need for longer dosing intervals for renally cleared
medications, such as vancomycin, to prevent accumulation.
• Glomerular filtration rate (GFR) is lowest in premature
neonates, increasing with age and peaking at 3 to 12 years of
age, after which there is a gradual decline to approximate adult
value.
• For example, vancomycin is often given:
Every 18 to 24 hours in a low birth weight (LBW) premature neonate,
Every 6 hours in children with normal renal function, and
Every 8 to 12 hours in adult patients with normal renal function.

77
 PK: Excretion

• Schwartz’s equation is a common method of estimating

pediatric CrCl for LBW infants up to 21 years of age
• This equation uses patient length (cm), serum creatinine
(mg/dL), and a constant, k, which depends on age for all
patients and also gender for those older than 2 years.
• Urine output is also a parameter used to assess renal
function in pediatric patients, with a urine output more
than 1 to 2 mL/kg/h considered normal.

78
 PK: Excretion
CrCl = k * L k = Proportionality constant
(muscle factor)
S Cr L = Length in cm
SCr = Serum creatinine in mg/dL
CrCl = Creatinine clearance in
mL/min/1.73 m2
Age k
Premature infant less than 0.33
1yr
Full term less than 1 yr 0.45
1–12 yr 0.55
13–21 yr (female) 0.55
13–21 yr (male) 0.70 79
 Case study, MM
MM is now 7 weeks old (weight: 4.5 kg; length: 60 cm)
and presents to the community pharmacy with a 2-day
history of lethargy, poor oral intake, and fever.
• The pharmacist refers the child to seek medical
attention at the emergency department.
• MM is admitted to the general pediatric ward for
further assessment including a neonatal sepsis and
meningitis rule-out.
• Blood samples, cerebral spinal fluid, and urine were
collected for Gram stain and culture, still pending
results. 80
 Case study, MM
• History of present illness reveals that his aunt who
had a considerable flare-up of cold sores was
babysitting him for the past week.
• He was empirically started on ampicillin 225 mg
(50 mg/kg/dose) IV q 6 h, cefuroxime 225 mg IV q
6 h (50 mg/kg/dose), and acyclovir 90 mg IV q 8 h
(20 mg/kg/dose).
• Given his poor oral intake on admission, the team
requests addition of maintenance IV fluids and a
nutrition consultation
81
 Case study, MM

Lab tests Result Normal ranges

WBC 18 × 103/μL 6–17 × 103/mm3
Bands 7% 4–12%
Segs 36% 13–33%
Lymphs 51% 41–71%
Monocytes 6% 4–7%
Serum creatinine 0.5 mg/dL ≤0.6 mg/dL

82
 Case study, MM

Questions
• How much maintenance fluid would you
recommend for MM now?
• Because acyclovir can affect renal function, MM’s
creatinine clearance should be assessed. Using the
most appropriate method, calculate a creatinine
clearance for MM.

83
 Issues in Pediatric Drug Therapy
Alteration of Dosage Forms
Many drugs used in pediatric patients are not available in suitable
dosage forms.
This necessitates dilution of high concentrations of drugs intended
for adult patients.
Can be associated with large errors in measurements
Administration of oral drugs continues to challenge parents and
nurses.
Alteration of these drugs by crushing or mixing, refusal of patients
to accept the medication, and loss of drug during administration are
some factors that can affect pediatric therapy.
A common practice is to mix medications in applesauce, syrup, ice
cream, or other vehicles just before administration to make the
drugs palatable 84
 Issues in Pediatric Drug Therapy
Medication Adherence
• The issue of medication adherence is more complex in pediatric
patients than in adults.
• Among the factors that can negatively affect adherence are:
Poor communication between the physician and patient or parent,
Insufficient prescribing information,
Lack of understanding about the severity of illness by the patient or
parent,
Lack of interest (e.g., among adolescents),
Fear of side effects,
Failure of the patient or parent to remember to administer the drugs,
Inconvenient dosage forms or dosing schedules involving administration
of three or more doses daily, and
Unpalatability of drug products 85
 Issues in Pediatric Drug Therapy
Dose Requirements
• Medication doses often are based on the body weight
of neonates, infants, and children (e.g., milligrams per
kilogram of body weight per day to be given in one or
more portions daily).
• However, certain drugs, including antineoplastic
agents, may be given based on BSA (e.g., milligrams
per square meter in one or more doses daily).
• An additional challenge in managing pediatric drug
therapy is understanding the effects of obesity on a
population that relies on weight-based dosing 86
 Issues in Pediatric Drug Therapy
Drug Interactions
• Drug interaction studies in pediatric age groups
generally are lacking.
• The data often are extrapolated from studies in
adult populations.
• Special attention should be given to adolescents,
who may concurrently use 
Alcohol,
Recreational or illicit drugs, or
Other prescription or nonprescription medications
87
 Issues in Pediatric Drug Therapy
Complementary and Alternative Therapy
• Little is known about the efficacy of herbal
products in infants, children, and adolescents.
• Healthcare professionals must ask caregivers
specifically about the use of complementary and
alternative treatments to minimize the adverse
effects and costs associated with ineffective
therapies

88
 Issues in Pediatric Drug Therapy
• Risk-reduction strategies include:
Placing a clinical pharmacist on pediatric wards in hospitals,
Simplifying the medication-use system,
Ordering standardized concentrations and doses,
Implementing computerized physician order-entry systems
with dose range checking,
Dispensing pharmacy-prepared or ready-to-administer doses,
Standardizing infusion equipment,
Using smart infusion pumps,
Using bar-coded medications and bar-coding systems that
check the medication at the point of care, and
Implementing computerized adverse event detection systems 89
GERIATRICS 
Therapeutic Considerations

90
 Objectives
Upon completion of the session, the you will be able
to:
1. Explain the physiologic changes with aging
2. Discuss age-related pharmacokinetic and
pharmacodynamic changes.
3. Identify drug-related problems and associated
morbidities commonly experienced by older
adults.

91
 Introduction
• Pharmacotherapy for older adults can cure or palliate disease as
well as enhance health-related quality of life (HRQOL).
• HRQOL considerations for older adults include focusing on
improvements in:
Physical functioning (e.g., activities of daily living),
Psychological functioning (e.g., cognition, depression),
Social functioning (e.g., social activities, support systems), and
Overall health (e.g., general health perception).
• Despite the benefits of pharmacotherapy, HRQOL can be
compromised by drug-related problems.
• Prevention of drug-related adverse consequences in older adults
requires that health professionals become knowledgeable about
a number of age-specific issues. 92
 Introduction
• The proportion of the population age 65 and older
is increasing.
– In 2013, persons age 60 and older accounted for 5% of
the total Ethiopian population
– By 2040, 25% of the population will purchase 50% of all
prescription drugs

93
 Physiologic Changes with Aging
• Clinical manifestations of normal aging include
Changes in the biochemical makeup of tissues,
Reduced capacity of body systems,
Reduced ability to adapt to physiologic stress, and
Increased vulnerability to disease.

94
 Physiologic Changes with Aging
Organ System Manifestation
 ↓ Stride length and slower gait
Balance and gait  ↓ Arm swing
 ↑ Body sway when standing

 ↓ Total body water

 ↓ Lean body mass
Body composition  ↑ Body fat
 ↔ or ↓ Serum albumin
 ↑ α1-Acid glycoprotein (↔ or ↑ by
several disease states)

95
 Physiologic Changes with Aging
Organ System Manifestation
• ↓ Cardiovascular response to stress
• ↓ Baroreceptor activity leading to ↑ orthostatic
hypotension
CVS • ↓ Cardiac output
• ↑ Systemic vascular resistance with loss of arterial
elasticity and dysfunction of systems maintaining
vascular tone
• ↓ Resting and maximal heart rate

• ↓ Size of the hippocampus and frontal and temporal

lobes
• ↓ Number of receptors of all types and ↑ sensitivity of
CNS remaining receptors
• ↓ Short-term memory, coding and retrieval, and
executive function
• Altered sleep patterns
96
 Physiologic Changes with Aging
Endocrine  ↓ Estrogen, testosterone, TSH
 Altered insulin signaling

 ↓ Motility of the large intestine

Gastrointestinal  ↓ Vitamin absorption by active transport
mechanisms
 ↓ Splanchnic blood flow
 ↓ Bowel surface area
Genitourinary  Atrophy of the vagina with decreased estrogen
 Prostatic hypertrophy with androgenic hormonal
changes
 Incontinence
Hepatic  ↓ Hepatic size
 ↓ Hepatic blood flow
 ↓ Phase I (oxidation, reduction, hydrolysis)
metabolism
97
 Physiologic Changes with Aging
 Immune  ↓ Antibody production in response to antigen
 ↑ Autoimmunity
 Oral  Altered dentition
 ↓ Ability to taste salt, bitter, sweet, and sour
 Pulmonary  ↓ Respiratory muscle strength
 ↓ Chest wall compliance
 ↓ Arterial oxygenation and impaired CO2 elimination
 ↓ Vital capacity
 ↓ Maximal breathing capacity
 ↑ Residual volume

 Renal  ↓ GFR
 ↓ Renal blood flow
 ↓ Filtration fraction
 ↓ Tubular secretory function
 ↓ Renal mass
98
 Physiologic Changes with Aging
Sensory  Presbyopia (diminished ability to focus on near
objects)
 ↓ Night vision
 Presbycusis (high-pitch, high-frequency hearing loss)
 ↓ Sensation of smell and taste
Skeletal  ↓ Skeletal bone mass (osteopenia)
 Joint stiffening caused by reduced water content in
tendons, ligaments, and cartilage
Skin/hair  Thinning of stratum corneum
 ↓ Langerhans cells, melanocytes, and mast cells
 ↓ Depth and extent of the subcutaneous fat layer
 Thinning and graying of hair caused by more hairs in
the resting phase and shortening of the growth phase
as well as changes in follicular melanocytes
99
 Altered Pharmacokinetics
PK Phase Pharmacokinetic Parameters
Gastrointestinal  Unchanged passive diffusion and no change in bioavailability for
absorption most drugs
 ↓ Active transport and ↓ bioavailability for some drugs
 ↓ First-pass metabolism, ↑ bioavailability for some drugs, and ↓
bioavailability for some prodrugs

Distribution • ↓ Volume of distribution and ↑ plasma concentration of water-

soluble drugs
• ↑ Volume of distribution and ↑ terminal disposition half-life (t1/2)
for lipid-soluble drugs

Hepatic • ↓ Clearance and ↑ t1/2 for some drugs with poor hepatic

metabolism extraction; phase I metabolism may be affected more than phase II
• ↓ Clearance and ↑ t1/2 for drugs with high hepatic extraction
ratios (flow-limited metabolism)

Renal excretion • ↓ Clearance and ↑ t1/2 for renally eliminated drugs and active
metabolites 100
 Absorption
• Fortunately, most drugs are absorbed via passive
diffusion, and age-related physiologic changes
appear to have little influence on drug bioavailability.
• Nutrients absorbed by active transport, such
as vitamin B12, iron, calcium, magnesium, and leucine,
may have impaired absorption in older adults.
• There is evidence for a decreased first-pass effect on
hepatic or gut wall metabolism
Results in increased bioavailability of drugs such
as propranolol and labetalol and reduced bioavailability of
some prodrugs such as enalapril and codeine
101
 Distribution
• The distribution of medications in the body depends on factors
such as
Blood flow,
Plasma protein binding, and
Body composition,
• For example, the volume of distribution of water-soluble drugs
is decreased, whereas lipophilic drugs exhibit an increased
volume of distribution.
• Changes in the volume of distribution can have a direct impact
on the amount of medication that must be given as a loading
dose.
• Older adults may also exhibit differences in the distribution of
drugs to their sites of action. 102
 Distribution
• Tissue perfusion may decrease with aging, slowing
the distribution to less highly perfused tissues such as
muscle and fat
• Blood–brain barrier permeability may also be altered
in older adults, thereby affecting distribution of
medications into the central nervous system (CNS).
• The brain of elderly individuals may be exposed to
higher than normal levels of drugs and toxins.

103
 Metabolism
• Variations in drug metabolism and consequently drug clearance
are a major source of variability in the response to medications in
older adults
• Hepatic metabolism of drugs depends on liver perfusion, capacity
and activity of drug metabolizing enzymes, and protein binding, all
of which may altered by the aging process.
• For drugs that have high intrinsic clearance (high hepatic extraction
ratio) and undergo rapid hepatic metabolism, drug clearance is
dependent on hepatic blood flow (flow-limited metabolism).
• For drugs that have low intrinsic clearance (low hepatic extraction
ratio) and are slowly metabolized by the liver, drug clearance is
dependent on hepatic enzyme activity (capacity-limited
metabolism).
104
 Metabolism
• Age-related decreases in hepatic blood flow can decrease
significantly the metabolism of high extraction ratio drugs
that undergo flow-limited metabolism.
• Hepatic blood flow may decline by 20% to 50%, and
hepatic clearance of propranolol and amitriptyline may be
reduced by 40% or more in older adults
• Serum albumin concentrations decline with age.
• For capacity-limited drugs with extensive protein binding,
older adults with reduced serum albumin concentrations
may experience a significant increase in fraction unbound,
leading to increased total hepatic clearance
– Example: Naproxen 105
 Excretion
• Age-related reductions in glomerular filtration rate
(GFR) are well documented.
• However, as many as one third of “normal” older adult
subjects may have no reduction as measured by
creatinine clearance, and older adults maintaining a
high protein diet have a GFR similar to younger adults.
• Additionally, declines in kidney function may be more
closely implicated to disease processes such as
hypertension and heart disease than aging itself.
• Therefore, age alone may not have as great impact on
renal excretion of drugs than previously thought 106
 Excretion
• Cockcroft and Gault created one of the most
commonly used equations for adults with stable
renal function whose actual weight is within 30%
of ideal body weight:
where age is given in years, actual
body weight in kilograms, and
serum creatinine concentration in
milligrams per deciliter.
The resulting creatinine clearance
is in units of mL/min. For women,
multiply this result by 0.85.
107
 Altered Pharmacodynamics
• There is a general trend of altered drug response or
increased “sensitivity” in older adults.
• Possible mechanisms that have been proposed include
(a) Changes in concentrations of the drug at the receptor,
(b) Changes in receptor numbers,
(c) Changes in receptor affinity,
(d) Postreceptor alterations, and
(e) Age-related impairment of homeostatic mechanisms. 

108
 Altered Pharmacodynamics
• Older adults are particularly sensitive to the CNS effects of
drugs.
• Changes in brain size and weight as well as changes in
neurotransmitter systems have been reported with advancing
age.
• In addition, drugs may penetrate the CNS more easily
• Increased sensitivity to the CNS effects of
Benzodiazepines,
Anesthetic agents,
Opioid analgesics,
Antipsychotics, 
Lithium, and
Anticholinergic medications 109
 Altered Pharmacodynamics
• There are multiple changes to the dopaminergic
system with age, including
Decreased levels of the dopamine transporter,
Decreased number of dopaminergic neurons, and
Decreased density of several types of dopamine
receptors.
• These changes are consistent with the increased
sensitivity of older adults to the adverse drug
effects of antipsychotics

110
 Altered Pharmacodynamics
• Aging is associated with numerous changes in the
structure and function of the cardiovascular system
• Older adults are more likely to experience
orthostatic hypotension as an adverse drug event.
• Age-related changes in pharmacodynamics have
been reported for:
Calcium channel blockers (increased hypotensive and
bradycardic effects), 
β-blockers (reduced blood pressure response),
Diuretics (reduced effectiveness), and 
Warfarin (increased risk of bleeding) 111
 Clinical Geriatrics
• Maintenance of independence and prevention of
disability are primary goals in the clinical care of
persons 65 years of age and older.
• Functional status is a proxy measure of a patient’s
ability to live independently
Determined by inquiring about an older person’s ability
to perform specific tasks.
• To fully assess functional status, the patient’s
psychological state, financial resources, physical
function, and social circumstances also must be
considered. 112
 Clinical Geriatrics
• Problems found more commonly in older persons sometimes
are referred to as the “Is of geriatrics”
• These problems are often the result of underlying disease
processes that may or may not be diagnosed.
• Examples of diseases and syndromes that can present as
common problems in older adults include:
Parkinson’s disease,
Falls,
Hip fractures,
Benign prostatic hypertrophy,
Dementia,
Glaucoma, and
Postherpetic neuralgia. 113
 Clinical Geriatrics
The Is of Geriatrics: Common Problems in Older Adults
• Immobility • Instability
• Isolation • Intellectual impairment
• Incontinence • Impotence
• Infection • Immunodeficiency
• Inanition (malnutrition) • Insomnia
• Impaction • Iatrogenesis
• Impaired senses

114
 Drug-Related Problems in Older Adults
• Three important and potentially preventable negative
outcomes caused by drug-related problems are
(a) Adverse drug withdrawal events (ADWEs), which are
clinically significant sets of symptoms or signs caused
by the removal of a drug;
(b) Therapeutic failure (inadequate or inappropriate drug
therapy and not related to the natural progression of
disease); and
(c) Adverse drug reactions (ADRs), defined as reactions
that are noxious and unintended and occur at dosages
normally used in humans for prophylaxis, diagnosis, or
therapy 115
 Drug-Related Problems in Older Adults
• Risk Factors
Polypharmacy 
Inappropriate Prescribing
Underuse
Medication Nonadherence

116
 Assessing and Monitoring Drug Therapy

• Match the medical problem list with the drug list.

Determine whether the patient has a chronic condition
and is taking a medication that has been shown to
improve the management of a particular condition
• Examine laboratory test results and vital signs that
can be used to monitor the efficacy and toxicity of
each medication

117
 Monitoring Medication Use
Drug Monitoring Interval (in
months)
Acetaminophen (>4 g/d) Hepatic function tests
Amiodarone Hepatic function tests,  6
TSH level
Antiepileptic agents Drug levels 3–6
(carbamazepine, phenobarbital, 
phenytoin, primidone, valproate)
ACEIs or ARBs Potassium levels 6
Antipsychotic agents Extrapyramidal side effects, 6
fasting serum glucose, serum lipid
panel
Digoxin Serum blood urea nitrogen, 6
creatinine, trough drug level

118
 Monitoring Medication Use
Erythropoiesis Blood pressure, iron and 1
stimulants ferritin levels, CBC
Fibrates Hepatic function test, CBC 6
Hypoglycemic agents Fasting serum glucose level or 6
glycated hemoglobin level

Iron Iron and ferritin levels, CBC

Lithium Trough serum drug levels 3
Metformin Serum blood urea nitrogen,
creatinine levels
Diuretic Serum sodium and potassium 3
levels
119
 Monitoring Medication Use

Niacin Blood sugar levels, hepatic function 6

tests
Statins Hepatic function tests 6
Theophylline Trough serum drug levels 3
Thyroid TSH level on tests 6
replacement

Warfarin Prothrombin time or international 1

normalized ratio

120
Thank You

121