Download Pharmacologic Implications for Special Patient Populations:

Pharmacologic Implications
for Special Patient
Populations:
Pregnant
Elderly
Pediatric
Judith A. Kaufmann, Dr PH, FNP-C
Associate Professor of Nursing
Robert Morris University
Vulnerable Populations:
At Most Risk for Adverse Drug
Effects and Reactions
Reasons: The 5 “toos”

Too few patients represented in studies to
detect rare events

30,000 people in each category would need to
receive the medication to detect 1 adverse
reaction in a drug that affects 1:10,000
Too simple: patients with multiple
conditions excluded from trials
 Too median-aged: studies exclude
patients at each end of the spectrum

2 More “Toos”

Too narrow: indications for newly
approved drugs are based on pre
marketing clinical trials for ONE very
specific condition


Once marketed, the drug may be used for
untested indications
Too brief: most clinical trials are short

Some adverse effects take years to manifest
clinically
Drugs in Pregnancy

Treatment Goals
Utilize appropriate resources to determine
teratogenic risk and excretion in breast milk
 Assess the risk: benefit ratio of
pharmacotherapy
 Utilize drug regimen that is safe, effective and
minimizes risk to fetus or infant
 Minimize drug exposure to neonate/infant
during lactation

Epidemiology

~35% of women take some medications during
pregnancy
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Range/pregnancy = 1-15 medications (M=2.9)
OTC medications not included
WHO study showed that non-white,
unmarried, less educated women less likely
to use medications
Today ~60% of women breastfeed
Over 1,000 drugs per year are evaluated for
teratogenic potential

~10% of children have abnormal physical or mental
development

Only 2-3% of these are associated with medications
Resources for Information

Data on drugs in pregnancy and lactation
are almost always POST marketing

Constantly being updated-need for immediate
access to drug updates
1979-FDA categories for Drug Use in
Pregnancy
 FDA’s Adverse Drug Reaction reporting
system underused

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MEDWATCH Program initiated in 1993
Lessons from the Past

Thalidomide first appeared in Germany on 1st
October 1957

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Pre-marketing tests conducted on rodents which
metabolize the drug in a different way to humans


marketed as a sedative with few side effects
Considered safe, used for morning sickness
Drug testing procedures were less rigorous
limited testing failed to reveal tetragenic side effects
Subsequent tests on rabbits and monkeys produced similar SEs as in
humans.
Late 1950’s: post marketing reports

Pharcomelia: babies born with flipper-like limbs
 AKA: 'Thalidomide Babies’
Pharcomelia
FDA Categories for Drug Use in Pregnancy

Category A:
Adequate, well-controlled studies in pregnant women have
not shown an increased risk of fetal abnormalities

Category B:
Animal studies have revealed no evidence of harm to the
fetus, however, there are no adequate and well-controlled
studies in pregnant women.
or
Animal studies have shown an adverse effect, but adequate
and well-controlled studies in pregnant women have failed to
demonstrate a risk to the fetus.
FDA Categories

Category C:
Animal studies have shown an adverse effect and there
are no adequate and well-controlled studies in pregnant
women.
or
No animal studies have been conducted and there are
no adequate and well-controlled studies in pregnant
women

Category D:
Studies, adequate well-controlled or observational, in
pregnant women have demonstrated a risk to the fetus.
However, the benefits of therapy may outweigh the
potential risk.
FDA Categories

Category X:
Studies, adequate well-controlled or
observational, in animals or pregnant
women have demonstrated positive
evidence of fetal abnormalities.

The use of the drug is contraindicated in
women who are or may become pregnant.
Excellent Website

Ob.Gyn. News - Editorial
X-Rated Drugs
Accutane
 Estrogen
 Isotrentinoin
 Vaccines: MMR, Varicella


CDC Advisory Committee on immunization
Practices
 Vaccinate
all pregnant women with INACTIVATED
influenza vaccine in the fall or throughout influenza
season
Addressing Patients’ Concerns for
Vaccine Safety


The US FDA approved Fluarix, an
inactivated influenza vaccine for adults in
2005
Fear of mercury and thimerosal


Spurred by media
IOM (2004) released results of analysis of
potential link between thimerosal and
neurobehavioral conditions and found no
evidence of association

BUT… urged “full consideration …to removing
thimerosal from any product given to infants, children
or pregnant women”
Current Vaccines Available

Thimerosal-free or Thimerosal-reduced
May be added at the end of manufacturing
process to prevent bacterial or fungal growth
 Results in minute traces in final product

Institute for Vaccine Safety - Thimerosal Table

Thompson, et al, (2007). Early thimerosal exposure
and neuropsychological outcomes at 7 to 10 Years.
NEJM. 357 (13). 1281-1292.

N= 1047 children between the ages of 7 and 10 years
and administered standardized tests assessing 42
neuropsychological outcomes

Findings: The detected associations were small and almost
equally divided between positive and negative effects.

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Higher prenatal mercury exposure associated with better
performance on one measure of language and poorer performance
on one measure of attention and functioning.
Increasing levels of mercury exposure from birth to 7 months were
associated with better performance on one measure of fine motor
coordination and on one measure of attention and executive
functioning.
Increasing mercury exposure from birth to 28 days was associated
with poorer performance on one measure of speech articulation and
better performance on one measure of fine motor coordination
Pregnancy alters the
Pharmacokinetics of Most Drugs

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Increase in total body water (~8L)
Increase in total body fat
Increase in GFR
Decrease in gastrointestinal motility
and changes in absorption and
gastric acidity
Increase in CO, blood volume and
plasma proteins
Decrease in plasma albumin
concentration

Changes in serum albumin effect the
bioavailability of protein-binding
Pregnancy and Pharmacokinetics

Pregnancy often accompanied by nausea
and vomiting, which may prevent
absorption of the medication, but…

Increased plasma volume, fetal growth,
and increased interstitial tissue result in a
wider distribution of medications
Bottom Line
Every woman requires thorough history of
pregnancy complaints prior to
pharmacologic treatment
 Dosages may need to be considered
based on the stage of pregnancy
 Prescribing in pregnant patient requires
more than just attention to FDA drug
categories

In Translation…

Absorption affected by decreased GI tone


Drug remains in stomach longer leading to increase in
absorption through stomach and delayed in
absorption of drugs
Distribution affected by increased plasma
volume causing prolonged half lives
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Fat soluble drugs stay longer in the body
Drugs with high protein binding and lower lipid
solubility (such as anticonvulsants) have longer half
lives
Hormones (strongly protein bound) compete for
available binding sites-resulting in wide distribution of
free, unbound drug in the body
Pregnancy and Pharmacokinetics

Metabolism of drugs in liver relatively
unchanged

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Drugs cleared through liver eliminated similar
to non pregnant women
Excretion-increased rates of clearance
Renal blood flow increases by 25-50%
 GFR increases by 50%
 Serum level of drug must fall to allow diffusion
of drug from the fetus’s circulation

Placental Transfer
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Simple diffusion: molecular size may/not permit
transfer
Active transport: where concentration of
substances are higher in fetus and transported
back to the mother
Pinocytosis: where soluble molecules (such as
viruses) cross membrane in small vesicles and are
released
Facilitated diffusion: glucose is rapidly transferred
to fetus
Leakage: fetal cells enter mother’s circulation
through small membrane breaks
Properties of Medications that
easily cross the placenta

Small molecular size and weight (250500d)

Most drugs have weights < 600d
Non-protein bound
 Non-ionized
 Lipophilic
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Selecting a Drug for a Pregnant or
Nursing Mother
Principles of teratology:

Timing of exposure in fetal development
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Based on fetal developmental stage when insult is applied can help
predict the possible defect
Exposure at time of conception and implantation may kill the fetus
(all or nothing effect)
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If exposure occurs in first 14 days after conception when the cells can
assume another cell’s function (totipotential), the fetus may not be
damaged
Most sensitive period: time from implantation to the end of
organogenesis (days 18- 60)
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Damage to developing organs
heart is most sensitive during the 3rd and 4th weeks of gestation,
external genitalia are most sensitive during the 8th and 9th weeks
brain and skeleton are sensitive from the beginning of the 3rd week to
the end of pregnancy and into the neonatal period.
Factors that Influence
Teratogenicity of a drug
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Genotypes of the mother and
fetus
Embryonic stage at exposure
Drug dose
Duration of exposure
Nature of the agent and
mechanism by which it causes a
defect
Simultaneous exposure to other
drugs and environmental agents
that potentiate a drug
Maternal and fetal metabolism of
the drug
Extent to which the drug crosses
the placenta
The safest pregnancy-related pharmacy is
as little pharmacy as possible
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However, women with a history of psychiatric,
seizure-related, or hematologic illnesses
frequently require medication throughout
pregnancy.
In such patients, care must to be taken to select
the safest drug from the necessary class of
medication.
Misri and Kendrick noted that prescribing drugs
for women during the antenatal and postnatal
period is a balancing act and that no risk-free
alternatives exist

Misri S, Kendrick K. Treatment of perinatal mood and
anxiety disorders: a review. Can J Psychiatry. Aug 2007
The Male Partner…
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Research is increasingly addressing the role of paternal
exposure to medications before conception or during his
partner’s pregnancy
Certain exposures may alter the size, shape,
performance, and production of sperm
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suggests that drug exposure in the male may put the fetus at risk
Animal studies have shown that paternal teratogenic
exposure may lead to pregnancy loss or failure of the
embryo to develop
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unlike teratogenic agents affecting pregnant woman, teratogenic
agents affecting the father do not seem to directly interfere with
normal fetal development
Animal studies showing that paternal teratogenic exposure may
lead to pregnancy loss or embryonic failure.

Austin, 1994; Chatenoud, 1998
For example:
Colchicine
 Pregnancy category - D
 Trimester of risk - Unknown
 Associated defects and complications potential chromosome aberrations
 Studies: Colchicine has been shown to
cause birth defects in animals. The drug
can lower sperm counts and cause sperm
defects, resulting in birth defects.
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Current EB Recommendations
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In humans, no evidence of birth defects after
paternal exposures, but to minimize any possible
risk, counseling in men exposed to radio and
chemotherapy should delay conception ~ 3
months after the end of therapy.
Male patients treated with drugs with maternal
teratogenic potential should be advised to practice
effective birth control during therapy and up to one
or two cycles of spermatogenesis and to avoid
semen contact with vaginal walls during first
trimester of pregnancy.

Reproductive Toxicology, 2008
Drug Exposure Options for Pregnant
and Lactating women
1.
Withhold the drug (e.g., headache medications)
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2.
E.g., Ergotamine: Pregnancy category - X
Trimesters of risk - all
Associated defects and complications: LBW, and
preterm birth, ergotamine-induced vasoconstriction
in the placenta of pregnant women.
The effect of ergotamine most obvious in male
newborn infants, particularly after treatment in the
third trimester.
Delay drug therapy (if woman is close to end of lactation)
Options
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Choose drugs that pass poorly into placenta or
breast milk- (e.g., some variations even within
same class of drug)
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e.g., Benzodiazepines-Pregnancy category - D
or X
Trimesters of risk: The first, second, and third
trimesters are times or risk for flurazepam
(dalmane), temazepam (restoril), and triazolam
(Halcion) (category X).
Avoid alprazolam (Xanax-cat D) during
pregnancy
Chlordiazepoxide(Librium) appears to be safest
choice during pregnancy.
Options
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Choose alternate routes of administration when
possible
Avoid long acting/medications with long half lives
Advise lactating women to time their medications
before the infant’s longest sleep period
Temporarily withhold breast feeding

Can safely resume after 1-2 half lives (50%-75%
elimination)
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For drugs with high toxicity, must delay 4-5 half lives
Discontinue nursing if medication is for life
threatening condition (e.g., chemotherapy)
Treatment of Select Conditions
during Pregnancy

Asthma:
Asthma complicates approximately 4% of
pregnancies
 In some cases, asthma improves during
pregnancy
 Those with poorly controlled asthma are at
risk for:

 Hyperemesis,
uterine hemorrhage, preeclampsia,
placenta previa, hypertension and premature labor
IMPLICATIONS of Pregnancy on
Asthma
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Pregnancy has a significant effect on the respiratory
physiology of a woman
Respiratory rate and vital capacity do not change in
pregnancy, but there is an increase in tidal volume,
minute ventilation (40%), and minute oxygen uptake
(20%) with resultant decrease in functional residual
capacity and residual volume of air due to elevation of
the diaphragm
Airway conductance is increased and total pulmonary
resistance is reduced, possibly as a result of
progesterone
Improved Outcomes associated
with controlled asthma

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Current EVIDENCE Supports Treatment
Almost all anti-asthma drugs are safe to use in
pregnancy and during breastfeeding.

Under-treating is a frequent occurrence for the
pregnant patient because patients are worried about
the medication effects on the fetus

With a few exceptions, the medications used to treat
asthma during pregnancy are similar to the
medications used to treat asthma at other times
during a person's life.
Choice of Asthma Medications

The type and dose of asthma medications will depend
upon many factors.
inhaled drugs are recommended because
there are limited body-wide effects in the
mother and the baby.
 It may be necessary to adjust the type or
dose of drugs during pregnancy to
compensate for changes in the woman's
metabolism and changes in the severity of
asthma.

Common Asthma medications

Inhaled B2 Agonists

Albuterol-Category C
 Mild,
infrequent episodic
 May cause maternal hyperglycemia, tachycardia,
hypotension or neonatal hypoglycemia
 Briggs, et al., 2002: study of 1090 infants
exposed to albuterol in 1st trimester-possible
association with polydactyly
 No congential defects link in 2nd, 3rd trimester
 No adverse effects during lactation

Possible B2Choice-Brethine (category B)
Theophylline (Cat C)
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Can be used along with inhalation therapy
Preferred treatment for patients requiring long term
therapy
Must monitor levels throughout pregnancy to avoid
toxicity
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Especially important in 3rd trimester d/t decrease in theophylline
clearance and increase in volume of distribution
Keep maternal plasma concentrations as low as therapeutically
possible
Crosses placenta in equal concentrations to mother
Not associated with congenital defects but can cause
jitteriness, cardiac arrythmias, hypoglycemia, feeding
difficulties in infants

Neonates more likely affected
Corticosteroids (Cat C)
Systemic corticosteroids are reserved for
patients who require more urgent
treatment.
 Conversely, cromolyn and nedocromil (Cat
B) inhibit antigen- and exercise-induced
asthma.
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They can be indicated as the first-line antiinflammatory medication for the treatment of
asthma
 Does not have systemic absorption
 ?crossing of placenta
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Corticosteroids (cat C)
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Can be given IV, PO, or inhaled
2 reports congenital cataracts in infants exposed
to prednisone throughout gestation
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No association found in other studies
Spontaneous abortion, prematurity, cardiac
abnormalities reported in one study
( Greenberger,1983)
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Prednisone <20mg/day safe in lactation
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In larger doses, delay nsg 3-4hours after dose
Epilepsy
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> 1 million women of childbearing age have epiliepsy
<1% of pregnancies are complicated by seizures
25% of women will have an increase in seizures during
pregnancy
Women with epilepsy (with or without medication) have a
higher incidence of delivering an infant with congenital
malformations and mental retardation

Rates of major malformations affecting the heart, skeletal or
nervous system in children born to women on anticonvulsants
are at least double the rate in the general population

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Occurrence: 4–6 per hundred births vs the 2-3 per hundred births
risk that all pregnant women face
Benefits v risk are overwhelmingly important to consider
Epilepsy in Pregnancy
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AAP recommends that a patient who is seizure free for 2
years undergo trial medication withdrawal before
becoming pregnant
Suggested waiting period of 6 months after d/cing
medication
Anticonvulsant pharmacokinetics change during
pregnancy:
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Lower serum concentrations due to increased renal and
hepatic clearance
Decreased protein-binding capacity
Increased volume distribution

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despite lower serum concentrations, seizures may not increase due
to increased free drug concentrations
Must monitor concentrations of anticonvulsants closely
Newborns exposed to
anticonvulsants

Hemorrhagic disease in newborns in first
24 hours can be fatal

Due to deficiency in Vit K clotting factors as a
result of anticonvulsant exposure
 All
infants should be treated with Vit K at birth
 Some physicians recommend Vit K for mother in
last 2-4 weeks of pregnancy

Anticonvulsants also causes folate
deficiencies
 Prophylactic
folic acid during gestation
recommended to prevent megaloblastic anemia
and/or neural tube defects
Fetal Anticonvulsant Syndrome
Can occur with all antiepileptic drugs
 Phenytoin (cat D) can cause fetal
hydratoin syndrome

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School, learning and developmental
problems, craniofacial abnormalities, growth
retardation, limb defects, cardiac lesions,
hernias, distal digital and nail hyoplasia
 10%
risk for all of above (FHS)
 30% risk of partial expression of syndrome
Phenobarbital (cat D)
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Less teratogenic that phenytoin but can
cause heart defects and cleft palate
Can also cause coagulopathies and folate
deficiencies
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Also has potential to cause neonatal addiction
Found in breast milk-causes newborn
drowsiness, feeding difficulties, and infantile
spasms after weaning
Carbazamine and Valproate
(Cat D)
At first, thought to be less harmful
to fetus
 Associated with the same
congenital abnormalities plus spina
bifida (1%)
 Can be used with caution in
lactation

Lamotrigine (Lamictal), Gabapentin
(Neurontin) and Oxcarbazine
(Trileptal)= Cat C
Recent results encouraging
 Appear to be less teratogenic or
associated with fetal loss in 1st trimester
 Caution: more data needed

So…the jury is still out…

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Although there appears to be a predisposition
for congenital malformations in the offspring of
women treated for epilepsy, it is hard to
establish a causal effect with the medication
It may be a complex interaction of the
medication, the nature of their disease, and
genetics rather than just the medication alone


Samuels, 2002
The three most common malformations noted in
children of women treated for epilepsy are
cardiac malformations, facial clefts, and
genital/renal malformations.
The Teratogenicity of Anticonvulsant
Drugs
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Holmes, et al: NEJM 2001Methods: screened 128,049 pregnant women at
delivery to identify three groups of infants: those
exposed to anticonvulsant drugs, those unexposed to
anticonvulsant drugs but with a maternal history of
seizures, and those unexposed to anticonvulsant drugs
with no maternal history of seizures (control group). The
infants were examined systematically for the presence of
major malformations, signs of hypoplasia of the midface
and fingers, microcephaly, and small body size.
Results

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The combined frequency of anticonvulsant embryopathy
was higher in 223 infants exposed to one anticonvulsant
drug than in 508 control infants (20.6 percent vs. 8.5
percent; odds ratio, 2.8; 95 percent confidence interval,
1.1 to 9.7).
The frequency was also higher in 93 infants exposed to
two or more anticonvulsant drugs than in the controls
(28.0 percent vs. 8.5 percent; odds ratio, 4.2; 95 percent
confidence interval, 1.1 to 5.1).
The 98 infants whose mothers had a history of epilepsy
but took no anticonvulsant drugs during the pregnancy
did not have a higher frequency of those abnormalities
than the control infants
Conclusions

A distinctive pattern of physical
abnormalities in infants of mothers with
epilepsy is associated with the use of
anticonvulsant drugs during pregnancy,
rather than with epilepsy itself
Coagulation Disorders

Pregnancy is a hypercoagulable state
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Incidence for DVT is still low: 0.2-0.4%
Current recommendations for prophylaxis
based on risk factors:
Hereditary factors (protein C
deficiencies/leiden factors)
 Hx of DVT/PE
 Age >35
 Multiple miscarriages

Heparin: anticoagulant of choice
(Cat C)
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Does not cross placenta
Not associated with congenital defects
Late pregnancy may be associated with
increased heparin doses
Perinatal mortality rates significantly improved
for patients on heparin v. coumadin (3.6% v.
26.1% mortality)
LMWH (Lovenox) safe and effective

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Less bleeding potential and less risk of osteoporosis
Does not cross fetal circulation
Not excreted in breast milk
Coumadin (cat D)

Exposure during 6-8th weeks can cause
fetal warfarin syndrome

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Exposure throughout pregnancy can
cause:

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Defects in CNS and skeletal system
Stillbirths, spontaneous abortion, facial
abnormalities
Compatible with breast feeding
Treating Common Problems in
Pregnancy
Common Cold
 Nausea/Vomiting
 Constipation
 Heartburn
 Hemorrhoids

Over the Counter Drug of Choice
Drug Class
During Pregnancy
During Lactation
analgesics
acetominophen
acetominophen
antacids
Calcium carbonate
Calcium carbonate
antihistamine
chlorpheniramine
chlorpheniramine
Hemorrhoidal
agents
Preparation H
ointment
Preparation H ointment
decongestant
Oxymetazoline nasal
spray
none
laxative
Psyllium or docusate
Psyllium or docusate
The Common Cold
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No value in treating with medications
If using medication, avoid combination products
Limit duration of treatment
Antihistamine of choice: chorpheniramine (cat B) or
Loratidine (cat B)
Avoid brompheniramine (Dimetapp-Bromfed)
Antihistamines excreted in breast milk
Nasal cromolyn, beclomethasone useful alternative
Clubfoot and inguinal hernias associated with first
trimester use of decongestants (e.g., Sudafed)
Anti-tussives and expectorants all category C

No epidemiologic studies demonstrate fetal harm
Nausea and Vomiting

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80% of women experience n/v during 1st
trimester
Hyperemesis gravidarum-intractable, causes
lyte imbalances, weight loss, possible end organ
damage

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Occurs in 1:1000 births
Requires hospitalization
Cause unknown-tx focused on sx
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Non pharmacologic measures not supported by
evidence
OTC phosphorated carbohydrate (EMETROL) safe
Meclizine (cat B) drug of choice
Constipation


Etiology: increased pressure on colon,
decreased peristalsis, increased progesterone,
decreased motilin, increased colonic absorption
of water
Bulk-forming laxatives (Metamucil) safe in
pregnancy and lactation

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Increase fluids to prevent intestinal obstruction
Surfactants/Stool softeners (docusate), mineral
oil Cat c
Heartburn
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Affects 72% women in 3rd trimester
d/t relaxation of LES and uterine displacement +
hormonal changes in gut motility
Magnesium, calcium carbonate, and/or
aluminum hydroxides considered safe
Avoid H2 blockers

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If necessary-ranitidine preferred over cimetidine (has
anti-androngenic effects)
Metoclopromide (Reglan) cat B
Hemorrhoids
OTC external preparations preferred
 Avoid suppositories d/t potential for
systemic absorption across rectal mucosa

General Principles
Limitations of Drug Therapy in
Children

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75% of FDA approved
medications lack indications in
children
Pediatric practitioners actually
prescibe “off label”
FDA indications for dosing
regimens are lacking
Safety is based on post marketing
reports of adverse events
Post Marketing Adverse Drug
Reports

MED WATCH
FDA
 http://www.fda.gov/safety/MedWatch/default.htm

https://www.accessdata.fda.gov/scripts/medwatc
h/medwatch-online.htm
Important Legislation




1994: first FDA regulations regarding drug product labeling
of known use and dosing
 Resulted in FDA approval of limited number of drugs in
children
1997: Pediatric Exclusivity Provision of FDA Modernization
Act passed
 Incentive for manufacturers to implement studies of their
products on children
1999: Pediatric Rule developed
 Mandated that manufacturers perform trials and provide
safety and efficacy data
2003- Pediatric Research Equity Act-outlined FDA authority
to enforce Pediatric Rule
Despite interest in pediatric
drug therapy research,
conducting clinical trials poses
unique challenges
Consider:
Recent reports of suicide with SSRI
Treatment/ over treatment of ADHD
Treatment of GERD
For Release: November 5, 2007,
ANTIREFLUX MEDICATION MAY BE OVERPRESCRIBED IN INFANTS
A majority of infants taking anti-reflux drugs did not meet the
diagnostic criteria for gastroesophageal reflux disease
(GERD), according to a new study, "Are We Overprescribing
Antireflux Medications for Infants With Regurgitation?"
Researchers conducted esophageal pH monitoring
(measuring the reflux or regurgitation of acid from the
stomach into the esophagus) of 44 infants in a New Orleans
medical center. Each of the children had persistent
regurgitation and was referred to a specialty service for
further management. The study showed that while only eight
of the infants had abnormal pH levels indicating GERD, 42 of
44 infants were on antireflux medication. When medication
was withdrawn from the infants who did not meet GERD
criteria, reflux symptoms did not worsen. The study authors
concluded that antireflux medications were unnecessary
in the majority of infants who were prescribed such
medication.
Developmental Pharmacology


Pharmacokinetic differences in children vary with
age
Drugs considered safe in one group of pediatric
patients may be ineffective or toxic in another
group

Hepatic enzymes and metabolic pathways mature at
different rates

E.g., maturation of each pathway is asynchronous


When a drug’s primary route of metabolism is immature, it may
be shunted through an alternate pathway
Drug dosing dilemmas can be avoided by using only
those drugs with scientifically supported dosing
Key Points

In infants, metabolism of most drugs is
reduced


GFR is 20-40% of adult capacity at birth and
increases after the 1st week of life-reaches
maximal level by 12 months
In general, children over 10 years have
organ development and metabolism
similar to adults

May require dosing adjustments based on
body surface area
Key Points (con’t)

GI tract acidity, enzymatic activity, and
motility differences in infants and young
children alter absorption of PO drugs
Drugs that are weak bases increase drug
absorption
 Drugs that are weak acids reduce drug
absorption
 Reduced gastric transit in infants delays
absorption and peak plasma concentration
time-but NOT the amount of drug absorbed

Key Points

Absorption from transcutaneous route is
enhanced in infants-increased risk of adverse
effects


Caution with use of topicals in infants
The volume of drug distribution in infants and
young children is increased due to increased
body water


Results in need for increased drug doses for watersoluble drugs (e.g., aminoglycosides)
Drugs that are lipophilic (e.g., diazepam) may exhibit
lower volume of distribution
Key Points

Alterations in protein binding and tissue
penetration of drugs may lead to reduced
OR exaggerated response
Practical Tips for Pediatric
Prescription Writing
1.
2.
3.
4.
5.
6.
Always obtain a weight at every pediatric visit
As a rule, start with smallest dose in neonates
and infants
“round up” the dose if it falls between the given
choices UNLESS it is a toxic drug or has
narrow therapeutic window
With acetominophen, calculate dosage using
weight, not age
Always specify preferred formulation (e.g.,
chewable tabs, suspension, etc)
Stay current with literature!!!
Geriatric Pharmacology
Baby Boomers and Beyond…
Medication Use Statistics

People >65 consume 30% of
prescription and 40% nonprescription drugs




(Cohen, 2000)
By 2030, the population >65 will
double-with largest increases in
85-older
Adverse drug reactions rank in
the top 5 causes of mortality and
morbidity in elderly
28% of elderly hospital
admissions are due to adverse
drug reactions
Adverse Drug Reactions
About 15% of hospitalizations in the
elderly are related to adverse drug
reactions
 The more medications a person is
on, the higher the risk of drug-drug
interactions or adverse drug
reactions
 The more medications a person is
on, the higher the risk of nonadherence

Costs of Drugs
Average prescription drug cost for an older
person is $500/year, but highly variable
 Nonprescription drugs and herbals can be
quite expensive and dangerous when mixed
with prescription drugs
 Many Medicare Managed Care Plans have
dropped or severely limited drug coverage
 Drugs cost more in US than any other country


Many elderly patients look toward “bootlegged”
drugs”
New drugs cost more-not covered
Non-prescription Drugs



Surveys indicate that elders take average of
2-4 nonprescription drugs daily
Laxatives used in about 1/3-1/2 of elders many who are not constipated
Non-steroidal anti-inflammatory medicines,
sedating antihistamines, sedatives, and H2
blockers are all available without a
prescription, and all may cause major side
effects
Prescription Drugs
Elderly account for 1/3 of
prescription drug use, while only
13% of the population
 Ambulatory elderly fill between 9-13
prescriptions a year (new and refills)
 One survey: Average of 5.7
prescription medicines per patient
 Average nursing home patient on 7
medicines

Pharmacokinetics


Decrease in total body water (due to
decrease in muscle mass) and increase
in total body fat affects volume of
distribution
Water soluble drugs: lithium,
aminoglycosides, alcohol, digoxin


Serum levels may go up due to decreased
volume of distribution
Fat soluble: diazepam, thiopental,
trazadone

Half life increased with increase in body fat
Pharmacokinetics
Absorption: Not highly impacted by
aging
 Variable changes in first pass
metabolism due to variable decline
in hepatic blood flow (elders may
have less first pass effect than
younger people, but extremely
difficult to predict)

Pharmacokinetics and the
Liver
Oxidative metabolism through
cytochrome P450 system decreases
with aging, resulting in a decreased
clearance of drugs
 Hepatic blood flow extremely variable

Drugs with Cytochrome P450 Effects
(partial)
Inhibitors
Inducers
Allopurinol
Metronidazole
Amiodorone
Quinolones
Barbiturates
Carbamazepine
Azole antifungals
Phenytoin
Cimetidine
Rifampin
INH
Tobacco
SSRIs
Tacrine
Pharmacokinetics: Excretion
and Elimination

GFR generally declines with aging, but is
extremely variable
 30%
have little change
 30% have moderate decrease
 30% have severe decrease
Serum creatinine is an unreliable marker
 If accuracy needed, do Cr Cl

The Cockroft and Gault Equation
Cr Cl = 140-age(yrs) X wt (kg) X .85 for women
Cr (mg/100ml)X72
May overestimate Cr Cl, especially in frail
elders
Useful equation, but must be aware of its
limitations
Pharmacodynamics:
What the Drug does to the Body

Some effects are increased



Alcohol causes increase is drowsiness and
lateral sway in older people than younger
people at same serum levels
Fentanyl, diazepam, morphine, theophylline
Some effects are decreased

Diminished HR response to beta -blockers
Undertreatment

CAD
Beta blockers
 ASA

Anticoagulation in AF
 HTN, especially systolic HTN
 Pain


Particular fear of narcotics in the elderly
Drug-Drug Interactions
Common cause of ADEs in elderly
 Almost countless – good role for
pharmacist and computer or on-line
programs
 Some common examples





Statins and erythromycin and other antibiotics
TCAs and clonidine or type 1Anti-arrythmics
Warfarin and multiple drugs
ACE inhibitors increase hypoglycemic effect of
sulfonylureas
Drug-disease Interactions


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Patient with PD have increased risk of drug
induced confusion
NSAIDs (and COX-2’s) s can exacerbate CHF
Urinary retention in BPH patients on
decongestants or anticholinergics
Constipation worsened by calcium,
anticholinergics, calcium channel blockers
Neuroleptics and quinolones lower seizure
thresholds
The “Prescribing Cascade”
Common cause of polypharmacy in
elderly
 Some common examples

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



NSAID ->HTN->antihypertensive therapy
Metoclopromide ->Parkinsonism ->Sinemet
Dihydropyridine -> edema ->furosemide
NSAID ->H2 blocker ->delirium ->haldol
HCTZ ->gout->NSAID ->2nd antihypertensive
Sudafed ->urinary retention ->alpha blocker
Antipsychotic ->akithesia ->more meds
NSAIDs

Acetaminophen as effective as NSAIDs in
mild OA

NSAIDs side effects

GI hemorrhage (less with COX-2)

Decline in GFR (COX-2 as well)

Decreased effectiveness of diuretics, antihypertensive agents

Indication should justify the increased
toxicity of NSAIDs
Drugs and Cognitive Impairment
Common cause of potentially
reversible cognitive impairment
 Demented patients are particularly
prone to delirium from drugs
 Anticholinergic drugs are common
offenders (TCAs, benadryl and other
antihistamines, many others)
 Other offenders cimetidine, steroids,
NSAIDs

Medical Letter 2000 Drug Safety 1999 Drugs and Aging
1999
Drugs and Falls




Biggest risk drugs are long acting
benzodiazepines and other sedative-hypnotics
Both SSRIs and TCAs associated with
increased risk of falling
Beta blockers NOT associated with increased
risk of falling in published literature
Mild increase in fall risk from diuretics, antiarrythmics, and digoxin
Leipzig, 2008
Drug-Food Interactions

Interactions between drugs and food




warfarin and Vitamin K containing foods
(remember green tea, as well)
Phenytoin & vitamin D metabolism
Methotrexate and folate metabolism
Drug impact on appetite


Digoxin may cause anorexia
ACE inhibitors may alter taste
Drugs And Dosages to Avoid in
Most Instances

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Meperidine
Diphenhydramine
The most anticholinergic tricyclics:
amitryptiline, doxepin, imipramine
Long acting benzodiazepines such as
diazepam
Long acting NSAIDs such as piroxicam
High dose thiazides (>25mg)
Iron: 325 mg once daily is enough
Anticipate SE’s

Narcotics



Steroids




Think about osteoporosis prevention
Remember steroid induced diabetes
Levothyroxine


Begin lactulose or sorbitol and a stimulant
laxative
Colace is NOT sufficient in most instances
Calcium interferes with absorption of
levothyroxine
?Biphosphonates and ? Atrial fibrillation
(NEJM, 2009)
Calcium and MI ??(BMJ, 2010)
High Risk Situations
Patient seeing multiple providers
 Patient on multiple drugs
 Patient lives alone and/or has
cognitive impairment
 Discharge from hospital or any
change in venue

Hospitalization: A High Risk
Time
At hospitalization:
 40% of admission medications
stopped
 45% of discharge medications were
started
 Serious prescribing problems in 22%
 Other prescribing problems in 66%


Beers JAGS 1989, Lipton Medical Care 1992
Non-adherence

Lack of understanding of how to take

High risk times: Hospital discharge, new meds
added, complex regimens
Unable to take
 Conscious nonadherence




Side effects
Lack of understanding of benefits of drug
Financial
Complementary Therapies







Very commonly used in the elderly
Some common herbs and alternative
therapies:
“Anti-aging”
DHEA, growth hormone
Dementia
Gingko biloba
BPH
Saw palmetto, PC-SPES
OA
Chondroiton sulfate,
glucosamine
Depression
St. John’s wort, SAMe
“Do No Harm?”

California Department of Health
Services, Food and Drug Branch





screened 250 Asian herbal products
collected from herbal stores in California
assayed products using gas chromatography,
mass spectrometry, and atomic-absorption
techniques
Ko, NEJM 1998; 339; 847
32% contained unlabeled
medications, 14% mercury, 14%
arsenic, 10% lead
Herbals and Supplements:
Regulation





Demonstration of safety is NOT required prior to
marketing
Manufacturing standards are not required
Can have health claims, but not claims about
treating, preventing, or curing
For glucosamine/chondroitin, 1/3 of
combinations did not contain listed ingredient
www.consumerlabs.com has drug information
Herbals and Supplements:Potential
interactions with Rx Drugs




SAMe may increase
homocysteine levels
St. John’s wort and Oral
contraceptives
Ginkgo may increase
anticoagulant effects of ASA,
warfarin, NSAIAs, ticlopidine,
and may interact with MAOIs
Bottom line: Try to know what
your patient is taking, and ask
in a nonjudgmental way
Mr. W. is a 86 year old man with pulmonary HTN, COPD,
CRI (creatinine of 2.2), CHF with an ejection fraction of
20%, mild dementia, depression, and severe anemia. He
is frequently admitted to the hospital because of severe
disease and poor adherence with his medical regimen. His
discharge medications on last admission one month ago
were aspirin 325mg, enalapril 20mg QD, furosemide
80mg BID, combivent, and sertraline 50mg. The inpatient
team decided that he was undertreated, and added
metoprolol 12.5mg BID, aldactone, FeSo4 325mg TID,
and 3 inhalers. He was readmitted within a week. How
might you approach his regimen?
Principles for Managing Drugs







Complete drug history, including herbs and
nonprescription drugs
Avoid medications if benefit is marginal or if
non-pharmacologic alternatives exist
Consider the cost
Start low, go slow, but get there!
Keep regimen as simple as possible
Write instructions out clearly
Have patient bring in medications at each visit
Principles (continued)





Consider medication box or “mediset”
If things don’t make sense, consider a
home visit
Discontinue drugs when possible if benefit
unclear or side effects could be due to drug
Be cautious with newer drugs
Consider if the benefit of the 7th or 8th drug
is sufficient to justify the cost, increase in
complexity of regimen, and risk of side
effects
Newer drugs
What is unique about this compound?
 What clinical data is available?
 How does it compare with traditional
therapy?
 How expensive is it?
 With third party payers cover this
product?
 Does the potential advantage of this new
drug justify the risk of using a new drug?

Summary






The elderly take more
medications than any other age
group
Pharmacokinetics and
pharmacodynamics are altered
Adverse drug reactions are
common
Risks go up with the number of
drugs used
Nonprescription and herbal
therapies are common
With care and common sense,
we can probably do a better job