Pharmacologic Implications for Special Patient Populations:

1
Pharmacologic Implications for Special Patient
Populations

• Pregnant
• Elderly
• Pediatric

Judith A. Kaufmann, Dr PH, FNP-C Associate
Professor of Nursing Robert Morris University
2
Vulnerable PopulationsAt Most Risk for Adverse
Drug Effects and Reactions
3
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 110,000
• Too simple patients with multiple conditions
  excluded from trials
• Too median-aged studies exclude patients at each
  end of the spectrum

4
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

5
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

6
Epidemiology

• 35 of women take some medications during
  pregnancy
• Range/pregnancy 1-15 medications (M2.9)
• 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

7
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
• FDAs Adverse Drug Reaction reporting system
  underused
• MEDWATCH Program initiated in 1993

8
Lessons from the Past

• Thalidomide first appeared in Germany on 1st
  October 1957
• 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
• Pre-marketing tests conducted on rodents which
  metabolize the drug in a different way to humans
• Subsequent tests on rabbits and monkeys produced
  similar SEs as in humans.
• Late 1950s post marketing reports
• Pharcomelia babies born with flipper-like
  limbs
• AKA 'Thalidomide Babies

9
Pharcomelia
10
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.orAnimal studies have shown an adverse
  effect, but adequate and well-controlled studies
  in pregnant women have failed to demonstrate a
  risk to the fetus.

11
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 DStudies, 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.

12
FDA Categories

• Category XStudies, 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.

13
Excellent Website

• Ob.Gyn. News - Editorial

14
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

15
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

16
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

17

• 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.
• 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

18
Pregnancy alters the Pharmacokinetics of Most
Drugs

• 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

19
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

20
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

21
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
• 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

22
Pregnancy and Pharmacokinetics

• Metabolism of drugs in liver relatively unchanged
• 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 fetuss circulation

23
Placental Transfer

• 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 mothers circulation
  through small membrane breaks

24
Properties of Medications that easily cross the
placenta

• Small molecular size and weight (250-500d)
• Most drugs have weights lt 600d
• Non-protein bound
• Non-ionized
• Lipophilic

25
Selecting a Drug for a Pregnant or Nursing Mother

• Principles of teratology
• Timing of exposure in fetal development
• 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)
• If exposure occurs in first 14 days after
  conception when the cells can assume another
  cells function (totipotential), the fetus may
  not be damaged
• Most sensitive period time from implantation to
  the end of organogenesis (days 18- 60)
• 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.

26
Factors that Influence Teratogenicity of a drug

• 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

27
The safest pregnancy-related pharmacy is as
little pharmacy as possible

• 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

28
The Male Partner

• Research is increasingly addressing the role of
  paternal exposure to medications before
  conception or during his partners pregnancy
• Certain exposures may alter the size, shape,
  performance, and production of sperm
• 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
• 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

29
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.

30
Current EB Recommendations

• 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

31
Drug Exposure Options for Pregnant and Lactating
women

• Withhold the drug (e.g., headache medications)
• 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)

32
Options

• Choose drugs that pass poorly into placenta or
  breast milk- (e.g., some variations even within
  same class of drug)
• 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.

33
Options

• Choose alternate routes of administration when
  possible
• Avoid long acting/medications with long half
  lives
• Advise lactating women to time their medications
  before the infants longest sleep period
• Temporarily withhold breast feeding
• Can safely resume after 1-2 half lives (50-75
  elimination)
• For drugs with high toxicity, must delay 4-5 half
  lives
• Discontinue nursing if medication is for life
  threatening condition (e.g., chemotherapy)

34
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

35
IMPLICATIONS of Pregnancy on Asthma

• 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 

36
Improved Outcomes associated with controlled
asthma

• 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.

37
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.

38
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)

39
Theophylline (Cat C)

• Can be used along with inhalation therapy
• Preferred treatment for patients requiring long
  term therapy
• Must monitor levels throughout pregnancy to avoid
  toxicity
• 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

40
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.
• They can be indicated as the first-line
  anti-inflammatory medication for the treatment of
  asthma
• Does not have systemic absorption
• ?crossing of placenta

41
Corticosteroids (cat C)

• Can be given IV, PO, or inhaled
• 2 reports congenital cataracts in infants exposed
  to prednisone throughout gestation
• No association found in other studies
• Spontaneous abortion, prematurity, cardiac
  abnormalities reported in one study
• (
  Greenberger,1983)
• Prednisone lt20mg/day safe in lactation
• In larger doses, delay nsg 3-4hours after dose

42
Epilepsy

• gt 1 million women of childbearing age have
  epiliepsy
• lt1 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
• Occurrence 46 per hundred births vs the 2-3
  per hundred births risk that all pregnant women
  face
• Benefits v risk are overwhelmingly important to
  consider

43
Epilepsy in Pregnancy

• 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
• Lower serum concentrations due to increased renal
  and hepatic clearance
• Decreased protein-binding capacity
• Increased volume distribution
• despite lower serum concentrations, seizures may
  not increase due to increased free drug
  concentrations
• Must monitor concentrations of anticonvulsants
  closely

44
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

45
Fetal Anticonvulsant Syndrome

• Can occur with all antiepileptic drugs
• Phenytoin (cat D) can cause fetal hydratoin
  syndrome
• 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

46
Phenobarbital (cat D)

• Less teratogenic that phenytoin but can cause
  heart defects and cleft palate
• Can also cause coagulopathies and folate
  deficiencies
• Also has potential to cause neonatal addiction
• Found in breast milk-causes newborn drowsiness,
  feeding difficulties, and infantile spasms after
  weaning

47
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

48
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

49
Sothe jury is still out

• 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.

50
The Teratogenicity of Anticonvulsant Drugs

• Holmes, et al NEJM 2001-
• Methods 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.

51
Results

• 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

52
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

53
Coagulation Disorders

• Pregnancy is a hypercoagulable state
• 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 gt35
• Multiple miscarriages

54
Heparin anticoagulant of choice (Cat C)

• 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
• Less bleeding potential and less risk of
  osteoporosis
• Does not cross fetal circulation
• Not excreted in breast milk

55
Coumadin (cat D)

• Exposure during 6-8th weeks can cause fetal
  warfarin syndrome
• Defects in CNS and skeletal system
• Exposure throughout pregnancy can cause
• Stillbirths, spontaneous abortion, facial
  abnormalities
• Compatible with breast feeding

56
Treating Common Problems in Pregnancy

• Common Cold
• Nausea/Vomiting
• Constipation
• Heartburn
• Hemorrhoids

57
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
58
The Common Cold

• 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

59
Nausea and Vomiting

• 80 of women experience n/v during 1st trimester
• Hyperemesis gravidarum-intractable, causes lyte
  imbalances, weight loss, possible end organ
  damage
• Occurs in 11000 births
• Requires hospitalization
• Cause unknown-tx focused on sx
• Non pharmacologic measures not supported by
  evidence
• OTC phosphorated carbohydrate (EMETROL) safe
• Meclizine (cat B) drug of choice

60
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
• Increase fluids to prevent intestinal obstruction
• Surfactants/Stool softeners (docusate), mineral
  oil Cat c

61
Heartburn

• 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
• If necessary-ranitidine preferred over cimetidine
  (has anti-androngenic effects)
• Metoclopromide (Reglan) cat B

62
Hemorrhoids

• OTC external preparations preferred
• Avoid suppositories d/t potential for systemic
  absorption across rectal mucosa

63

• General Principles

64
Limitations of Drug Therapy in Children

• 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

65
Post Marketing Adverse Drug Reports

• MED WATCH
• FDA
• http//www.fda.gov/safety/MedWatch/default.htm
• https//www.accessdata.fda.gov/scripts/medwatch/m
  edwatch-online.htm

66
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

67
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

68
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.

69
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 drugs 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

70
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

71
Key Points (cont)

• 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

72
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
  water-soluble drugs (e.g., aminoglycosides)
• Drugs that are lipophilic (e.g., diazepam) may
  exhibit lower volume of distribution

73
Key Points

• Alterations in protein binding and tissue
  penetration of drugs may lead to reduced OR
  exaggerated response

74
Practical Tips for Pediatric Prescription Writing

1. Always obtain a weight at every pediatric visit
2. As a rule, start with smallest dose in neonates
   and infants
3. round up the dose if it falls between the given
   choices UNLESS it is a toxic drug or has narrow
   therapeutic window
4. With acetominophen, calculate dosage using
   weight, not age
5. Always specify preferred formulation (e.g.,
   chewable tabs, suspension, etc)
6. Stay current with literature!!!

75
Geriatric Pharmacology

• Baby Boomers and Beyond

76
Medication Use Statistics

• People gt65 consume 30 of prescription and 40
  non-prescription drugs
• (Cohen, 2000)
• By 2030, the population gt65 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

77
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 non-adherence

78
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

79
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

80
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

81
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

82
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)

83
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

84
Drugs with Cytochrome P450 Effects(partial)
Inhibitors Inducers Allopurinol Metronidazole
Barbiturates Amiodorone Quinolones Carbamazepin
e Azole antifungals Phenytoin Cimetidine Ri
fampin INH Tobacco SSRIs Tacrine
85
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

86
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
87
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

88
Undertreatment

• CAD
• Beta blockers
• ASA
• Anticoagulation in AF
• HTN, especially systolic HTN
• Pain
• Particular fear of narcotics in the elderly

89
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

90
Drug-disease Interactions

• Patient with PD have increased risk of drug
  induced confusion
• NSAIDs (and COX-2s) 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

91
The Prescribing Cascade

• Common cause of polypharmacy in elderly
• Some common examples
• NSAID -gtHTN-gtantihypertensive therapy
• Metoclopromide -gtParkinsonism -gtSinemet
• Dihydropyridine -gt edema -gtfurosemide
• NSAID -gtH2 blocker -gtdelirium -gthaldol
• HCTZ -gtgout-gtNSAID -gt2nd antihypertensive
• Sudafed -gturinary retention -gtalpha blocker
• Antipsychotic -gtakithesia -gtmore meds

92
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,
  anti-hypertensive agents
• Indication should justify the increased toxicity
  of NSAIDs

93
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
  
  

94
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,
  anti-arrythmics, and digoxin
• Leipzig, 2008

95
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

96
Drugs And Dosages to Avoid in Most Instances

• Meperidine
• Diphenhydramine
• The most anticholinergic tricyclics
  amitryptiline, doxepin, imipramine
• Long acting benzodiazepines such as diazepam
• Long acting NSAIDs such as piroxicam
• High dose thiazides (gt25mg)
• Iron 325 mg once daily is enough

97
Anticipate SEs

• Narcotics
• Begin lactulose or sorbitol and a stimulant
  laxative
• Colace is NOT sufficient in most instances
• Steroids
• Think about osteoporosis prevention
• Remember steroid induced diabetes
• Levothyroxine
• Calcium interferes with absorption of
  levothyroxine
• ?Biphosphonates and ? Atrial fibrillation (NEJM,
  2009)
• Calcium and MI ??(BMJ, 2010)

98
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

99
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

100
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

101
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. Johns wort, SAMe

102
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

103
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

104
Herbals and SupplementsPotential interactions
with Rx Drugs

• SAMe may increase homocysteine levels
• St. Johns 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

105
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?
106
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

107
Principles (continued)

• Consider medication box or mediset
• If things dont 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

108
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?

109
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