Pharmacotherapy of Special Populations

Melody Ryan, PharmD, MPH Associate Professor

Pharmacy Practice & Science and Neurology

Objectives

• Define current FDA categories for use of medications during pregnancy

• Review the proposed changes to the current FDA categories

• Explain the principles of drug transfer across the placenta and into breast milk

• Discuss common conditions associated with pregnancy and review the medications used for treatment

Objectives

• List physiologic considerations for children

• Compare pediatric and adult pharmacokinetic properties

• Outline pediatric considerations for therapeutic drug monitoring

Objectives

• Identify the physiologic changes in the older adult that alter the effects of medications

• Discuss causes of and contributors to polypharmacy

• Discuss ways to utilize Beer’s list criteria as a tool, not a rule, in assisting with determination of inappropriate medications in the older adult

• Give examples of medications and/or medication classes to avoid in older adults

Drug Therapy in Pregnancy and Lactation

• Maternal pharmacokinetic changes

• Drug use in pregnancy

• Drug use in lactation

Pregnancy

• Between 50 and 70% of women use at least one medication during pregnancy

• Adherence may be a problem – Women concerned

about effect of medicine on fetus

– Risk usually overestimated

Mitchell AA, et al. Am J Obstet Gynecol 2011;205:51 e1-e8.

Neilsen MJ, et al. Aliment Pharmcol Ther 2010;32:49-58.

Nordeng H, et al. Eur J Clin Pharmacol 2010;66:207-14.

Maternal Pharmacokinetic Changes - Absorption

• Gastric emptying and small intestinal motility decreased

– Particularly in 3rd trimester

• Nausea and vomiting

Maternal Pharmacokinetic Changes - Distribution

• Plasma volume expansion of 50% – Vd increase, particularly with

small Vd medicines, decreases serum concentration; most important for loading doses

– Hypoalbuminemia due to dilution, decreased plasma protein binding, increased Cf; also increased availability for metabolism

Loebstein R, Koren G. Ther Drug Monit 2002;24:15-22.

Maternal Pharmacokinetic Changes - Metabolism

• Increased hepatic blood flow

– Increased metabolism of some medicines; particularly in 3rd trimester

• CYP3A4, CYP2D6, CYP2A6, CYP2C9, and UGT activity increased

• CYP1A2, CYP2C19 activity decreased

Hodge LS, Tracy TS. Expert Opin Drug Metab Toxicol 2007;3:557-71.

Pavek P, et al. Curr Drug Metab 2009;10:520-9.

Dawes M, Chowienczyk PK. Best Pract Res Clin Obstet Gynaecol 2001;15:819-26.

Maternal Pharmacokinetic Changes - Elimination

• Renal blood flow increases by 25-50%

• Glomerular filtration rate increases by 50%

Loebstein R, Koren G. Ther Drug Monit 2002;24:15-22.

Summary of Pharmacokinetic Changes

Process Changes

Absorption ↓↑

Distribution ↑

Metabolism ↑↓

Elimination ↑

• Consult literature • Therapeutic drug monitoring • Cautions

• Inter-individual variation • Small studies • Changes in each trimester of pregnancy • Drug-drug interactions • Therapeutic ranges are usually not validated for pregnant

individuals

Drug Use in Pregnancy • Teratogenesis: dysgenesis of fetal organs as evidenced

either structurally or functionally

• Congenital malformations: structural abnormalities of prenatal origin that are present at birth and seriously interfere with viability or physical well being

• Congenital anomalies: malformations and those defects related to change in function

Pregnancy Outcomes

• 3-6% of pregnancies have malformations or anomalies

1%

25%

10% 64%

Medications

Genetic

Maternalconditions/infections

Unknown

Placental Transfer

• Passive diffusion

• Molecular weight – MW= 250-500 kDa – easily cross

– MW= 500-1000 kDa – cross more slowly

– MW = >1000 kDa – generally don’t cross

• Protein binding – Maternal albumin decreases

– Fetal albumin increases

– Protein-bound medicines may have higher concentrations in the fetus

Yaffe SJ. Drugs in pregnancy and lactation. 2005;7: xiii-xix.

Placental Transfer

• Lipophilicity

• Ionization

– Fetal pH is lower than maternal pH

– Weak bases cross placenta easier

– Ionization occurs and then molecule can’t return to maternal circulation

Yaffe SJ. Drugs in pregnancy and lactation. 2005;7: xiii-xix.

Placental Transfer

• Pharmacogenomics

– Polymorphisms of CYP isoenzymes and P-glycoproteins

– Poor maternal metabolizers increase fetal drug exposure

– Placenta genetic characteristics are the fetus’

Example • ABCB1 gene codes for P-glycoprotein

• Polymorphism in exon 26 is C3435T

• TT individuals have ↓ transport activity and ↑ serum concentrations

Maternal genotype

Fetal (placental)

Effect on fetal exposure

CC or CT CC or CT Most commonly expected genotype representing normal transport of drugs

TT CC or CT No effect or some increase

CC or CT TT Increased exposure

TT TT Increased exposure relative to other genotypes

DeVane CL, et al. J Psychopharmacol 2006;20, S54-9.

Fetal Outcome • Factors affecting fetal outcome

– Stage of development at time of insult

– Concentration of the drug or offending chemical

Yaffe SJ. Drugs in pregnancy and lactation. 2005;7: xiii-xix. Wells BG. Pregnancy and lactation. 2003;(5)300-10.

Timing Potential Effect

Blastogenesis (0-15 days) “all or nothing”

Organogenesis (15-56 days) Structural abnomalities Ex: chemo, lithium, thalidomide, certain AEDs

Fetal Period (56- birth) Growth retardation, CNS abnormalities, death

Fetal Development

Weeks 0-13 – 1st trimester

Weeks 14-26 – 2nd trimester

Weeks 26-40 – 3rd trimester

Determinants of Teratogenicity

• Animal studies - extrapolated to humans not always valid

• Case reports – may have occurred by chance

• Epidemiological studies

– Case-control – recall bias may be a problem

– Cohort studies – expensive and need large numbers

• Pregnancy registries – voluntary reporting

FDA Categories for Medication Use in Pregnancy

• A controlled studies in women fail to demonstrate fetal risk during first trimester; fetal harm is remote

• B either: – Animal studies do not indicate risk to fetus and

there are no controlled studies in human women

OR

– Animal studies have indicated risk, but human studies failed to demonstrate risk

Yaffe SJ. Drugs in pregnancy and lactation. 2005;7: xiii-xix.

FDA Categories for Medication Use in Pregnancy

C either Animal studies demonstrate fetal risk and there are

no controlled studies in human women

OR

No animal studies have been conducted and there are no controlled studies in pregnant women

D positive evidence of fetal risk, however there may be certain situations where benefits outweigh risks

X definite fetal risk and risk outweighs any benefit in pregnant women (CONTRAINDICATED)

Yaffe SJ. Drugs in pregnancy and lactation. 2005;7: xiii-xix.

Problems with Current System

• Less than 1% of medication have category ‘A’ rating

• Greater than 65% of medications have category ‘C’ rating

• Current categories are outdated and difficult to understand

• Single letter cannot adequately summarize clinical information and summarize scientific data

• Inconsistent with current information

• Increase ability to make well-informed decision

Proposed FDA Changes • Elimination of current A,B,C,D, X categories

• Elimination of labor and delivery subsection

• Development of new ‘pregnancy’ and ‘lactation’ subsections

– 3 main components of each subsection

• Risk summary

• Clinical considerations

• Data section

http://www.regulations.gov/#!documentDetail;D=FDA-2006-N-0515-0001

Pregnancy Subsection • Risk summary

– One sentence summary of risk that the medication may or may not increase likelihood of various fetal abnormalities

• Clinical considerations – Prescribing considerations (ex: dose adjustments, unique

ADR during pregnancy, complications in neonates, etc) – Medication effects during labor and delivery – Inadvertent exposure

• Supporting data – Study type – Dose exposure information – Nature of fetal abnormalities and ADR – Data from pregnancy exposure registries

http://www.regulations.gov/#!documentDetail;D=FDA-2006-N-0515-0001

Lactation Subsection • Risk summary

– Statement of compatibility with breast feeding

• Clinical considerations

– Options to minimize exposure

– Dose adjustments during lactation

– Medication effects and monitoring parameters in an exposed child

• Supporting data

– Synopsis of data used to derive summary of risk and clinical considerations

http://www.regulations.gov/#!documentDetail;D=FDA-2006-N-0515-0001

Database Review • Review of 8 insurance databases

• Study period from Jan. 1, 1996- Dec. 31, 2000

• Average of 2.7 medications dispensed and 1.7 medications other than vitamins and minerals

• In the 270 days prior to delivery

– 37.8% received a medicine from category C

– 4.8% received a medicine from category D

– 4.6% received a medicine from category X

Andrade S, et. al. Am Jour Obst Gyne 2004;191:398-407.

Common Medical Issues during Pregnancy

• Constipation - 25-40% – Non-pharmacologic treatment

– Fiber or stool softener

– Osmotic laxatives – occasional use

– Senna and biscodyl – occasional use

• Gastroesophageal reflux disease – 80% – Non-pharmacologic treatment

– Aluminum, calcium, or magnesium antacids or sucralfate

– Ranitidine or cimetidine (famotidine, nizatidine)

Common Medical Issues during Pregnancy

• Nausea and vomiting – 90% – Most common weeks 5-13; 15% throughout

whole pregnancy; 1-3% hyperemesis gravidarum

– Non-pharmacological treatment

– Multivitamins, pyridoxine 10-25 mg 3-4 times/day, doxylamine 12.5 mg 3-4 times/day, ginger

– Phenothiazines (promethazine 12.5-25 mg every 6 hours) and metoclopramide 12.5-25 mg 2-3 times/day

– Ondansetron if other treatments fail

Common Medical Issues during Pregnancy

• Gestational diabetes – 1-14%

– Non-pharmacological treatment

– Insulin

– Glyburide is occasionally used

– Need to monitor blood glucoses

• Thromboembolism – 0.06-0.13%

– Low-molecular weight or unfractionated heparin

– Continue until 6 weeks after delivery

Common Medical Issues during Pregnancy

• Hypertension – 10% – Severe (≥170/110) may cause hospitalization and

premature delivery

– Calcium 1-2 g/day reduces risk by 30% and is recommended for all pregnant women

– Aspirin 75-81 mg/day after 12 weeks gestation in women at risk for preeclampsia reduces risk by 17% • Risks – previous preeclampsia, renal disease, autoimmune

disease, diabetes, chronic hypertension

– Treatment • Methyldopa, labetalol, calcium channel blockers

Common Medical Issues during Pregnancy

• Preeclampsia - 2-8% – Symptoms – blood pressure elevation, proteinuria,

persistent severe headache, persistent epigastric pain, visual changes, vomiting, hyperreflexia, sudden and severe edema, low platelets, hemolytic anemia, increased serum creatinine, elevated liver enzymes

– Complications - renal failure, coagulopathy, preterm delivery, intrauterine grown restriction

– Treat hypertension and may use magnesium sulfate to prevent eclampsia

• Eclampsia – preeclampsia + seizures – Treat seizures with magnesium sulfate

Common Medical Issues during Pregnancy

• Eclampsia – preeclampsia + seizures

– Treat seizures with magnesium sulfate

• Initial dose: 4 g IM of 50% solution every 4 hours as necessary or 1-2 g/hr IV infusion of a 10-20% solution

• Maintenance: 1-2 g/hr IV; not to exceed 30-40 g/day

• 5-7 days total

• Delivery of baby as soon as possible

Common Medical Issues during Pregnancy

• Urinary tract infections – 1-4%

– E. coli in 80-90%; P. mirabilis, K. pneumoniae, group B Streptococcus

– Treat asymptomatic bacteriuria

• Progresses to pyelonephritis in 20-40% of pregnant women vs. 1-2% of non-pregnant women

– Cephalexin, nitrofurantoin (except for Proteus or after week 37 in women with glucose-6-phosphate dehydrogenase deficiency), sulfa (avoid in last weeks), trimethoprim (avoid during first trimester)

Common Medical Issues during Pregnancy

• Headache

– Non-pharmacologic treatment

– Acetaminophen

– Codeine

– No aspirin or NSAIDs during the third trimester

Chronic Conditions during Pregnancy

• Weigh risk of no treatment

• Weigh risk of switching therapies

Drug Use in Lactation

• Passive diffusion

– Protein binding

– Molecular weight

– Lipid solubility – of medicine and milk fat content

– Plasma concentration– as mother metabolizes medicine, her serum concentration decreases and medicine may re-distribute back to serum from breast milk

Drug Use in Lactation

– Half-life – will have higher breast milk concentrations

– pH – breast milk pH=6.8, weak bases distribute to breast milk, ionize, and stay in breast milk – “ion trapping”

• Drug stability in gastric acid of infant

– Aminoglycosides, omeprazole, heparin, insulin are not stable

Drug Use in Lactation

• Infant-related factors

– Amount of milk taken – is baby exclusively breast fed?

– Ability to metabolize and excrete medication, particularly if premature

• Resource – LactMed from National Library of Medicine

– http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT

Case

• GS is a 30 y/o F is in clinic for her first prenatal visit. She is 8 weeks pregnant. You notice she is taking 2 anti-hypertensive medications

• Which of the following would be acceptable in this patient?

Lisinopril Amlodipine HCTZ

Valsartan Labetalol Methyldopa

Case

• GS is a 30 y/o F is in clinic for her first prenatal visit. She is 8 weeks pregnant. You notice she is taking 2 anti-hypertensive medications

• Which of the following would be acceptable in this patient?

Lisinopril Amlodipine HCTZ

Valsartan Labetalol Methyldopa

Case

• When she is in her second trimester, GS has an urinalysis. It reveals bacteria in the urine; however, she denies dysuria, fever or increased frequency of urination.

• Should you treat asymptomatic bacteriuria?

Case

• Later, in week 34 of her pregnancy, GS presents complaining of constipation despite increasing fluids and she states she walks daily for exercise.

• PMH: chronic constipation

• What should you recommend?

Case

• GS has been maintained on methyldopa for her hypertension during her pregnancy.

• She delivers a beautiful term baby girl at 40 weeks gestation.

• Can she continue on her current antihypertensive medicine while she breastfeeds?

Case

• Methlydopa: limited data from four nursing women who were taking methyldopa 750-2000 mg/day revealed milk concentrations ranging from 0.1-0.9 mcg/mL. Adverse effects in the infant are unlikely.

Drug Therapy in Pediatrics

• Physiology of children and its impact on the pharmacokinetics of children

• Drugs which should be used with caution in children

• Calculation of dosage for children

Definitions

• Gestational age (GA): number of weeks from the first day of the mother’s last menstrual cycle until birth

• Postnatal age: chronological age after birth

Definitions

• Term: > 38 weeks GA

• Preterm: < 38 weeks GA at birth

• Extremely low birth weight: < 1 kg

• Very low birth weight: < 1.5kg

• Low birth weight: < 2.5kg

Definitions Postnatal Age Classification

< 1month of age

Neonate

1 month to 1 year old

Infant

1 year to 12 years old

Child

12 to 16 years old

Adolescent

Developmental Differences

• Differences between pediatrics and adults

– Bioavailability

– Pharmacokinetics

– Pharmacodynamics

– Efficacy

– Adverse effects

Pharmacokinetic Effects

ADME

Age

Clinical Conditions

Disease States

Pharmaco-genomics

Drug Interactions

Medical Devices

Oral Absorption

• Gastrointestinal pH at birth • Full term 1 – 3 • Premature 6 – 8

• Reduced gastric emptying/motility – Particularly in premature infants, gastroesophageal reflux,

respiratory distress syndrome, and congenital heart disease • Decreased first pass metabolism • Drugs affected

• Acetaminophen, ampicillin, iron, penicillin, phenobarbital, phenytoin

Topical Absorption

• Skin – Thinner stratum corneum in newborns – Larger skin surface area vs. body weight –Better hydration and perfusion

• Potential systemic toxicity • Drugs affected

–Antibiotics, corticosteroids, silver sulfadiazine

Body Composition

Increased total body water

~94% in fetus

~85% in premature infant

~78% in full term infants

~60% in adults

Increased extracellular fluid

~50% body weight in premature infants

~35% in 4-6 mo old

~25% in 1 yo

~19% in adults

Higher Vd for water-soluble drugs

Body Composition

• Muscle constitutes 25% in newborns

• Increase in adipose tissue peaks at 4 to 6 months

• Lower Vd for fat-soluble drugs

Distribution

• Protein binding

–Decreased in newborns and infants

• Drugs affected

–Aminoglycosides, phenytoin, sulfamethoxazole, vancomycin

Metabolism

• Generally reduced in newborns and infants • Hepatic enzyme activity may be double adult

levels in children 6 mo - adolescence • Drugs affected

– Acetaminophen (glucuronidation) – Chloramphenicol (glucuronidation) – Ethanol and propylene glycol (oxidation and

alcohol dehydrogenase) – Phenobarbital (hydroxylation) – Phenytoin (saturable metabolism)

Excretion

• Immature at birth

• Drugs affected:

–Aminoglycosides, diuretics, penicillins, vancomycin

N Engl J Med 349;12.

Summary

Pediatric TDM Considerations

• Minimize the number of blood samples and draw blood during routine samplings whenever possible

• Obtain minimal blood

• Utilize available data instead of obtaining subsequent sampling

• Check that intravenous lines are flushed appropriately before obtaining samples

Pediatric Drug Dosage

• Pediatric dose information

– Manufacturer package insert

• Pediatric doses stated as mg/kg or mg/m2

Pediatric Drug Dosage

• Young’s Rule – Dose = Adult dose x Age(yrs)/(Age + 12)

• Clark’s Rule – Dose = Adult dose x [Weight (kg)/70]

• Body surface area (BSA)

BSA (m2) = height(cm) x wt(kg)

Basic & Clinical Pharmacology, 8th Ed., 2001.

3600

Pediatric Drug Dosage

• Creatinine clearance – Schwartz equation for 6 mo-21 yrs

CrCl = kL k=proportionality constant

SCr L=length (cm)

SCr=serum creatinine (mg/dL)

CrCl=creatinine clearance (mL/min/m2)

Age k

Low birth weight < 1 yr 0.33

Full-term < 1 yr 0.45

1-12 yr 0.55

13-21 yr (female) 0.55

13-21 yr (male) 0.70

Drug Dosage Based on Surface Area Weight

(kg) Approximate

Age Surface area

(m2) Percent of Adult Dose

3 Newborn 0.2 12

6 3 months 0.3 18

10 1 year 0.45 28

20 5.5 years 0.8 48

30 9 years 1 60

40 12 years 1.4 78

50 14 years 1.5 90

60 Adult 1.7 102

70 Adult 1.76 103

Basic & Clinical Pharmacology, 8th Ed., 2001.

Medications to Use with Caution in Children

• Aspirin – Reye’s syndrome • Ceftriaxone – neonates, particularly premature • Codeine – poor metabolizers, increased

respiratory depression • Ethanol - intoxication • Fluroquinolones – bone growth • Propylene glycol - seizures • Sulfamethoxazole/trimethoprim –

hyperbilirubinemia and kernicterus • Tetracycline – calcium deposits

Case

• GS names her baby PS. At six months of age, she brings him to the clinic with a runny nose and fever. She states that he has been irritable.

• The physician diagnoses otitis media.

• Which medications would be appropriate to use for PS?

Drug Therapy in Geriatrics

• Age-related changes in physiology and special pharmacotherapy considerations in elderly adults

• Age-related changes in pharmacokinetics

• General principles of rational drug therapy in the elderly

• Drugs which should be used with caution in the elderly

Age-Related Changes in Medication Effects

• Physiologic changes in the older adult occur in all organ systems

• These changes are not universal; we all age differently

68

Age-Related Changes in Medication Effects

• Impact of Aging: increased sensitivity to many drugs and reduced clearance; therefore, increased adverse effects and longer duration

– Doses generally need to be decreased

– Examples: warfarin, morphine, and diazepam

69

Age-Related Changes in Medication Effects

• Cardiovascular – ↓ cardiac output

– ↓ arterial elasticity

– ↑ vascular resistance

– ↑ blood pressure

– Myocardial irritation ↑ irregular heartbeat

• Endocrine – ↑ blood glucose

– ↓ bone mass

• Respiratory – ↓ cough reflex

– Impaired gas exchange

– ↓ pulmonary blood flow-contributes to lower O2 saturation

– ↑ lung rigidity

• Genitourinary – ↓ in creatinine clearance

– ↓ bladder capacity

– ↑ incontinence 70

Age-Related Changes in Medication Effects

• Neurologic

– Overall slowed reaction time • Changes sleep patterns

– Nerve fibers ↓

– Dopamine levels ↓

• Skin

– Thinning of epidermis

• Musculoskeletal

– ↓ muscle cells

– ↓ locomotion

• Gastrointestinal

– ↓ taste buds

– ↓ peristalsis

– ↓ secretions of acid in stomach

– ↓ hepatic & pancreatic enzymes

• Immunologic

– ↓ overall function • ↓ temperature regulation

71

Age-Related Changes in Medication Effects-Summary

• Effects of medications are altered in the older adult due to age-related physiologic changes: – Are at increased risk for side effects

– START LOW!! GO SLOW!! - Start medications at lower doses than younger adults; increase doses in smaller increments

– Doses may need to be reduced; may begin having adverse effects due to slowly increasing blood levels and increased sensitivity

72

Age-Related Changes in Pharmacokinetics

Process Clinical Change

Absorption Little change in absorption, but may have thinner skin or changes in gastrointestinal motility

Distribution ↓ in body water ↑ concentration of water-soluble drugs (e.g., digoxin and theophylline) ↑ in body fat ↑ Vd of fat-soluble drugs which can delay elimination and result in longer duration of action (e.g., diazepam)

Metabolism ↓ liver mass and blood flow; ↓ metabolism by the liver clearance ↓; longer duration of action and more accumulation with chronic use (e.g., diazepam, diphenhydramine, meperidine)

Excretion ↓ renal mass and blood flow; ↓ elimination by the kidneys clearance ↓; longer duration of action and more accumulation with chronic use (e.g., furosemide, hydrochlorothiazide, lithium)

73

Pharmacokinetic Changes Excretion/Elimination

• Renal function generally decreases with age

• CrCl decreases ~ 10%/decade after age 40 in 2/3 persons

• Serum creatinine is NOT a good indicator of renal function in the elderly – Creatinine is a product of muscle breakdown

• Decreased muscle mass in agedreduced production of SCrcould produce normal SCr in person with reduced renal function

– Creatinine clearance (CrCl) is a better indicator of renal function

74

Pharmacokinetic Changes Excretion/Elimination

Cockcroft-Gault Equation

Estimated CrCl = (140-age) x weight in kg

72 x creatinine

x 0.85 for females

Round creatinine up to 1.0 in older adults!

GlobalRPh: http://www.globalrph.com/crcl.htm

75

Pharmacokinetic Changes Excretion/Elimination

Common Renally Eliminated Medications

Allopurinol

Ranitidine

Ciprofloxacin

Levofloxacin

Gabapentin

Pregabalin

Meperidine

Magnesium

Metformin

Aminoglycosides

Most ACE inhibitors (except

fosinopril)

Digoxin

Lithium

Diuretics

Vancomycin

76

Age-Related Changes in Medication Effects

• Impact of aging: increased sensitivity to many drugs and reduced clearance; therefore, increased adverse effects and longer duration

– Doses generally need to be decreased

– Examples: warfarin, morphine, and diazepam

77

Age-Related Changes in Medication Effects

• Cardiovascular – ↓ cardiac output

– ↓ arterial elasticity

– ↑ vascular resistance

– ↑ blood pressure

– Myocardial irritation ↑ irregular heartbeat

• Endocrine – ↑ blood glucose

– ↓ bone mass

• Respiratory – ↓ cough reflex

– Impaired gas exchange

– ↓ pulmonary blood flow-contributes to lower O2 saturation

– ↑ lung rigidity

• Genitourinary – ↓ in creatinine clearance

– ↓ bladder capacity

– ↑ incontinence 78

Age-Related Changes in Medication Effects

• Neurologic

– Overall slowed reaction time • Changes sleep patterns

– Nerve fibers ↓

– Dopamine levels ↓

• Skin

– Thinning of epidermis

• Musculoskeletal

– ↓ muscle cells

– ↓ locomotion

• Gastrointestinal

– ↓ taste buds

– ↓ peristalsis

– ↓ secretions of acid in stomach

– ↓ hepatic & pancreatic enzymes

• Immunologic

– ↓ overall function • ↓ temperature regulation

79

Rational Drug Therapy in Older Adults

• Goal:

– Devise an effective therapeutic regimen that minimizes the number of medications and doses required

– Results in reduction of potential for adverse reactions, drug interactions, and medication errors

80

Risks of Medication Use in the Elderly • Polypharmacy

• Side effects

• Adverse drug reactions

• Fall risk

• Interactions (drug, food, disease)

• Cost

• 2.3 – 15.2% of all hospital admissions are due to medication-related problems

• As many as 28% of all emergency room visits are medication-related and 70% of these visits are preventable

81

Polypharmacy Definition • Means “many drugs”

• Refers to problems that can occur when a patient is taking several medications at the same time

Polypharmacy

• Actual number of medications per patient not as important

• More important to ensure

– Each medication is necessary and effective

– Each medication is the safest medication within its class in terms of potential for ADRs, drug interactions, etc.

83

Polypharmacy – Causes

• Multiple disease states – Chronic illnesses more common in elderly:

• Evidence-based medicine – Clinical guidelines/criteria for treatment of chronic disease,

many of which promote multiple medications for single condition

– Increasingly aggressive treatment goals

• Complicated by age-related changes in medication effects

84

Polypharmacy – Causes

• Patient barriers – Psychological dependence

– Reluctance to admit to all medications

– Reluctance to discard old medications

– Multiple providers visited

– Multiple pharmacies visited

– Inaccurate record of medications

– Don’t remember instructions to change/stop medication

85

Polypharmacy – Causes

• Provider barriers – Assuming medication compliance/adherence

– Failure to ask about other providers

– Reluctance to change other providers’ orders

– Increased need for/frequency of follow-up visits

– Failure to ask about non-prescription, sample, and herbal medicines

– Lack of routine medication reviews

– “Prescribing cascade”

86

“Prescribing Cascade”

• Treating adverse reactions with another drug • Adverse reactions misinterpreted as a “new”

medical condition • Agitation antipsychotic stiffness, tremor Parkinson’s disease medication

• Arthritis NSAID increased BP antihypertensive medication

87

Polypharmacy – Causes

• Payment considerations

– Insurance pays for prescription but not lifestyle modification

• Lack of strong clinical trial data involving older patients

88

Polypharmacy – Causes

• Self medication

– Non-prescription medications

– Herbals and botanicals

• Public perception that “natural” = “safe”

– Using medications from friends/family

89

Polypharmacy - Consequences

• Medication non-adherence, non-compliance

• Adverse drug reactions

• Drug-drug interactions

• Increased risk of hospitalization or nursing home placement

• Medication errors

• Increased medication or treatment costs

90

Medication-Related Problems

• A equal dose of medication produces a different, and sometimes unexpected, response in an elderly patient compared to a younger patient of the same gender and similar body weight

• Medication-related problems are among the top five greatest threats to the health of older adults

• 28% of hospitalizations among older adults are due to medication-related problems

91

Risk Factors

• Physiologic changes of aging – Age-related decrease in kidney/liver function

– Hearing/vision impairment

– Changes in body composition

– Decreased physical stature

• Increased incidence of multiple chronic diseases and conditions

• Greater consumption of medications

92

Risk Factors

• Multiple prescribers

• Socioeconomics

• Under-representation in clinical trials, particularly those over age 75

• Shortage of trained professionals in geriatric pharmacotherapy

• Poor nutrition

• Cognitive impairment, dementia

93

Symptoms of Medication-Related Problems

• Confusion

• Depression

• Delirium

• Insomnia

• Parkinsonian symptoms

• Incontinence

• Weakness or lethargy

• Loss of appetite

• Falls

• Changes in speech

94

Most Commonly Prescribed Medication Categories

Medication Categories Percent of Patients

Cardiovascular 53.2%

Antibiotics/anti-infectives 44.5%

Diuretics 29.5%

Opioids 21.9%

Antihyperlipidemic 21.7%

Nonopioid analgesics 19.8%

Gastrointestinal 19.0%

Respiratory 15.6%

Dermatologic 14.8%

Antidepressants 13.2%

Sedatives/hypnotics 12.9%

Nutrients/supplements 12.3%

Hypoglycemics 11.5%

95

Frequency of Adverse Drug Events by Medication Categories

Medication Categories Percentage of Patients

Cardiovascular 26.0%

Antibiotics/anti-infectives 14.7%

Diuretics 13.3%

Non-opioid analgesics 11.8%

Anticoagulants 7.9%

Hypoglycemics 6.8%

Steroids 5.3%

Opioids 4.9%

Antidepressants 3.2%

Antiseizure 2.3%

Antihyperlipidemics 2.0%

Antineoplastics 1.7%

Gastrointestinal tract 1.3%

96

Common Adverse Reactions in Elderly

• Falls – Sedatives/hypnotics, anticonvulsants,

antihypertensives, antipsychotics, antineoplastics, hypoglycemics

• GI distress – Aspirin, non-steroidal anti-inflammatory drugs,

iron, metformin, anticholinesterase inhibitors, lipid-lowering agents, antibiotics

• Incontinence – Caffeine, diuretics, alcohol, sedative/hypnotics

97

Common Adverse Drug Reactions in the Elderly

• Constipation – Verapamil/diltiazem, antipsychotics,

antidepressants, narcotics, diuretics, antacids (aluminum/calcium), anticholinergics

• Confusion – Any central nervous system-active agent, anti-

Parkinson’s agents, digoxin, metoclopramide, beta-blockers

• Anxiety/insomnia – Caffeine, serotonin reuptake inhibitors,

decongestants, steroids

98

Anticholinergic Effects

• Dry mouth

• Dry skin

• Urinary retention

• Constipation

• Palpitations

• Tachycardia

• Blurred vision

• Confusion

• Agitation

Anticholinergics: #1 cause of medication-induced delirium in older adults

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Anticholinergics

• Antihistamines – dihenhydramine, chlorpheniramine

• Antivertigo – meclizine, scopolamine

• Antiemetics – promethazine, prochlorperazine

• Antispasmodics – hyoscyamine, dicyclomine

• Urinary antispasmodics – oxybutynin

• Antiparkinsonian – benztropine, trihexyphenidyl

• Antiarrhythmics – disopyramide, quinidine

• Antidepressants – tricyclics, paroxetine

• Antipsychotics – haloperidol, clozapine

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Beers Criteria

• Developed in 1991 (by Dr. Mark Beers) for nursing home residents; expanded/revised in 1997 and 2003 to include all settings of geriatric care; reviewed/updated in 2012

• Goal: to improve care of older adults by minimizing their exposure to potentially inappropriate medications

• Useful tool for evaluating medications in the older adults with goal to improve prescribing/selection of prescriptions medications

• Somewhat controversial – Inappropriate does not necessarily mean contraindicated

– Risk-benefit ratio must be assessed for each patient

– Does not propose alternative therapies with better tolerabilities or outcomes

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Beers Criteria

• Potentially inappropriate medications and classes to avoid in older adults – Should be avoided in favor of a safer medication alternative

or non-drug approach

• Potentially inappropriate medications and classes to avoid in older adults with diseases and syndromes that the drugs listed can exacerbate – Particularly important because older adults often take

multiple medications for multiple comorbidities resulting in potentially greater consequence due to age-related decline in physiologic systems

• Medications to be used with caution in older adults

102 American Geriatrics Society. J Am Geriatr Soc. 2012.

Beers Criteria

Meds to generally avoid: • Alpha1 blockers (doxazosin,

proazosin, terazosin) – high risk of orthostatic hypotension

• First-generation antihistamines (diphenhydramine, hydroxyzine, promethazine) – highly anticholinergic

• Megestrol – increases risk for thrombotic events

• Sliding scale insulin – higher risk of hypoglycemia without improvement in overall control

Meds to avoid with certain diseases

• Chronic kidney disease – nonsteroidal anti-inflammatory drugs

• History of falls – benzodiazepines, antipsychotics

• Insomnia – oral decongestants or stimulants

• Syncope – alpha1 blockers

• Heart failure – nonsteroidal anti-inflammatory drugs, glitazones

103 American Geriatrics Society. J Am Geriatr Soc. 2012.

Commonly-used Drugs on Beers List

Drug Concern

Diphenhydramine, hydoxyzine, promethazine

Highly anticholinergic

Benzodiazepines (alprazolam, diazepam, temazepam) Non-benzodiazepine hypnotics (zolpidem, eszopiclone)

Increased sensitivity and slower metabolism; increase risk of cognitive impairment, falls, fractures; non-benzodiazepine hypnotics have similar risks

Alpha1 blockers (doxazosin, proazosin, terazosin)

High risk of orthostatic hypotension

Sliding scale insulin Higher risk of hypoglycemia without overall improvement

Digoxin (>0.125mg/day) In heart failure, higher doses associated with greater toxicity with no additional benefit

Antipsychotics Increased risk of CVA and mortality in persons with dementia

Megestrol Risk of thrombotic events; minimal effect on weight

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Alternatives to Potentially Inappropriate Medications

Potentially

Inappropriate

Alternative Choice

Diphenhydramine Loratadine

Doxazosin, prazosin,

terazosin

Tamsulosin

Amitriptyline, doxepin Nortriptyline, desipramine,

SSRIs, gabapentin/pregabalin

Flurazepam, diazepam Lorazepam, oxazepam,

temazepam (LOT)

Glyburide Glipizide

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Case

GS is now 65 years old and reports to the clinic complaining of an “upset stomach” x 3 weeks (burning pain). She goes to her provider who prescribes esomeprazole as treatment. Two weeks later, she returns with the same complaints. At this point, the provider orders a gastrointestinal consult. Endoscopy is negative for H. pylori and no ulceration is identified. The provider changes esomeprazole to lansoprazole and asks her to take it for another 3 weeks.

106

Case

At the visit 3 weeks later, you perform a medication review and discover that a week before the stomach pain started, GS began using ibuprofen 400 mg every 4 hours for dental pain. She was scheduled for a visit to the dentist, but he had to reschedule her which delayed the visit 20 days. She did not report ibuprofen use to the primary provider because she didn’t think it was important.

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Case • What happened?

– Two office visits to primary provider

– Gastrointestinal specialty consult

– Endoscopy

– Multiple prescriptions

– Missed days at work?

– Cancellation of social activities?

– Frustration and fear?

• What were the contributors?

• How could this have been prevented?

108