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Pharmacotherapy of Special Populations - Fudan...
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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
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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
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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
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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
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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
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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.
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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?
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