drugs in infants and children

7/27/2019 Drugs in Infants and Children

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DRUGS ININFANTS ANDCHILDREN

Bagian Farmakologi & Terapi

Fakultas Kedokteran

Universitas Gadjah Mada

Jarir At Thobari


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95,6 95,8

92,5

96,2

98,9 99

92,9

84,6

94

97,6

75

80

85

90

95

100

NGAN

JUK

TULUNG

AGUN

G

TREN

GGALEK

NGAW

I

BOND

OWOS

O

Under 5

Adult

Use of antibiotics for ARI in children/adult

patients visiting primary health centres


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ARI treatment indicators over time, including only

studies of medicines use in children < 5 years with

ARI


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Amoxicillin mg 250

Paracetamol tab

Dexamethasone tab

GG tab

Phenobarbiton mg 30

Vitamin C mg 20

Mfla dtd no. XII S 3dd I

Infant, 7 months with ARI

Inappropriate prescribing


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Pediatric Catastrophes

ChloramphenicolSulphonamides


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Infants & Children are NOT Little Adults

Adapted from Lessons from AHRQs Pediatric Patient Safety ResearchMarlene R. Miller, MD, MSc, FAAP; AHRQ, 2002

Children medication errors :Weight-based drug and nutrition dosing

Less ability to safety check own care

Limited research/data on pediatric-

specific issues


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Drug Use in Infants and

Children

developmental changes are often discovered whenunexpected or severe toxicity in infants and children

Scaling adult doses based on body weight orsurface area does not account for developmentalchanges that affect drug disposition or tissue/organsensitivity.

Therapeutic tragedies could be avoided byperforming paediatric pharmacologic studies duringthe drug development process


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PHARMACOLOGY &

ONTOLOGYExcretory organ (liver and kidneys) development hasthe greatest impact on drug disposition(pharmacokinetics)

The most dramatic changes occur during the firstdays to months of life

Anticipate age-related differences in drug dispositionbased on knowledge of ontogeny

Effect of ontogeny on tissue/organ sensitivity todrugs (pharmacodynamic) is poorly studied

Disease states may alter a drugs PK/PD


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Drug enter to body

Metabolite drugs in

urine, feces, and bile

Drug process in human body

Drugs in plasma

1 Absorption (input)

Drug in tissue

Metabolite

2 Distribution

3 Metabolism

4 Elimination (output)


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Children are not little adults

Age related differences in a childs

physiology alter the pharmacokinetic

action of drugs.

Pharmacokinetics


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Pharmacokinetics Absorption

Release from dosage form

Dissolution in biologic fluids

Gastric (per oral)

Extracellular fluid ( IM, SC, Topical)

Reach systemic circulation

First pass hepatic clearance for per oral and rectal meds

decreases systemic absorption


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Gastric pH:

Varies with age

Varies with food and beverage ingestion

Gastric Motility:

Prolonged in infants and children

Intestinal Transit Time:

Faster and highly variable in infants and

children

Pharmacokinetics Absorption


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Absorption Pediatric ConsiderationsVariable Age Group Result Examples

Inc gastric pH Neonates, infants, young

children

Inc bioavailability of basic

drugs and acid labile drugs

Dec. bioavailability of acidic

drugs

Ampicillin

Phenobarbital (acidic)

Dec. gastric and intestinal

motility

Neonates, infants Unpredictable bioavailability Digoxin

Inc. gastric and intestinal

motility

Older infants, children Unpredictable bioavailability Digoxin

Dec. bile acid production Neonates Dec. bioavailability Vit E, Vit K


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Bodily Fluids:

increased body fluid = increased volume of distribution or dilution of a drug

Children have a greater proportion of fluid per weight. (see chart)

Serum Protein Levels:

decreased protein binding of a drug leads to an increased concentration ofunbound active drug in the body

Reaches adult levels at 6 months of age.

Decreased protein binding increases risk

of toxicity.

Distribution


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Ontogeny of Body Composition

% of Total Body Weight

EC H2O IC H2O

Protein Other

Fat

0 20 40 60 80 100

Premature

Newborn

4 mo

12 mo

24 mo

36 mo

Adult

0 20 40 60 80 100

Premature

Newborn

4 mo

12 mo

24 mo

36 mo

Adult


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Table I. Percentage of Body fluid at Different Ages

Age Weight % of Body WaterInter-

cellular

Extra-

cellular

Premature Infant 1.5 kg 83 ------- -------

Term newborn 3.5 kg 74 to 78 34% 40 - 45%

Three months -------- -------- 43% -------

Five months 7 kg 60 ------- -------

One year 10 kg 55 - 60 ------- 27%

0ne to three years -------- -------- 34% -------

Mature woman -------- 55 ------- 15 - 20%

Mature man -------- 60 -------- 15 - 20%

Adapted from references 3, 6 & Family Community Health 1983, p. 31-40

Distribution


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DistributionPhysiologic features of the patient

Total body water (TBW) and extracellular fluid (ECF)

Total Body Water

Fetus 94%Preemies 85%

Full-term infant 78%

Adults 60%

Extracellular Fluid Gentamicin Vd

Preemies 50% 0.48 L/kg4-6 mo old 35%

1 yr old 25%

Adults 19% 0.2 L/kg


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Body fat composition

a. decreased body fat in neonates vs. adults

Age % body fat29 weeks post-conception 1%

full-term infant 12-16%

1 year old 20-25%

adults varies

b. highly lipid soluble drugs have lower Vd in neonates than in adultsc. e.g. diazepam: 1.4-1.8 L/kg in neonates vs. 2.2-2.6 L/kg in adults

Distribution


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Plasma Proteins

Change from Adult Values

Newborn Infant Child

Total protein =

Albumin = =

1-Acid glycoprotein =

Fetal albumin Present Absent Absent

Globulin =


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Protein Binding in Cord and Adult Plasma

Plasma Protein Binding (%)

Cord Adult

Acetominophen 36.8 47.5

Chloramphenicol 31 42

Morphine 46 66

Phenobarbital 32.4 50.7

Phenytoin 74.4 85.8

Promethazine 69.8 82.7

7

Kurz et al., Europ J Clin Pharmacol II:463-7, 197


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Volume of Distribution of Sulfa (water soluble)

0 0.1 0.2 0.3 0.4 0.50 0.1 0.2 0.3 0.4 0.5

Volume of Distribution [L/kg]

Newborn

Infant

Children

Adults

Elderly


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Distribution Pediatric Considerations

Variable Age Group Result ExamplesInc. total body

water &

extracellularwater

Neonates, young

infants

Inc. Volume of

distribution

Aminoglycosides

, caffeine,

theophylline

Dec. albumin

conc; Dec.

protein binding

Neonates,

infants

Inc. volume of

distribution; Inc.

free fraction

(active);

competetion with

endogenous

bilirubin

(displacement)

Phenytoin

Sulfonamides


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Metabolism

Generally produces water soluble product that then is

either renally eliminated or excreted in bile

Half life is usual kinetic determinant


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1 2 3 4

Hydrophilic

drug

Lipophilic

drug

Slow metabolism

Lipophilic

drug

No metabolism

Lipophilic

drug

Rapid metabolism

Metabolism


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Bodily Fluids:

Infants are at higher risk of fluid imbalance due to higher rate of

metabolism, increase insensible water loss, and immature kidneys.

Organs and Tissues Involved:

Liver, kidneys, lungs, plasma, and intestinal mucosa.

Metabolism


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Exc

retion

Metabolism

0 10 20 30 2 3 4 5 6

Age Days Months

Glomerular

filtration

Tubular

secretion

Sulfation

Acetylation Glucuronidation

Conjugation

Source: Massanari M, McLockin A, Sayles R, et al. J Pediatr Pharm Pract 1997;2:139-57.

Metabolism


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Phase 1 (oxidation, hydrolysis, reduction, demethylation)

Activity low at birth

Mature at variable rates Oxidative metabolism increases rapidly after birth

Alcohol dehydrogenase reaches adult levels at 5 yrs

Activity in young children exceeds adult levels

Phase 2(conjugation, acetylation, methylation)

Conjugation: Glucuronidation: - at birth

Sulfatation: at birth

Acetylation: - at birth

fast or slow phenotype by 12-15 mo.

Hepatic Ontogeny


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Cytochrome P450 Enzymes

PRESENT IN FETUS

APPEAR AFTER

BIRTH

APPEAR3-4

MONTHS OF AGE

CYP3A7* CYP2D6 CYP1A2

CYP1A1 CYP3A4*

CYP3A5 CYP2C9

CYP2C18/19

CYP2E1

* Most abundant form


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CYP3A Ontogeny

0

0.5

1

1.5

0

0.05

0.1

0.15

0

0.5

1

1.5

0

0.05

0.1

0.15

30w

1yr

Adult

Fetus Postnatal Age

CYP3A7

Activity

CYP3A4

Activity


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Variable Age Group Result ExamplesDec. enzyme

capacity

Neonates, young

infants

Inc t ; dec

clearance

Phenobarbital

Inc. enzyme

capacity

Children Dec t ; Inc.

clearance

Theophylline

Metabolism Pediatric Consideration


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Acetaminophen Metabolism

0 20 40 60 80 100

Newborn

3-9 years

12 years

Adults

AcetaminophenGlucuronideSulfate

0 20 40 60 80 100

Newborn

3-9 years

12 years

Adults

AcetaminophenGlucuronideSulfate

% of Dose


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Theophylline Urinary Metabolites

0 20 40 60 80 100

28-32 weeks

40-50 weeks

2-3 years

4-9 years

10-16 years

TheophyllineCaffiene3-MeX1-MeUA1,3-diMeUA

0 20 40 60 80 100

28-32 weeks

40-50 weeks

2-3 years

4-9 years

10-16 years

TheophyllineCaffiene3-MeX1-MeUA1,3-diMeUA

% Recovered in Urine

Post-

conception

Age

Age

Range


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Elimination Renal

Glomerular filtration

Tubular secretion

Primary component of Half-life

Primary determinant of dosing frequency


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Elimination Half Life (t )

Period of time needed to

eliminate of the drug

Time needed to decrease blood

concentrations by


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GFR

Chen et al, Pediatr Nephrol (2006) 21: 160-168


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Elimination Pediatric Considerations

Variable Age Group Result Examples

Dec. Glomerular

filtration (GFR)

Neonates, infants Inc t ; reduce

clearance

Aminoglycoside

Dec. Tubular secretion Neonates, infants Inc t ; reduce

clearance

Beta-Lactam antibiotics


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GFR and Tubular transport markedly suppressed at birth ( ~20% of adult

max)

GFR is more developed than tubular function

Pre-term neonates (< 36 weeks) GFR markedly reduced from term infants

Max reached at 1 -3 years (~120-140ml/min/1.73 m2

Elimination Pediatric Considerations


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0.04 0.06 0.08 0.1 0.12

0-2 days

3-7 days

8 days

0.04 0.06 0.08 0.1 0.12

0-2 days

3-7 days

8 days

Gentamicin Clearance

Postnatal

Age

Gentamicin Clearance [L/kghr]

Premature (


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C e et a , ed at Nep o ( 006) : 60 68


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DRUGS USED INELDERLY

Bagian Farmakologi & Terapi

Fakultas Kedokteran

Universitas Gadjah Mada

Jarir At Thobari


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Objectives

1. Understand key issues in drug used inelderly

2. Understand the effect age on

pharmacokinetics and pharmacodynamics3. Discuss risk factors for adverse drug

events and ways to mitigate them

4. Understand the principles of drugprescribing for older patients


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The Aging Imperative

Persons aged 65y andolder constitute 13% ofthe population and

purchase 33% of all

prescription medications

By 2040, 25% of thepopulation will purchase50% of all prescriptiondrugs


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Challenges of Geriatric

Pharmacotherapy

New drugs available each year

Changing managed-care formularies

Advanced understanding of drug-drug interactions

Multiple co-morbid states

Polypharmacy

Medication compliance

Effects of aging physiology on drug therapy

Medication cost


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Pharmacokinetics (PK)

Absorption bioavailability: the fraction of a drug dose reaching the systemic

circulation

Distribution

locations in the body a drug penetrates expressed as volume per weight(e.g. L/kg)

Metabolism drug conversion to alternate compounds which may be

pharmacologically active or inactive

Elimination a drugs final route(s) of exit from the body expressed in terms of half-

life or clearance


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Effects of Aging on Absorption

Rate of absorption may bedelayed

Lower peak concentration

Delayed time to peakconcentration

Overall amount absorbed

(bioavailability) isunchanged


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Hepatic First-Pass Metabolism

For drugs with extensive first-pass

metabolism, bioavailability may increase

because less drug is extracted by the liver

Decreased liver mass

Decreased liver blood flow


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Effects of Aging on Volume of

Distribution (Vd)

Aging Effect Vd Effect Examples

body water Vd for hydrophilic

drugs

ethanol, lithium

lean body mass Vd for for drugsthat bind to muscle

digoxin

fat stores Vd for lipophilic

drugs

diazepam, trazodone

plasma protein(albumin)

% of unbound orfree drug (active)

diazepam, valproic acid,phenytoin, warfarin

plasma protein

(1-acid glycoprotein)

% of unbound or

free drug (active)

quinidine, propranolol,

erythromycin, amitriptyline


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Aging Effects on Hepatic

Metabolism

Metabolic clearance of drugs by the liver

may be reduced due to:

decreased hepatic blood flowdecreased liver size and mass

Examples: morphine, meperidine,

metoprolol, propranolol, verapamil,amitryptyline, nortriptyline


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Metabolic Pathways

Pathway Effect Examples

Phase I: oxidation,

hydroxylation,

dealkylation, reduction

Conversion to

metabolites of lesser,

equal, or greater

diazepam, quinidine,

piroxicam,

theophylline

Phase II:

glucuronidation,

conjugation, or

acetylation

Conversion to inactive

metabolites

lorazepam, oxazepam,

temazepam

** NOTE: Medications undergoing Phase II hepatic metabolism aregenerally preferred in the elderly due to inactive metabolites (noaccumulation)


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Other Factors Affecting Drug

Metabolism

Gender

Comorbid conditions

Smoking

Diet

Drug interactions

Race

Frailty


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Concepts in Drug Elimination

Half-life

time for serum concentration of drug to decline

by 50% (expressed in hours)

Clearance

volume of serum from which the drug is

removed per unit of time (mL/min or L/hr)

Reduced elimination drug accumulationand toxicity


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Effects of Aging on the Kidney

Decreased kidney size

Decreased renal blood flow

Decreased number of functional nephrons

Decreased tubular secretion

Result: glomerular filtration rate (GFR)

Decreased drug clearance: atenolol, gabapentin,

H2 blockers, digoxin, allopurinol, quinolones


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Estimating GFR in the Elderly

Creatinine clearance (CrCl) is used to estimate

glomerular rate

Serum creatinine alone not accurate in the elderly

lean body mass lower creatinine production

glomerular filtration rate

Serum creatinine stays in normal range, masking

change in creatinine clearance


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Determining Creatinine Clearance

Measure Time consuming

Requires 24 hr urine collection

Estimate

Cockroft Gault equation

(BW in kg) x (140-age)------------------------------ x (0.85 for females)

72 x (Scr in mg/dL)


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Example: Creatinine Clearance vs.

Age in a 160, 55 kg Woman

301.190

411.170

531.150

651.130

CrClScrAge


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Limitations in Estimating CrCl

Not all persons experience significant age-

related decline in renal function

Some patients muscle mass is reduced

beyond that of normal aging

Suggest using 1 mg/dL if serum creatinine is

less than normal (


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Pharmacodynamics (PD)

Definition: the time course and intensity of

pharmacologic effect of a drug

Age-related changes:

sensitivity to sedation and psychomotor impairmentwithbenzodiazepines

level and duration of pain relief with narcotic agents

drowsiness and lateral sway with alcohol

HR response tobeta-blockers

sensitivity to anti-cholinergic agents

cardiac sensitivity to digoxin


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PK and PD Summary

PK and PD changes generally result in

decreased clearance and increased

sensitivity to medications in older adults

Use of lower doses, longer intervals, slower

titration are helpful in decreasing the risk of

drug intolerance and toxicity

Careful monitoring is necessary to ensuresuccessful outcomes


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Optimal Pharmacotherapy

Balance between overprescribing andunderprescribing

Correct drug

Correct doseTargets appropriate condition

Is appropriate for the patient

Avoid a pill for every ill

Always consider non-pharmacologic therapy


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Consequences of Overprescribing

Adverse drug events (ADEs)

Drug interactions

Duplication of drug therapyDecreased quality of life

Unnecessary cost

Medication non-adherence


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Adverse Drug Events (ADEs)

Responsible for 5-28% ofacute geriatric hospitaladmissions

Greater than 95% of ADEs inthe elderly are considered

predictable andapproximately 50% areconsidered preventable

Most errors occur at theordering and monitoringstages

M t C M di ti


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Most Common Medications

Associated with ADEs in the Elderly

Opioid analgesics

NSAIDs

Anticholinergics

Benzodiazepines

Also: cardiovascular agents, CNS agents,

and musculoskeletal agents

Adverse Drug Reaction Risk Factors in Older Outpatients. Am J Ger Pharmacotherapy 2003;1(2):82-89.


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The Beers Criteria

High Potential for

Severe ADE

High Potential for

Less Severe ADE

amitriptyline

chlorpropamide

digoxin >0.125mg/ddisopyramide

GI antispasmodics

meperidine

methyldopa

pentazocine

ticlopidine

antihistamines

diphenhydramine

dipyridamoleergot mesyloids

indomethacin

muscle relaxants


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Patient Risk Factors for ADEs

Polypharmacy

Multiple co-morbid conditions

Prior adverse drug eventLow body weight or body mass index

Age > 85 years

Estimated CrCl


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Drug-Drug Interactions (DDIs)

May lead to adverse drug events

Likelihood as number of medications

Most common DDIs:

cardiovascular drugspsychotropic drugs

Most common drug interaction effects:

confusion

cognitive impairment hypotension

acute renal failure


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Concepts in Drug-Drug Interactions

Absorption may be or

Drugs with similar effects can result

additive effects

Drugs with opposite effects can antagonize

each other

Drug metabolism may be inhibited or

induced


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Common Drug-Drug Interactions

Combination RiskACE inhibitor + potassium Hyperkalemia

ACE inhibitor + K sparing diuretic Hyperkalemia, hypotension

Digoxin + antiarrhythmic Bradycardia, arrhythmia

Digoxin + diuretic

Antiarrhythmic + diuretic

Electrolyte imbalance; arrhythmia

Diuretic + diuretic Electrolyte imbalance; dehydration

Benzodiazepine + antidepressant

Benzodiazepine + antipsychotic

Sedation; confusion; falls

CCB/nitrate/vasodilator/diuretic Hypotension

Doucet J, Chassagne P, Trivalle C, et al. Drug-drug interactions related to hospital admissions in older adults: aprospective study of 1000 patients. J Am Geriatr Soc 1996;44(9):944-948.


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Drug-Disease Interactions

Obesity alters Vd of lipophilic drugs

Ascites alters Vd of hydrophilic drugs

Dementia may sensitivity, induce

paradoxical reactions to drugs with CNS or

anticholinergic activity

Renal or hepatic impairment may impair

metabolism and excretions of drugs

Drugs may exacerbate a medical condition


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Common Drug-Disease Interactions

Combination Risk

NSAIDs + CHF

Thiazolidinediones + CHF

Fluid retention; CHF exacerbation

BPH + anticholinergics Urinary retention

CCB + constipation

Narcotics + constipation

Anticholinergics + constipation

Exacerbation of constipation

Metformin + CHF Hypoxia; increased risk of lactic acidosis

NSAIDs + gastropathy Increased ulcer and bleeding risk

NSAIDs + HTN Fluid retention; decreased effectiveness of

diuretics

Principles of Prescribing in the


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Principles of Prescribing in the

Elderly

Avoid prescribing prior to diagnosis

Start with a low dose and titrate slowly

Avoid starting 2 agents at the same timeReach therapeutic dose before switching or

adding agents

Consider non-pharmacologic agents


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Prescribing Appropriately

Determine therapeutic endpoints and plan for assessment

Consider risk vs. benefit

Avoid prescribing to treat side effect of another drug

Use 1 medication to treat 2 conditions

Consider drug-drug and drug-disease interactions

Use simplest regimen possible

Adjust doses for renal and hepatic impairment

Avoid therapeutic duplication

Use least expensive alternative


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Preventing Polypharmacy

Review medications regularly and each time

a new medication started or dose is changed

Maintain accurate medication records

(include vitamins, OTCs, and herbals)

Brown-bag


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Non-Adherence

Rate may be as high as 50% in the elderly

Factors in non-adherence

Financial, cognitive, or functional statusBeliefs and understanding about disease and

medications


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Enhancing Medication Adherence

Avoid newer, more expensive medications

that are not shown to be superior to less

expensive generic alternatives

Simplify the regimen

Utilize pill organizers or drug calendars

Educate patient on medication purpose,

benefits, safety, and potential ADEs


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Summary

Successful pharmacotherapy means using

the correct drug at the correct dose for the

correct indication in an individual patient

Age alters PK and PD

ADEs are common among the elderly

Risk of ADEs can be minimized by

appropriate prescribing


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Questions

drugs in infants and children

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