DRUGS IN INFANTS AND CHILDREN

Jarir At Thobari
Bagian Farmakologi & Terapi Fakultas Kedokteran Universitas Gadjah Mada

Use of antibiotics for ARI in children/adult patients visiting primary health centres
100
95,6 95,8 96,2 94 92,5 92,9 Adult 99 97,6 Under 5

98,9

95

90
84,6

85

80

75
N K JU N GA NG U L TU NG U AG EN TR K LE A GG N WI A G ND O B OS W O O

ARI treatment indicators over time, including only studies of medicines use in children < 5 years with ARI

Inappropriate prescribing 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

Pediatric Catastrophes

Sulphonamides

Chloramphenicol

Infants & Children are NOT Little Adults

Children medication errors :
Weight-based drug and nutrition dosing Less ability to safety check own care Limited research/data on pediatricspecific issues

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

Drug Use in Infants and Children

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

Scaling adult doses based on body weight or surface area does not account for developmental changes that affect drug disposition or tissue/organ sensitivity.
Therapeutic tragedies could be avoided by performing paediatric pharmacologic studies during the drug development process

PHARMACOLOGY & ONTOLOGY

Excretory organ (liver and kidneys) development has the greatest impact on drug disposition (pharmacokinetics) The most dramatic changes occur during the first days to months of life

Anticipate age-related differences in drug disposition based on knowledge of ontogeny

Effect of ontogeny on tissue/organ sensitivity to drugs (pharmacodynamic) is poorly studied Disease states may alter a drugs PK/PD

Drug process in human body

Drug enter to body
1

Absorption (input)
2

Drugs in plasma

Distribution

Drug in tissue
3

Metabolism
Metabolite

Elimination (output)

Metabolite drugs in urine, feces, and bile

Pharmacokinetics
Children are not little adults Age related differences in a childs physiology alter the pharmacokinetic action of drugs.

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

Pharmacokinetics Absorption
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

Absorption Pediatric Considerations

Variable
Inc gastric pH

Age Group
Neonates, infants, young children

Result
Inc bioavailability of basic drugs and acid labile drugs Dec. bioavailability of acidic drugs

Examples
Ampicillin

Phenobarbital (acidic)

Dec. gastric and intestinal motility

Inc. gastric and intestinal motility Dec. bile acid production

Neonates, infants
Older infants, children Neonates

Unpredictable bioavailability
Unpredictable bioavailability Dec. bioavailability

Digoxin
Digoxin Vit E, Vit K

Distribution
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 of unbound active drug in the body Reaches adult levels at 6 months of age. Decreased protein binding increases risk of toxicity.

Ontogeny of Body Composition

Protein Other EC H2O
Premature Newborn 4 mo 12 mo mo 24 mo mo 36 mo mo Adult 0 20 40 60 % of Total Body Weight 80 80 100 100

IC H2O

Fat

Distribution
Table I. Percentage of Body fluid at Different Ages Intercellular Extracellular Age Weight % of Body Water

Premature Infant

1.5 kg

83

-------

-------

Term newborn Three months Five months One year 0ne to three years

3.5 kg -------7 kg 10 kg --------

74 to 78 -------60 55 - 60 --------

34% 43% ------------34%

40 - 45% ------------27% -------

Mature woman

--------

55

-------

15 - 20%

Mature man

--------

60

--------

15 - 20%

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

Distribution
Physiologic features of the patient Total body water (TBW) and extracellular fluid (ECF) Total Body Water 94% 85% 78% 60% Extracellular Fluid 50% 35% 25% 19% Gentamicin Vd 0.48 L/kg

Fetus Preemies Full-term infant Adults

Preemies 4-6 mo old 1 yr old Adults

0.2 L/kg

Distribution
Body fat composition a. decreased body fat in neonates vs. adults Age 29 weeks post-conception full-term infant 1 year old adults % body fat 1% 12-16% 20-25% varies

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

Plasma Proteins
Change from Adult Values Newborn Total protein Albumin 1-Acid glycoprotein Fetal albumin Globulin Present Absent Infant Child

= = =
Absent

Protein Binding in Cord and Adult Plasma

Plasma Protein Binding (%) Cord Acetominophen Chloramphenicol Morphine Phenobarbital Phenytoin Promethazine 36.8 31 46 32.4 74.4 69.8 Adult 47.5 42 66 50.7 85.8 82.7

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

7

Volume of Distribution of Sulfa (water soluble)

Newborn
Infant

Children
Adults Elderly
0 0.1 0.2 0.3 0.4 0.4 Volume of Distribution [L/kg] 0.5 0.5

Distribution Pediatric Considerations

Variable
Inc. total body water & extracellular water Dec. albumin conc; Dec. protein binding

Age Group

Result

Examples
Aminoglycosides , caffeine, theophylline Phenytoin Sulfonamides

Neonates, young Inc. Volume of infants distribution

Neonates, infants

Inc. volume of distribution; Inc. free fraction (active); competetion with endogenous bilirubin (displacement)

Metabolism
Generally produces water soluble product that then is

either renally eliminated or excreted in bile Half life is usual kinetic determinant

Metabolism

Hydrophilic drug

Lipophilic Lipophilic drug drug No metabolism Slow metabolism

Lipophilic drug Rapid metabolism

Metabolism
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
Metabolism
Acetylation Sulfation Glucuronidation Conjugation

Excretion

0 Age

10

20 Days

30

Months

Glomerular filtration

Tubular secretion

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

Hepatic Ontogeny
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 fast or slow phenotype by 12-15 mo.

Acetylation: - at birth

Cytochrome P450 Enzymes

APPEAR AFTER PRESENT IN FETUS CYP3A7* CYP1A1 CYP3A5
BIRTH

APPEAR 3-4
MONTHS OF AGE

CYP2D6 CYP3A4* CYP2C9 CYP2C18/19 CYP2E1

CYP1A2

* Most abundant form

CYP3A Ontogeny
1.5 0.15 0.15

0.1 0.1

CYP3A7 Activity
0.5 0.05 0.05

CYP3A4 Activity

0
Adult >1yr 1-7d <24h <30w

0 0
>30w
1-3mo 8-28d 3-12mo

Fetus

Postnatal Age

Metabolism Pediatric Consideration

Variable
Dec. enzyme capacity Inc. enzyme capacity

Age Group

Result

Examples
Phenobarbital

Neonates, young Inc t ; dec infants clearance Children Dec t ; Inc. clearance

Theophylline

Acetaminophen Metabolism
Acetaminophen Acetaminophen Glucuronide Glucuronide Sulfate Newborn

3-9 3-9 years years

12 years years

Adults 0 20 40 60 60 80 80 100 100

% of Dose

Theophylline Urinary Metabolites

Theophylline Theophylline Caffiene Caffiene 3-MeX 3-MeX 1-MeUA 1-MeUA 1,3-diMeUA 1,3-diMeUA 28-32 28-32 weeks weeks

Postconception Age

40-50 40-50 weeks weeks 2-3 2-3 years years 4-9 4-9 years years

Age Range

10-16 10-16 years years 0 20 40 60 80 80 100 100

% Recovered in Urine

Elimination
Renal Glomerular filtration Tubular secretion
Primary component of Half-life

Primary determinant of dosing frequency

Elimination Half Life (t )

Period of time needed to

eliminate of the drug

Time needed to decrease blood concentrations by

GFR

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

Elimination Pediatric Considerations

Variable
Dec. Glomerular filtration (GFR) Dec. Tubular secretion

Age Group
Neonates, infants Neonates, infants

Result
Inc t ; reduce clearance Inc t ; reduce clearance

Examples
Aminoglycoside Beta-Lactam antibiotics

Elimination Pediatric Considerations

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

max)

Pre-term neonates (< 36 weeks) GFR markedly reduced from term infants Max reached at 1 -3 years (~120-140ml/min/1.73 m2

GFR is more developed than tubular function

Gentamicin Clearance
Premature (<37 weeks)
0-2 0-2 days days

Full term Postnatal Age

3-7 3-7 days days

8 days days

0.04

0.06

0.08

0.1 0.1

0.12 0.12

Gentamicin Clearance [L/kghr]

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

DRUGS USED IN ELDERLY

Jarir At Thobari
Bagian Farmakologi & Terapi Fakultas Kedokteran Universitas Gadjah Mada

Objectives
1. Understand key issues in drug used in

elderly 2. Understand the effect age on pharmacokinetics and pharmacodynamics 3. Discuss risk factors for adverse drug events and ways to mitigate them 4. Understand the principles of drug prescribing for older patients

The Aging Imperative

Persons aged 65y and

older constitute 13% of the population and purchase 33% of all prescription medications
By 2040, 25% of the

population will purchase 50% of all prescription drugs

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

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 halflife or clearance

Effects of Aging on Absorption

Rate of absorption may be

delayed
Lower peak concentration Delayed time to peak concentration

Overall amount absorbed

(bioavailability) is unchanged

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

Effects of Aging on Volume of Distribution (Vd)

Aging Effect
body water lean body mass fat stores

Vd Effect
Vd for hydrophilic drugs Vd for for drugs that bind to muscle Vd for lipophilic drugs

Examples
ethanol, lithium digoxin diazepam, trazodone

plasma protein (albumin)

plasma protein (1-acid glycoprotein)

% of unbound or free drug (active)

% of unbound or free drug (active)

diazepam, valproic acid, phenytoin, warfarin

quinidine, propranolol, erythromycin, amitriptyline

Aging Effects on Hepatic Metabolism

Metabolic clearance of drugs by the liver

may be reduced due to:

decreased hepatic blood flow decreased liver size and mass

Examples: morphine, meperidine,

metoprolol, propranolol, verapamil, amitryptyline, nortriptyline

Metabolic Pathways
Pathway Effect Examples
diazepam, quinidine, piroxicam, theophylline lorazepam, oxazepam, temazepam Phase I: oxidation, Conversion to hydroxylation, metabolites of lesser, dealkylation, reduction equal, or greater Phase II: glucuronidation, conjugation, or acetylation Conversion to inactive metabolites

** NOTE: Medications undergoing Phase II hepatic metabolism are generally preferred in the elderly due to inactive metabolites (no accumulation)

Other Factors Affecting Drug Metabolism

Gender Comorbid conditions Smoking Diet Drug interactions Race

Frailty

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 accumulation

and toxicity

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

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

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)

Example: Creatinine Clearance vs. Age in a 160, 55 kg Woman

Age 30 50 70 90 Scr 1.1 1.1 1.1 1.1 CrCl 65 53 41 30

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 (<0.7 mg/dL) Not precise, may underestimate actual CrCl

Pharmacodynamics (PD)
Definition: the time course and intensity of

pharmacologic effect of a drug Age-related changes:

sensitivity to sedation and psychomotor impairment with benzodiazepines level and duration of pain relief with narcotic agents drowsiness and lateral sway with alcohol HR response to beta-blockers sensitivity to anti-cholinergic agents cardiac sensitivity to digoxin

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 ensure successful outcomes

Optimal Pharmacotherapy
Balance between overprescribing and

underprescribing
Correct drug Correct dose Targets appropriate condition Is appropriate for the patient

Avoid a pill for every ill Always consider non-pharmacologic therapy

Consequences of Overprescribing
Adverse drug events (ADEs)
Drug interactions Duplication of drug therapy

Decreased quality of life

Unnecessary cost

Medication non-adherence

Adverse Drug Events (ADEs)

Responsible for 5-28% of

acute geriatric hospital admissions Greater than 95% of ADEs in the elderly are considered predictable and approximately 50% are considered preventable Most errors occur at the ordering and monitoring stages

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.

The Beers Criteria

High Potential for Severe ADE amitriptyline chlorpropamide digoxin >0.125mg/d disopyramide GI antispasmodics meperidine methyldopa pentazocine ticlopidine High Potential for Less Severe ADE antihistamines diphenhydramine dipyridamole ergot mesyloids indomethacin muscle relaxants

Patient Risk Factors for ADEs

Polypharmacy
Multiple co-morbid conditions Prior adverse drug event

Low body weight or body mass index

Age > 85 years Estimated CrCl <50 mL/min

Drug-Drug Interactions (DDIs)

May lead to adverse drug events Likelihood as number of medications Most common DDIs: cardiovascular drugs psychotropic drugs Most common drug interaction effects: confusion cognitive impairment hypotension acute renal failure

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

Common Drug-Drug Interactions

Combination
ACE inhibitor + potassium ACE inhibitor + K sparing diuretic Digoxin + antiarrhythmic Digoxin + diuretic Antiarrhythmic + diuretic

Risk
Hyperkalemia Hyperkalemia, hypotension Bradycardia, arrhythmia Electrolyte imbalance; arrhythmia

Diuretic + diuretic
Benzodiazepine + antidepressant Benzodiazepine + antipsychotic CCB/nitrate/vasodilator/diuretic

Electrolyte imbalance; dehydration

Sedation; confusion; falls Hypotension

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

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

Common Drug-Disease Interactions

Combination
NSAIDs + CHF Thiazolidinediones + CHF

Risk
Fluid retention; CHF exacerbation

BPH + anticholinergics CCB + constipation Narcotics + constipation Anticholinergics + constipation

Metformin + CHF NSAIDs + gastropathy NSAIDs + HTN

Urinary retention Exacerbation of constipation

Hypoxia; increased risk of lactic acidosis Increased ulcer and bleeding risk Fluid retention; decreased effectiveness of diuretics

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 time

Reach therapeutic dose before switching or

adding agents Consider non-pharmacologic agents

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

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

Non-Adherence
Rate may be as high as 50% in the elderly
Factors in non-adherence Financial, cognitive, or functional status Beliefs and understanding about disease and medications

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

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

Questions