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Altered Pharmacokinetics In Pediatrics & Geriatrics

By: Yalda.H.Ardakani

Introduction

• Pediatrics :

Branch of medicine dealing with the development of

disease and disorders in children.

• Children are not “miniature adults”

Subdivisions in children

• Subdivision in children:

Preterm newborn infant

Newborn infant (Birth-28 days)

Infant (28 Days-23 months)

Young Child (2-5 years)

Old Child (6-11 years)

Adolescent (12-18 years)

General considerations

• Pediatric patients were always considered in the past for treatment as MINI ADULTS.

• In 1998, FDA required drug manufacturers to determine

whether existing were sufficient to support information on

pediatric use for drug labeling purpose .

• Only 20-30% of approved drugs have pediatric labeling.

General considerations

• Infancy and childhood is a period of rapid growth

and development of organ systems and so …..

Scaling adult doses to infants based on body

weight or surface area does not account for

developmental changes that affect drug

disposition.

Dose adjustment in pediatrics

Dosage is adjusted based on

pharmacokinetic data of a given age

group for the desired response.

Pediatric dosage forms

• Pediatric dosage forms should permit more accurate

dosing and patient compliance.

• Pediatric drug formulations may also contain different drug concentrations compared to the adult drug formulation.

• Alternative drug delivery may be required.

potential sources of differences in pharmacokinetics

Differences in pharmacokinetics

body composition

Kidney function

maturity of liver

Receptor response

Absorption

Absorption in the Pediatric Patient

• Absorption in the Pediatric Patient Gastrointestinal absorption

Percutaneous absorption

Intra muscular absorption

Absorption - GI

• Gastrointestinal pH changes

• Gastric enzymes

• Gastrointestinal flora

• Gastric emptying & GI motility

• Bile acids & biliary function

Absorption - GI

• Gastrointestinal pH changes

• Gastric pH is neutral at birth, and approaches adult values

approximately in 3 month in full-term infants, so….

– Bioavailability increased for acid-labile drugs

(penicillin derivatives)

– Bioavailability decreased for drugs requiring

acid to be absorbed.

(Phenobarbital)

Absorption - GI

• Gastric emptying

– Delayed and unpredictable in newborns .

– Reaches adult values at ~ 6 month.• GI motility

– Slow in newborns; may be increased in

children.

– Usually affects the rate but not the fraction

of drug absorbed.

– The impact on absorption is usually

minimal but is unpredictable.

Absorption - Skin

• Percutaneous absorption

– Directly related to the degree of skin

hydration.

– Directly related to the perfusion of

subcutaneous layer

– Inversely related to the thickness of the

stratum corneum.

• Thinnest in premature neonate

• Premature infant has a significantly less

effective skin barrier to absorption of

drugs and toxins

– Hexachlorophene toxic to immature infants

– hydrocortisone over dosage

Absorption - Intramuscular

• Intramuscular

– Highly susceptible to variance in absorption due to...

- reduced blood flow to skeletal muscles,

-weak muscle contractions .

- Because of pain associated with injection and the

risk of nerve damage….

Infants 0.5ml

Older children 1ml

Pediatric Distribution

• Body Composition

– total body water & extracellular fluid

– adipose tissue & skeletal muscle

• Protein Binding

– albumin, bilirubin, 1-acid glycoprotein

• Tissue Binding

– compositional changes

Pediatric Distribution-Body Composition

total body water & extracellular fluid

adipose tissue & skeletal muscle

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

Extra Cellular water

Intra Cellular water

Protein

Fat

Others

Pediatric Distribution

Volume of Distribution of sulfisoxazole

Newborn

Infant

Children

Adults

Elderly

Pediatric Distribution-Protein Binding

Protein Binding (%)

Cord Adult

Acetaminophen 36.8 47.5

Chloramphenicol 31 42

Mophine 46 66

Phenobarbital 32.8 50.7

Phenytoin 74.4 85.8

Promethazine 69.8 82.7

30.2 17.3

• Glomerular filtration rate

– Low at birth

– GFR doubles by 1 week of age

– Adult values by 6-12 months of age

• Tubular function

– Secretory function impaired at birth

– Glomerulo-tubular imbalance

– Adult values by 1 year of age

Pediatric Renal Function

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/kg•hr]

Premature (<37 weeks)

Full term

Pediatric Renal Function

• Therapeutic implications

– Estimation of renal function necessary for

determining dose regimen for drugs with

extensive renal clearance

• Ex. Ceftazidime, famotidine, aminoglycosides.

• Measurement of drug levels often necessary

• Some drugs also alter renal maturation

or renal blood flow .

– Ex betamethsone, indomethacin

Elimination Half-Lives of Drugs in Infants and Adults

Drug Neonates (hr) Adults (hr)

Penicillin G 3.2 0.5

Ampicillin 4 1-1.5

Methicillin 3.3/1.3 0.5

Carbenicillin 5–6 1–1.5

Kanamycin 5–5.7 3–5

Gentamicin 5 2–3

• 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

• Phase I enzyme activity in young children

can actually exceed adult levels.

Pediatric Hepatic Function

• Phase 2 (conjugation, acetylation, methylation)

– Conjugation:

• Glucuronidation: - at birth

• Sulfatation: at birth

– Acetylation: - at birth

Pediatric Hepatic Function

0.3

0.75

1.6

1.8

G:S

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

0.15

0.17

0.19

0.18

kel

% of Dose

Cytochrome P450 (CYP) Enzymes

• Half of all drugs metabolized by CYP3A subfamily.

• CYP3A4 is most abundant hepatic P450 enzyme and

metabolizes at least 50 drugs.

>30w0

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

<24h1-7d

8-28d

1-3mo

3-12mo

>1yrAdult

FetusPostnatal Age

CYP3A7

CYP3A4

Relative Half-lives of CYP3A Substrates

Relative Half-lives of CYP1A2 Substrates

Dosing of Drugs in Infants and Children

Dosing of Drugs in Infants and Children

Dosing of Drugs in Infants and Children

Practice Problem

• The elimination half-life of penicillin G is 0.5 hr in adults and 3.2 hr in neonates (0 to 7 days old).Assuming that the normal adult dose of penicillin G is 4 mg/kg every 4 hours, calculate the dose of penicillin G for an 5 Kg infant.

hr

Practice Problem (cont.)

Dose=4 mg/kg

Weight= 5 kg

Alternatively, 10 mg every 12 hr would achieve the

same .

Dose=4*5=20 mg every 24 hr

? خداوند برکتی عظیم به تو بخشیده است. تو چه چیزی به ”او“ تقدیم می کنی

.هر روز، چیزی، هر چند کوچک به ”او“ تقدیم کن. از روی عشق و به نیازمندان

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

Definition

• Chronologically, the elderly have been classified as the…

young old (ages 65–75 years),

old (ages 75– 85 years),

old old (age > 85 years).

Specific Therapeutic Challenge of Prescribing for the Elder Patient

• Principle factors:

– Altered Pharmacokinetics

– Multiple and severe illness

– Multiple drug therapy

– Poor adherence

Aging

• Most body organs in size with age fewer cells to

carry out organ functions

• Pharmacological changes:

• Drug absorption

• Drug distribution

• Drug metabolism

• Drug excretion

Pharmacokinetic changes (Absorption)

• Changes to intestinal tract:• decreased blood flow• reduced absorptive surface area• decreased gastric secretions• decreased motility

• Result:– SLOWED rate of drug absorption– Delayed time to peak concentration

• Peak drug level:– tends to decrease with age– same amount of drug will be absorbed but over a longer

period of time

Pharmacokinetic changes (Absorption)

Pharmacokinetic changes (Distribution)

• Distribution of Drugs:

– Increased body fat

– Decreased lean muscle mass

– Decreased serum albumin

– Decreased cardiac output

– Decreased total body water

Effects of Aging on Volume of Distribution

Aging Effect Vd Effect Examples

body water Vd for hydrophilic drugs ethanol, lithium

lean body mass Vd for drugs that bind to muscle digoxin

fat stores Vd for lipophilic drugs diazepam, trazodone

plasma protein (albumin) % of free drug diazepam, valproic acid,

phenytoin, warfarin

plasma protein (1-acid glycoprotein) % of free drug quinidine, propranolol,

erythromycin,

Pharmacokinetic changes (Metabolism)

• For drugs with extensive first-pass metabolism, BA may

increase because less drug is extracted by the liver

– Decreased liver mass

– Decreased liver blood flow

– Decreased activity of hepatic enzymes

– morphine, meperidine, metoprolol, propranolol,

verapamil, amitryptyline, nortriptyline

Metabolic Pathways

Pathway Effect Examples

Phase I:

oxidation,

hydroxylation,

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

Medications undergoing Phase II hepatic

metabolism are generally preferred in the

elderly due to inactive metabolites

(no accumulation)

Pharmacokinetic changes (Metabolism)

Pharmacokinetic changes (Excretion)

• Excretion of Drugs:

– Decreased renal blood flow

– Decreased glomerular filtration rate

– Decreased tubular secretion

– Decreased number of nephrons

– Decreased drug clearance:

atenolol, gabapentin, H2 blockers, digoxin,

allopurinol

Determining Creatinine Clearance

• Measurement of Creatinine Clearance – Time consuming– Requires 24 hr urine collection

• Estimate– Cockroft Gault equation

(IBW in kg) x (140-age)------------------------------ x (0.85 for females) 72 x (Scr in mg/dL)

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

Creatinine Clearance vs. Age in a 5’5”, 55 kg Woman

301.190

411.170

531.150

651.130

CrClScrAge

Example:

Practice Problems

• The clearance of lithium was determined to be 41.5 ml/min

in a group of patients with an average age of 25 years. In a

group of elderly patients with an average age of 63 years,

the clearance of lithium was 7.7 ml/min.

• What percentage of the normal dose of lithium should be

given to a 65-year-old patient?

Practice Problems

Practice Problems

Dose1= 100 %

Dose2 = ? %

The dose of lithium may be reduced to about 20% of the regular dose in the 65-year-old patient without affecting the steady-state blood level.

Practice Problems

• An aminoglycoside has a normal elimination half-life

of 107 min in young adults. In patients 70 to 90 years

old, the elimination half-life of the aminoglycoside is

282 min. The normal dose of the aminoglycoside is

15 mg/kg per day divided into two doses. What is the

dose for a 75-year-old patient, assuming that the

volume of distribution per body weight is not

changed by the patient's age?

Practice Problems

τ1= 12 hr

τ2= ? hr

Therefore, the same dose may be administered every 32 hr without affecting the average steady-state level of drug.

Clinical Example

• The pharmacokinetics of felodipine, was studied in young and elderly

subjects. After a dose of 5 mg oral felodipine, the AUC and C max in

the elderly patients were three times that of the young subjects.

• Side effects of felodipine in the elderly patients was reported in 3 of 11

subjects, whereas, only 1 of 12 of the young subjects reported side

effects. Systemic clearance in the elderly was 248 ± 108 L/hr compared

to 619 ± 214 L/hr in the young subjects. The bioavailability of

felodipine was reported to be about 15.5% in the elderly and 15.3% in

the young subjects.

Clinical Example

• What is the main cause for the difference in the

observed AUC between the elderly and young

subjects?

• The higher AUC in the elderly compared to young

adults is due to the decreased drug clearance in the

older subjects.

Clinical Example

• What would be the steady-state level of felodipine in the

elderly if dose and dosing interval are unchanged?

• If Dose, F, and τ are the same, the steady-state drug

concentration will be inversely proportional to clearance:

Pharmacodynamics

• Age-related changes:

– sensitivity to sedation and psychomotor

impairment with benzodiazepines

– level and duration of pain relief with narcotic

agents

– 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.

وصیت نامه پاستور

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بی حاصل آلوده شوید و نه بگذارید که بعضی لحظات تاسف

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زندگی کنید. نخست از خود بپرسید:“برای یادگیری و

?“ و این پرسش را آنقدر ادامه دهید خودآموزی چه کرده ام

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