Drug Therapy in Infants

PHARMACODYNAMICS
Factors Affecting Drug Effects on the Infant:
I. Drug Absorption
II. Drug Distribution
III. Drug Metabolism
IV. Drug Excretion

Drug Therapy in Infants

I. Drug Absorption
Absorption in infants and children follows the
same rules as in adults.
Factors affecting absorption are determined by
the physiologic status of the infant or child and
are influenced by:
1.) Blood flow at the site of administration.
2.) Gastrointestinal function.

Drug Therapy in Infants

Drug Absorption in
Drug
Acetaminophen
Ampicillin
Diazepam
Digoxin
Penicillin G
Phenobarbital
Phenytoin
Sulfonamides

the neonate compared to adults.

Oral Absorption
Decreased
Increased
Normal
Normal
Increased
Decreased
Decreased
Normal

Drug Therapy in Infants

1.) Blood flow at the site of administration.
- Physiological conditions that might affect blood flow are: cardiovascular
shock, vasoconstriction (sympathomimetic agents), and heart
failure.
- Diminished muscle mass in i/ch may reduce blood flow causing
irregular and unpredicatble absorption. Drug will concentrate in the
muscle and if perfusion suddenly increases, drug may reach toxic
concentrations.
e.g. cardiac glycosides, aminoglycoside antibiotics, and anticonvulsants.

2.) Gastrointestinal function.

2.) Gastrointestinal function.

Significant changes occur in the neonate shortly after
birth.
Gastric acid secretion commences soon after birth
and increases gradually over several hours. In
preterm infants it appears slowly. Drugs affected by
gastric pH should not be administered orally.
Gastric emptying is prolonged in the first day of life.
Thus, drugs absorbed through GI may be more
completely absorbed than anticipated.
Peristalsis in the neonate is slow. If drugs are
absorbed in the small intestine, their effect may be
delayed. Diarrhea causes decrease absorption in
small intestine.

Drug Therapy in Infants

II. Drug Distribution
As body composition changes with development so
does the distribution volume of drugs.
In the neonate, 70-75% of body weight is water vs
85% in preterm vs 50-60% in the adult.
Most neonates will experience diuresis in the first
24-48hrs of life.
In neonate 40% of body weight is extracellular
water vs 20% in the adult.
In the neonate total body fat is 15% vs 1% in
preterm.

Drug Therapy in Infants

II. Drug Distribution
Binding to Plasma protein
Protein binding of drugs is reduced in the
neonate. Therefore, concentration of free drug
in plasma is increased => increased effect or
increase toxicity.
Drugs (e.g. sulfonamide antibiotics) that
displace bilirubin from albumin may cause
kernicterus. Conversely, bilirubin may also
displace protein-bound drugs (e.g. phenytoin).

III. Drug Metabolism

Metabolism of most drugs occurs in the liver.
The metabolizing activity of cytochrome P450dependent mixed-function oxidases is reduced in
neonates (50-70% of adult values).
Glucoronide formation doesnt occur until the 3th
-4rd years of life. Thus, in the neonate, drugs
have slow clearance rates and prolonged halflives.
If the mother was taking phenobarbital, neonatal
liver enzymes could have been induced. The
ability of the neonate to metabolize certain drugs
would be greater than expected and the effect
could be less.

IV. Drug Excretion

Glomerular filtration is much lower (30-40% of
adult) in neonates for the first few days of life.
Within a week glomerular filtration and plasma
flow increase by 50% and reach adult values
within 6-12 months. Drugs that depend on renal
flow are eliminated very slowly in the first few
weeks of life (penicilins, aminoglycoside
antibiotics, digoxin)
Ampicillin
< 7 days old=> 50-100 mg/Kg/d , 2d at 12 hr
intervals.
> 7 days old => 100-200 mg/Kg/d, 3d at 8 hr
intervals.

Drug

Neonates t1/2
(hours)

Adults t1/2
(hours)

Acetaminophn

2.25

0.92.2

Diazepam

25100

4050

Digoxin

6070

3060

05 days

200

64140

515 days

100

130 months

50

02 days

80

314 days

18

1450 days

Phenobarbital

Phenytoin

Neonatal Age

Salicylate
Theophylline

1218

4.511

1015

Neonate

1326

1015

Child

34

Dosage Forms and Compliance:

To ease administration and compliance,
drug manufacturers prepare drugs
as:
Elixirs. Alcoholic solutions in which the
drug molecules are dissolved and evenly
distributed.
b) Suspensions. Contain undissolved
particles of drug which must be
distributed throughout the vehicle by
shaking to prevent uneven drug
dispensing.
a)

Weight
(kg)

(lb)

Age

Surface
Area
(m2)

Percent of
Adult
Dose

6.6

Newborn

0.2

12

13.2

3 months

0.3

18

10

22

1 year

0.45

28

20

44

5.5 years

0.8

48

30

66

9 years

60

40

88

12 years

1.3

78

50

110

14 years

1.5

90

60

132

Adult

1.7

102

70

154

Adult

1.76

103

Age (Young's rule):

Weight (somewhat more precise is Clark's rule):

Compliance may be difficult to achieve in

pediatric medicine and may prove a
challenge when taking into account:
measuring errors
spills
spitting
A calibrated medicine spoon should be
recommended.
Parents should be told to repeat dosage or not after
spitting or whether to wake up the child every 6
hr dose day or night. Possible drug-drug
interactions with ODC medications should be
discussed.

Drug

Effect on
Infant

Comments

Ampicillin

Minimal

No significant adverse effects; possible

occurrence of diarrhea or allergic
sensitization.

Aspirin

Minimal

Occasional doses probably safe; high

doses may produce significant
concentration in breast milk, but infant
dose is nevertheless low.

Caffeine

Minimal

Caffeine intake in moderation is safe;

concentration in breast milk is about
1% of that in maternal blood.

Chloral
hydrate

Significant

May cause drowsiness if infant is fed at

peak concentration in milk.

Chloramphe
nicol

Significant

Concentrations too low to cause gray

baby syndrome; possibility of bone
marrow suppression does exist;
recommend not taking chloramphenicol
while breast-feeding.

Thiazide

Minimal

No adverse effects reported.

CPZ

Minimal

Appears insignificant.

Codeine

Minimal

No adverse effects reported.

Diazepam

Significant May cause sedation in breast-fed infants; clinical

monitoring recommended.

Dicumarol

Minimal

No adverse side effects reported.

Digoxin

Minimal

Insignificant quantities enter breast milk.

Ethanol

Moderate

Large amounts consumed by mother can produce

alcohol effects in infant.

Heroin

Significant Enters breast milk and can prolong neonatal narcotic

dependence.

Iodine (rad) Significant Enters milk in quantities sufficient to cause thyroid

suppression in infant.
Isoniazid
(INH)

Minimal

Milk concentrations equal maternal plasma

concentrations. Possibility of pyridoxine deficiency
developing in the infant.

Kanamycin

Minimal

No adverse effects reported.

Lithium

Significant Breast-feeding with caution; levels can be measured in

milk.

Methadone

Significant (See heroin.) Under close physician supervision, breastfeeding can be continued. Signs of opioid
withdrawal in the infant may occur if mother stops
taking methadone or stops breast feeding abruptly.

Oral
contraceptives

Minimal

May suppress lactation in high doses.

Penicillin

Minimal

Very low concentrations in breast milk.

Phenobarbital

Moderate

Hypnotic doses can cause sedation in the infant. Close

monitoring of infant.

Phenytoin

Moderate

Amounts entering breast milk are not sufficient to cause

adverse effects in infant.

Prednisone

Moderate

Low maternal doses (5 mg/d) probably safe. Doses two or

more times physiologic amounts (> 15 mg/d) should
probably be avoided.

Propranolol

Minimal

Very small amounts enter breast milk.

Propylthiouracil

Significant

May suppress thyroid function in infant.

Spironolactone

Minimal

Very small amounts enter breast milk.

Tetracycline

Moderate

Possibility of permanent staining of developing teeth in

the infant. Should be avoided during lactation.

Theophylline

Moderate

Can enter breast milk in moderate quantities but not likely

to produce significant effects.

Thyroxine

Minimal

No adverse effects in therapeutic doses.

Tolbutamide

Minimal

Low concentrations in breast milk.

Warfarin

Minimal

Very small quantities found in breast milk.

Drug Therapy in Infants

Drugs
Contraindicated
Amphetamine
Bromocryptine
Cocaine
Cyclophosphamide
Cyclosporine
Doxorubicin

during Lactation:
Ergotamine
Heroin
Lithium
Marijuana
Methotrexate
Nicotine
Phenindione

OBAT PADA MANULA

Noor Wijayahadi

Medications Most Commonly Used

in the Community
Analgesics
Diuretics
Cardiovascular
Sedative-hypnotics

Medications Most Commonly Used

in the Nursing Home
Antipsychotics
Sedative-hypnotics
Diuretics
Antihypertensives
Analgesics
Cardiovascular
Antibiotics

Manula Resiko tinggi mengalami

efek merugikan dari obat
Faktor penderita

Age-associated changes in pharmacokinetics

Age-associated changes in pharmacodynamics
Comorbidity: drug-disease interactions
Polypharmacy: drug-drug interactions
Kemampuan homeostasis berkurang
Fungsi organ berkurang

Faktor sistem layanan medik

Fragmentation of care (Poly-doctoring)

Inadequate training in principles of geriatric practice

Therapeutic Response
Therapeutic Window

Toxic Response

Age

The Precipice
Physiologic
Reserves
Available
Physiologic
Reserves
Already In Use

Increasing Age

Masalah Utama
Pilihan obat atau dosis yang tidak tepat
Concomitant disease affect metabolism
of or response to drug
Polypharmacy drug - drug interactions
Patient behavioural factors

Perubahan PHARMACOKINETICS
Absorption
active transfer

Body composition
lean body mass
body fat
plasma albumin

Liver metabolism
oxidation / microsomal enzymes

Renal clearance

Perubahan
PHARMACODYNAMICS
Brain sensitivity

Benzodiazepines and

narcotic analgesics more effective

Coagulation mechanism control
Anticoagulants more potent
Adrenergic receptor sensitivity
B-blockers less effective

Penurunan fungsi homeostasis

Baroreceptor sensitivity
postural hypotension

Thermoregulation
hypothermia

COMMON PITFALLS 1 :
Gagal mengobati kondisi yang seharusnya
bisa diobati (treatable conditions)
Thrombolytic therapy
the older the patient, the greater the benefit
the older the patient, the less likely to be
thrombolysed

Hypertension
30 - 40% decrease in risk of CVA if ISH treated

BLOOD PRESSURE AND AGE

160
140
120
100
80
60
40
20
0
30

40

50

60

70

80

COMMON PITFALLS 2 :
Prescribing for symptom and not for
diagnosis

A pill for every ill

PRESCRIPTIONS BY AGE
(Items per person per year)
40
35
30
25
20
15
10
5
0

42 46 50 54 58 62 66 70 74 78 82 86 90

EFFECTIVE PRESCRIBING 1
Utamakan non-pharmalogical treatment
modify diet
stop smoking, reduce alcohol
physical exercise
walking aids, household adaptations
social supports

EFFECTIVE PRESCRIBING 2
Treat conditions in order of priority
Pertimbangkan kegagalan fungsi organ
Start low mulai dosis kecil , naikkan
dengan hati-hati
Gunakan formularium yang terbatas
Monitor compliance and response
Review pemakaian obat secara reguler
Ikut sertakan PENDERITA

Who Takes the Most Medications?

Women
Individuals with
multiple health
conditions
Frail elderly
Nursing home
residents

Medications Most Commonly Used

in the Community
Analgesics
Diuretics
Cardiovascular
Sedative-hypnotics

Umur mempengaruhi
metabolisme obat?
Pada manula:
Slower organ function
Slower blood circulation
Increased body fat

obat bertahan lama di dalam tubuh

resiko terkena efek samping obat
meningkat

Age-Related Changes:
Total body water menurun konsentrasi dalam
darah obat yang larut-air meningkat
Perubahan berat badan mempengaruhi dosis
yang diperlukan dan lama obat dalam tubuh:
More body fat prolonged half-life
Less lean body mass increased drug concentration

Perubahan sistem pencernaan

mempengaruhi kecepatan absorbsi obat
onset obat lebih lama

Age-Related Changes:
Slower circulation delay drugs getting
to liver and kidneys
Slow down of liver and kidneys affects
time it takes for medication to break down
and leave body
Less absorption from transdermal patches
Drug receptor sites may be different in
older adults

Changes in Pharmacokinetics
Perubahan fisiologis dan fungsi organ pada
manula perubahan Farmakokinetik
Pharmacokinetics is the time course of a drug
and its metabolites through the body
Absorption
Distribution
Clearance: elimination (renal), metabolism (liver)

2004: Cusack, Amer. J of Geriatric Pharmacotherapy

Volume of Distribution (Vd)

Proporsi lemak meningkat dan volume otot
berkurang merubah Vd
Vd obat larut lemak (fat soluble drug)
meningkat waktu paro meningkat:
diazepam, thiopental, trazadone
Vd obat larut air (water soluble drug)
menurun kadar obat dalam plasma
meningkat: ethanol, lithium,
aminoglycosides, alcohol, digoxin

Protein Binding
albumin berkurang chronic disease:
e.g.,malnutrition, liver or kidney conditions.
obat dengan ikatan protein tinggi kadar
obat bebas meningkat.
ceftriaxone,diazepam, phenytoin,
warfarin.

Eliminasi Obat menurun

Fungsi ginjal menurun eliminasi oleh ginjal
berkurang.
Even in the absence of kidney disease renal clearance
may be reduced 35-50%.
therapeutic effect dan resiko toksisitas meningkat
perlu pengurangan dosis atau perubahan interval
pemberian obat.

Metabolisme hepar berkurang

Phase I, terutama reaksi oksidatif menurun

Phase II, terutama reaksi konjugasi relatif tidak berubah.

diazepam is metabolized via Phase I reactions in the liver,
at least initially.

Drugs with Cytochrome P450 Effects

(partial)
Inhibitors

Inducers

Allopurinol

Metronidazole

Barbiturates

Amiodorone

Quinolones

Carbamazepine

Azole antifungals

Phenytoin

Cimetidine

Rifampin

INH

Tobacco

SSRIs
Tacrine

Hepatic Metabolism
Decreased liver size and hepatic blood flow.
Regional blood flow to the liver at age 65 is reduce
by 40-45% compared to a 25 year old.
Metabolic clearance of drugs by the liver may be
reduced.
Disease effects: liver congestion from heart failure
decreases warfarin metabolism and an increased
pharmacologic response.
Environmental effects: smoking stimulates
monoxygenase enzymes and increases clearance
of theophylline.

Changes in Pharmacodynamics
Older patients may have more sedation and
impaired function after a single dose of
benzodiazepines than younger persons.
After single dose of nitrazepam older patients
made more mistakes on psychomotor testing
compared to placebo while younger patients
had no impairment .

Suboptimal Quality
Typology of Quality Problems:
Overuse (Polypharmacy)
Underuse
Misuse (Inappropriate Prescribing)
Errors

Suboptimal Prescribing
Polypharmacy
Underuse of Effective Medications
Drug-Drug Interactions
Drug-Disease Interactions
Inadequate Monitoring
Inappropriate Dosing
Inappropriate Duration
Drugs to Avoid

Drug-Drug Interactions
Penyebab tersering ESO pada manula
Jumlahnya sangat banyak Almost
countless peresepan elektronik
Some common examples

Statins and erythromycin and other antibiotics

TCAs and clonidine or type 1Anti-arrythmics
Warfarin and multiple drugs
ACE inhibitors increase hypoglycemic effect of
sulfonylureas

Drug-disease Interactions
Patient with PD have increased risk of drug
induced confusion
NSAIA (and COX-2s) s can exacerbate CHF
Urinary retention in BPH patients on
decongestants or anticholinergics
Constipation worsened by calcium,
ahticholinergics, calcium channel blockers
Neuroleptics and quinolones lower seizure
thresholds

Polypharmacy
Polypharmacy = pemberian banyak
obat melebihi indikasi penggunaan
59% manula mendapat obat tanpa
indikasi yang jelas.
55% manula mendapat obat tanpa
indikasi, 32.7% mendapat obat yang
tidak efektif, 16.8% mendapat obat
duplikasi
2001: Hanlon, JAGS

Underuse
Among patients elderly patients with
cardiovascular disease and diabetes, only
19.1% of patients were prescribed statins. In
patients 66 to 74 years old, the adjusted
probabilities of statin prescription were 37.7%,
26.7%, and 23.4% in the categories of low,
intermediate, and high baseline risk,
respectively.
The likelihood of statin prescription was 6.4%
lower (adjusted odds ratio, 0.94; 95%
confidence interval, 0.93-0.95) for each year of
increase in age and each 1% increase in
2004: Ko, JAMA
predicted
3-year mortality risk.

Inappropriate Prescribing
20-27% manula mendapat resep yang
tidak diperlukan (inappropriate).
Inappropriate prescribing meningkatkan
resiko jatuh, fraktur femur, cognitive
impairment, diminished independence,
dan mortalitas

inappropriate drug prescribing to

the elderly?
The Beers List.
List
a list of medications identified by an expert
panel as being inappropriate for older persons
because of ineffectiveness or because they
pose a high risk for adverse drug events.
Beers MH Arch Intern Med 1997

The Beers List

The Beers List, berisi 33 obat dalam 3
kategori:
1. Drugs that should always be avoided.
2. Drugs that are rarely appropriate.
3. Drugs with some indications, but that are often
misused.

Zhan et al. JAMA 2001

Drugs And Dosages to Avoid

Meperidine
Diphenhydramine
The most anticholinergic tricyclics:
amitryptiline, doxepin, imipramine
Long acting benzodiazepines such as
diazepam
Long acting NSAIDs such as piroxicam
High dose thiazides (>25mg)
Iron: 325 mg once daily is enough

11 drugs that should always be

avoided in the elderly:
Barbiturates
Chlorpropamide
Flurazepam
Meperidine
Meprobamate
Pentazocine

Belladonna alkaloids
Dicyclomine
Hyoscyamine
Propantheline
Trimethobenzamide

Zhan et al. JAMA 2001

Tangga Peresepan
(Prescribing Cascade)
The prescribing cascade terjadi
bila satu obat diresepkan,
Menyebabkan timbulnya
efek samping obat / adverse
drug event (ADE),
Mendorong peresepan obat
kedua untuk mengatasi ESO
sebelumnya

Drug 1

ADE

Drug 2

Rochon PA et al, BMJ 1997

The Prescribing Cascade

There are numerous examples of the prescribing cascade in the
medical literature.
For example, it has been observed that patients prescribed
metoclopramide ( a gastric motility agent) are more likely to be initiated
on treatments generally reserved for the management of idiopathic
Parkinsons Disease (e.g. Drugs containing Levodopa).
Metoclopramide
In this case, metoclopramide use
can lead to extrapyramidal
symptoms, which may be
misdiagnosed as Parkinsons
Disease.

Extrapyramidal Effects

Levodopa Rx
Avorn J et al, JAMA 1995

The Prescribing Cascade

Another example relates to the fact that older persons who have
been prescribed NSAIDs appear to be at increased risk for being
initiated on antihypertensive therapy.
NSAID Rx
In this case, NSAID use
increases blood pressure
leading to the need for blood
pressure lowering therapy.

Blood Pressure
Antihypertensive Rx

In both examples, the initiation of new drug treatments in older persons

could have been avoided if there was recognition of the risks of certain
drug treatments (e.g. metoclopramide and NSAIDs) in elderly patients.
Gurwitz JH et al, JAMA 1994

The Prescribing Cascade

Penyebab utama polypharmacy pada
manula
Some common examples

NSAID ->HTN->antihypertensive therapy

Metoclopromide ->Parkinsonism ->Sinemet
Dihydropyridine -> edema ->furosemide
NSAIA ->H2 blocker ->delirium ->haldol
HCTZ ->gout->NSAIA ->2nd antihypertensive
Sudafed ->urinary retention ->alpha blocker
Antipsychotic ->akithesia ->more meds

NSAID (Anti-inflamasi non-steroid)

Efektifitas Parasetamol = NSAIDs pada
osteoartritis ringan
NSAIDs side effects
GI hemorrhage
Decline in GFR
Decreased effectiveness of diuretics, antihypertensive agents
Indication should justify the increased toxicity
of NSAIDs

Drugs and Cognitive Impairment

Anticholinergic drugs are common
offenders (TCAs, benadryl and other
antihistamines, many others)
Other offenders cimetidine, steroids,
NSAIAs
Medical Letter 2000 Drug Safety 1999 Drugs and Aging 1999

Drugs and Falls

Biggest risk drugs are long acting benzodiazepines
and other sedative-hypnotics
Both SSRIs and TCAs associated with increased
risk of falling
Beta blockers NOT associated with increased risk
of falling in published literature
Mild increase in fall risk from diuretics, type 1A
anti-arrythmics, and digoxin
Leipzig, JAGS

Drug-Food Interactions
Interactions between drugs and food
warfarin and Vitamin K containing foods
(remember green tea, as well)
Phenytoin & vitamin D metabolism
Methotrexate and folate metabolism

Drug impact on appetite

Digoxin may cause anorexia
ACE inhibitors may alter taste

Anticipate Side Effect

Narcotics
Begin lactulose or sorbitol and a stimulant laxative
Colace is NOT sufficient in most instances

Steroids
Think about osteoporosis prevention
Remember steroid induced diabetes

Levothyroxine
Calcium interferes with absorption of levothyroxine

Drug Discrepancies
Difference between medical record and
medication bottles in 76% of cases
51% of time medication not recorded
29% medication recorded that patient not
taking
20% dosage discrepancy

Risk Factors: Age, number of medications

Bedell et al Arch Intern Med 160, 2000

High Risk Situations

Patient seeing multiple providers
Patient on multiple drugs
Patient lives alone and/or has
cognitive impairment
Discharge from hospital or any
change in venue

Hospitalization: A High Risk Time

At hospitalization:
40% of admission medications stopped
45% of discharge medications were started
Serious prescribing problems in 22%
Other prescribing problems in 66%
Beers JAGS 1989, Lipton Medical Care 1992

Nonadherence
Lack of understanding of how to take
High risk times: Hospital discharge, new meds
added, complex regimens

Unable to take
Conscious nonadherence

Side effects
Lack of understanding of benefits of drug
Financial

Complementary Therapies
Very commonly used in the elderly
Some common herbs and alternative therapies:

Anti-aging
Dementia
BPH
OA

Depression

DHEA, growth hormone

Gingko biloba
Saw palmetto, PC-SPES
Chondroiton sulfate,
glucosamine
St. Johns wort, SAMe

Adulterants in Products
California Department of Health
Services, Food and Drug Branch
screened 250 Asian herbal products
collected from herbal stores in California
assayed products using gas chromatography,
mass spectrometry, and atomic-absorption
techniques
Ko, NEJM 1998; 339; 847

32% contained unlabeled medications,

14% mercury, 14% arsenic, 10% lead

Herbals and Supplements:

Regulation
Demonstration of safety is NOT required prior to
marketing
Manufacturing standards are not required
Can have health claims, but not claims about
treating, preventing, or curing
For glucosamine/chondroitin, on third of
combinations did not contain listed ingredient
www.consumerlabs.com has some drug
information

Herbals and Supplements:Potential

interactions with Rx Drugs
SAMe may increase homocysteine
levels
St. Johns wort and Oral contraceptives
Ginkgo may increase anticoagulant
effects of ASA, warfarin, NSAIAs,
ticlopidine, and may interact with MAOIs
Bottom line: Try to know what your
patient is taking, and ask in a
nonjudgmental way

Prinsip Manajemen Obat

Riwayat pemakaian obat yang lengkap,
termasuk obat herba/tradisional/obat bebas
Hindari pemberian obat bila
keuntungan/benefit kecil , atau ada alternatif
pengobatan non-farmakologis
Pertimbangkan harga
Start low, go slow, but get there!
Buat cara pemberian yang sederhana
Tulis cara pemakaian sejelas mungkin
Minta penderita membawa seluruh obat yang
sedang diminum setiap kali periksa

Principles (continued)
Pertimbangkan pemakaian kotak obat harian
atau mediset
Hentikan pemakaian obat yang tidak jelas
keuntungannya atau resiko efek sampingnya
lebih merugikan
Hati-hati pemakaian obat baru (newer drugs)
Hindari penggunaan obat > 5 macam
Consider if the benefit of the 7th or 8th drug is
sufficient to justify the cost, increase in
complexity of regimen, and risk of side effects

Newer drugs
What is unique about this compound?
What clinical data is available?
How does it compare with traditional
therapy?
How expensive is it?
With third party payers cover this
product?
Does the potential advantage of this new
drug justify the risk of using a new drug?

The Message for Today

Start low
Go slow (but get to therapeutic levels)
Sometimes say no (how about other non-drug
treatments?)