APLIKASI

FARMAKOKINETIKA
PADA NEONATUS DAN
PAEDIATRIK

NURLELY, M.SC (PHARM)., APT

 INTRODUCTION

• Neonates and paediatric patients : special

population for drug therapy
• Many physiologial changes take place during this
time  impact on pharmacokinetics and dynamics
of a compound.
• More sensitive to drugs than other patients are
• Show greater individual variation
• Sensitivity due mainly to organ system immaturity
• Increased risk for adverse drug reaction
• Factors that influence tissue drug concentrations
overtime include : absorbption, distribution,
metabolism and distribution
 INTRODUCTION

• Based on International Conference on

Harmonization (ICH) Paediatric population is
divided into :
• Preterm newborn
• Newborn (0-28 days)
• Infant (>28 days-12 months)
• Toddler (>12 months-23 months)
• Preschool child (2-5 years)
• School age child (6-11 years)
• Adolescent (12-18 years)
 ABSORPTION

• Liberation of drug  differ in children since gut

transit time and intestinal fluid composition affect
drug dissolution

• Intestinal transit time  shorter in young children 

reduce the amount of drug absorbed (for poorly
soluble drugs or SR products ex: theophylline)

• Absorption is the process of drug movement from

the site of administration or applicatin into the
systemic circulation.
 ABSORPTION : ORAL

• Gastric pH is neutral at birth within 24-48 hours after

birth, pH= 1-3

• After 72 hours or 10 day neutral

• Higher pH  have a protective effect on acid-labile

drugs and higher bioavailability of beta lactam
antibiotics

• For weak acids drug (phenytoin, acetaminophen,

phenobarbital)  bioavailability is reduced (increased
ionization under achlorhydric conditions)
 ABSORPTION : ORAL

• Gastric emptying and intestinal motlity are

prolonged  delayed absorption (phenobarbital,
digoxin, sulfonamides)
• Reduced intestinal absorption surface area and
shorter gut transit time  delayed absorption
• Bile secretion in the first 2-3 weeks of life is poor  it
can compromise the body’s ability to solubilize and
absorb some lipophilic drugs such as erythromycin
 ABSORPTION : ORAL

• Intestinal permeability alters the bioavailability of

drugs
• Immature intestinal CYP3A4 enzyme system 
decreased midazolam’s oral Cl and increased BA
• P-glycoprotein is an efflux transporter playing a part
in intestinal absorption.
• P-gp can affect the bioavailability of certain drugs
particularly with low solubility.
 ABSORPTION : PERCUTANEOUS

• Percutaneous absorption of drugs through skin 

high due to several factors : better hydration of the
epidermis, gretaer perfusion of the subcutaneous
layer and the larger ratio of total BSA to body mass
compared to adults.

• Topically applied steroids may be toxic

 ABSORPTION : INTRAMUSCULAR

• May be delayed  reduced blood flow to skeletal

muscles and increased capillary density
 ABSORPTION : RECTAL

• Very efficient when oral / iv routes are

contraindicated
• Can undergo absorption into the inferior mesenteric
arteries and the hemorrhoidal veins, bypassing the
portal circulation (eg first pass).
 DISRIBUTION

• The distribution of drugs affects efficacy and

duration of action

• After a drug enters the systemic circulation, it is free

to distribute in plasma or tissue as dictated by the
physiologic constitution of the host and the
physicochemical properties of the drug.

• Hydrophylic drugs are mainly distributed into body

water while liphophilic drugs are mainly distributed
into fat.
 DISTRIBUTION

• Lipophilic drugs have a relatively larger Vd in infants

compared with older children owing to their higher
comparative levels of fat (22.4% at 12 months vs. 13% at
15 years)
• Example : diazepam as a lipophilic drug

• Hydrophilic drugs also have larger Vd in preschool

children as extracellular water decreases during
development, from 70% total body weight in newborns
to 61.2% in 1-year-old infants
• Example : gentamicin, higher doses per kilogram
bodyweight must be given to infants compared with
adults
 DISTRIBUTION

• Plasma protein binding of drugs tends to be

reduced in neonates and infants
• Protein binding affects the Vd of drugs
• Drugs where lower protein binding has been
documented in newborn babies include phenytoin,
salicylates, ampicillin, nafcillin, sulfisoxazole and
sulfamethoxyphrazine.
• Consequently, greater free fractions of these drugs
are circulating and thus are able to penetrate
various tissue compartments, yielding higher
distribution volumes
 METABOLISM

• Drug metabolism can be divided into Phase I and

Phase II metabolism.
• Phase I metabolism involves small structural
alterations to the drug molecule to decrease
lipophilicity and enhance renal excretion of the
molecule.
• Phase II metabolism involves the conjugation of a
functional group on the molecule (parent drug or
Phase I metabolites) with hydrophilic endogenous
substrates (e.g. glucuronidation, sulfation,
acetylation).
 METABOLISM

• Liver blood flow may be relatively high in infants

(hepatic clearance is also higher).

• This could affect first-pass metabolism particularly

for drugs with a high extraction ratio, like
propranolol
 ELIMINATION

• Two organ systems are responsible for most drug

excretion:
• the liver (via bile) and
• the kidneys (via urine).

• Hepatic drug clearance relies primarily on active

transport processes,
• whereas both active and passive processes work in
concert in the kidneys.
 ELIMINATION

• The glomerular filtration rate (GFR) is 2 to 4ml min−1

1.73m−2 in term neonates, and it doubles by 1 week
of age, reaching adult values by the end of the first
year of life
• The renal excretion of unchanged drug is generally
lower in newborns owing to the immaturity of renal
function.
• a similar or greater rate of renal excretion has been
observed in infants and preschool children
compared with adult values for some drugs
(levetiracetam , cimetidine and cetirizine).
 ELIMINATION

• Digoxin serves as an excellent example for

ontogeny of renal elimination.
• Digoxin is extensively secreted via P-gp within the
tubular cell.
• Preschool children require three-fold higher doses of
digoxin kg−1 body weight than adults, which may
be linked to P-gp ontogeny
• Infant urinary pH is lower than adult values which
may increase the reabsorption of weakly acidic
drugs.
 24

APLIKASI
FARMAKOKINETIKA
PADA PASIEN GERIATRI
Nurlely, M.Sc (Pharm)., Apt

Program Studi Profesi Apoteker

FMIPA ULM
 25

Introduction
 Around the world, the proportion of the population aged 80
years and above will range between 3.7%-7.5%.

 Ageing is not a single entity but collective term representing

the sum of cumulative local effects at the molecular, cellular
and tissue level

 Ageing is not solely a progression of functional decline but

produces anatomical and physiological changes which might
lead to decompensation of the relevant system when they
progress beyond a threshold
 26

Cardiac structure and function

 Reduced elasticity and compliance of the aorta and great arteries

 Reduced intrinsic heart rate and increased sinoatrial node

conduction time

 During exercise the tachycardic response is reduced.

 cardiac output is maintained by an increase in stroke volume (

 27

Renal System
 Decreased renal mass

 Reduced blood flow

 Renal plasma flow and GFR decline

 The ability to concentrate the urine during water deprivation is

reduced

 Changes in salt and water regulation also interact with age-related

change in thirst mechanisms
 28

Gastrointestinal system
 Stomach and duodenum
 the secretion of hydrochloric acid and pepsin are decreased
 gastric emptying in elderly subjects is similar to that of young subjects
 Small intestine
 reduced absorption of several substances (e.g. sugar, calcium, iron)
while digestion and motility remain relatively unchanged
 Colon
 slower colonic transit time
 Pancreas
 some enzymes (amylase) remain constant whereas others (lipase,
trypsin) decrease dramatically
 Liver
 a progressive reduction n liver volume and liver blood flow.
 Alteration of hepatic structure and enzymatic functions with ageing is
moderate.
 29

Neuroendocrine responses
 learning and memory impairment due to excessive HPA activation
and hypersecretion of glucocorticoids can lead to dendritic atrophy
in neurones in the hippocampus.

 Damage or loss of hippocampal neurones results in impaired

feedback inhibition of the HPA axis and glucocorticoid secretion,
leading to further damage caused by elevated glucocorticoid
concentrations.

 glucocorticoids may sensitize hippocampal neurones to cell death

and/or functional impairment,
 30

Body composition
 a progressive reduction in total body water and lean body mass 
a relative increase in body fat
 31

Pharmacokinetic Principles
Age-related changes which affect 32

pharmacokinetics
• decreased lean body mass
 affects drug distribution

• decreased levels of serum albumin

 affects drug distribution

• decreased liver function

 affects drug metabolism/biotransformation

• decreased renal function

affects drug elimination
 33

Drug absorption
 Reduced the amount of saliva  reduced the rate of drug
absorption by influencing the gastric pH

 Reduced gastric secretion and reduced acidity (increased pH) 

delay dissolution of oral medication
 Galactose, thiamine, iron, azoles, calcium
 BUT increaesd the absorption of levodopa

 For drugs absorbed by passive diffusion  not affected to a

significant extent (e.g. oral antiarrhytmic drugs).

 34

Drug distribution
 Polar drugs  smaller Vd  higher serum level
 E.g. gentmicin, digoxin, ethanol, theophylline and cimetidine
 Loading doses of digoxin need to be reduced

 Nonpolar drugs tend to be lipid soluble  increased Vd  a

prolongation of half life
 E.g. diazepam, thiopentone, lignocaine, chlormethiazole
 35

Drug distribution
 Body fat is increaesed 15% to 30 %

 decreased lean body weight.

 Vd is lower for drugs which stay in the central compartment

 36

Protein binding
 Acidic compounds (diaepam, phenytoin, warfarin, salicylic acid) 
bind to albumin

 Basic drugs (lignocaine, propranolol)  bind to α1 acid

glycoprotein

 Albumin  reduced in malnutrition whereas 1 acid glycoprotein 

increased during acute illness  clinical rlevance is limited
Effects of Aging on Volume of 37

Distribution (Vd)
Aging Effect Vd Effect Examples

 body water  Vd for hydrophilic ethanol, lithium

drugs
 lean body mass  Vd for for drugs digoxin
that bind to muscle
 fat stores  Vd for lipophilic diazepam, trazodone
drugs
 plasma protein  % of unbound or diazepam, valproic acid,
(albumin) free drug (active) phenytoin, warfarin
 plasma protein  % of unbound or quinidine, propranolol,
(1-acid glycoprotein) free drug (active) erythromycin, amitriptyline
 38

Drug metabolism

enzymatic reactions preparing drugs for elimination

Phase I reactions:
• oxidation: catalyzed by cytochrome P450 enzymes
Phase II reactions:
• conjugation: addition of small chemical groups which increase
solubility to facilitate elimination
 39

Drug metabolism
 Reduced liver mass and blood flow  reduction in first pass
metabolism

 The bioavailability of propranolol, labetalol , quinidine, lignocaine

are increased  extensive first pass metabolism

 Several ACE inhibitors (enalapril and perindopril)  prodrugs 

need to be activated in the liver first pass acivation might be
slowed
 40

Metabolic Pathways

** NOTE: Medications undergoing Phase II hepatic metabolism are

generally preferred in the elderly due to inactive metabolites (no
accumulation)
 41

Drug clearance : liver

 Depends o the capacity of the liver to extract the drug from the
blood passing throuh the organ and the amount of hepatic blood
flow

 E = steady-state extraction ratio,

 Q = liver blood flow (sum of hepatic portal and hepatic arterial
blood flow
 Ca = concentration of drug in portal vein and hepatic artery
 Cv = concentration of drug leaving the liver in the hepatic vein, and
 CL liver = clearance by the liver.
 Clerance by the liver depends on : blood flow and extraction ratio
Drug classification based on 42

extraction ratio
 High (E>0.7)
 Chlormetiaole, dextropropooxyphone, ligocaine, propranolol, glyceryl
nitrate
 Intermediate (E 0.3-0.7)
 Aspirin, codein, morphine, triaolam
 Low (E< 0.3)
 Carpamaepim, diaepam, theophylline, phenytoin and warfarin
 E is high  Cl is rate limited by perfusion
 E is low  Cv is similar to Ca and changes in blood flow produce
little changes in Cl

 Therefore : reduced liver blood flow in elderly px  affect drug Cl

with a high extraction ratio
 43

Drug clearance : kidney

 Reduced GFR  affects Cl of water soluble drug suc as : water
soluble antibiotics, diuretics, digoxin, water soluble beta
adrenoreceptor blockers, lithium and NSAIDs  depends on the
likely toxicity of the drug

 Drugs with narrow therapeutic index (amynoglycosides, digoxin,

lithium)  have serious ADR

 Reduced Cl  atenlol, HCT, triamerene  similar to young

subjects

Age related pharmacokinetic 44

changes in specific situations

 Digoxin
 Time to Cmax is prolonged  time to reach steady state plasma conc
concentration is increased (from 7 to 12 days)

 Vd is decreased  LD is reduced 20%

 Cleraed mainly by renal  reduced digoxin Cl  daily dose of digoxin is

reduced
Age related pharmacokinetic 45

changes in specific situations

 Diuretics
 Vd is similar for furosemide as compared with young subjects

 It is caused by prolonged half life and a reduced renal clearance

Age related pharmacokinetic 46

changes in specific situations

 ACE inhibitors
 Some are active compounds (lisinopril) and most are pro drugs
undergoing activation in the liver (enalapril, perindopril)

 Biotransformation might be imaired in patients with severe heart failure

and hepatic congestion

 ACE inhibitors are excreted through kidney need to be adjusted when

Cl Cr is below 30 ml/min

 Newer ACE inhibitors (benaepril, fosinopril, spirapril, ofenopril) are

eliminated by the biiary route  potenstially compensating for the
reduced renal clearance in elderly px
 47

Dosing of drug in elderly

 An aminoglycoside has a normal elimination half-life of 107 minutes
in young adults. In patients 70 to 90 years old, the elimination half-
life of the aminoglycoside is 282 minutes. 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?
 48

 Solution

 Keeping the dose constant,

 Where Dn is the new dose and Do is the old dose

 Therefore, the same dose of the aminoglycoside may be administered

every 32 hours without affecting the average steady-state level of the
aminoglycoside
 49

 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 7.7mmL/min.
 What percentage of the normal dose of lithium should be given to a
65-year-old patient?
 50

 The dose should be proportional to clearance; therefore,

 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.