Drug use in children and the

elderly
Dr Michelle Munyoro
MBChB, MSc (UZ)
Department of Clinical Pharmacology
 Lessons from the past
Thalidomide first appeared in Germany on 1st October 1957
• marketed as a sedative with few side effects
• Considered safe, used for morning sickness
• Drug testing procedures were less rigorous
• limited testing failed to reveal teratogenic side effects
Pre-marketing tests conducted on rodents which metabolize the drug
in a different way to humans
• Subsequent tests on rabbits and monkeys produced similar SEs as
in humans.
• Early 1960’s: post marketing reports
• Phocomelia: babies born with flipper-like limbs
AKA: 'Thalidomide Babies’
Phocomelia
Optimal pharmacotherapy
Balance between over-prescribing and under-
prescribing
• Correct drug
• Correct dose
• Targets appropriate condition
• Is appropriate for the patient
it
Avoid “a pill for every ill”
Always consider non-pharmacologic therapy
 Paediatrics
• Infant skin is thin and percutaneous absorption can cause systemic toxicity
• Lower volume of distribution of fat soluble drugs (e.g. diazepam) in infants
• Plasma protein binding of drugs is reduced in neonates
• Subsequently, during toddlerhood, it exceeds adult values, often necessitating
larger doses per kilogram. E.g. the dose per kilogram of digoxin is much higher
in toddlers than in adults
Paediatric
s•
In infants, metabolism of most drugs is reduced
• GFR is 20-40% of adult capacity at birth and increases after the 1st week
of life-reaches maximal level by 12 months
• In general, children over 10 years have organ development
and metabolism similar to adults
• May require dosing adjustments based on body surface area
Oral
absorption
• Gastric fluid volume is greatly reduced at birth.
• Gastric acid production is decreased, giving the neonate a higher,
nearly neutral pH in the stomach. This results in a greater
absorption of acid-labile drugs such as penicillin G and
erythromycin, but reduced absorption of weakly acidic drugs such
as phenobarbital and phenytoin.
• Amylase activity is minimal at birth and remains low until the
third month of life.
• Gastric emptying time is delayed and intestinal transit time is
prolonged at birth, but both quickly increase within the first few
days of life
Oral
absorption
For drugs absorbed through passive diffusion, reduced splanchnic
•
blood flow during the first weeks of life can reduce the rate and
extent of absorption by altering concentration gradients across
the intestinal villi
PEDIATRIC PHARMACOKINETIC
DIFFERENCES – Oral
•absorption
QUESTION 1: A.H., a 1.5-kg, 4-week-old infant girl born at 29 weeks’
gestational age, is being treated with phenobarbital for seizures
associated with a period of asphyxia at birth. She is currently
receiving a maintenance dose of 7.5 mg (5 mg/kg) given
intravenously
(IV) once daily. The team wishes to transition her to oral therapy
now that she is receiving full enteral feeds. A trough serum
phenobarbital concentration obtained during IV therapy was 17.5
mcg/mL, within the desired range of 15 to 40 mcg/mL. Switching
the patient to phenobarbital elixir 7.5 mg given orally once daily
results in a serum concentration of only 8.9 mcg/mL after 1 week
of therapy. What factors might explain the lower concentration,
and how should A.H. be managed?
IM drug
absorption
• Drug administration by IM injection typically results in a delay in
time to reach peak serum concentrations in neonates.
• This delay is related to reduced muscle size, weaker muscle
contractions, and an immature vasculature resulting in more
erratic blood flow to and from the muscle
INTRAMUSCULAR DRUG
ABSORPTION
• C.B. is a 3.6-kg newborn boy, born at 39 weeks’ gestational age, who
was transferred to the newborn nursery after delivery. Routine care
for neonates during the first hours of life generally includes
administration of tetracycline eye ointment for prevention of
neonatal ophthalmia and 1 mg of phytonadione (vitamin K1) given
intramuscularly (IM) to prevent vitamin K–deficiency bleeding of the
newborn. C.B.’s parents question the need to give their baby a shot
so soon after birth. How would you explain the rationale for giving
phytonadione IM rather than orally?
Rectal drug
administration
A week after C.B.’s discharge from the hospital, he is brought into
•
the emergency department after becoming lethargic and febrile at
home. His parents have tried giving him oral acetaminophen, but
he is vomiting and unable to take liquids. Is rectal administration of
acetaminophen an acceptable option for C.B. in the hospital after
he has been stabilized?
Body water a case of
gentamycin
• The pharmacokinetic profile of gentamicin has been well described
in infants and children as a result of its role in empiric antibiotic
therapy for neonatal sepsis and meningitis.
• The volume of distribution of gentamicin in premature neonates
ranges from 0.5 to 0.7 L/kg, reflecting the higher extracellular
water content at this age.
• This value falls to 0.4 L/kg by the end of the first year of life
and further declines to 0.2 to 0.3 L/kg by adulthood.
Protein
binding
Plasma protein binding is reduced in neonates as a result
•
of decreased circulating levels of both albumin and α1-
acid glycoprotein, as well as decreased binding affinity
Paediatrics -
Kinetics
• Blood–brain barrier is more permeable in neonates and
young children, increasing risk of CNS adverse effects
• Eg. Kernicterus was reported in neonates receiving
sulfonamides, which displaced bilirubin from protein-binding
sites in the blood to cause hyperbilirubinemia
• At birth, the hepatic microsomal enzyme system is
relatively immature
• Drugs administered to the mother can induce neonatal
enzyme activity (e.g. barbiturates)
• All renal mechanisms (filtration, secretion and reabsorption)
are reduced in neonates
Principles of paediatric
prescribing
• Always obtain a weight at every pediatric visit
• As a rule, start with smallest dose in neonates and infants
• “Round up” the dose if it falls between the given choices UNLESS
it is a toxic drug or has narrow therapeutic window
• With acetaminophen, calculate dosage using weight, not age
• Always specify preferred formulation (e.g., chewable
tabs, suspension)
• Stay current with literature!!!
Drug use in the elderly
Effects of aging on volume of distribution (Vd)
Aging Effect Vd Effect Examples
 body water  Vd for hydrophilic ethanol, lithium
drugs
 lean body mass  Vd for drugs that digoxin
bind to muscle
 fat stores  Vd for lipophilic diazepam, trazodone
drugs
 plasma protein  % of unbound or diazepam, valproic
(albumin) free drug (active) acid, phenytoin,
warfarin

 plasma protein  % of unbound or quinidine, propranolol,

(1-acid glycoprotein) free drug (active) 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
Other factors affecting drug metabolism
Gender
Comorbid conditions
Smoking
Diet
Drug interactions
Race
Frailty
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
Aging
• Decrease in total body water (due to decrease in muscle
mass) and increase in total body fat affects volume of
distribution
• Water soluble drugs: lithium, aminoglycosides, alcohol,
digoxin (Serum levels may go up due to decreased volum
of distribution)
• Fat soluble: diazepam, thiopental, trazadone
• Half life increased with increase in body fat
Aging
• Absorption: Not highly impacted by aging
• Variable changes in first pass metabolism due to variable
decline in hepatic blood flow (elders may have less first pass
effect than younger people, but extremely difficult to
predict)
• Oxidative metabolism through cytochrome P450 system
decreases with aging, resulting in a decreased clearance of
drugs
• Hepatic blood flow extremely variable
Drugs with Cytochrome P450 Effects
(partial)

Inhibitors Inducers
Allopurinol Metronidazole Barbiturates
Amiodorone Quinolones
Carbamazepine
Azole antifungals Phenytoin
Cimetidine Rifampin
INH Tobacco
SSRIs
Tacrine
Aging
GFR generally declines with aging, but is extremely
variable
30% have little change
30% have moderate decrease
30% have severe decrease
Serum creatinine is an unreliable marker
If accuracy needed, do Cr Cl
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