Paediatric Pharmacology

Question 1

the safe and effective use of drugs in children is complicated by

Answer 1

1. A lack of acute dosage data
2. A lack of appropriate formulations allowing accurate dosage and delivery
3. Difficulty in detecting ADRs

Question 2

basic principles of paeds prescribing

Answer 2

In the immediate postnatal period problems may arise through in utero exposure and transplacental transfer of drugs to the infant. Breast fed infants can be affected by their mothers medication. When prescribing drugs for children the simplest dosage regimen should be used. Pay attention to route, formulation and duration of therapy. Parents and children should be provided with information about the disease, treatment and dosage regimen. Is therapy needed? What can be expected from the drug? How long should treatment continue? How do we monitor efficacy and ADRs?

Question 3

give examples of unlicensed prescribing in paeds

Answer 3

• Formulation administered via a route not intended
• Medicines used for an indication not intended
• Medicines used at a different dose to that recommended
• Children below stated recommended age limit
• Medicines without a licence, including those being used in clinical trials

Question 4

early post natal period and pharmacology

Answer 4

The early post-natal period is a phase of physiological immaturity during which there is rapid growth. Highly variable alterations in drug metabolism and elimination, lower tolerance to ADRs, higher incidence of therapeutic errors and difficulty in identifying efficacy and toxicity. Almost all medicines (98%) used during this phase are prescribed and used off label

Question 5

infancy and pharmacology

Answer 5

Infancy is an extension of the first stage, but the type and severity of disorders being treated are different. Body weight gain and body water composition change rapidly as does the ratio of bodyweight or surface area to organ size and function

Question 6

toddler and pharmacology

Answer 6

The toddler stage is associated with minor illnesses, leading to multiple short courses of therapy. There is problems with compliance at this stage.

Question 7

young children and pharmacology

Answer 7

Young children have enhanced metabolism and excretion. Clearance can change significantly during a single dose regimen.

Question 8

adolescence and pharmacology

Answer 8

Adolescence results in sexual development with produces major changes in body size and composition. Both of which affect drug metabolism. Psychological changes and peer pressure result in behaviour such as smoking, alcohol and illicit drug use which can alter drug metabolism.

Question 9

paroxetine in children

Answer 9

increases suicide by 4 x

Question 10

drug absorption in children: oral

Answer 10

• Reduced gastric acid and delayed gastric emptying. Adult levels reached at 3 years
• Absorption reaches adult values by 6-8 months.
• Bioavailability of drugs with high hepatic clearance and first pass elimination is reduced and highly variable.
• Drugs which rely on entero-hepatic circulation such as cyclosporin also highly variable.

Question 11

drug absorption in children: parenteral

Answer 11

• Intravenous

o Delayed or uncertain delivery

Question 12

drug absorption in children: topical

Answer 12

• Percutaneous (Skin)
o Is enhanced in infants and children, especially with damaged skin of an occlusive dressing.
o STEROIDS

Question 13

drug absorption in children: rectal

Answer 13

• Used in patients who are vomiting or who are unwilling to take oral medication.
• Avoids first-pass metabolism.
• Not ideal as significant variation, few preparations, trauma.

Question 14

drug distribution in kids

Answer 14

• Body composition
o Newborn infants have high extracellular fluid volume of 45%. At one year 25%, and
 Adults 20-25%.
o Total body water is high 75-92%.
 Adults are about 50-60%.
o Fat content is low 12% in term infants, 30% at 1 year and
 18% in the adult.
o These differences have significant effects on drug distribution.

In terms of drug dosage this means that larger initial doses on a mg/kg body weight need to be given to achieve correct plasma concentration. However, after the loading dose the dosage interval may need to be increased or the daily dose decreased to compensate for the decreased hepatic function or decreased renal elimination. Assuming that pharmacodynamic response is similar to the adult.

In neonates the plasma binding protein is reduced resulting in greater unbound or active drug.

At birth the BBB is not fully developed. Drugs and other chemicals have relatively easy access to the CNS. Infants are especially sensitive to drugs that affect the CNS function causing CNS toxicity.

Question 15

drug elimination in kids

Answer 15

There are significant differences in drug elimination in neonates, infants and children which relate to developmental and physiological states. In the neonate liver metabolism is immature, thus drugs eliminated by the liver have a longer half-life. This results in a longer time to reach the steady state (4x t1/2), an increase in steady state concentration. The same applies to drugs eliminated by the kidneys.

Question 16

hepatic metabolism in kids

Answer 16

Hepatic metabolism is very slow in the neonatal period due to immaturity of drug metabolising enzymes. Oxidation and glucuronidation are reduced. Interindividual and pharmacogenetically determined differences in the rate of hepatic metabolism are seen in children. Neonates are especially sensitive to drugs eliminated by hepatic metabolism. Metabolic activity increases rapidly from about 1 month after birth with adult activity by 1 year of age.

The Older Child

Because of significant changes in hepatic metabolism the dosage of some drugs such as antiepileptics need to be greater on a mg/kg basis in 1-8 year old children than in adults. This is because hepatic metabolism is more rapid and t1/2 shorter.

Question 17

renal excretion in kids

Answer 17

Renal excretion is decreased in neonates and shows progressive maturation with age. Adult values are achieved at 3-6 months and tubular function at 12 months. Consideration of renal function is most important in the neonate. For most drugs t1/2 is prolonged.

As a consequence of organ immaturity, newborns and babies in the first year of life have different pharmacokinetics from adults:
	↓Albumin proteins  ↑free drug
	↑Free drug levels  ↑response
	↓Hepatic metabolism  ↑response
	↓Renal elimination  ↑response
	↓Blood-brain-barrier  	↑CNS effects

Question 18

sensitivity to drugs is increased by

Answer 18

• Fever
• Dehydration (increases the effects of many drugs)
• Acidosis (decreased cellular penetration of basic drugs)