S4: Paediatric Pharmacology

Question 1

Definitions

Answer 1

Premature baby = baby <37 weeks gestation.
Full term baby = born between 37-42 weeks.
Neonate = Baby up to 4 weeks old (first month).
Infant = Firs month up to 1 year old.
Child - 1 to 12 year old.
Young Adult = Teen upwards.

Question 2

Describe scientific basis of pregnancy

Answer 2

Need to think about:
- Is drug in a suitable dosage form -> pharmaceutics.
- How does the drug get into the body, get to the site of action, metabolised and excreted -> pharmacokinetics.
- How does the drug produce effects on the body -> pharmacodynamics.
Together this forms the pharmacology and whether the drug will be beneficial or harmful.

Question 3

What factors will determine drug dose and response

Answer 3

• Growth and development (will help determine dose).
• ADME (will determine what happens to dose):
• Absorption e.g. oral (swallowed, nasogastric tube etc.), IM, rectal, IV, gut, skin etc.
• Distribution: drug distributed around body, the extent of which dependent on water volume, fat content, extent of protein binding, bilirubin, BBB.
• Metabolism: Drug metabolised by liver, but note that neonatal liver is less developed.
• Excretion: Through the kidneys, dependent on renal function.

Question 4

List some absorption route

Answer 4

• Oral/enterally.

Question 5

Describe oral/enteral route of absorption + gastrointestinal (compare adult to neonate)

Answer 5

• This is dependent on gastric pH which is the main difference between adult and neonate at birth.
• At birth pH is 6-8 while in an adult it is nearer to 1.5-3.5 pH. Adult levels are usually established by age 2 years.
• pH affects drug absorption so needs to be thought about when prescribing to neonates (drug needs to be unionised to be absorbed).
• Premature neonate also have immature gastric mucosa leads to reduced acid secretion which increase the absorption of acid labile medicines e.g. Penicillin. Therefore needs to be thought about when prescribing e.g. Using lower dose.
• Peristalsis is also reduced for the first 6 months of life and is affected by gestational and postnatal age as well as being affected by diet.
• There is also a reduction of bile in neonates.

Question 6

Describe intramuscular absorption (compare adult to neonate)

Answer 6

• This is from injection directly into muscle. The problem here is that absorption from the injection site can be erratic, varying from patient to patient.
• Extent of absorption also depends on the vascular perfusion of the muscle, the muscular contraction and amount of muscle mass.
• If tissue is avascular or patient is in shock, there is no point in giving an IM injection because the drug will not be able to get into the circulation to the extent we want.
• Another aspect to be considered is that in ill neonates blood flow varies considerably and this may be due to sepsis or hypotension that is occurring in the baby. Unfortunately, IM is also not a suitable method for quite a large number of drugs e.g. a drug which requires a high volume shot into their muscle.
• Another reason could be it can be painful.
• In general, IM injections are discouraged in children.

Question 7

Describe percutaneous absorption (compare adult to neonate)

Answer 7

• This is absorption through the skin. Neonates and young children have decreased thickness of the stratum corneum and increased skin hydration and surface area. So absorption from the topical route is significantly enhanced in newborns.
• If skin is burnt or excoriated, absorption will be enhanced even more so potentially there could be systemic absorption.
• An example would be topically applied corticosteroids, as the newborn skin is easy barrier to be passed it can lead to significant systemic drug levels leading to cushingnoid symptoms.
• Topical aminoglycosides (antibiotics, cover gram -ve), e.g. Polymyxins have led to permanent hearing loss in neonates, this demonstrates the caution that must be taken with topical application in neonates due to their skin.

Question 8

Describe rectal absorption (compare adult to neonate)

Answer 8

The variation in the rectal venous drainage leads to erratic absorption between patients. It is a useful route however in patients who are vomiting or nil-by mouth. It is also useful in infants and young children who are reluctant to take oral.
On the other hand it is not always popular or a convenient method. Examples include paracetamol, NSAIDs etc.

Question 9

Describe intravenous administration (compare adult to neonate)

Answer 9

• With IV there is 100% bioavailability! It is very commonly used in neonates. There are problems however, such as with access (neonates don’t like the cannula’s), some drugs need to be delivered centrally not peripherally.

Question 10

What factors decide the extent of distribution of drug out of plasma?

Answer 10

Once absorbed into the circulation the drug will be distributed amongst body compartments and tissues. Factors:

• The sizes of the body water compartments.
• How much the drug binds plasma proteins.
• The degree of development of the BBB (can the drug cross into the CNS?).
• Any metabolic disturbances going on e.g. acidosis.
• The specificity of the drug to tissue receptor sites.

Question 11

Describe drug distribution: water compartments in neonates and adult

Answer 11

• Total body water is higher in neonates and young infants than in adults. They also do have some adipose tissue but it has a higher ratio of water to lipid.
  Neonates have a large extracellular fluid compartment, making up 40% of the body weight at term and 20% by 3 months old.
• Because of this, when administering drugs to neonates it may require large loading doses on a mg/kg basis in order to achieve a steady state. The maintenance doses depend on clearance.
• Body fat is reduced in neonates and adipose tissue composition is different.

Question 12

Describe drug distribution: plasma protein binding in neonates and adult

Answer 12

• Various plasma proteins such as albumin can bind to drugs. Phenytoin is an example and about 98% of the drug is protein bound. Plasma protein concentrations in the newborn are reduced, therefore the amount of bound drug will be reduced and there will be an increased free fraction of the drug. Therefore more of the drug can be distributed to compartments outside the plasma.
• Also in neonates the binding capacity of plasma proteins are reduced (they don’t bind as well!) so this also will lead to an increased free fraction of drug.
• Both of these will mean increased plasma concentration of the free drug (active) and therefore therapeutic levels in the adult may be toxic in neonates as more of the drug is free. For example phenytoin, there are different doses for adult and neonate due to protein binding differences.
• There can be competition for binding sites on proteins between drugs and endogenous substances. For example if we give two drugs, both may compete to bind to the protein and one drug may be better than the other.
• In terms of competition of drugs with endogenous substances there is the example of how some drugs may displace bilirubin from binding site on the protein resulting in more free bilirubin. This can cause more bilirubin to cross the BBB and lead to kernicterus, this leads to long term neurological damage.
  Bilirubin can also displace drugs, an example being phenytoin and this will increase the free fraction of the drug and this can mean it may hit toxic levels.

Question 13

Factors affecting protein binding

Answer 13

Malnutrition: Low levels of plasma protein seen, characterised by hypoalbuminaemia.
Nephrotic syndrome: Loss of plasma proteins in urine.
Hepatic disease: Will not be able to produce as much plasma proteins.
Kwashiorkor Disease (linked to malnutrition): Hypoalbuminaemia.

Question 14

Describe drug distribution: BBB in neonates and adult

Answer 14

The blood brain barrier is functionally incomplete in the newborn meaning that there is increased penetration of some drugs into the brain/CNS. The rate of transfer into the CNS depends on the lipid solubility and degree of ionisation of the drug. The more lipid soluble and unionised the drug the greater the transfer into the CNS. We can take advantage of this though e.g. giving antibiotics that get into the CNS readily to treat meningitis. Other factors can also affect the amount of transfer like acidosis, hypoxia and hypothermia.

Question 15

Describe drug distribution: hepatic metabolism in neonates and adult

Answer 15

Once the drug has started circulating and being distributed, it will start getting metabolised primarily by the liver.
Neonates have immature drug metabolising systems due to enzymes not functioning as well as in adults. The age at which the enzyme processes reach adult levels varies with the drug and pathway of metabolism. Do note however that liver function changes rapidly after birth!

Question 16

What are the two phases of metabolism?

Answer 16

• There are two phases of metabolism, phase 1 and phase 2. Phase 1 involves addition of reactive groups to make the drug more reactive. Phase 2 involves conjugation with other compounds to make the drug more soluble. Some of these reactions are immature/deficient in the neonate.
• Hydroxylation (phase 1 reaction) is deficient in the term neonate and is even more deficient in the preterm neonate! Luckily it matures rapidly.
• Sulfation and methylation (phase 2) in the neonate are not significantly impaired at birth and functions similar to adults.
• Glucoronidation (phase 2) is significantly immature at birth and reaches adult values by 6-18 months of age. Therefore if we give a drug broken down by glucoronidation we must be careful when prescribing it, as the drug will not be metabolised and there is risk of toxicity.

Question 17

Examples of drugs metabolised by glucoronidation

Answer 17

Chloramphenicol (antibiotic) -> There can easily be accumulation of the drug in the neonate, giving risk of “grey baby syndrome”. So we only use it as a last resort.
Indomethacin -> Prolonged elimination of drug and platelet dysfunction .

Question 18

What are the alternative metabolic pathways that neonates have developed to metabolise drugs?

Answer 18

• Neonates have developed some alternative pathways to metabolise drugs to compensate for other immature pathways.
• An example is paracetamol that normally goes through glucoronidation to be metabolised, however in neonates and young children it can be alternatively metabolised by sulphation until glucoronidation is ready.
  Note though it doesn’t do it completely so still need to give lower doses of paracetamol.
• Theophylline is metabolised to caffeine in neonates! We use caffeine to help treat bradycardia etc. Caffeine is easy to monitor and its therapeutic index is not narrow.
  (Theophylline does have a narrow therapeutic index).
• Some elimination processes may be superior to by late infancy or childhood! Therefore it is required to give higher doses on mg/kg basis in this age group (compared to neonates and adolescents). Drug examples include aminophylline, aciclovir.

Question 19

Describe renal function of neonates and adult

Answer 19

• Renal function is immature at birth but it does mature quite rapidly in the first few weeks of life.
• In neonates glomerular filtration rate is more mature than tubular reabsorption. Thus clearance of renally excreted drugs are primarily by GFR during the first few weeks of life. This fact significantly alters the elimination rates for some drugs e.g. penicillins, gentamicin.
• The dose of a drug that is safe and effective in the first week of life may be inadequate in the third week. E.g. increasing penicillin dose as weeks go on because clearance of drug is increasing. We have to monitor gentamicin as has narrow therapeutic range.

Question 20

Describe drug licensing in children

Answer 20

• Many manufacturers state on the product information ‘should not be used in children’. Paediatric market is quite small and therefore a lot lack clinical trial data for licensing in children.
• This can be because medications and dosage information may be limited to specific age groups.
• However, medicines are used off-label (outside their licensing) and you should do more research on whether these type of drugs can be used in children (e.g. maybe use drug but lower dose rather than not using at all due to labelling).

Question 21

Describe dosage form for children

Answer 21

• In the ideal world there will be suspensions for all medicines.
• However, in reality suspensions are only available for a few medications and suspensions can be quite expensive for liquid form on medication.
• So alternative administration is often used (e.g. alternative route considered, tablets that can be crushed and injection that can be given orally).

Question 22

Describe ADR between neonates and adults

Answer 22

• ADRs are more common in neonates, this may be due to immature liver function resulting in a lack of detoxification and excretion of the drug. Thus because they can’t break the drug down it leads to a higher concentration of free drug accumulating in the plasma leading to an ADR.
• Interestingly, toxic reactions occurring at one stage of child development may be absent at another stage. An example of this is with sulphonamides (broad-spectrum antibiotics) is contraindicated in neonates as displaces bilirubin, giving risk of kernicterus. Once bilirubin has cleared from the neonate, the sulphonamides can be used.
• Infants are more likely to experience unusual/idiosyncratic ADRs than older children or adults.
  There is a lack of information concerning many drugs and formulations in this age group as most drug trials are done on adults not neonates/children. Thus we take caution with using new drugs on children and especially neonates. A lot of the information we get is via trial and error in the population.
• All ADRs seen in young children MUST be reported!

Question 23

Describe factors for high error rate in medications in paediatrics

Answer 23

Error rates in paediatric units are quite high, estimated at about 25%.
This is due to various reasons such as:
- Misplacement of decimal point.
- Wrong units prescribed.
- Wrong frequency.
- Wrong route of administration.
- Dose calculated wrong (mg/M2 or mg/kg).