Paeds

Question 1

What are the 5 possible signs from parent/carer showing abuse?

Answer 1

• Delays seeking medical treatment or advice and/or reluctant to allow treatment or examination
• Detachment from the child
• Lacks concern at the severity or extent of injury to the child or vulnerable person
• Is reluctant to give information or information does not ‘add up’
• Aggressive towards child or other vulnerable person.

Question 1

What is safeguarding?

Answer 1

Safeguarding means protecting people’s health, wellbeing and human rights, and enabling them to live free from harm, abuse and neglect. It’s fundamental to high-quality health and social care.

Question 2

What is vulnerable adult?

Answer 2

A vulnerable adult may be a person who
- Is elderly or frail
- Has learning disabilities
- Suffers from mental illness
- Has physical disability
- Is a substance misuser
- Is homeless

Vulnerability depends upon surrounding circumstances and environment - each case must be judged on its own merits. Vulnerability can be transient, temporary or enduring

Question 3

What is physical abuse?

Answer 3

This includes assault, hitting, slapping, pushing, giving the wrong (or no) medication, restraining or restricting someone.

Question 4

What is domestic abuse?

Answer 4

This includes psychological, physical, sexual, financial or emotional abuse. It also covers so-called ‘honour’ based violence.

Question 5

What is sexual abuse?

Answer 5

This includes rape, indecent exposure, sexual harassment, inappropriate looking or touching, sexual teasing or innuendo, taking sexual photographs, making someone look at pornography or watch sexual acts, sexual assault or sexual acts the person didn’t consent to.

Question 6

What is psychological abuse?

Answer 6

This includes emotional abuse, threats of harm or abandonment, depriving someone of contact with someone else, humiliation, blaming, controlling, intimidation, pressuring, harassment, verbal abuse, cyber bullying, isolation or unreasonable and unjustified withdrawal of services or support networks.

Question 7

What is financial or material abuse?

Answer 7

This includes theft, fraud, internet scamming, putting pressure on someone about their financial arrangements (including wills, property, inheritance or financial transactions) or the misuse or stealing of property, possessions or benefits.

Question 8

What is modern slavery?

Answer 8

This covers slavery (including domestic slavery), human trafficking and forced labour.

Question 9

What is discrimination?

Answer 9

This includes harassment because of someone’s race, gender or gender identity, age, disability, sexual orientation or religion.

Question 10

What is organisational abuse?

Answer 10

This includes neglect and poor care in an institution or care setting such as a hospital or care home, or if an organisation provides care in someone’s home. The abuse can be a one-off incident or repeated, on-going ill treatment. The abuse can be through neglect or poor professional practice, which might be because of structure, policies, processes and practices within an organisation.

Question 11

What is neglect and act of omission?

Answer 11

This includes ignoring medical, emotional or physical care needs, failure to provide access to educational services, or not giving someone what they need to help them live, such as medication, enough nutrition and heating.

Question 12

What is self-neglect?

Answer 12

This covers a wide range of behaviour which shows that someone isn’t caring for their own personal hygiene, health or surroundings. It includes behaviour such as hoarding.

Question 13

What are the red flags for sepsis/meningitis in children?

Answer 13

• A progressively ill child
• Signs of dehydration (look for dry nappies)
• Blue, pale or blotchy skin, lips or tongue, cold skin
• A rash that does not fade when you roll a glass over it
• Difficulty breathing, breathlessness or fast breathing
• A weak, high-pitched cry (or one that’s different to normal)
• Not responding like they normally do, or not interested in feeding or normal activities
• Being sleepier than normal or difficult to wake
• Confusion, slurred speech or not making sense, change of mental state
• Fit or convulsion
• High temperature or low temperature
• High heart rate
• Low blood pressure

Question 14

What are the referral symptoms of chicken pox in clinic?

Answer 14

Symptoms in an adult or adolescent, especially if severe
Secondary infection due to scratching - S. aureus
Signs of chest infection
Severely ill
Any signs of chicken pox in pregnancy or new born (< 4weeks old)
Coexisting conditions
Dehydration

Question 15

What are the treatments for chicken pox in children?

Answer 15

For majority of children, chicken pox is uncomplicated and treatment is purely symptomatic
Antipyretics - avoid ibuprofen
Antihistamines
Calamine
Lifestyle advice

Question 16

What do you do with measles in children in clinic?

Answer 16

Offer symptomatic relief but refer on

Question 17

What are the symptoms of measles in children?

Answer 17

• Fever 39oc
• Cough and cold
• Sore throat – swollen lymph nodes
• Reddish eyes
• Sensitivity to light
• Koplik’s spots
• Rash emerges which is red, confluent and starts at the hair line and progresses rapidly over 24-48 hours to cover the whole body – lasting for 3 days

Question 18

What are the complications associated with measles in children?

Answer 18

• Otitis media (7-9% children)
• Pneumonia (1-6% children)
• Febrile convulsions (about 1 in 200 children)
• Encephalitis (about 1 in 1000 children)
• Blindness

Question 19

What are the symptoms of mumps in children?

Answer 19

• Begins with 2 days of discomfort
• Increasing temperature (up to 40oc)
• Head ache, ear ache, sore throat and pain on opening mouth
• Jaw stiffness
• Swollen parotid glands
• Earlobes may stick out
• Face looks swollen

Question 20

What are the complications associated with mumps in children?

Answer 20

Orchitis
Oophoritis
Pancreatitis
Meningitis

Transient hearing loss
Myocardial – ECG changes
Pancreatitis

Question 21

What to do if food allergies are suspected in children?

Answer 21

Most common foods that cause an allergy are: milk, eggs, peanuts, fish, shellfish, wheat and tree nuts
Signs to spot – itching in mouth, throat or ears, skin rash, angioedema, vomiting, anaphylaxis
May already have signs of eczema as an infant
Immediate 999 referral if there are symptoms of anaphylaxis with or without angioedema
Referral needed to discuss potential allergy
Advise keeping a food diary since identifying the causative food is needed and avoiding it
Different to intolerance that might lead to GI symptoms alone

Question 22

What should be done with whooping cough in children in clinic?

Answer 22

AKA pertussis, spread via highly contagious Bordetella bacterium
Spread via droplets, 7-10 day normal incubation period
Characteristic cough follows a catarrhal phase, which then might result in a long lasting cough (3 months).
Prevalence should be low, unless vaccinations are missed
Refer if there is any suspicion of infection, since antibiotics will probably be needed and ND (contacts might be treated also)

Question 23

What should be done with croup in children in clinic?

Answer 23

Characteristic seal like barking cough, often following an upper respiratory tract viral infection. Presence of stridor (noisy breathing)
Most common between 5 months and 3 years of life
Generally self limiting, but refer for GP diagnosis and consideration whether treatment is needed
Consider analgesics, regular fluids, close observation of child especially at night (especially prior to GP appointment)

Question 24

What should be done with impetigo in children in clinic?

Answer 24

Caused by bacterial infection S. aureus (+/- fluid filled lesion)
Most common in young children
Often is self limiting, and will heal without scaring
Stay away from school/nursery/work till healed, or for 48hrs after antibiotics started
Full assessment and antibiotics (topical or systemic)/covered by pharmacy first
Hygiene

Question 25

What should be done with slapped cheek syndrome in children?

Answer 25

Spread via droplets (parvovirus B19)
More common in children but can be more serious in adults
Systemic infection presents 1st – high temperature, sore throat and headache
Bright red rash develops on cheeks after 1-3 days, doesn’t always present on cheeks of adults
Body rash may develop later
Adults may get joint pain and stiffness
Only refer if pregnant, immunocompromised or blood disorders
Self help advice – rest, fluids, analgesics, antihistamines for itch

Question 26

What should be done with hand, foot and mouth disease in children?

Answer 26

Acute viral infection (CoxsackieA16 virus), often mild and self limiting
Spread via droplets, fluid filled vesicles and faeco-oral transmission (faeco transmission can last for 4-8 weeks)
Most common in young patient groups
Few serious complications (dehydration most common)
Sore throat, fever and rash as described
Often self limiting, self care, analgesics, hygiene care to avoid transmission, avoid school or nursery if too unwell to attend, refer in pregnancy if immunocompromised or within 3 weeks of delivery, refer if dehydration

Question 27

What should be done with scarlet fever in children?

Answer 27

Bacterial infection caused by Streptococcus pyogenes – ‘Strep A’
Sore throat, fever, headache, N&V and red sandpaper like rash (on abdomen and chest, spreading to neck, limbs and extremities)
Highly contagious via saliva or mucus, short incubation period (2-3 days)
Care to avoid spread (very contagious) and immunocompromised pts
Refer for antibiotic treatment and ND

Question 28

What should be done with glandular fever?

Answer 28

Caused by Epstein Barr virus
Long incubation period, spread via salvia usually via asymptomatic carriers (many people have antibodies against virus but never showed clinical signs)
In most people, infections lasts 2-3 weeks
Severe sore throat
Fatigue, fever, sweats, headache, anorexia
Swollen lymph nodes which can be sore

Consider referral if symptoms severe in adults and children
Analgesics, rest within reason but not imposed bed rest, avoid spreading
Avoid contact sports or heavy lifting for the four weeks after illness (increased risk of splenic rupture)

Question 29

Why is breastfeeding promoted?

Answer 29

Unique, complex fluid containing energy, all essential nutrients and protection against infection and allergies

More convienent

Cheaper, sterile, easier to digest

Closer bonding, natural

Releases oxytocin – helps uterus contract

Thought to decrease risk of pre-menopausal breast cancer

Question 30

Why do people bottle feed?

Answer 30

Other people can feed baby
Did not like idea of breastfeeding/difficulty breastfeeding
Mother’s own experience
Embarrassed to breastfeed
Medical condition (eg, HIV)

Question 31

What are the main types of infant milks available?

Answer 31

Whey based milks – birth to 12 months – (Aptamil 1)
Very similar composition to breast milk
60% whey protein: 40% casein protein
Caesin based - Follow on milk – (Aptamil 2)
Suitable from 6-12 months as part of weaning diet
Not always needed, but stay with 1st milks and wean
Toddler milk
Suitable from 1 year
Similar to cow’s milk in protein composition but fortified with additional minerals & vitamins

Question 32

What are the specialist milks available?

Answer 32

Soya based - suitable for babies with cow’s milk intolerance (free from cow’s milk protein and lactose)

Staydown - suitable for babies experiencing significant reflux from birth

Lactose free - suitable for infants with proven lactose intolerance

High Energy - suitable for infants with medically identified increased energy and nutrient requirements(e.g faltering growth)

Preterm range – suitable for preterm/low birthweight babies

Question 33

What is the main barrier of oral formulations in children?

Answer 33

Taste

Question 34

How must exipients in chldrens medicines be controlled?

Answer 34

To optimize the formulation of the medicine
 to improve palatability, shelf-life and/or manufacturing processes.
Certain excipients not to be used in children’s medicines:
 e.g. Ethanol, propylene glycol, benzyl alcohol and parabens can retard on-going organ
development.

Question 35

What are the benefits of using liquids for childrens medicines?

Answer 35

provides maximal dosing flexibility
 possible to use for a wide range of age range
(including neonates)
 But volume needs to be acceptable to the patient and
dosing device must be fit for purpose

Question 36

How can solids for reconstitution be made for children?

Answer 36

 popular strategy in both paediatrics and geriatrics
formulations.
Better stability compared to a formulated liquid.
Reconstitution either at the point of dispensing
or at the point of administration (depending on the product)
Instructions can be complicated for untrained individuals
Volume of liquid larger than volumes for typical conventional oral liquids
( EMA: up to 20 ml for children < 4 year old; up to 50 ml for those > 4 year old)

Question 37

What are the problems associated with incorrectly reconstiuting products?

Answer 37

risk of local tissue injury
delay in onset of action as drug needs to dissolve prior to absorption.

Question 38

How have conventional tablets been modified for children?

Answer 38

Conventional tablets:
 limited by their rigid dose content.
Limited by the ability of a child to swallow a tablet.

General thinking:
Children will accept tablets based on size.
A smaller tablet is more likely to be acceptable

Mini-tablets:
Tablets < 3mm
(Thomson et al, 2009): Mini-tablets were found as suitable dosage form for 2-6 year olds (based on placebo tablets 3mm in diameter).
(Spomer et al, 2012): Very young children (6-12 months) were fully capable of swallowing
mini-tablets of 2mm diameter, in preference to sweet liquid formulations.

Question 39

How have capsules been modified for children?

Answer 39

Standard capsule sizes range from 11.1 mm (size 5) to
23.3 mm (size 00) in length.
No data available on acceptability of capsule size in children,
although considered equivalent to tablets.

Capsules can be opened and the contents be taken to improve acceptability in children.
This only be undertaken when justified.
But capsule content : Taste unpleasant; the bioavailability different from intact product

Recommended volume taken with tablets: 250 ml in adults (FDA, 2000).
The use of smaller volumes can delay onset of absorption and reduce bioavailability of drugs (particularly poorly water soluble) (e.g. Sunesen et al, 2005).
No literature reports providing similar volume of water used in children.
Water ingestion : Variability in exposure observed following tablet administration in children.

Question 40

Why are chewable tablets and orodispersible tablets preferred for children?

Answer 40

1/3 of patients in long term care facilities experience serious difficulties with swallowing solid oral dosage
forms  Alternative: use oral solutions, the major disadvantage  stability.

chewable tablets, orally disintegrating (or orodispersible) tablets can overcome
obstacles proposed by conventional dosage forms.
Chewable tablets:
Defined by US Pharmacopoeia (USP), “Chewable tablets are formulated and manufactured so that they may be chewed, producing a pleasant tasting residue in the oral cavity that is easily swallowed and does not leave a bitter or unpleasant aftertaste”.

The route of delivery of chewable tablets is via the GI tract of the patient.

The major difference is that disintegration is initiated in the oral cavity, by the patient chewing the dosage form.

Once disintegrated to smaller sized pieces, the dosage form is swallowed by the patient and the drug dissolves in the GI tract and is absorbed.
In essence, the route of absorption is practically identical to that of a conventional dosage form except that the majority of the disintegration step takes place in the oral cavity as
opposed to the GI tract.

This dosage form was primarily used an alternative formulation for delivery of vitamin
supplements for children and antacids.

Recent successful attempts in developing formulations, such as montelukast, atorvastatin (Lipitor) and carbamazepine.

Main excipients used in chewable tablets: Mannitol (sweetening agent)/Xylitol (sugar free) 50%.

Other excipients part of the tablet include colourings, lubricants and binders.

Chewable tablets can improve compliance of patients to their medication. Disadvantages include the need for taste masking.
In children, especially under 2 years of age  risk of aspiration of the chewable tablet if not chewed properly which could result in death of the patient.
However, this is quite a rare event in children above 3 years of age.
Also known as ‘orally dispersible tablets’ or ‘orally disintegrating tablets’ (ODTs)

Defined by European Pharmacopoeia (EP) and British Pharmacopoeia (BP)
as “uncoated tablets intended to be placed in the mouth where they disperse
rapidly before being swallowed”.

Defined by FDA as a “solid dosage form containing medicinal substances which disintegrates rapidly, usually within a matter of seconds, when placed upon the tongue”.

With ODTs no need to chew the tablet, swallow it whole or take the tablet with liquids.

ODTs are NOT the same as sublingual tablets, buccal tablets and lozenges as they require at least more than a minute to dissolve in the oral cavity.

Tablets disintegrate in the oral cavity and the active pharmaceutical ingredient is absorbed through pre gastric (i.e. oromucosal tissues), gastric (i.e. stomach) and post gastric (i.e. small and large intestines) segments of the GI tract.
ODTs usually formulated as an extension to the conventional oral dosage form of
the drug.

ODTs can be absorbed through a variety of routes  could affect the bioavailability and safety profile of the drug.

The bio availabilities of the dispersible and conventional forms are compared to ensure bioequivalence.

ODTs formulated using very water soluble excipients (interaction with water or saliva to assist in disintegration of the tablet.

ODTs formulated by # of methods: e.g. Direct compression (i.e. DuraSolv), lyophilisation (Zydis) and moulding (e.g. WOWTAB).

Tablets tend to include a relatively large proportion of highly water soluble sugars, such as mannitol, lactose, glucose and sucrose, which can confer rapidly dissolving properties to the ODT.

Some of the directly compressed tablets e.g. OraSolv, make use of effervescent excipients to assist in rapid disintegration when in contact with saliva.
Lyophilisation, or Zydis technology, is initiated by removal of water by
sublimation of the liquid mixture of drug and excipients. The mixture is
then freeze dried, to yield drug in a highly porous, water soluble matrix.

Tablets prepared using Zydis technology are amongst the most rapidly disintegrating
tablets on the market ( a reported disintegration time of < 5 seconds).

Ease in administration of ODTs increases patient compliance for both young children and the elderly.

A disadvantage of formulating the tablet is that is contains highly water soluble excipients, rendering it susceptible to hygroscopicity  strategies needed for the storage of ODTs.

There are higher costs in developing a fast dissolving formulation due to the use of more specialised manufacturing techniques and ensuring the tablet has suitable palatability.

The volume of liquid taken with ODTs should also be considered.

Question 41

How does the pH of the stomach change from birth?

Answer 41

Near neutral gastric pH (pH 6-8) at birth related to the presence of amniotic
fluid in the stomach.

The resting pH of the neonatal stomach shortly after the initiation of feeding is similar to that in adults
(~ pH 2).

Hydrochloric acid secretion in neonates is lower than in adults, resulting in a lower buffering capacity of the stomach, which in turn leads to a protracted high pH following feeding.

This lower buffer capacity has been linked to an increased bioavailability of the acid-labile drug, penicillin G, in premature and term neonates < 2 weeks old compared to infants and children.

Since the non-ionized drug is better absorbed, a higher pH is expected to decrease the rate and/or extent of absorption of weak acids (e.g. phenytoin, rifampicin ), while weak bases such as atropine, caffeine as well as other methylxanthines may be absorbed more readily from the stomach.

However, the primary site of absorption is the small intestine. While studies of small intestinal pH in neonates are not available, from the age of 6 months on the small intestinal pH in the fasted state is similar to that in adults.

Question 42

How does gastric emptying time differ between ages?

Answer 42

The time taken for the stomach to empty its contents into the small
intestine is prolonged in neonates and infants in comparison to children and
adults.

The volume of stomach contents in the fasted state is ~3 ml for neonates and infants, ~10 ml for children and 50-222 ml for adults.

The volume can increase 50-fold after feeding.

The volume of a meal, its osmotic pressure and its composition of macronutrients all has a major effect on the rate of gastric emptying.
E.g. The type of fatty acids fed to infants affects the rate of gastric emptying
i.e. slower emptying is observed after feeding with long-chain fatty acids compared to medium-
chain triglycerides.

     Because of the differences in the type of food and gastric contractions in neonates and infants (less   
         pronounced in neonates than infants), GET is prolonged in neonates and infants compared to children 
        and adults.

Question 43

How is pepsin activity different in infants?

Answer 43

The secretion of pepsin is increased 3-fold between week 35 of gestational age and term and a further 4-fold increase is observed during the first two days after birth.

Pepsin activity is relatively low in preterm neonates, whereas hydrochloric acid secretion is about the same as in term neonates.

The secretion of pepsin gradually increases during the first months and is comparable with that of adults when expressed on a body-weight basis by the age of 2 years.

Question 44

How is bile activity different in infants?

Answer 44

Bile is a complex fluid, containing water, electrolytes and bile acids,
phospholipids, cholesterol and bilirubin.

Bile aids the solubilization of the poorly-water soluble products of lipid digestion, e.g. fatty acids, as well as enhancing the solubility of poorly water soluble drugs.

Near term, bile flow is low compared to adult levels.

In neonates and infants the bile is composed of only primary bile acids; in neonates the bile acids were preferentially conjugated with taurine but the glycine/taurine ratio increased with postnatal age.

Bile acts to some extent as a surfactant, and is involved in the digestion and absorption of lipids.

Inefficient intestinal fat digestion in neonates can occur as a consequence of low bile excretion.

Reduced absorption of fat-soluble vitamins, vitamin D and vitamin E in neonates can probably be attributed to the inadequate bile salt pool and low intra-luminal levels, despite the higher circulating systemic concentrations.
Similarly, lipophilic agents that require solubilization in the intestine may display capacity-limited absorption in the neonate.

Question 45

What considerations are required for paediatric intranasal formulations?

Answer 45

Convenient with fast onsets of action , its action close to that of
intravenous therapy , routinely used within paediatric populations.

Drugs delivered via several methods: instilled from a syringe,
nebulised or given through a pressurized aerosol (all effective).

 No reports on the difference in nasal mucus , nasal pH or
mucociliary clearance in paediatric patients compared with adults.

Assumed these properties remain the same in children as in adults.

No reported paediatric specific nasal formulations that differ from adult
products.

However, similarities in anatomy and physiology ensure that
products are likely to perform in the same way in adults
compared with children (few reported adverse effects).

Question 46

What considerations are required for paediatric ocular formulations?

Answer 46

Ocular medicaments : Drops, ointments, gels and inserts used in
children.
Treatment bacterial and viral infections, inflammation and allergy,
uveitis and glaucoma, as well as conditions such as myopia.

Eye of newborn ~ 2/3 of its adult size, reaching an adult size around ages 3 to 4 years.

In the eye, membranes are thin in neonates and infants, so drug absorption and corneal permeation may be more rapid in these groups.

The cornea of the neonates has 70% of the absorption surface of the adult cornea, but the total intraocular volume is barely 1/3 of the adult eye.

Topical application of ocular drugs may cause serious adverse ocular or systemic side effects  high risk of systemic side effects in children
Because ocular dosing is not weight-adjusted.
Infants especially vulnerable particularly in cases where drug metabolism is reduced in the young and/or an immature blood brain barrier.
The increased systemic exposure observed in paediatric patients has
been attributed to absorption of eye drops into the systemic circulation:
Reduced size of the patient results in higher plasma concentration of
circulating drug.

Calculating dosages for paediatric patients is complex.
Body weight, surface area, development, metabolism, other medications taken and physiological function : all affect the dosage.

Estimated: a newborn requires ½ of the adult dosage of eye drops to obtain an equivalent ocular concentration: 2/3 of the adult dosage is required at age 3 years and 90% of this dosage at age 6 years (Patton and Robinson, 1976).

Overall anatomical & physiological differences in the eyes of neonates and infants leave them vulnerable to systemic effects of topically administered ocular drugs.

There may be a need for a bespoke paediatric delivery device to provide a smaller dose of topically applied medicines.

Question 47

What considerations are required for paediatric otic formulations?

Answer 47

Routinely used within paediatric populations for therapies
of otitis externa, otitis media and the removal of ear wax.

Most frequently ear drops and sprays

Small volume is used as excess will be lost out of the ear passage.
The outer ear in humans is not completely mature at birth.
Various anatomical and physiological changes occur with age.
The external auditory canal (EAC)of an infant is straighter, narrower and much shorter than in the adult.
EAV volume increases with age from a mean value of 0.56 ml at 4-5 years of age up to 0.70-0.98 ml in adults.

Dosing devices allow smaller doses to be administered in paediatric patients (no significant systemic uptake from medicines administered aurally).

There may be a need for a bespoke paediatric delivery device to provide a smaller dose of topically applied medicines.

Question 48

What considerations are required for paediatric rectal formulations?

Answer 48

Routinely used to treat both local and systemic disorders in
children.
Typically delivered as creams, ointments, suppositories, foams,
sprays and enemas.

The rectal route particularly useful for infants & children who have
difficulty in swallowing oral medicine.

Useful route in the case of nausea and vomiting or where upper intestinal disorders present may affect oral drug absorption.

The diameter, length and volume of the rectum changes during the development , with adult dimensions reached at about 10 years of age.

(van Lingen, 1999): Rectal delivery of paracetamol in pre-term infant  Rapid absorption with higher concentrations attained in patients aged from 28-32 weeks compared to those over 32 weeks.
Historically, oral liquid preparations or injectable solutions have been
administered rectally when oral administration was not appropriate.

(Dhillon et al, 1982): diazepam rectal solution provided rapid systemic concentrations and improved clinical outcomes compared with a diazepam suppository in children.

Dose adjustments in paediatric patients are typically made based on weight, height or body surface area.

In terms of rectal drug delivery for systemic effects, the rectal absorption surface area is an important factor to consider.

Paediatric suppositories are typically manufactured as an appropriate size for children ( 1g nominal weight).

Where necessary, portions of adult suppositories are used in paediatric patients (assuming uniform distribution of the active substance in the suppository matrix (not optimal shape, no accuracy or stability data fir such practices).

Question 49

What considerations are required for paediatric transdermal formulations?

Answer 49

The skin undergoes many changes during the development.
Important for paediatric formulations.
The stratum corneum is intact shortly after birth (<1 month),
yet storage and transporting water becomes adult-like after first year
of life.
The ratio of surface area to body weight is much higher in a neonate
compared with an adult  volume of distribution is lower per unit
area of skin within the paediatric population.

Preparation for dermal administration include liquid preparations
(lotions and shampoos), semi solid preparations (ointments and creams) and
solid preparations (powders).

Although these products are considered safe in term of absorption, higher levels may be reached in paediatric patients or where skin is broken.

New born infants are exposed to topical agents for treatment for rashes, antimicrobial agents, solvents and skin barriers or moisturisers.
The excipients for such products need careful consideration (absorption of propylene glycol from an antiseptic dressing used in a preterm infant resulted in the infant going to coma; complete recovery occurred following cessation of topical treatment).

Question 50

What considerations are required for paediatric pulmonary formulations?

Answer 50

Inhaled medications are commonly administered to infants
and small children with asthma and cystic fibrosis.
Airway size, respiratory rate, inspiratory/expiratory flow rates
and breathing patterns as well as lung volumes and capacities
change dramatically during the first months and years of life.

Delivery devices are similar to adults one, although they are
frequently modified by attaching a small infant or child size mask.

Nebulised liquids are potentially suitable for young children who cannot use metered dose inhalers (MDIs) and dry powder inhalers (DPIs)

MDIs may be suitable for children from birth when combined with a spacer (i.e. eliminates the need for the patient to co-ordinate actuation with inhalation).

A face mask is required until the child is able to manage with a mouth piece.

DPIs may be used for children from the age of 4-5 years, as minimum inspiratory flow is required.
MDIs and DPIs are preferred for older children because of their portability and convenience.
Dose adjustment for inhaled medications is typically based on body weight where extrapolation from adults is acceptable for children from 3-12 years of age.

Question 51

What are the pk differences of neonate to infant?

Answer 51

differences in therapeutic efficacy and toxicant susceptibility at a given dose
immature PK processes
significant growth and maturational changes of physiological and biochemical processes with postnatal development
genetic and environmental factors influence maturation
tremendous interindividual variability: changes at different rates and patterns
premature birth: more pronounced anatomical and functional immaturity of the organs involved in PK processes

Question 52

What are the pk implications to absorption in paediatrics?

Answer 52

gastric acidity
rates of gastric and intestinal emptying
surface area of the absorption site
GI enzyme systems
gastrointestinal permeability
biliary function
I.M., subcutaneous, percutaneous absorption: skin, muscle, fat, water content, degree of vascularization

Question 53

What are the pk implications related to gastric secretions in paediatrics?

Answer 53

High gastric pH:
enhanced BA of basic compounds (ampicillin and penicillin G)
reduced BA of acidic compounds (phenobarbital)
Deficiency of bile salts and pancreatic enzymes
reduced BA of drugs that require solubilization or intraluminal hydrolysis for adequate absorption (pro-drug esters)

Question 54

What are the pk implications related to gastric motility in paediatrics?

Answer 54

Effect on drug BA:
physico-chemical properties
interaction with anatomical and physiological factors of the GI tract.

Question 55

What are the pk implications related to gastrointestinal metabolism and transport in paediatrics?

Answer 55

Bacterial flora
extent of drug absorption: GI motility, ability to metabolize compounds
approaches adult populations by 4 years of age

Question 56

What are the pk implications related to gastrointestinal first-pass effects in paediatrics?

Answer 56

improved oral BA (Immature GI metabolic reactions; transporters and other active efflux processes )
reduced oral BA (drugs dependent upon carrier-mediated uptake systems)

Question 57

What are the pk implications to distribution in paediatrics?

Answer 57

High relative proportion of total body water and low proportion of fat (relative to adults ):
Increase in Vd for water-soluble compounds
Lower Vd for fat-soluble drugs
enhancements in cardiac output, organ blood flows and tissue perfusion
changes in membrane permeabilities and maturation of carrier-mediated transport systems
changes in tissue binding affinities

        Developmental changes in Vd

Question 58

What are the pk implications to plasma binding protein in paediatrics?

Answer 58

Distribution and elimination of compounds
Larger unbound fractions
Lower total plasma protein levels
Lower binding affinities to albumin and a1 –acid glycoprotein (penicillin, phenobarbital, phenytoin and theophylline)

Question 59

What are the pk implications to hepatic clearance in paediatrics?

Answer 59

Same metabolites as adults; rates of metabolite formation can be different
Underdeveloped and inefficient hepatic and/or renal elimination pathways
hepatic blood flow, plasma protein binding and intrinsic clearance (maximal enzymatic or transport capacity of the liver)
Phase I reactions: cytochrome P450 (CYP) enzymes (rate and pattern of postnatal development; genetic polymorphisms; interindividual differences)

Question 60

What are the pk implications to renal clearance in paediatrics?

Answer 60

Incompletely development
Glomerular filtration, tubular secretion, and tubular reabsorption: different maturation rates, interindividual variability
Renal functions reach adult levels before 1 year of age

Question 61

What is phenylketonuria?

Answer 61

Phenylketonuria is a very common inherited error in metabolism.
Results from deficiency in Phenylalanine hydroxylase (PAH), which converts S-Phe to S-Tyr.
Overall incidence is ~ 1 in 10,000 - 15,000 in Caucasians and East Asians and ~1 in 25,000 in Latin Americans. However, this can vary considerably with region (1 in 1,800 in Turkey; 1 in 4000 in Northern Ireland; 1 in 200,000 in Thailand).
It results in accumulation of S-Phe and reduced levels of S-Tyr in cells.
High blood levels of S-Phe result (can be > 800 μM in patients cf. 21 – 137 μM in normal children and 35 - 85 μM in adults).
This causes gross neurological defects such as microcephaly (small brain size) and mental retardation.
More subtle injuries occur with milder disease (ADHD, autism?).
Because of high incidence neonatal screening is performed.

Question 62

What is the phenylalanine hydroxylase (PAH) reaction?

Answer 62

PAH is an allosteric liver enzyme with respect to S-Phe (exhibits an S-shaped curve).
~90% of S-Phe is converted to S-Tyr in normal subjects and released into blood.
The S0.5 value is ~145 μM (cf. blood S-Phe concentrations).
The enzyme is a tetramer with each monomer possessing catalytic, regulatory and tetramization domains.

Question 63

How is phenylketonuria diagnosed?

Answer 63

All newborn infants are screened for PKU soon after birth (usually at ~24 hours old).
Screening was introduced into Europe and North America by the middle of the 1960s.
Current methods use mass spectrometry / mass spectrometry (MS/MS) to quantify levels of S-Phe in the blood.
Several other amino acids and metabolites are also quantified including S-Tyr. This allows differentiation of PKU due to PAH-deficiency, BH4-deficiency and other amino acidaemias.
Blood levels of S-Phe can be as high as 1200 μM.
Blood S-Phe levels can fluctuate quite a lot during the day and over longer periods.
It is Central Nervous System levels that appear to determine disease progression.
There are >600 different mutations known so genotyping can be helpful. However, it is difficult to correlate mutations with S-Phe levels and symptoms.

Question 64

What are the consquences of phenylketonuria?

Answer 64

Highly elevated S-Phe levels cause severe mental retardation in the patient. The standard treatment is therefore to restrict S-Phe dietary intake.
Blood S-Phe levels of > ~ 800 μM appear to increase reactive oxygen species production (inflammation).
Reduced levels of S-Tyr mean reduced production of neurotransmitters (see above) – could be responsible for mood disturbance, seizures etc.
Having PKU also appears to disturb nitric oxide (NO) levels, which is also a neurotransmitter.
Reduced levels of S-Tyr also often result in hypopigmentation (due to reduced melanin levels).
Patients are prone to fractures due to poor bone metabolism – not clear if this is a primary manifestation of PKU or a due to malnutrition because of the restricted diet.

Question 65

How can phenylketonuria be treated with diet?

Answer 65

Diets low in S-Phe were introduced in the 1950’s.
This means restricting foods high in amino acids (such as meat).
Patients also need to avoid foods containing aspartame, an artificial sweetener containing S-Phe.
Dietary treatment should start as soon as possible and are life-long (diets relaxed in adulthood result in poorer outcomes with patients suffering cumulative neurological injuries).
Due to the restrictive diet patients need to take S-Tyr and other amino acid supplements.
Diet is unpalatable and so compliance can be poor (especially for adolescents).
Patients can become deficient in other nutrients including vitamins D and B12.
Ideally a serum S-Phe level of < 360 μM should be achieved (lower in pregnant women due to potential risks to the foetus).
The cost of treatment is ~£15,000 p.a. (as of 2017), mostly due to having to buy special foods.

Question 66

How can phenylketonuria be treated with Large Neutral Amino Acids?

Answer 66

Increased levels of LNAAs (tyrosine, tryptophan and branched aliphatic amino acids) appears to decrease absorbance of S-Phe from the digestive system and hence lower blood S-Phe levels.
LNAAs also compete for the amino acid transporter allowing access of amino acids to the brain.
Inclusion of LNAAs in the diet appears to have some positive influence of executive function (decision making) by patients, but this appears to be largest in patients who are poorly compliant with their diet.
Treatment often uses glycomacropeptides (a protein derived from milk whey which is naturally low in S-Phe and contains LNAAs).

Question 67

How can Sapropterin be used as a treatment for PKU?

Answer 67

~30% of patients respond to BH4 (Sapropterin HCl) supplements.
These patients often have ‘milder’ forms of PKU where PAH retains some activity.
In some cases, it appears that the therapy works because the mutation reduces binding of the BH4 cosubstrate to the PAH enzyme (reduces cooperativity of substrate binding).
Cosubstrate binding appears to stabilize the enzyme.
Thus, increased cosubstrate concentrations increases enzyme activity.
In the most favourable cases dietary treatment can be discontinued but for some patient’s dietary therapy is still required (but is less restrictive).
Difficult to determine responsiveness to therapy based on genotyping (presence of mutations), therefore a loading test is required. The test is considered positive if a >30% reduction in S-Phe levels are observed.
However, the cost of therapy is high (~£100,000 p.a.).

Question 68

How can gene therapy be used as a treatment for PKU?

Answer 68

Replaces missing enzyme expression of wild-type enzyme within target tissues.
Requires use of a safe vector (adenovirus) to deliver gene to patient.
In mouse models delivery of the gene resulted in reduction of S-Phe levels are resolution of hypopigmentation.
But gender difference in response – female mice required 3x the dose of vector than for male mice.
This difference appears to be linked to androgen signalling pathways, but exact mechanism is unknown.
Treatment became ineffective after a few weeks due to the mounting of an immune response to the vector.
There are concerns about potential safety issues with using the therapy.
Non-viral delivery systems can also be used but suffer from low efficiency of delivery

Question 69

How can enzyme therapy be used as a treatment for PKU?

Answer 69

Can directly replace missing enzyme (PAH). However, this is difficult due to complex nature of the enzyme.
Targeting to the correct tissue and organelle is required.
Alternative enzymes (bacterial Phenylalanine Ammonia Lyase; PAL) that degrade S-Phe can be used.

This enzyme is a monomer and requires no cofactors.
Targets S-Phe in the blood, but dosing is gender specific. The small amount of NH3 produced is non-toxic and excreted in urine.
However, enzyme must be given i.v. to avoid degradation by proteases in the stomach and it is rapidly cleared due to immune reaction.
PEGylation of enzyme improves stability.

Question 70

How can probiotics be used as a treatment for PKU?

Answer 70

The main problem with enzyme therapy is that the drug has be delivered intravenously (i.v.).
It is also very expensive (in part due to the need for a treatment centre, trained staff to administer the drug, risk of infection, etc.).
Probiotics containing live bacteria expressing recombinant enzyme potentially allow delivery of drug to the lower digestive system.
Alternative host bacteria (e.g., L. lactis) to E. coli are used due to safety concerns and need to colonise the correct part of the bowel.
The bacteria survive the acidic conditions of the stomach but lyse in the lower intestines (alkali pH) to release the enzyme.
The enzyme reduces S-Phe levels in the digestive system.
Promising results in animal studies but results need to be translated to humans and safety issues need to be addressed.