Medicine Optimisation for Children

What is the legal definition of a child? Anyone under 18 years of age (Legal age of sexual consent is 16) What is a preterm neonate? A baby born before 37+0 weeks gestation What is gestation? Pregnancy It relates to the number of weeks since the first day of the mothers last menstrual period (listing the number of weeks and days) What is a term neonate? A baby born 37+0 to 41+6 weeks gestation What is a post term neonate? A baby born at 42+0 weeks gestation onwards What is a neonate? A newborn child less than 28 days old What is an infant? 1 month to 2 years of life What is a child? 2 years to 12 years of life What is an adolescent? 12 years to 18 years of life • Gastrointestinal: constipation, diarrhoea and vomiting, reflux, breastfeeding issues, teething concerns • Respiratory: viral coughs and colds, asthma, allergic rhinitis • Cardiovascular: heart failure • Infestations: head lice, threadworms What are common conditions that a child • Dermatology: rashes, insect bites, would experience? eczema, dry skin, atopic dermatitis, chicken pox, acne, molluscum • Neurological: epilepsy • Endocrine: diabetes (type 1) • Congenital (present at birth): Down syndrome • First aid or pain relief: cuts or grazes • Infections: otitis media, conjunctivitis 1 / 10 • Physiological growth and development • Developmental pharmacology - pharmacokinetics: ADME - pharmacodynamics: physiology differences, maturation and development • Pharmacogenetics/ pharmacogenomics • Licensing of children's medicines • Formulation considerations eg excipients, palatability, flavour and storage What factors do you consider when at- • Adverse drug reactions tending to a paediatric patient? • Dose according to weight, age or body surface area and height • Giving an appropriate and measurable dose eg 2.5ml or 5ml, with suitable equipment eg syringes, spoons, measuring cups - make sure the syringes have the right graduations to be able to measure the dose • Counselling points • Safeguarding concerns • Using growth charts, which show the age, weight and height of chidlren - if the growth chart shows an increased rate of growth, there is a likelihood of obesity - if there is a decreased rate of growth, How do we assess physiological growth there is a likelihood of the child becoming and development? underweight/ malnutrition • Using milestones, which are the first time a baby does something eg first word - at 6 months, a child should sit upright without support, to be able to take medication. - at 18 months, a child should be walking • Changes in gastric pH • Changes in GI transit time 2 / 10 What factors affect drug absorption in a child? • Changes in enteric metabolism • Reduced stratum corneum thickness • The gastric pH in neonates is neutral when they are born, and this decreases with age as the digestive system develops, reaching ph 1.5-2 (normal adult pH) at around 2 years • Some medicines need an increased pH for their absorption as they are acidic • Most drugs are either a weak base or a weak acid. In a higher pH alkaline environment, weak acids are charged and therefore ionised. In a lower pH environment, weak bases are ionised. If the drug How does gastric pH affect absorption? compound is ionised, the drug is more water soluble and it is harder to transfer across lipid membranes, which reduces absorption - therefore drugs that are weak bases eg itraconazole will have a better absorption in newborns, and drugs that are weak acids will have a reduced absorption in newborns • Drugs that are acid labile eg phenoxymethylpenicillin, will be absorbed to a greater extent in neonates • Pre-term neonates can have a gastric emptying time of around 60-75 minutes, and around 10 minutes for calorie free How does GI transit time affect absorpliquids, and this time would increase as tion? the digestive system matures • The longer the transit time in the GIT, the more absorption 3 / 10 • Passive and active transport mechanisms of drug absorption in the small intestine reach adult values at around the age of 4 months. The efflux transporter P-glycoprotein expression quickly increases during 3-6 months of life and reaches adult values at about 2 years of How does enteric metabolism affect abage. Expression of cytochrome p450 ensorption? zymes, particularly 3A4, within the wall of the GI tract are also limited in children. • Reduced production of bile salts means that absorption of lipid soluble drugs is reduced leading to a reduced absorption of highly lipid soluble drugs e.g. phenytoin or phenobarbital. • Stratum corneum thickness is reduced in younger children with the thickness being 10-20 layers thick in chidlren and 2-3 layers thick in preterm infants • A reduced stratum corneum thickness means absorption of topical products is faster • The skin's pH is also different at birth, with a pH of 6, which reduces to 5.1 How does stratum corneum thickness afwithin 1-2 weeks after birth fect absorption? • The skin is also immature and susceptible to damage and injury due to breakdown • Due to the skin layer being thinner in younger children, it is important that topical products are used in caution, particularly topical corticosteroids. The lowest potency of a corticosteroid should be used, for the shortest possible duration 4 / 10 • How a drug is distributed within the body to its relevant site of action also differs in children due to the total body water content and the apparent volume of distribution. • Total body water content decreases through development, from 85% in pre term neonates to 60% in adults • Drugs with a large volume of distribution (Vd) will require loading doses to achieve the same therapeutic effect. • Younger children need higher doses of some drugs (on a mg/kg basis) eg gentamicin, which is highly water soluble. • Adipose tissue is also reduced in younger children, therefore drugs with a large Vd due to their lipophilicity (eg phenytoin) need a loading dose to ensure adequate therapeutic concentraWhat factors affect drug distribution in a tions child? • There is a reduced protein binding in younger children due to a liver immaturity and reduced plasma levels of albumin, alpha-1 acid glycoprotein, glubulins and lipoproteins which are the main proteins involved in drug binding sites. If there is a reduced level of protein binding there is an increase in the concentration of unbound drug and therefore dosing adjustments need to be made for highly protein bound drugs. Drugs will only exert their pharmacological action if they are free to attach to their active site and in their unbound form. Neonates have a higher level of bilirubin (neonatal jaundice) and so bilirubin will also contribute to the albumin binding and drugs may also have reduced binding as a result of endogenous bilirubin binding to albumin. 5 / 10 • Metabolism occurs throughout various organ systems, but the main organ system is the hepatic system • In phase 1 metabolism, the cytochrome P450 (CYP) enzymes play a role. CYP levels rise rapidly from birth and are 40% What factors affect drug metabolism in a of the adult range about 1 month of age. child? The different subtypes of the CYP enzyme mature at different rates. • In phase 2 metabolism, the drug can be conjugated through glucuronidation. Adult levels of glucuronic acid are reached by 3 years of age. What factors affect drug excretion in a child? • Excretion is mainly via the renal system, and the development of the renal system occurs during early foetal period. • Accumulation of drugs in the body can lead to toxicity • Therapeutic drug monitoring is required for nephrotoxic drugs eg gentamicin and vancomycin • Legislation- eg Medicines Act 1968 • Marketing authorisation • PUMAs- Paediatric Use Marketing Authorisation • Drug discovery pipelines • Ethics of clinical trials for children - should children be used in clinical trials - how safe is it to extrapolate findings What is involved in licensing of children's from clinical trials in adults to determine medicines? the safety of a drug in children • Drugs that are used off-label or are unlicensed - medicines that are used off-label are those that are used differently than suggested eg not given in the correct dose, frequency, quantity, condition being treated or age 6 / 10 - medicines that are unlicensed are not present on the EMC and do not exist in the UK in that specific dosage form • Specials Tariff • Orphan Drugs What are MAs and PUMAs? • Marketing authorisations are the manufacturers rules/ regulations for how the product can be used. It is not financially viable for pharmaceutical companies to invest in paediatric medication unless marketing authorisations and patents will provide income • PUMAs give manufacturers an additional 10 years of marketing exclusivity and patents will not allow generic medication to be authorised, which provides financial incentives for pharmaceutical companies eg Buccolan was the first PUMA What is the Specials Tariff? • It aims to standardise the cost of specials formulations • Specials formulations are unlicensed medicinal products made in the UK for human use. They have been specially prepared to meet a prescription ordered for individual patients without the need for the manufacturer to hold a marketing authorisation for the medicinal product concerned. What are Orphan Drugs? Drugs for very rare conditions, which are provided under a scheme for the treatment of rare and severe conditions eg glibenclamide for neonatal diabetes mellitus 7 / 10 • Pharmaceutical form - consider when liquid dosage forms are needed over solid dosage forms. Sometimes children are fine with tablets so be sure to always ask and don't assume a suspension is needed as it might not be. However liquid preparations can be much easier for children to take - avoid modified release preparations • Excipients What factors do you consider when - consider allergies choosing which formulation to dispense • Flavouring, taste and palatability for children? - patient preference to encourage compliance - some sweeteners can have adverse effects - consider sugar free preparations for some patients who want it • Licensing • Cost • Colour • Storage • Ethanol, which is a problem as some cultures do not consume alcohol, and some parents are concerned about adverse effects of alcohol on a child, as ethanol can cause drowsiness • Sorbitol, which is a sweetener that can What are some excipients that may be cause osmotic diarrhoea concerning? • Sucrose, which is a sugar that can rot the teeth and cause dental caries • Propylene glycol, which can cause CNS depression • Aspartame and saccharin- avoid aspartame in phenylketonuria • Use alternative formulations How can the adverse effects of excipi• Consider licensing of alternative formuents be reduced? lations 8 / 10 What are some adverse drug reactions that would affect children? • The long-term use of corticosteroids can stunt growth • Aspirin use in children under 16 is linked to Reye's syndrome • Tetracyclines given to children under 8 can cause permanently discoloured teeth • Age is the most commonly used factor to decide dose in primary care • Weight (in kg) is used most commonly in secondary care and hospitals • Body surface area and height is the most accurate when deciding the dose How do you decide the dose according • An incorrect estimation of a child's to body measurements? weight can lead to medication errors, as the dose based on weight would vary, leading to either overdose or underdose and causing ADRs. To avoid this, weigh the baby if possible or ask the parent/carer (use the red book for previous measurements) How do you counsel a child? • Use child friendly terminology so they can understand • Be aware of patient information leaflet suitability for children, and use medicines for children leaflets where available since they have more images and are more clear to understand • Make sure the dose administered is provided in both weight (mg) and volume (ml) • Advise on what to do if a child is sick after a dose • Advise on missed doses • Advise on safe storage • Consider medication use in school 9 / 10 • They are a vulnerable patient group • They can be a target of abuse eg physical, emotional, sexual, financial, neglectful- always report any possible risks • Always question whether any accidents were truly an accident - is the story of what happened clear? - was the injury attended to straight Why is safeguarding important in chil- away? dren? • Children over 16 usually give consent for treatment on their own behalf, rather than their parents/ carers • Children under 16 can consent to their own treatment if they're believed to have enough intelligence, competence and understanding to fully appreciate what's involved in their treatment, which is known as Gillick competence. 10 / 10