Pharmacokinetics in Special Age Groups: Pediatrics and Geriatrics

Learning Outcome

• Describe the effects of age on drug pharmacokinetics
• The special age group covering are the your Paediatrics Geriatrics

Paediatrics

Paediatric Medicine

· Paediatrics is the branch of medicine dealing with the development, diseases and disorders of children. · Paediatric medicine differs from adult medicine: - pharmacokinetic factors - more rapid growth - child not a "little" adult NOTE: Rapid growth and development in infancy and childhood. Pharmacokinetic changes in childhood are important and have a big influence on drug handling and need to be considered when choosing an appropriate dosage regimen for a child.

Paediatric Drug Prescribing

· Unlicensed / off-label . "Scaled down" adult doses - drug must be non-toxic with wide therapeutic index - dose based on age, bodyweight, surface area · Drugs with narrow therapeutic index - dose based on surface area or bodyweight - Therapeutic Drug Monitoring Compared to adult medicine, drug use in children is not extensively researched and the range of licensed drugs in appropriate dosage forms is limited. There is a high potential for errors - dose calculation errors, small doses used which sometimes calls for unusual levels of dilution when drawing up drugs. Many of the drugs used in children are not licensed for such use or are used off-label. The use of unlicensed drugs in children is not illegal, but use must be supported by evidence. Patient details such as age, weight and surface area need to be kept accurate and up-to-date to ensure appropriate dosing. Weight and surface area can change significantly in a short time period.

Common Dosage Formulae

These are examples of dosage formulae used to calculate childrens doses where there is no current guidance e.g. Childrens BNF. Within pharmacy practice you must use Childrens BNF to check prescribing in children, you will not be required to use these formulae. . Age: Young's rule child's age x adult dose = paediatric dose (child's age+12) • Bodyweight: Clarke's bodyweight rule child's weight x adult dose = paediatric dose 68 • Body surface area: Clarke's surface area rule surface area of child (m2) x adult dose =paediatric dose 1.73

Age Ranges for Drug Dosing

For information - Do NOT learn the tables! For the purpose of drug dosing, children older than 12 years are often classified as adults, but this is not always appropriate. The age ranges shown here better reflect key biological changes

Terms Definition Pre- term neonate 27- 37 weeks of gestation Rapid growth, fully formed, most systems not developed Neonate Birth to one month (corrected gestation) Normal initial period of human development and growth Infant One month to one year High growth rates and rapid changes Child 1- 12 years Slower growth and development Term 37- 42 weeks Post- term Born beyond 42 weeks

Terms Age Key stages Gestational age The age of the fetus in completed weeks counted from the first day of the mother's last menstrual period Post- natal age Number of days after delivery Corrected gestational age Gestational age plus post- natal age Pre-term Less than 37 weeks Adolescent 13- 18 years Final period of growth and puberty, stretching into adulthood

Drug Absorption in Neonates and Infants

Oral Absorption

· Reduced gastric acid secretion in neonates. - gastric acid secretion occurs more slowly in premature neonate - absorption of some drugs can be affected e.g. penicillin - adult values attained at ~ 2 years · Gastric emptying time prolonged in neonates. - adult values attained at 6-8 months NOTE: Ability of child to use different oral dosage forms changes with age.

Intramuscular Absorption

· Cannot assume rapid and complete absorption after IM injection. - reduced muscle mass - variable blood flow - variable absorption - IM absorption faster in infants and children - IM injections generally avoided as painful NOTE: IM injections are considered potentially harmful - generally avoided because of pain and small muscle mass. Occasionally it may be necessary to use IM route if other preferred routes not available.

Topical Absorption

· Enhanced in neonates and infants, particularly in premature. · Thin stratum corneum. · Large surface area to bodyweight ratio. · Possible adverse drug reactions. · Significant absorption of some drugs. - e.g. topical corticosteroids - Cushingoid symptoms and growth suppression - e.g. EMLA cream - < 1yr methaemoglobinaemia -

Rectal Absorption

· Useful if vomiting or nil by mouth. · Inter-individual variation in retention and rectal venous drainage. · Variable rate and extent of drug absorption. · Limited use of rectal route e.g. antipyretics (paracetamol), anticonvulsants (diazepam).

Drug Distribution in Children

Body Composition and Drug Distribution

· Premature neonate has greatest % body water and extracellular fluid volume. - most significant for water-soluble drugs e.g. gentamicin · % body water and extracellular fluid volume decrease with age. · Premature neonate has lowest body fat. 1 year infant has greatest % body fat. - most significant for lipid-soluble drugs Body composition, which affects drug distribution within body, changes with age. Percent of Water in the Human Body 100% 80% 70% 50% Fetus Baby at Birth Normal Adult Elderly Person

Plasma Protein Binding

• Plasma protein binding low in neonates, particularly in premature. • Low plasma protein conc. especially albumin. • Albumin low until 10-12 months. . Potentially higher levels of free drug in plasma. Plasma protein binding, which affects drug distribution within body, changes with age. What is the significance of plasma protein binding being low? Schematic Representation of Protein Binding Pharmacologic effect and clearance . Free drug Protein-bound drug Protein-bound molecules are not available to exert pharmacologic effects

Blood Brain Barrier

· Blood brain barrier functionally incomplete in neonates. · Lipid-soluble drugs penetrate into brain better than water- soluble drugs. · Some drugs penetrate into brain in greater amounts e.g. antibiotics in meningitis, opioids, sedatives. Lumen of blood vessel Pericyte Astrocyte Basement membrane Endothelial cell Neuron Tight junction Blood Monocyte Neutrophil Tight junction Blood-brain barrier - Endothelial cell - Basement membrane Astrocyte Brain Microglia The blood-brain barrier (BBB) Expert Reviews in Molecular Medicine2003 Cambridge University Press Lymphocyte

Drug Metabolism in Children

Neonatal Drug Metabolism

. Immaturity of hepatic drug metabolising enzymes, which mature at different rates. · Metabolism of many drugs slow. - e.g. chloramphenicol • Inter- and intra-individual differences. · Potential for maternal drugs to induce neonatal metabolism. · Immature liver proportionally larger than at any other age.

Childhood Drug Metabolism

· Rate of metabolism more rapid in 1-9 year old child. - clearance greater, half-life shorter . In 1-9 year old child, dosage of some drugs greater than adults on mg/kg bodyweight basis. - e.g. theophylline, carbamazepine, phenytoin · Larger daily doses needed, more frequent dosing or SR preps. · Liver larger relative to bodyweight.

Examples of Drug Dosing in Children

· Chloramphenicol - "Grey baby" syndrome. · vomiting, flaccidity, hypothermia, grey colour, shock, collapse - Slow glucuronidation. - Caution in newborn and premature. · Under 2 weeks - 25mg/kg/day · 2 weeks to 1 year - 50mg/kg/day · Theophylline - More rapid metabolism in 1-9 year old. · 1 to 9 years - 24mg/kg/day · Adult - 13mg/kg/day

Renal Excretion in Children

Anatomical and functional immaturity of kidneys at birth limits renal excretory capacity. · GFR decreased in neonate. - GFR very low prior to 34 weeks gestation · Tubular function lower in neonate. · Impaired renal excretion of drugs. - e.g. gentamicin · Progressive maturation with gestational and postnatal age. · Adult GFR values after 3-6 months. · Tubular function matures at about 6-8 months. • Example Gentamicin - Renal clearance · Premature <1.5kg - t1/2 11.5hours · Neonate < 1week - t1/2 5.5hours · 1 week to 6 months - t1/2 3- 3.5hours . 6months to adult - t1/2 2- 3hours

Selecting a Drug Dosage Regimen for Paediatric Patients

The following factors should be considered when selecting a drug dosage regimen for a paediatric patient. ((Age-appropriate formulations) · Age / weight / surface area . Dose and frequency · Timing of doses · Route of administration · Response to treatment and monitoring · Legal considerations · Interactions BNF for Children 2022 2023 September 2022-23 bnf.org

Pharmacy Stamp Age D.O.B Number of days' treatment N.B. Ensure dose is stated Title, Forename, Surname & Address Jay Jefferies 16 Pinotage Street Portsea NHS Number 234567891 Co-amoxiclav 625mg Tabs 1 every 8 hours Mitte 21 Signature of Prescriber LMCEwan Date TODAY For dispense r Dr L McEwan 45678 No. of The Surgery Prescrns. on form 1 Festing Avenue Portsea FP10SS NHS FP10P 0406 Co-amoxiclav has been prescribed for a chest infection. The clinical appropriateness can only be established in relation to age of patient. Inclusion of age is a legal requirement in the case of POMs for children under 12 years of age, but it is preferable to state the age for ALL prescriptions for children. BNF Adult: 250/125mg every 8 hours; increased to 500/125mg every 8 hours for severe infection Child 12-17 years: 250/125mg every 8 hours; increased to 500/125mg every 8 hours for severe infection Child 6-11 years: 0.15ml/kg tds, alternatively 5ml tds, dose doubled in severe infection (250/62 suspension) Child 1-5 years: 0.25ml/kg tds, alternatively 5ml tds, dose doubled in severe infection (125/31 suspension) Child 1-11 months: 0.25ml/kg tds, dose doubled in severe infection (125/31 suspension) UNIVERSITYOF PORTSMOUTH

Geriatrics

Geriatric Population and Prescribing

· ~ 19% of population aged 65yrs + · ~ 60% of NHS prescriptions are issued to people 60yrs + · ADRs occur frequently in elderly - multiple disease states - multiple drug therapy - age related pharmacokinetic and pharmacodynamic changes Chronic health problems are more common in the elderly. As a result more of the elderly take medicines regularly. On average the elderly take 2-5 medicines regularly, and about 1/3 take 5 or more regularly. Polypharmacy increases the possibility of interactions between different medicines, and the elderly are more sensitive to these interactions and experience more ADRs. As we age our bodies handle and react to medicines differently and can be more sensitive to some medicines. The ageing process affecting drug handling in the elderly starts at about the beginning of the 5th decade. The changes slowly develop, and in most individuals the ageing process, though advancing, has not yet become clinically significant to drug handling. However, some 'young elderly' will already be suffering from long- term conditions. There is considerable variation in onset, rate and extent of the ageing process. At about 75 years the ageing process has become clinically significant to drug handling. This is the age group that is considered for admission to specialist elderly care facilities. NB Chronological age is a poor guide to a persons biological age, and prescribing decisions should never be based on chronological age alone.