PHARMACOKINETICS AND PHARMACODYNAMICS OF DRUGS IN PAEDIATRICS DR

PHARMACOKINETICS AND PHARMACODYNAMICS OF DRUGS IN PAEDIATRICS DR. AZMAH BT. SA’AT

CHILDREN (Paediatrics) �Neonate : birth to 1 month �Infant : 1 month to 2 year �Child : 2 year to 12 years �Adolescents : 12 years to 18 years

Unique Pharmacokinetics and Pharmacodynamics in Pediatrics �Continuous development from embryo to adolescent �“Everlasting pharmacologic moving target” �Pharmacodynamics and pharmacokinetics unstable, change with time. �The most profound differences occur in the first weeks through first year of life. �Administration of drugs during the first year of life can be a challenge due to rapid changes in body size, body composition & organ function.

Pediatric Pharmacology History �Some of the most disastrous therapeutic misadventures occurred in pediatrics. �Thalidomide 1957 : Phocomelia �Directly led to the “modern era” of pharmaceutical regulation with Kefauver-Harris Drug Amendments of 1962 �Requirement for demonstrated efficacy and safety for FDA approval and USA marketing. �It was not until the 1970’s that the effects of drug on the neonate & young infant was studied.

Pediatric Pharmacology – Challenges �Descriptive pharmacology (especially for new drugs) in pediatric patients is often lacking. �Only 20 -30% of approved drugs have pediatric labeling. �Children are not “miniature adults” �Dosing based on “rule” (Young’s, Clark’s) or scaling (by body weight or body surface area) not always predictable for a given drug. �Animal studies not always predictive. �Clinical studies in children fraught with ethical & financial hurdles. �Administration of drug can also be problematic.

Drugs pharmacokinetics in children �ABSORPTION �ORAL ABSORPTION IN PAEDIATRICS �Variable gastric and intestinal transit time: in young infants, gastric emptying time is prolonged and only approaches adult values at around 6 months of age. In older infants, intestinal hurry may occur. (needs longer period of time to reach plasma conc. ) �Increased gastric p. H: gastric acid output does not reach adult values until the second year of life. �Other factors: gastrointestinal contents, posture, disease states and therapeutic interventions, such as drug therapy, can also affect the absorption

Oral absorption of drugs in Paediatrics Physiological Changes Effects • Variable gastric emptying time: • �drug absorption In young infants, gastric at intestinal site. emptying time is prolonged and only approaches adult values at around 6 months of age. • Peristalsis in the neonate is irregular & slow. • In older infants, irritable bowel • �contact time, syndrome may occur. drug absorption & bioavailability.

Physiological Changes Effects • Differences in GIT • influence the absorption normal flora. of vitamin K & other lipid soluble vitamins & drugs. • �gastric p. H: Gastric acid • �acidic drug absorption output does not reach due to ionization. adult values until 2 nd • �drug that destroyed by year of life. gastric acid, � • In the premature infants, absorption. p. Hpancreatic remain �due • �drug basicdegradation. drug absorption • gastric Immature to immature acid due to unionization. enzymes functions. • secretion. �bile secretion. • �lipid-soluble drug absorption.

Rectal Absorption of Drugs in Paediatrics �Use in nausea and vomitting, status epilepticus, induction of anaesthesia and sedation, febrile seizures, drugs with large first pass effect (Because blood supply to the anus and lower rectum drain directly to the inferior vena cava). �Eg. Diazepam suppository (rectal) better than I/M in convulsions. Bioavailability is higher after rectal than oral.

Intramuscular Drug Absorption in Paediatrics �Determinants affecting drug absorption are �Blood flow (local factors) eg. Decrease cardiac output, Respiratory distress syndrome, circulatory disturbances, decreased blood supply. �Transport form the injection site is governed by muscle blood flow – deltoid>gluteus maximus �Administered in the upper outer quadrant of buttock to prevent the risk of sciatic nerve palsy.

• Muscular activity - immobile infants decrease absorption. Exercise increased absorption. �Drugs: phenytoin salt precipitates at site, will cause painful low erratic absorption. �The use of intramuscular injections in the neonatal population is limited due to vasomotor instability, lower muscular mass, lower subcutaneous fat and a higher proportion of water. �Other common pathological states experienced by premature neonates, such as hypovolemia, hypothermia and hypoxemia, also affect the use of the intramuscular route

Pediatrics Percutaneous Absorption �Percutaneous absorption of drugs is influenced by the thickness of the epidermal stratum corneum & state of skin hydration. Physiological Changes Effects • Immature and thin �Absorption of drug into epidermis • �skin moisture • Ratio of skin surface area to weight is much greater (3 X) than in adults

Pediatrics Intravenous Administration �Expected bioavailability following intravenous administration is 100% is not guaranteed, especially in a small infant. �Factors influence rate & extent of IV: �Slow infusion rates. �Various injection sites. �Variable injection volumes. �Different relative densities of injected solutions. �In children with dehydration due to vomiting and diarrhea, fluids and solutions (eg. 0. 45% Normal Saline/Sodium chloride solution) are given intravenously according to its body weight.

Accidental Administration of Drugs During Lactation �Most drugs used by lactating women detectable in breast milk. �[ ] of most drugs in breast milk is usually � ; amount the infant received is < than “therapeutic dose. ” �However, some drugs could achieve [ ] in breast milk sufficient to produce pharmacologic effects in infants. �E. g: Most sedatives & hypnotics: barbiturates, chloral hydrate, diazepam cause lethargy, sedation, poor suckling reflex. �Opioids : heroin, methadone & morphine cause neonatal narcotic dependence. �In pregnant woman : the mother's system metabolizes & eliminates drugs �In the breastfed newborn : the infant himself must

Drugs Transportation into Milk : Factors 1. Mammary alveolar cells lining gap junction > than blood brain barrier cells lining gap junction. 2. Ion trapping in milk �Milk has < p. H than plasma. �Basic drugs entered into milk are ionized & could not escape (not reabsorbable into plasma). 3. Transporters for natural molecules secrete drugs that resemble natural molecules’ structures into milk (e. g: iodine transporter will secrete iodide & radioactive iodine-131 into milk) 4. Drug properties : drugs with low lipid solubility, low molecular weight & low protein binding will be > absorbable into milk.

Drug Distribution in Paediatrics �Drug distribution is equally as important as absorption �For a medication to be effective, it must be absorbed and then delivered to the site of action. �As for absorption, several determinants of drug distribution also are markedly different in neonates, infants and children compared with adults.

�Factors influencing the distribution of drugs, such as protein binding and compartmentalization of body water and fat, change continuously during the first year of life. �Thus, as body composition changes with development, the relative volume into which a drug is distributed also changes.

Drug Distribution: Total Body Water (Paeds) �Increased total body water: as a percentage of total body weight, the total body water and extracellular fluid volume decrease with increasing age. Eg. Water soluble drugs (Aminoglycosides) distributed through out the extracellular compartment increases drug concentration at receptor site. �Premature neonates : 85% of total body wt �Full term neonates. : 70 -75% of total body wt �Adults : 50 -60% of total body

Drug Distribution: Total Body Fat (Paeds. ) �In premature infants, the total body fat is 1% of the total body weight. �In full term neonates, the total body fat is 15% of the total body weight �This will lead to a decrease drug concentration in receptor site eg. lipid soluble drugs such as digoxin. Lower volume of distribution of lipid soluble drugs in the paediatric population

Drug Distribution: Protein Binding (Paeds) �Decreased plasma protein binding: Drug protein binding in neonates is reduced as a result of low levels of albumin and globulins and an altered binding capacity. �Proteins are qualitatively different and generally have altered binding capacity. �High circulating bilirubin levels in neonates may displace drugs from albumin. (eg. Salicylates causes increase effect or toxicity)

Drug Distribution: Membrane Permeability in Paediatrics �At birth, the blood-brain barrier (BBB) is still not fully mature and medicinal products may gain access to the central nervous system with resultant toxicity. �This neonatal greater permeability in turn allows some drugs with low penetration capacity to achieve higher concentrations in brain than those reached in children or adults.

Plasma Drug Concentration in Paediatrics �Drugs injected intravenously are removed from the plasma through two primary mechanisms: (1) Distribution to body tissues and (2) metabolism + excretion of the drugs. �The resulting decrease of the drug's plasma concentration follows a biphasic pattern

�Alpha phase: An initial phase of rapid decrease in plasma concentration. The decrease is primarily attribute to drug distribution from the central compartment (circulation) into the peripheral compartments (body tissues). This phase ends when an equilibrium of drug concentration is established between the central and peripheral compartments. �Beta phase: A phase of gradual decrease in plasma concentration after the alpha phase. The decrease is primarily attribute to

�In neonates and young infants, alpha phase is very short relatively compared to beta phase, thus equilibrium of drug concentration is reached faster than adults. �Therefore, there is a need to decrease the loading dose and decrease the maintenance dose with longer drug intervals, to prevent further adverse effect or toxicity of the drugs.

Drug Metabolism in Paediatrics �Enzyme systems (hepatic) mature at different times and may be absent at birth, or present in considerably reduced amounts. Plasma half life 2 -3 times longer than adults) (eg phenytoin, analgesics). Maturity is normally achieved at 6 months �Altered metabolic pathways may exist for some drugs. �Metabolic rate increases dramatically in children and is often greater than in adults. Compared with adults, children may require more frequent dosing or higher doses on an

Drug Excretion in Paediatrics �Depends on GFR and effective renal blood flow �GFR (neonates) – 30%-40% of adult �GFR (1 st week) - 50% of adult �GFR (3 rd week) - 50 -60% of adult �GFR (12 months) - adult values �Reduce gentamycin dosage to be given in neonates. �Reduce clearance and increase half-life of drug

Route of administration and drug regimes in Paediatrics �Compliance in children is influenced by the formulation, taste, appearance and ease of administration of a preparation. �Prescribed regimens should be tailored to the child's daily routine. Where possible, treatment goals should be set in collaboration with the child. �Whenever possible, the use of products which avoid the need for administration during school hours should be considered (e. g. modified-release preparations or drugs with long half-lives). �Whenever possible, painful intramuscular

Pharmacodynamic of drugs in Paediatrics �Systemic drugs � The magnitude of drug action is related to plasma drug concentration which in turn is related to loading dose and/or dosage interval. Too high doses will produce toxicity. Therefore dosage adjustment is needed. �Children more vulnerable to adverse effects of some drugs (NSAIDs, hepatotoxic drugs). Caution or contraindication. �Drugs with high selected toxicity: Little effect on host tissues, high safety margin can give relatively high doses (eg. Penicillin or

Prescription writing �Inclusion of age is a legal requirement in the case of prescription-only medicines for children under 12 years of age, but it is preferable to state the age for all prescriptions for children. �It is particularly important to state the strengths of capsules or tablets.

Pediatrics Dosage Form �Suspension medications contain undissolved particles of drug. �Must be distributed throughout the vehicle by shaking. �If shaking is not done, first doses from the bottle may contain < drug than the last doses less than the expected plasma concentration / effect of the drug at early of therapy. �Toxicity may occur at the end of therapy, when it is not expected. �Liquid preparations suitable for children, but contain sugar : encourages dental decay.

Drugs Used During Pregnancy � Most drugs taken by pregnant women can cross the placenta & expose the developing embryo & foetus to their pharmacologic & teratogenic effects. � Critical factors affecting placental drug transfer & drug effects on the foetus : �The physicochemical properties of the drug �The rate at which the drug crosses the placenta �The amount of drug reaching the foetus �The duration of exposure to the drug �Distribution characteristics in different fetal tissues �The stage of placental & foetal development at the time of exposure to the drug; �The effects of the drug

Pharmacokinetics of Drugs Used During Pregnancy (1) Properties Effect Lipid solubility • Drugs with �Lipid solubility & �ionization will � & ionization placental crossing Molecular weight Ion trapping • Drugs with small molecular weight can cross easily (250 -500) • Drugs with moderate molecular weight has difficulty (500 -1000) • Drugs with large molecular weight cross poorly (> 1000) • Heparin is indicated in pregnancy compared to warfarin • Maternal blood p. H : 7. 4, foetal blood : 7. 3 • Weak basic drugs > ionized in the foetal ion

Pharmacokinetics of Drugs Used During Pregnancy (2) Properties Effect Existence of • Transporters that can carry larger molecules to the Placental foetus. Transporter • For example, a variety of maternal antibodies cross the placenta and may cause fetal morbidity (Rh incompatibility). Protein • P-glycoprotein transporter pumps drugs back into the maternal circulation (eg, vinblastine, doxorubicin) • BCRP transporter & MRP 3 transporter located in the placental brush border membrane pump back glyburide (anti-diabetic) from foetal to mother. • Drugs with � protein binding will � placental

Teratogenic Drug Actions (1) �Exposure to a drug can affect the fetal structures that undergoing rapid development at the time of exposure. �Mechanisms : �Direct effect of drugs on maternal tissues with secondary or indirect effects on fetal tissues. �Drugs may interfere with the passage of oxygen or nutrients through the placenta and therefore have effects on the most rapidly metabolizing tissues of the fetus. �Drugs directly interfere with the processes of differentiation in developing tissues.

Pediatrics Compliance �Compliance is influenced by the formulation, taste, appearance & ease of administration of a preparation. �Compliance involves parent’s conscientious & technical matters. �Ways to improve compliance: �Tailored the regimens to the child's daily routine. �Use medicines that require less frequency to administer (e. g. modified-release preparations or drugs with long half-lives). �Avoid painful injections if possible. �Give a calibrated medicine spoon or syringe to parents to improve the accuracy of dose measurements. �Told why it is important to continue giving the medicine for the prescribed period even if the child seems to be “cured. ” (especially antibiotics) �Avoid adding medication with food since the drug may

Pediatrics Adverse Drug Effects (1) �Factors: �Children are > vulnerable to adverse effects of some drugs (NSAIDs, hepatotoxic drugs, opioids). �Drugs are not extensively tested in children. �Many drugs are not specifically licensed for use in children & are used 'off-label'. �Suitable formulations may not be available to allow precise dosing in children. �The nature & course of illnesses & adverse drug reactions may differ between adults &

Pediatrics Adverse Drug Effects (2) � Examples of age-dependent adverse drug events: � Valproate hepatotoxicity increased in young children. � Thalidomide only causes phocomelia whilst the limb is forming. � Grey baby syndrome – chloramphenicol in young children. Two pathophysiologic mechanisms are thought to play a role in the development of grey baby syndrome after exposure to the antimicrobial drug chloramphenicol. This condition is due to a lack of glucuronidation reactions in the liver occurring in the baby, thus leading to an accumulation of toxic chloramphenicol metabolites. � The UDP-glucuronyl transferase enzyme system of infants, especially premature infants, is immature and incapable of metabolizing the excessive drug load. � Insufficient renal excretion of the unconjugated drug. � Insufficient metabolism and excretion of chloramphenicol leads to increased blood concentrations of the drug, causing blockade of the electron transport in the liver, myocardium, and skeletal muscles, resulting in the hypotension, cyanosis, vomiting and ashen grey colour of the skin. � Tetracyclines only stain developing enamel.