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GASTROINTESTINAL FUNCTION DRUGS FOR SPECIAL POPULATION ACID SECRETION NEONATES AND CHILDREN...

GASTROINTESTINAL FUNCTION DRUGS FOR SPECIAL POPULATION ACID SECRETION NEONATES AND CHILDREN Full term infant (pH 6-8) During the first-year life particularly in the first few months o Gastric acid secretion begins soon after birth there are significant changes in the physiologic process that o Gradual increase over several hours influence pharmacokinetic variables. One should pay attention to this age groups. Pre-term infants o Slow increase in gastric acid secretion PHARMACOKINETICS o Highest concentration -> on the 4th day of life “Drugs partially or totally inactivated by LOW pH should not Absorption be given orally” The rate and extent of oral absorption depends primarily on the pH-dependent passive diffusion and motility of the Distribution stomach and intestinal tract as both of these factors will influence transit time of the drug. Metabolism Gastric pH changes significantly throughout development with the highest (alkaline) values occurring during the neonatal period. Elimination Effects: 1. increased bioavailability of acid labile drugs like Critical factors affecting placental drug transfer and drug Penicillin or ampicillin. effects on the fetus include the following: 2. Absorption of weak organic acid like phenobarbital The physicochemical properties of the drug and phenytoin are decreased -> need to increase the o Molecular weight dose in the very young to achieve the therapeutic o Degree of ionization under physiologic condition o Product formulation plasma levels. Disintegration and dissolution of solid dosage form Drug release characteristic Co-solutes and complex formation The rate at which the drug crosses the placenta and the amount of drug reaching the fetus The duration of exposure to the drug Distribution characteristics in different fetal tissues The stage of placental and fetal development at the time of exposure to the drug The effects of drugs used in combination ABSORPTION What is the implication of these? Drug absorption follows the same general principles as that o Gastric acid - approaches adult values ~ 3 of adult. Unique factors may be present: mos. in full-term infants. o Blood flow at the site of administration- o Drugs that are partially or totally inactivated by determined by the physiologic status of the acid should not be administered orally infant or child o Gastrointestinal function for orally taken o Labile- rapidly undergoing chemical changes drugs- which rapidly changes during the first GASTRIC EMPTYING TIME few days. Factors unique in children First few days o Parenteral route o Prolonged (6-8 hours) Blood flow o Complete absorption of drugs absorbed in the o Oral route stomach GI function o Delayed for drugs absorb in the SI Stomach o Reach/exceed adult values – 6-8 months of life Intestine Gastric emptying time is prolonged throughout infancy and Biliary tract childhood consequent to reduced motility which may retard o Age drug passage into the intestine where the majority of the most important factors that influence drug absorption absorption takes place are related to the function of the stomach, intestine and Effects: biliary tract. o the rate of absorption of drugs with limited water solubility like phenytoin, carbamazepine can be dramatically altered due to changes in gastrointestinal motility [JLMP] Checked by: [Transhead] Page 1 of 6 PHARMACOLOGY NOV/05/2020 GASTRIC MOTILITY Age dependence in the thickness, extent of perfusion, and Neonatal period extent of hydration of the skin and the relative size of the o Irregular and slow skin surface area (reflected by the ratio of body surface area o Unpredictable SI absorption to body weight). o Slow peristalsis- more drug absorbed -> potential Although skin thickness is similar in infants and adults, the toxicity with standard dose extent of perfusion and hydration diminishes from infancy to o Increased peristalsis – decrease contact time -> adulthood. decreased absorption Transdermal drug absorption in the neonate and very Example: diarrheal condition young infant is increased as the result of a more Neonates, particularly the premature have a reduced hydrated stratum corneum. bile acid pool and biliary function -> decreased ability The ratio of body surface area to body weight is greater to solubilize and absorb lipophilic drugs. in infants and children compared to adults. Although biliary functions develop in the 1st few Percutaneous absorption months of life, it may be difficult for the neonate and o Directly related to the degree of skin hydration. young infant to absorb fat-soluble vitamins as low o Inversely related to the thickness of the stratum concentrations of bile acids are necessary for their corneum. absorption. Thinnest in premature neonate o Greater extent of cutaneous perfusion Premature infant has a significantly less effective skin barrier to absorption of drugs and toxins. o Ex. Hexachlorophene toxic to immature infants Newborn skin surface area: body weight is 3x > adult These developmental differences may predispose the child to increased exposure and risk for toxicity for drugs/chemicals placed on the skin (e.g., silver sulfadiazine, topical corticosteroids, benzocaine, diphenhydramine) with higher likelihood of occurrence during the 1st 12 months of life. BLOOD FLOW Intramuscular/ subcutaneous o Depends mainly on the blood flow at the site Transdermal drug absorption in the neonate and very young o DECREASE: infant is increased as the result of a more hydrated stratum Cardiovascular shock corneum Vasoconstrictive drugs The ratio of body surface area to body weight is greater in (sympathomimetic agents) infants and children compared to adults Heart failure Little muscle mass in preterm GASTRIC ENZYMES Intramuscular blood flow changes with age, which can Neonatal period result in variable and unpredictable absorption. o Lower than adults Conditions wherein blood perfusion is compromised leads o A-amylase and other pancreatic enzymes in the to unpredictable absorption of drugs, it may be slower than duodenum are low in infants up to 4 months of usual. When the blood flow suddenly improves, absorption age. becomes better but may result to high concentration of o Low concentration of bile acids and lipase drugs that are absorbed and may result to toxicity. Decrease the absorption of lipid-soluble drugs SKIN [JLMP] Checked by: [MDA] Page 2 of 6 PHARMACOLOGY NOV/05/2020 Oral drug absorption: Neonate vs children and adults expressed as a percentage of total body weight, as compared with older infants and adults. DRUGS ORAL ABSORPTION Acetaminophen Decrease ONTOGENY OF BODY COMPOSITION Ampicillin Increase Diazepam Normal Digoxin Normal Penicillin G Increase Phenobarbital Decrease Phenytoin Decrease Sulfonamides Normal DISTRIBUTION Physicochemical properties of the drug o (e.g., molecular size and weight, apparent partition coefficient, pKa) Cardiac output/ regional blood flow Blood tissue pH Degree of protein/ tissue binding Body composition (MAJOR FACTOR) o Extracellular water In the fetus and premature infant water makes up 85- o Adipose tissue 90% of body weight and 60% of body weight is extracellular Drug distribution is influenced by a variety of drug-specific fluid. early maturation of liver enzymes reduced binding of acidic drugs to glycated albumin in o Effects: patients with poorly controlled diabetes mellitus) faster metabolism less therapeutic effect lower drug concentration with usual neonatal dose Children between 1 to 3 years has metabolic rate exceeding that of adult. These are the ages wherein you need to give a higher dose per kg as compared to later in life. While if the mother is receiving drugs that stimulates maturation of hepatic enzyme like in Phenobarbital, this will result to faster metabolism or less therapeutic effect because of low drug concentration when given a normal neonatal dose. PHASE 1: Oxidation, Reduction, Hydrolysis Activities of cytochrome p450 mixed function oxidase and conjugate enzymes is slower (50–70% of adult values) in early neonatal life than later. Consequences of protein binding of drugs o Prolonged elimination of drugs that depend on o The degree of drug binding to plasma proteins is oxidation pathway inversely related to the Vd (keeps drugs in the Phenytoin vascular compartment) Diazepam o Affects the rate of renal clearance (only free drug is Because of the neonate's decreased ability to filtered) metabolize drugs, many drugs have slow clearance o Affects the amount of drug reaching the target site rates and prolonged elimination half-lives. (proportional to the free drug concentration) If drug doses and dosing schedules are not altered o Plasma proteins which bind drugs are low at birth appropriately, this immaturity predisposes the neonate compared to adults, but reach adult levels by the 3rd to adverse effects from drugs that are metabolized by year of life for acidic drugs, but not until the 5th7th the liver. The process of maturation must be considered year of life for basic drugs because of lower globulin when administering drugs to this age group, especially in levels. the case of drugs administered over long periods. o Acidic drugs are usually bound to albumin, whereas basic drugs bind to a1 - acid glycoprotein or PHASE 2: Conjugation globulins Conjugation with glycine, glucuronide and sulfate o The binding properties of fetal albumin are similar to Responsible for synthesis of more water-soluble those of the adult form. compounds augmenting renal or biliary elimination o Higher levels of free fatty acid and bilirubin (bound to albumin) in newborns can also lower the fraction of drug that is bound to plasma proteins. METABOLISM Major Factor: hepatic enzymes Metabolism reflects the biotransformation of an endogenous or exogenous molecule by 1 or more enzymes [JLMP] Checked by: [MDA] Page 4 of 6 PHARMACOLOGY NOV/05/2020 RENAL ELIMINATION ELIMINATION Therapeutic implications o Estimation of renal function necessary for determining dose regimen for drugs with extensive renal clearance o Ex. Ceftazidime, Famotidine, Aminoglycosides o Measurement of drug levels often necessary o Measurement of drug levels often necessary Some drugs also alter renal maturation or renal blood flow. The kidney is the primary organ responsible for the excretion of drugs and their metabolites Factors: o Maturation o Glomerular filtration MATURATION OF RENAL FUNCTION Fetal nephron development completes by 32 weeks gestational age GFR- 30-40% of adult values; lower before 34 weeks of The clearance of gentamycin is significantly lower in gestation premature newborns than in full term babies and drug o Improves during the first week of life clearance increases by 50% to 100% in the first week of life. o After 1 week 50% from first day o End of 3rd week- 50-60% adult value GFR and CREATININE o 60-12 months- adult vaccines GFR quite low at birth and then slowly increases Drugs eliminated by the kidney Reaches adult levels (corr. To 1.73m2 by 12-18 months) o Slow elimination during the first week Creatinine- higher the more premature the baby and takes o 1-3 years- exceeds that of adult requiring higher longer to stabilize dose Creatinine values reflect maternal levels for first few days. The development of renal function begins during early fetal development and is complete by early childhood The same as hepatic drug metabolism, only free (unbound) drug and/or metabolite can be filtered by a normal glomerulus and/or either secreted or reabsorbed via a renal tubular transport protein. RBF= 12 mL/ min at birth adult rate 5-12 months GFR= 2-4 mL/ min FT o 8-20 mL/min by 2-3 days of life o Adult values 3-5 months [JLMP] Checked by: [MDA] Page 5 of 6 PHARMACOLOGY NOV/05/2020 DRUG DOSAGES Dispensing Administration o Double check calculations PEDIATRIC ADMINISTRATION ISSUES Dispensing errors o Limited range of suitable formulations o Dose ranges 0.1 mL-10mL o Fractions of tablets Measuring small volumes o Hundredths of a mL confused with tenths o 0.03 mL intended measured as 0.3 mL Prepare difficult doses in Pharmacy COMPLIANCE Adherence (formerly called compliance) may be more difficult to achieve in pediatric practice than otherwise, since it involves not only the parent’s conscientious effort to follow directions but also such practical matters Challenges in compliance: AD – adult dose; o Effort to follow directions Example adult dose of 1 mg/kg- in 3 months old it will o Measuring errors be 0.18 mg/kg o Spilling YOUNG’S RULE o Spitting o Timing of medications 𝑎𝑔𝑒 𝑖𝑛 𝑦𝑒𝑎𝑟𝑠 o Not completing the course 𝐷𝑜𝑠𝑒 = 𝑎𝑑𝑢𝑙𝑡 𝑑𝑜𝑠𝑒 𝑥 𝑎𝑔𝑒 + 12 For example, the measured volume of “teaspoons” ranges from 2.5 to 7.8 mL. The parents should obtain a calibrated CLARK’S RULE medicine spoon or syringe from the pharmacy. These devices improve the accuracy of dose measurements and simplify administration of drugs to children. 𝑤𝑒𝑖𝑔ℎ𝑡 𝑖𝑛 𝑘𝑔 𝐷𝑜𝑠𝑒 = 𝑎𝑑𝑢𝑙𝑡 𝑑𝑜𝑠𝑒 𝑥 70 Dose based on surface area is more accurate Dr. Elizabeth R. Reyes- Telado’s lecture DRUG FORMULATION Katzung Basic and Clinical Pharmacology 14th E Elixirs alcoholic solutions in which the drug molecules are dissolved and evenly distributed No shaking is required, and unless some of the vehicle has evaporated, the first dose from the bottle and the last dose should contain equivalent amounts of drug. Suspensions contain undissolved particles of drug that must be distributed throughout the vehicle by shaking. If shaking is not thorough each time a dose is given, the first doses from the bottle may contain less drug than the last doses, with the result that less than the expected plasma concentration or effect of the drug may be achieved early in the course of therapy. o Not shaken well – 1st dose may be less o Concentration is less if not shaken well This uneven distribution is a potential cause of inefficacy or toxicity in children taking phenytoin suspensions. It is thus essential that the prescriber know the form in which the drug will be dispensed and provide proper instructions to the pharmacist and patient or parent. CHILDREN’S ISSUES Developmental pharmacology o Weight or SA based dosing o Additional calculations Prescribing [JLMP] Checked by: [MDA] Page 6 of 6