Features of farmakogenetiki drugs in childhood

In the life of a child a few isolated periods, during which the pharmacokinetics and pharmacodynamics of drugs differ greatly: antenatal, intrapartum period of delivery, neonatal (to 4 weeks), to 1 year, from 1 Year to 3 years. After 5 years of basic clinical and pharmacological parameters in children do not differ from those of adults.

On the absorption of drugs in the gastrointestinal tract is influenced by many factors, including physical and chemical properties of drugs and especially the body of a sick child (pH of the gastric juice, length of stay of food in the stomach, content of bile acids, bacterial flora of the gastrointestinal tract, comorbidities).

Release time on the first day of the stomach or the first few days of life increased to 6-8 hours. Therefore, the preparations, are absorbed mostly in the stomach, absorbed more fully, than assumed. When, if the drugs are absorbed in the small intestine, therapeutic effect can be delayed. Irregular peristalsis in newborns and can be eased. When an impaired motility may be absorbed more of the drug, than usual, whereby a standard dose becomes potentially toxic. The table presents data on enteral bioavailability of various drugs in infants compared with older children and adults.

Increased peristalsis, e.g. diarrhea, It leads to a decrease in volume of the suction, It decreases as the time of contact with the absorbing surface of the intestine.

The drugs are absorbed mainly in the small intestine, therefore the rate of gastric emptying to a certain extent affect the process. The rate of gastric emptying in infants below, than in adults, however, for 1-8 Months. it increases. Gastric motility is reduced in premature infants, in the presence of respiratory distress syndrome, congenital heart disease. The evacuation of food from the stomach depends on its composition. Mother's milk increases the rate of gastric emptying, while at higher caloric content of the fatty acids and long chain (bottle-feeding) it decreases. In general, children in early 6 Months. life of absorption of drugs is slower, than in adults.

The rate and total synthesis of bile salts in newborn reduced; This reduces the rate and extent of absorption of fat soluble vitamins D and E, that is taken into account in the appointment of these drugs to children.

Absorption of drugs after subcutaneous or intramuscular injections in newborn, as in adults, It depends primarily on the rate of blood flow in the muscle or subcutaneous administration area. Typically, patients are premature infants, needing intramuscular injections, They have very little muscle mass. Absorption of drugs is further complicated by a decrease in peripheral perfusion in these areas. In such cases, the suction becomes difficult to predict, since the substance may remain in the muscle and absorbed more slowly, than expected. If you suddenly improves perfusion, may prompt an unexpected increase in the quantity of substance, entering into circulation, leading to high and potentially toxic concentrations. Examples of drugs, particularly dangerous in those situations, are cardiac glycosides, aminoglikozidy, aminoglycoside antibiotics and anticonvulsants.

Parenteral drugs when it is impossible it is advisable to introduce enteral application with a sharp violation intestinal absorption. Intravenous efficiency preferable intramuscular.

The drugs, that a newborn can be administered intramuscularly:

• antibacterial substances - Amikacin, ampicillin, benzilpenicillin, gentamicin, kanamycin, karbenicillin, klindamiцin, moxalactam, methicillin, nafцillin, oxacillin, piperacillin, tikarцillin, tobramycin, tsefazolyn, cefotaxime, ceftazidime, ceftriaxone;
• vitamins — витамин D, витамин K; hormone - ACTH, vasopressin, gidrokortizon, glucagon, desoxycorticosterone; diuretiki - aцetazolamid, ʙumetanid, furosemid;
• drugs - Trimeperidine (meperidine);
• anticonvulsant agents - Diazepam, phenobarbital;
• sedatives - Promethazine, chlorpromazine;
• cardiovascular agents - Gidralazin, prokaynamyd.

Many chemicals can easily penetrate through the skin of newborns, and can cause severe poisoning. In the literature there are reports of toxic action of certain drugs (gidrokortizon) and chemical (pentachlorophenol, contained in the detergent powder; disinfection solutions, soderzhashtie aniline) matter, gets on your newborn. Theoretically,, If the skin of a newborn baby and adult cause drug in the same dose, calculated on a body surface, the dose 1 kg body weight will be in newborn 2-3 times, than adult. Premature babies showed no congenital barrier function, reduce percutaneous absorption.

Rectally administered drugs, if the child can not take them through the mouth, and intravenous administration is not feasible. Lipophilic drugs (barbiturates, benzodiazepines) They are ideal for rectal use, since they are non-ionized form and easily penetrate through the cellular membrane.

The binding capacity of proteins in neonates and infants as a result of reduced congestion proteins endogenous metabolic products (bilirubin, free fatty acids), reduce the amount of albumin in the blood, qualitative changes in the protein structure. After birth, the protein content in the blood and affinity of albumin to pharmaceutical agent is gradually increased, Although aged 10-12 Months. do not always reach the norm for adults. Binding of certain drugs in newborn and adult differs considerably (indicated by an asterisk in Table).

Many endogenous substances, that bind to plasma proteins, can displace the drug from the complex with the protein and thereby increase its volume distribution. The clinical significance of this fact becomes only, if the drug binds to a protein on 80-90%, and clearance depends on its binding protein. Due to the displacement of the substance increases the amount of blood, that can lead to transient enhanced pharmacological actions.

Because in the process of development of an organism is changed, The volume of distribution of drugs also vary. Newborns have a higher percentage of water content of the body weight (70-75%), than adults (50-60%). There may be discrepancies between the full-term (70% body weight is water) and premature babies (85% water by weight of the body). Similarly, the extracellular fluid is in infants 40% body weight as compared with 20% adult. Many drugs are distributed through the extracellular fluid, however, its volume is important for determining the concentration of substances in the receptor. This is particularly important for water-soluble substances (such as aminoglycosides) and to a lesser degree - for liposoluble.

Premature babies have significantly less fat, than full-term. The amount of body fat in preterm babies account for about 1% of total body weight compared to 15% term infants. Therefore preterm infants soluble drugs accumulate in smaller amounts, than older children and adults.

The biotransformation of drugs It occurs primarily in the liver, as well as the adrenal glands, kidney, intestine, skin. As a result of biotransformation are formed more polar molecule, which are rapidly excreted in the urine or bile. However, the metabolism of some substances are transformed into the pharmacologically active.

The period of development, when the maximum enzymatic activity depends on the specific enzyme systems, not fixed. Education glucuronide (per kilogram of body weight) It reaches adults between the third and fourth years of life. Due to the low rate of metabolism of drugs in neonates many are slowly eliminated and have a longer half-life. If you do not take into account the immaturity of newborns when taking drugs, metabolized in the liver, may develop toxic effects. The table shown, as the half-lives vary drugs in infants and adults.

For the newborn, it is important, accepted or not his mother drugs, capable of inducing early maturation of fetal liver enzymes (Taki how phenobarbital). In this case, the ability to metabolize certain substances newborns will be more, than expected. In this therapeutic effect will be less pronounced, and the concentration of substances in the plasma lower, than usual characteristic of the neonatal period. Due to the relatively low speed and biotransformation of medicinal substances increases their excretion of unchanged.

The status of other enzyme systems of metabolism (In addition to oxidation) children less studied.

Excretion of drugs

Medicinal preparations glomeruliarna filtering rate in neonates is much lower, than in infants, children or adults, and this restriction is maintained during the first few days of life. Filtering clubockov, calculated surface area, is the newborn only 30-40% the values for adults. Therefore, drugs, Elimination of which depends on the kidney, excreted in the first weeks of life very slowly. Penicillin, eg, preterm infants are displayed at the level 17% from the values in adults, If we take into account the surface area of the, and at the level of 34% weight comparison. Infant patients kidney function may not rise before the predicted magnitude during the first weeks and months of life, Therefore, the appropriate dose adjustment and sometimes difficult assignment schemes.