**3.1 Absorption**

296 Complementary Pediatrics

enzyme maturation is completed. Glycogen stores are minimal at the liver of premature infants; they cannot stockpile large protein molecules. The albumin and other proteins which are involved in drug metabolism are kept in minimum amounts; subsequently, the

Drug response in infants varies according to the body's muscle – fat – water distribution, protein binding, body temperature, the cardiac outflow, physiological maturation of heart, maturation of blood – brain barrier, efficiency of the liver and kidneys, and whether a congenital malformation exists or not. Total body water is higher in premature newborns comparing to a newborn, and in newborns in comparing to a 2 years old. The rate of fat and muscle increases with the age, a significant characteristic for the clinical applications of newborn. Water-soluble drugs have higher volume-distribution. Thus, starting doses are greater to attain desired blood-levels. Because the fat-rate is lower in newborns, drugs redistributed to the fatty tissues, as well as those redistributed to muscle-tissues have longer effects. There are also other factors affecting a newborn's drug-response. Since the volumedistribution is wider, the excretion is delayed. Liver and kidney functions are insufficient; the rate of protein binding is low. Moreover, the presence of prematurity, sepsis, congestive cardiac failure, increased intra-abdominal pressure, controlled ventilation, and insufficient nutrition do affect the drug response adversely. Ultimately, reviewing the drug pharmacokinetics and pharmacodynamics are required for each and every newborn

For a drug to be used in the body, first, it should be absorbed (should pass to the blood from its entry point), be distributed (its delivery through circulation to the impact area) and be transformed to its active state. Later on, it is broken up with the metabolism, and egested from body as a drug metabolite. This mechanism prevents the toxicity of regular medication due to accumulation in body. For infants and children, absorption, distribution, metabolism, and excretion mechanisms differ from those in adults due to the immaturity of their body

The term *pharmacokinetics refers to the way a drug is handled by the body. Pharmacokinetic*  measures, such as area under the curve (AUC) and concentration at the maximum (Cmax) and parameters calculated from those measures, such as clearance, half-life, and volume of distribution, reflect the absorption (A), distribution (D), and elimination (E) of a drug from the body. A drug can be eliminated by both metabolism (M) to one or more active and inactive metabolites and excretion of the unchanged drug. The overall set of processes is often referred to as ADME, which ultimately controls systemic exposure to a drug and its

This systemic exposure, reflected in plasma drug and/or metabolite concentrations, is generally used to relate dose to both beneficial and adverse effects. All drugs show interand intra-individual variance in pharmacokinetic measures and/or parameters (Buxton & Benet, 2011). Variances can sometimes be substantial. In the pediatric population, growth and developmental changes in factors influencing ADME also lead to changes in pharmacokinetic measures and/or parameters. To achieve AUC and Cmax values in children similar to values associated with effectiveness and safety in adults, it may be

free fractionation of drugs increases (Ozcengiz, 2011).

(Özcengiz, 2011).

systems (Çetinkaya &Tengir, 2006).

metabolites after drug administration (Buxton & Benet, 2011).

**3. Drug pharmacokinetics** 

*Absorption is* the period of a drug to pass into body-liquids and to be brought to its receptor zone (Çetinkaya &Tengir, 2006).

Similarly, developmental changes in skin, muscle, and fat, including changes in water content and degree of vascularization, can affect absorption patterns of drugs delivered via intramuscular, subcutaneous, or percutaneous absorption (Buxton & Benet, 2011).

Drugs are delivered through intravascular (*intravenous*) or extravascular (*intramuscular, oral, sublingual, subcutaneous, or rectal*) routes. A drug administered via extravascular route should be absorbed in order to reach its receptor zone (Çetinkaya &Tengir, 2006).

The absorption of most drugs at the gastrointestinal system is through passive diffusion. Absorption is affected by the delivery route, drug density, medium's acidity, and the local circulation. For newborns and infants, the drugs given orally usually have a belated absorption (Çetinkaya &Tengir, 2006).

A drug to pass from cell-membrane shouldn't be ionized. Acidic drugs ionize at alkaline medium. Since these drugs do not ionize at the acidic medium they are absorbed well. The stomach pH of a newborn is acidic (1-3); by the 4th month the acidity approaches to that of an adult's 50%, and around the age of 3 it gets near-adult-values (0.9-1.5) (Çetinkaya &Tengir, 2006).

Decreasing stomach activity for newborns and infants affect the drug absorption, too. For newborns, stomach is empties in 6-8 hours; this number reaches to adult values of 2 hours at the age of 6-8 months. Irregular peristaltic movements until the 8th month cause this procrastination, also delaying drug's blood-levels. Furthermore, newborns do not exhibit efficient absorption since their intestinal enzyme developments were delayed (Çetinkaya &Tengir, 2006).

Absorption of intramuscular or subcutaneous drugs depends on the tissue perfusion at the primer application zone. Since the circulation at muscles and various tissues are less than sufficient, the absorption of intramuscular or subcutaneous drugs is decreased (Çetinkaya &Tengir, 2006).

Slow blood circulation can also affect the drug absorption in newborns. Drug distribution can be limited for the infants carrying cardiovascular disease (Çetinkaya &Tengir, 2006).

Oral use: Although oral use is the most frequent drug administration type, this is not preferred for newborns. Stomach acids secretion in newborns and infants is low; their digestive juice is close to neutral. The bioavailability of basic drugs is decreased, whereas

The Administration and Dose of Most Frequently Used Drugs in Pediatrics 299

delivery, liver enzymes begins to maturate; at about the 4th week liver functions are fully developed and the excess drugs can be metabolized. If this period is not taken into account, the non-metabolized drugs begin to accumulate at toxic levels (Çetinkaya &Tengir, 2006).

Because the metabolism rate of an infant (and small child) is faster than an adult, certain drugs can be metabolized also faster. Another factor is the change in liver size. Fetal liver is the 4% of total weight in infants, while this is 2% for adults. This alone explains why many drugs are disposed more quickly, and, accordingly, why the children require medication in

The volume of body liquids vary comparing to adults. Comparing to total weight, body

The relative mass of fatty tissues and skeleton muscle tissues are less than those at adults. Especially fat-soluble drugs have greater distribution volume; they should be used in lower

The rate of drugs' protein binding is lower since the total protein concentration is lower than that in adults. Since the free drug concentration in the blood is higher, so is for the toxicity

The blood-brain barrier isn't fully developed. There is a risk for hypersensitivity against the

Drug metabolism usually occurs in the liver, but may also occur in the blood, gastrointestinal wall, kidney, lung, and skin. Developmental changes in metabolizing capacity can affect both absorption and elimination, depending on the degree to which intestinal and hepatic metabolic processes are involved. Although developmental changes are recognized, information on drug metabolism of specific drugs in newborns, infants, and children is limited. In general, it can be assumed that children will form the same metabolites as adults via pathways such as oxidation, reduction, hydrolysis, and conjugation, but rates of metabolite formation can be different (Buxton & Benet, 2011).

There are qualitative and quantitative differences in biotransformation between a newborn

The metabolism capacity of most drugs is rudimental in newborns; on the contrary, various metabolism pathways show significant development during the first one year (Pala &

In some cases, the dominant metabolic route differs at the infants and children. Caffeine synthesis due to the methylation of teophylline is developed well at infants (Pala & Baktr,

Sulfide conjugation is developed at infants. Paracetamol absorption is similar to adults (Pala

liquids in children are more than they are in adults (Pala & Baktr, 2011).

higher-doses (Çetinkaya &Tengir, 2006).

drugs affecting the central (Pala & Baktr, 2011).

and other age groups. (Pala & Baktr, 2011).

Glucuronidation at infants is insufficient (Pala & Baktr, 2011).

doses (Pala & Baktr, 2011).

risk (Pala & Baktr, 2011).

**3.3 MetabolIsm** 

Baktr, 2011).

& Baktr, 2011).

2011).

that of acidic ones (*Ampicillin*) is increased. Moreover, gastro-intestinal motilities are irregular; these are slower in newborn and infants, while they are faster than adults in children (Pala & Baktr, 2011).

Rectal use: It is an alternative route when oral use is not applied due to nausea, vomiting, or other reasons. Some analgesic – antipyretic drugs, valproic acid, Diazepam, Phenobarbital, and some corticosteroids can be administered this way. Absorption of the drugs that are applied as a suppository in the rectum is neither regular, nor exact (Pala & Baktr, 2011).

Intramuscular use (IM): it is weak and irregular for newborns and infants. This is caused by the irregularities in blood circulation and vasomotor functions (Pala & Baktr, 2011).

Percutaneous use: With the stratum corneum layer too thin, skin hydration is excessive in newborns. Therefore, locally applied drugs are absorbed more than that in the adults, making undesired toxicity quite possible. Especially, topical preparations containing corticosteroid require significant attention (Pala & Baktr, 2011).
