**2.5.2 Side effects / adverse effects**

Drugs can result in undesired, and sometimes, unexplained reactions in the body. No drug is completely safe. The side-effects can be predictable; these effects can show up even if drug is taken at the appropriate doses. Should the severity of side-effects start exceeding the desired effects, this medication should be abandoned by whom it was prescribed (Dinç, 2011).

Adverse drug reactions are undesired, and, most often, unpredictable effects. They may result in anomalies which would incapacitate the patient. Some of them may show up at short notice, some may take even months (Dinç, 2011).Side effects are those which surface as an unsettling effect to the patient although the dose was appropriate. These may result from the preservatives and other ingredients, or even the drug itself (Çetinkaya &Tengir, 2006).

Nurses should be alarmed for any side effects especially when dealing with new drugs. A nurse should be aware of the fact that even mildly occurring adverse effects may result in severe allergic reactions with high toxicity. Early detection of adverse effects may prevent the patient from getting harmed (Dinç, 2011).

#### **2.5.2.1 Toxic effects**

Toxicity determines the level of toxication a substance can cause. The toxicity occurs with the accumulation of drug in the blood due to either high dosage, or oral administration and digestion of an non-oral medication, or failure in metabolism and excretion mechanism. Depending on the drug activity, toxic effects can be deadly (Dinç, 2011).

#### **2.5.2.2 Idiosyncratic reactions**

These are unusual reactions in which the patient shows either excessive or too little reaction against a medication. These are unpredictable and it is not possible to determine which patient might develop an idiosyncratic reaction (Dinç, 2011).

#### **2.5.2.3 Allergic reactions**

Drug reaction, according to the UN World Health Organization, is defined as "unexpected and harmful reactions that a medicine provided with appropriate doses for the intent of diagnosis, treatment, or preservation is causing" (Çetinkaya et al, 2008; Sin, 2005). Allergic reactions constitute only one part of undesired drug reactions (Çetinkaya et al, 2008; Sin,

Nurse should be aware of the curing, thus, desired effect of a drug before administering it. Since drugs are chemical compounds they may result in more than one effect, therefore,

These are the desired physiological effects of a drug. Every drug has an intended curing purpose. Aspirin can be used to wear off a pain, reduce fever, help inflammations over edema. It is important for a nurse to know about the curing effects of prescribed medicines. By this way, nurse can properly brief the patient and assess the desired effects of medicine.

Drugs can result in undesired, and sometimes, unexplained reactions in the body. No drug is completely safe. The side-effects can be predictable; these effects can show up even if drug is taken at the appropriate doses. Should the severity of side-effects start exceeding the desired

Adverse drug reactions are undesired, and, most often, unpredictable effects. They may result in anomalies which would incapacitate the patient. Some of them may show up at short notice, some may take even months (Dinç, 2011).Side effects are those which surface as an unsettling effect to the patient although the dose was appropriate. These may result from the preservatives and other ingredients, or even the drug itself (Çetinkaya &Tengir, 2006).

Nurses should be alarmed for any side effects especially when dealing with new drugs. A nurse should be aware of the fact that even mildly occurring adverse effects may result in severe allergic reactions with high toxicity. Early detection of adverse effects may prevent

Toxicity determines the level of toxication a substance can cause. The toxicity occurs with the accumulation of drug in the blood due to either high dosage, or oral administration and digestion of an non-oral medication, or failure in metabolism and excretion mechanism.

These are unusual reactions in which the patient shows either excessive or too little reaction against a medication. These are unpredictable and it is not possible to determine which

Drug reaction, according to the UN World Health Organization, is defined as "unexpected and harmful reactions that a medicine provided with appropriate doses for the intent of diagnosis, treatment, or preservation is causing" (Çetinkaya et al, 2008; Sin, 2005). Allergic reactions constitute only one part of undesired drug reactions (Çetinkaya et al, 2008; Sin,

Depending on the drug activity, toxic effects can be deadly (Dinç, 2011).

patient might develop an idiosyncratic reaction (Dinç, 2011).

effects, this medication should be abandoned by whom it was prescribed (Dinç, 2011).

they may not react the same way for every patient (Dinç, 2011).

**2.5 Drug effects** 

**2.5.1 Curing effects** 

**2.5.2 Side effects / adverse effects** 

the patient from getting harmed (Dinç, 2011).

**2.5.2.1 Toxic effects**

**2.5.2.2 Idiosyncratic reactions** 

**2.5.2.3 Allergic reactions** 

(Dinç, 2011).

2005). Due to lack of feedback, the frequency of reactions on the patients obtaining their medication at outpatient services cannot be determined (Çetinkaya et al, 2008; 2005; Sin, 2005; Tomaç & Üstündağ). As for the hospitalized incidents, the observation rate for drug reactions is 15 – 30% (Çetinkaya et al, 2008; Sin, 2005).

Allergic reactions can be mild as well as they could be serious. Allergic symptoms vary according to patient and medication. With respect to different drug types, antibiotics have the highest incidence rate for allergic reactions (Dinç, 2011).

Allergic medicine reactions, to get her with the most common form of skin reactions constitute 5-10% of the medicine side effects. It is presumed that the hospital expenses due to medicine reactions are 7000 per unit bed year and morbidity and mortality costs are presumed to be more than 136 million dollars only in USA (Çetinkaya & Tengir, 2008).

Antibiotics like Vancomycin, Cephalosporins, and Penicillins, besides, anticonvulsant drugs, narcotic analgesics, and anti-emetics are of the examples to the drugs that cause undesired effects on children. Because most of these effects proceed mildly, the situation can be brought under control easily. However, every three out of ten reactions last longer and require hospitalization. An example to such most serious reactions is "respiratory arrest" which is caused by anaphylaxis, or application of benzodiazepine – narcotic analgesic combination, following a Cephalosporin antibiotic treatment (Pala & Baktir, 2011).

Penicillin was found by Fleming in 1928. Penicillin group of drugs are the most frequently prescribed antibiotic, and they usually are the most common reasons of medicine allergy (Çetinkaya & Tengir, 2008).

Indeed, penicillin allergy is one of the most encountered problems (Çetinkaya et al, 2008; Tomaç & Üstündağ, 2005). It was determined in a study that three out of five antibiotics prescribed in the world in 1999 were derivatives of penicillin. For this reason, penicillin, among all drugs, constitutes the most researched antibiotic group for their allergic reactions (Çetinkaya et al, 2008; Mungan, 2005).

It is estimated that the chance for an allergic reaction to occur following penicillin is 2% for every treatment cure (Çetinkaya et al, 2008; Mungan, 2005). Among children, rate for penicillin allergy is not determined (Cetinkaya & Cag, 2004; Çetinkaya et al, 2008). For the children having medical history of their parents with penicillin allergy, the rate of allergy development by the age of 16 is 26%. The 39% of children who were hospitalized due to drug reactions later showed life-threatening incidents (Çetinkaya et al, 2008; Park & James, 2005).

A research to analyze the knowledge and application of nurses in Penicillin Allergy Test and the factors underlying has been conducted; a total of 161 nurses and midwifes working in twenty-two healthcare centers located in Konya, Turkey has participated. The 83.5% of the participants told that penicillin should be administered at the healthcare centers, 92.1% opted for a nearby medical facility in case of an emergency, and 91.3% of them told that a doctor, at least, should be present at the site of administration for the same reasons. In the end, it was suggested that nurses and midwifes should acquire knowledge about the penicillin test before any penicillin treatment was placed in order, so as precautionary actions could be taken during the application (Çetinkaya et al, 2008).

Patients should definitely be given adequate written material. They should be asked to carry special id cards indicating what drugs they had allergic reaction against. On these allergy

The Administration and Dose of Most Frequently Used Drugs in Pediatrics 295

The term "bio-availability" is used for the part of the dose that reaches to the circulatory system. The dose interval between the beneficial part of a drug and that causing side effects is called "therapeutic index". The time it takes for drug concentration in blood serum to be halved is called "half-life". Half-life is affected by other drugs, tissue perfusion and organ functions. Determination of the blood level is easier than that of a tissue, in most of the cases. Volume of distribution is a parameter, used to determine the relation between the applied dose and blood concentration of a drug. Volume of distribution is affected by the chemical properties of the drug and patient's physiological condition. "Stable drug level" indicates the egested amount of drug matching the amount of drug which was taken.

"Clearance" is the term showing the excretion rate of a drug. Clearance of any drug depends on the volume of distribution, half-life, and patient's physiology, blood circulation of organs, the organ functions, and drug's chemical properties. In clinical terms, clearance is studied in two types: linear (first degree) and nonlinear (zero degree). A drug showing linear pharmacokinetics results in proportional increase to blood and tissue concentrations as the dose increases. Most of the drugs used in newborns (amino glycosides, Vancomycin, Phenobarbital, caffeine, catecholamine) are egested this way. As for the drugs showing nonlinear pharmacokinetic properties, there will be a sharp increase in blood concentration even if there is a mild change in the dose level. Such an unpredictable change is related to enzyme saturation levels in the liver. Therefore, almost all of the drugs egested from liver have nonlinear pharmacokinetics. These drugs, on the other hand, tend to show linear excretion properties if given in therapeutic doses. Approaching to the toxicity levels, this relation becomes nonlinear. Phenytoin is a good

In order to measure the effects of some drugs, checking blood levels may be required. In the use of amino glycosides, the measurement of both the lowest and the highest concentrations in the blood might be useful. Should the lowest concentration be observed above expected, an excretion problem can be considered, thus, dose intervals are extended (or narrowed when the concentration was lower). Deviations in the maximum values, on the other hand, require changes in the dose amount, not in the interval. Because those inspections require considerable amount of blood taking, for the infants, it is a better idea to make with clinical overview instead of following the routine, unless the drug levels are required in case of

Factors related to the growth and development of a child may affect the drug effect and its excretion. Maturation lag or natal disorders do affect the drug absorption, its effect and

Comparing to adults, newborns exhibit great differences physiologically, anatomically, and pharmacologically. Renal functions in the newborn are reduced since the glomerular and tubular functions are infrequent, and blood circulation at the kidneys is low. Glomerular filtration and tubular functions reach to their mature levels after 20 weeks from delivery, whereas, this is 2 years for renal functions. Newborn's ability for water-retention and excretion of solutes are insufficient. All of these reasons cause extended half-lives. On a fullterm infant the liver is immature. Enzymes playing role in drug mechanisms are not sufficient. Only through the infant's growth, the blood circulation in liver increases, and the

Usually in clinical practices, stable drug level is attained following 4-5 half-lives.

example to such drugs (Ovali, 2008).

necessity (Oval, 2008).

excretion (Kavakl et al, 1998).

cards, name of the active agent, drug's trade name, severity of the reactions that was observed, assessment tests (history, skin test, IgE test, IPT), suggested alternative drug and its doses should be indicated (Çetinkaya et al, 2008; Dursun & Bavbek, 2005).Administration method, the treatment and its length may affect allergic reactions' development. This is what all healthcare personnel should adequately know about. Physicians should monitor these reactions very carefully, because it will be decisive in respect to patient's future drug regime; and if ignored, the treatment will become more and more complicated, effectively requiring much higher costs (Çetinkaya & Tengir, 2008).

#### **2.5.2.4 Drug tolerance and addiction**

Any decrease in physiological response following the repeated use of medication or chemical compounds is called "drug tolerance". This tolerance is discovered when the patient starts requiring new doses after steady use of lower doses for a long period. For acute cases, this is not often the case, and tolerance does not develop. The time period required to observe such development can be one month, or even more. Moreover, "cross tolerance" may develop should any drug tolerance occurred initially, and caused other drugs of the similar pharmaceutical properties fail over the same receptor area (Dinç, 2011).

Drug tolerance is not drug addiction. There are two types of drug addictions: psychological and physical. In psychological addiction patient requires the medication not for its desired effects, but for other benefits (Dinç, 2011).

Opioid resistance develops among the long-time opioid users. Despite the increasing doses it gets never enough, and patient gradually starts showing abstinence syndrome (Anand, 2007).

#### **2.5.2.5 Drug interactions**

If a drug alters the effect of another drug, the matter at hand is a drug interaction. The occurrence of such is frequent among the people taking multiple medicines at once. Any drug can increase or decrease the effectiveness of another drug, can affect the metabolism and alter the rate of absorption and / or excretion (Dinç, 2011).

If the combined effects of two drugs equal to the sum of the effect of each drugs individually, drug accumulation takes place (Dinç, 2011).

Synergistic effect is told when two drugs are taken simultaneously. By this effect, the physiological effectiveness is increased comparing to that if taken one by one (Dinç, 2011).

#### **2.6 Dose responses of drugs**

The differences in people's drug responses are called polymorphism. Factors contributing to this can be environmental, genetic or cultural ones (Dinç, 2011).

The reason for treatment with medicine is to prevent diseases, decrease the effect of a disease or keep that under control. To this end, sufficient amount of medicine should be delivered to the targeted tissues without causing intoxication. Pharmacokinetics studies the period of time a medicine is absorbed, distributed inside, metabolized, and egested from the body. This period involves a steady and dynamic interaction between the human bodies and drugs (Çetinkaya &Tengir, 2006).

cards, name of the active agent, drug's trade name, severity of the reactions that was observed, assessment tests (history, skin test, IgE test, IPT), suggested alternative drug and its doses should be indicated (Çetinkaya et al, 2008; Dursun & Bavbek, 2005).Administration method, the treatment and its length may affect allergic reactions' development. This is what all healthcare personnel should adequately know about. Physicians should monitor these reactions very carefully, because it will be decisive in respect to patient's future drug regime; and if ignored, the treatment will become more and more complicated, effectively requiring

Any decrease in physiological response following the repeated use of medication or chemical compounds is called "drug tolerance". This tolerance is discovered when the patient starts requiring new doses after steady use of lower doses for a long period. For acute cases, this is not often the case, and tolerance does not develop. The time period required to observe such development can be one month, or even more. Moreover, "cross tolerance" may develop should any drug tolerance occurred initially, and caused other drugs of the similar pharmaceutical properties fail over the same receptor area (Dinç,

Drug tolerance is not drug addiction. There are two types of drug addictions: psychological and physical. In psychological addiction patient requires the medication not for its desired

Opioid resistance develops among the long-time opioid users. Despite the increasing doses it gets never enough, and patient gradually starts showing abstinence syndrome (Anand, 2007).

If a drug alters the effect of another drug, the matter at hand is a drug interaction. The occurrence of such is frequent among the people taking multiple medicines at once. Any drug can increase or decrease the effectiveness of another drug, can affect the metabolism

If the combined effects of two drugs equal to the sum of the effect of each drugs

Synergistic effect is told when two drugs are taken simultaneously. By this effect, the physiological effectiveness is increased comparing to that if taken one by one (Dinç, 2011).

The differences in people's drug responses are called polymorphism. Factors contributing to

The reason for treatment with medicine is to prevent diseases, decrease the effect of a disease or keep that under control. To this end, sufficient amount of medicine should be delivered to the targeted tissues without causing intoxication. Pharmacokinetics studies the period of time a medicine is absorbed, distributed inside, metabolized, and egested from the body. This period involves a steady and dynamic interaction between the human bodies and

much higher costs (Çetinkaya & Tengir, 2008).

**2.5.2.4 Drug tolerance and addiction** 

effects, but for other benefits (Dinç, 2011).

and alter the rate of absorption and / or excretion (Dinç, 2011).

this can be environmental, genetic or cultural ones (Dinç, 2011).

individually, drug accumulation takes place (Dinç, 2011).

**2.5.2.5 Drug interactions** 

**2.6 Dose responses of drugs** 

drugs (Çetinkaya &Tengir, 2006).

2011).

The term "bio-availability" is used for the part of the dose that reaches to the circulatory system. The dose interval between the beneficial part of a drug and that causing side effects is called "therapeutic index". The time it takes for drug concentration in blood serum to be halved is called "half-life". Half-life is affected by other drugs, tissue perfusion and organ functions. Determination of the blood level is easier than that of a tissue, in most of the cases. Volume of distribution is a parameter, used to determine the relation between the applied dose and blood concentration of a drug. Volume of distribution is affected by the chemical properties of the drug and patient's physiological condition. "Stable drug level" indicates the egested amount of drug matching the amount of drug which was taken. Usually in clinical practices, stable drug level is attained following 4-5 half-lives.

"Clearance" is the term showing the excretion rate of a drug. Clearance of any drug depends on the volume of distribution, half-life, and patient's physiology, blood circulation of organs, the organ functions, and drug's chemical properties. In clinical terms, clearance is studied in two types: linear (first degree) and nonlinear (zero degree). A drug showing linear pharmacokinetics results in proportional increase to blood and tissue concentrations as the dose increases. Most of the drugs used in newborns (amino glycosides, Vancomycin, Phenobarbital, caffeine, catecholamine) are egested this way. As for the drugs showing nonlinear pharmacokinetic properties, there will be a sharp increase in blood concentration even if there is a mild change in the dose level. Such an unpredictable change is related to enzyme saturation levels in the liver. Therefore, almost all of the drugs egested from liver have nonlinear pharmacokinetics. These drugs, on the other hand, tend to show linear excretion properties if given in therapeutic doses. Approaching to the toxicity levels, this relation becomes nonlinear. Phenytoin is a good example to such drugs (Ovali, 2008).

In order to measure the effects of some drugs, checking blood levels may be required. In the use of amino glycosides, the measurement of both the lowest and the highest concentrations in the blood might be useful. Should the lowest concentration be observed above expected, an excretion problem can be considered, thus, dose intervals are extended (or narrowed when the concentration was lower). Deviations in the maximum values, on the other hand, require changes in the dose amount, not in the interval. Because those inspections require considerable amount of blood taking, for the infants, it is a better idea to make with clinical overview instead of following the routine, unless the drug levels are required in case of necessity (Oval, 2008).

Factors related to the growth and development of a child may affect the drug effect and its excretion. Maturation lag or natal disorders do affect the drug absorption, its effect and excretion (Kavakl et al, 1998).

Comparing to adults, newborns exhibit great differences physiologically, anatomically, and pharmacologically. Renal functions in the newborn are reduced since the glomerular and tubular functions are infrequent, and blood circulation at the kidneys is low. Glomerular filtration and tubular functions reach to their mature levels after 20 weeks from delivery, whereas, this is 2 years for renal functions. Newborn's ability for water-retention and excretion of solutes are insufficient. All of these reasons cause extended half-lives. On a fullterm infant the liver is immature. Enzymes playing role in drug mechanisms are not sufficient. Only through the infant's growth, the blood circulation in liver increases, and the

The Administration and Dose of Most Frequently Used Drugs in Pediatrics 297

important to evaluate the pharmacokinetics of a drug over the entire pediatric age range in which the drug will be used. Where growth and development are rapid, adjustment in dose within a single patient over time may be important to maintain a stable systemic exposure. Developmental changes in the pediatric population that can affect absorption include effects on gastric acidity, rates of gastric and intestinal emptying, surface area of the absorption site, and gastrointestinal enzyme systems for drugs that are actively transported across the

*Absorption is* the period of a drug to pass into body-liquids and to be brought to its receptor

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

Drugs are delivered through intravascular (*intravenous*) or extravascular (*intramuscular, oral, sublingual, subcutaneous, or rectal*) routes. A drug administered via extravascular route

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

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

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

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

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

intramuscular, subcutaneous, or percutaneous absorption (Buxton & Benet, 2011).

should be absorbed in order to reach its receptor zone (Çetinkaya &Tengir, 2006).

gastrointestinal mucosa, gastrointestinal permeability, and biliary function.

**3.1 Absorption** 

&Tengir, 2006).

&Tengir, 2006).

&Tengir, 2006).

zone (Çetinkaya &Tengir, 2006).

absorption (Çetinkaya &Tengir, 2006).

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 free fractionation of drugs increases (Ozcengiz, 2011).

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 (Özcengiz, 2011).

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 systems (Çetinkaya &Tengir, 2006).
