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Important pharmacodynamic and pharmacokinetic differences in drug handling are observed in newborns, infants, and children when compared to adult patients.
Therefore, knowledge of pharmacokinetic and pharma- codynamic principles in the pediatric population may better assure safe and effective medication prescribing.
8.1 Definitions
Pharmacodynamics is the study of the biochemical and physiological action or effects of drugs on living organisms. Pharmacokinetics is the study of the pro- cesses by which drugs move through the body, gener- ally, referring to processes of absorption, distribution, metabolism, and excretion.
8.2 Absorption
Drugs that are administered extravascularly undergo absorption. The bioavailability of a drug is defined as the fraction of a given drug dose that is available in the systemic circulation to exert a pharmacologic effect.
The extent or efficiency of systemic drug absorption is dependent upon characteristics including hydrophobic or hydrophilic properties, molecular weight, and drug ionization at biologic pH. Drug penetration through biologic membranes, most often occurs through pas- sive diffusion dependent upon drug concentrations.
The absorption of a drug is also dependent upon
the dosage form selected and the pharmaceutical characteristics of the formulation.
Orally-administered medications require drug absorption in the gastrointestinal tract, determined by variables including surface area of the gastrointestinal tract, rates of stomach emptying and intestinal transit, pH of the stomach and small intestines, as well as blood flow to the absorption site [1]. There are important considerations regarding the use of oral medication and drug absorption in pediatric patients. For example, gastric pH in newborns is high, around 6–8 at birth, decreasing to a pH of 1–3 within 24 h of birth [2], and reaching adult values by 3–7 years of age. This is an important consideration when administering acid labile medications via the oral route. For example, higher serum concentrations of penicillin may be achieved in early infancy [1] while weak acids, such as phenobarbital or phenytoin, may require higher daily doses to achieve comparable serum concentrations due to pH values.
Medications may also be absorbed through the respiratory tract via the inhalation route. Water soluble particles will be absorbed to a greater extent from the lung alveoli. Small particles (<1µm) can penetrate into the tracheobronchial area. During respiratory adminis- tration of drugs, it should be noted that inadvertent swallowing of drug into the gastrointestinal tract may significantly contribute to systemic bioavailability.
The skin is also a route of drug absorption. The stratum corneum is the most important layer in the regula- tion of medication penetration. Cutaneous absorption of medications may be increased in children due to a greater relative body surface area to body mass ratio compared to adults [1, 3]. The topical route in infants and children has potential for a greater risk of systemic absorption as a result of a greater skin-surface-to-body-weight- ratio, a decreased subcutaneous fat layer, as well as a thinner stratum corneum and epidermis [1, 2].
In pediatric patients, and specifically newborns, efficiency of intramuscular drug absorption may be decreased and unpredictable due to decreased muscle mass and tone, reduced muscle blood flow and decreased muscle activity.
8.3 Distribution
Drug distribution is extensively altered in children when compared to drug handling in adults. Drugs are distributed throughout the body through tissues and fluids under the control of variables including body composition (body water, fat, bone, muscle etc.), extent of plasma protein binding, and organ blood flow [4].
Total body water varies depending on the age of a pediatric patient. Total body water ratio, when com- pared to body mass progressively, decreases with age:
pre-term newborns 85%, term newborns 75%, infants approximately 78%, a one year old approximately 75%, adults 60% [2, 3]. Variation in total body water content effects distribution of hydrophilic medications, so that higher loading doses and maintenance doses (when compared by body weight) may be required.
For example, aminoglycoside daily dose requirements are increased: 7.5 mg/kg/day in infants and young chil- dren as compared to adult doses of 3–5 mg/kg/day to achieve similar therapeutic serum concentrations.
A hypothetical drug “volume of distribution” (Vd) may be calculated, reflecting the extent of distribution into body fluids and tissues, and relates the amount of drug in the body to the measured plasma concentra- tion. An apparent Vd may be calculated as:
Vd (L/Kg) = dose (mg/kg)/ plasma concentration (mg/L)
The larger the volume of distribution, the larger the medication dose needed to achieve a target drug concentration. For example, if the Vd of a particular drug is 1 L/kg, and the therapeutic serum concentra- tion is 20 mg/L, then the necessary loading dose of the medication would be 20 mg/kg. Phenytoin and phenobarbital loading doses in status epilepticus are examples of clinical applications of this pharmacoki- netic principle.
Plasma protein binding is another important deter- minant of drug distribution, as many important drugs in pediatrics demonstrate high extent of binding to albumin and alpha-1-acid-glycoproteins. Lower serum
albumin concentrations and decreased affinity of acidic drugs at albumin binding sites, most evident in newborns and young infants, result in higher free concentrations for drugs such as phenytoin, valproate, and salicylates with risks of enhanced toxicity and/or enhanced clear- ance, and subtherapeutic effects. Drug displacement interactions may also be more evident in infancy where highly albumin-bound drugs such as ceftriaxone or sulfonamides, for example, may displace bilirubin and other physiologic substances from albumin-binding sites resulting in toxicity.
Plasma concentration of alpha-1-acid-glycoprotein, a carrier of basic drugs, is decreased in newborns, reaching approximately 50% of adult values during infancy and slowly increasing during the first year [3].
Effects of age-based changes may be important for agents such as lidocaine. Disease states can also affect changes in alpha-1-acid glycoprotein, with elevations as an acute phase reaction caused by inflammation (e.g., myocardial infarction in adults). This could result in lower free concentrations of drugs, including quini- dine, lidocaine, and propranolol, necessitating careful laboratory and clinical monitoring.
8.4 Metabolism
Drug metabolism is the process by which a substance is biochemically transformed through chemical reactions in the body. Primary route of drug metabo- lism is via the liver, but metabolism also may occur to lesser extents in the kidney, gastrointestinal tract, lung, blood, and kidney. Drugs may demonstrate “first pass effects” in which metabolism of an orally administered medication occurs in the intestinal lumen and liver before reaching systemic circulation. Medications which demonstrate high first pass effects include beta-blockers such as propranolol, opioids such as hydromorphone, isoproterenol, and nitroglycerin. It is important to note that when a drug has a high first pass effect, the oral dose of the medication is considerably greater than the intravenous route, and dosing conver- sions from parenteral to oral routes or vice versa may result in errors.
Hepatic drug metabolism may occur through a variety of processes. Phase I reactions including oxi- dation (CYP450), reduction, and hydroxylation [3]
allow formation of more polar, water soluble molecules
that can be more easily eliminated by the body. Rates of metabolism through Phase I pathways generally are approximately 50% of activity at birth and mature over time [3]. Phase II reactions, including conjugation, glucuronidation, sulfation, and acetylation, vary in activ- ity from 20 to 70% at birth and mature with age [5].
The cytochrome P450 enzyme system is responsible for oxidative metabolism. Four major isoenzyme pathways are responsible for metabolism of approxi- mately 95% of all drugs: CYP3A4, CYP2D6, CYP2C9, CYP1A2 Knowledge of drug metabolism via these enzyme pathways is useful because significant drug–drug interaction may be anticipated.
The CYP3A4 enzyme pathway is responsible for metabolism of the greatest number of medications.
Drugs may act as substrates for this enzymes family;
drugs may also act as inhibitors or inducers of this family. Examples of medications that are substrates include prednisone, dexamethasone, cyclosporine, tacrolimus, benzodiazepines, calcium channel blockers,
“statins,” and lidocaine [6]. Medications that are inhib- itors of this enzyme pathway such as amiodarone, erythromycin, azole anti-fungals such as fluconazole and voriconazole, and diltiazem may produce signifi- cant drug–drug interactions through reduced drug metabolism of competing substrates. Medications that are enzyme “inducers” such as carbamazepine, phenytoin, rifampin, and phenobarbital would decrease substrate drug concentrations and, therefore, therapeutic responses. There are large differences reported in CYP3A4 activity with a four to thirteen fold variations in clearance rates [7].
CYP2D6 isoenzyme family encompasses approxi- mately 25% of medications. Substrates of this pathway include tricyclic antidepressants, opioids, mexilitine, flecanaide, haloperidol, and beta blockers. Dextro- methorphan is the standard marker for efficiency of drug metabolism through this pathway. Examples of CYP2D6 inhibitors include amiodarone, halo- peridol, and quinidine; inducers include phenytoin, phenobarbital, carbamazepime, and rifampin.
CYP2C9 enzyme substrates include: omeprazole, phenytoin, S-warfarin, diazepam, and propranolol.
Inhibitors include amiodarone, fluconazole, omepra- zole, and topiramate. Inducers include phenytoin, phenobarbital, carbamazepine, and rifampin.
The CYP1A2 isoenzyme family is responsible for approximately 5% of medications such as theophyl- line, R-warfarin, and caffeine. Inhibitors include:
erythromycin, clarithromycin, fluconazole, and ciprofloxacin. Example of inducer include: phenytoin, carbamazepine, phenobarbital, and rifampin.
8.5 Excretion
Excretion of drugs and metabolites occurs primarily through the urine and feces, although other routes include saliva, sweat, respiratory tract, tears, semen, and breast milk. Renal excretion of drug proceeds via glomerular filtration, tubular secretion, and tubular reabsorption. There is age-specific maturation of renal processes of elimination that affects rates of drug elimination. For example, glomerular filtration func- tion is reduced in premature infants and newborns, with progressive maturation by 8–12 months of age.
Therefore, drugs such as vancomycin and gentamicin require extended dosing intervals in neonates due to immature renal function.
8.6 Describing Drug Pharmacokinetics Through Pharmacokinetic Models
Pharmacokinetic parameters expressed in mathematical terms may be used to generate visual descriptions of drug movement. The most simplistic model of drug movement is referred to as a single compartment model in which the body is a single compartment, there is no absorption phase and the drug rapidly equilibrates through all tissues (Fig. 8.1). In this model, it is assumed that a drug follows first order elimination when the amount of drug eliminated from the body in a specified amount of time is dependent upon the rate of elimination and the concentration of drug at that time. An increase in drug dosage results in increased serum concentra- tions and the amount of drug eliminated over that period (Fig. 8.2). For example, the amount of drug eliminated from the body may change, but the fraction of the drug removed over a period of time remains constant [8].
Aminoglycosides, cephalosporins, and vancomycin follow first order elimination.
Pharmacokinetic models may reveal pattern of elimination best described as zero order elimination, also referred to as non-linear or Michaelis–Menten kinetics. Zero order pharmacokinetics describes drug
elimination as a saturable process at the serum concen- trations commonly achieved in patients. In zero order elimination profiles, the amount of drug eliminated does not change with the amount (concentration) of drug in the body at a given time; however, the fraction of drug that is removed changes [8] (Fig. 8.2). Aspirin, phenytoin, and ethanol are example of medications that exhibit zero order kinetics within recommended dosage regimens. The impact of this pharmacokinetic
profile can be understood in its application to practice for phenytoin. A given patient may require a dosage increase to achieve a targeted therapeutic plasma con- centration. With zero order elimination, phenytoin dose increases by 15% and will result in a dispropor- tionate increase in serum concentration, as much as two to three -fold, resulting in serious toxicity. In this setting a fixed amount of drug is eliminated per hour regardless of serum concentration.
Fig. 8.1 Log of concentration vs. time for one and two compartment models
Fig. 8.2 Log of concentration vs. time for first and zero order pharmacokinetic models
8.7 Drug Half-life
Another important pharmacokinetic concept is half-life, defined as the time for drug concentration to decrease by one-half of its initial value. Clinical application of this value lies in the ability to predict timing of steady-state drug concentrations when the rate of drug administration equals the rate of drug elimination. For example, as serum steady concentrations are achieved at approxi- mately 4–5 half-lives, dosage adjustments are best made at that time [8].
In conclusion, understanding pharmacokinetic and pharmacodynamic principles for specific drugs and age-related differences in the pediatric population may aid in therapeutic decision-making. Anticipation of patient-specific variable, such as hepatic and renal function and drugs affecting the CYP450 enzyme sys- tem, enhances appropriate drug selection, dosage, and therapeutics.
References
1. Kearns GL, Abdel-Rahman SM, Alander SW et al (2003) Developmental pharmacology- drug disposition, action, and therapy in infants and children. N Engl J Med 349:
1157–167.
2. Tetelbaum M, Finkelstein Y, Nava-Ocampo AA et al (2005) Understanding drugs in children:pharmacokinetic matura- tion. Pediatr Rev 26:321–327.
3. Benedetti MS, Blates EL (2003) Drug metabolism and disposition in children. Fund Clin Pharmacol 17:281–299.
4. Howrie DL, Schmitt C. Clinical pharmacokinetics: Applications in pediatric practice. In: Munoz RM, Schmitt CG, Roth SJ, DaCruz E, eds. Handbook of Pediatric Cardiovascular Drugs.
London: Springer-Verlag; 2008:17–32.
5. Mann HJ (2006) Drug associated disease: cytochrome P450 interactions. Crit Care Clin 22:329–345.
6. Trujillo TC, Nolan PE (2000) Antiarrhythmic agents. Drug Safety 23:509–32.
7. deWildt SN, Kearns GL, Leeder JS et al (1999) Cytochrome P4503A: ontogeny and drug disposition. Clin Pharmacokinet 37:485–505.
8. Murphy JE, editors. Clinical Pharmacokinetics. 4th ed., Bethesda, MD: American Society of Health-System Pharmacists; c2008.
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The major goals for postoperative sedation and analgesia in infants, undergoing cardiothoracic surgery are to alleviate pain and to aid the transition of patients from the intensive care unit to home. The type of agents used for pediatric sedation varies with the medical needs of the patients. For postoperative pediatric patients, children need to be comfortable and nonagitated.
Ideal sedative analgesic agents should have a rapid onset and offset of action, and be nontoxic, noncumula- tive, nonaddictive, and have minimal interactive effects with other drugs. In addition, ideal sedatives should provide the patient with cardiorespiratory stability and be cost effective. Historically, intravenous midazolam, lorazepam, and opioids were the mainstay sedative agents used in pediatrics. However, respiratory depres- sion, tolerance, and withdrawal syndromes frequently complicate their use. More recently, the use of alpha-2 agonists, the administration of intravenous opioids, and the intraoperative placement of neuroaxial opioids have been used for postoperative sedation and analgesia.
9.1 Alpha-2 Adrenergic Agents
The use of alpha-2 adrenergic agonists has emerged as adjunct for pediatric anesthesia and sedation. Specifically dexmedetomidine, either as a sole agent or in conjunc- tion with opioids and benzodiazepines, has evolved as a sedative agent for children [1–4].
Alpha-2 adrenergic receptors are composed of G proteins. These consist of 3 isoreceptors (alpha-2a, alpha-2b, and alpha-2c), which bind both agonists and
antagonists with similar affinity. The receptors are present in both the central and peripheral nervous sys- tem at autonomic ganglia and at pre and postsynaptic sites. Activation of central nervous system leads to sympathetic inhibition, while binding of alpha-2 ago- nists in the spinal cord results in analgesia. Central nervous stimulation and sympathetic stimulation in the locus ceruleus in the brainstem affect sedation and anxiolysis [5].
The titrateable alpha-2 agonist for sedation is dex- medetomidine. Dexmedetomidine is a member of the imidazolines subclass. It exhibits a high affinity to the alpha-2 receptor compared to the alpha-1 receptor. At present, dexmedetomidine is FDA approved for use in adult patients in the intensive care unit, when its use is limited to a short-term sedation of less than 24 h.
However, a number of off-label uses involving the use of dexmedetomidine in children have been reported.
9.1.1 Pharmacokinetics
Dexmedetomidine is 94% protein-bound and undergoes hepatic elimination. In healthy adult volunteers, the pharmacokinetic profile of dexmedetomidine includes a rapid distribution phase T1/2 of 6 min, a terminal elimi- nation half-life of 2 h, and a steady state VD of 118L. In adult patients with hepatic failure, there is an increased Vd, increased elimination half-life, and a decreased clearance [6]. Pediatric PK studies are limited. In a study of 36 children aged 2–12 years from Canada and South Africa, where patients received a 10-min infusion of one of three different doses of dexmedetomidine, Petroz, and others noted no dose-dependent changes in the kinetics and that the kinetic parameters in children were similar to that in adults [7].