Absorption

Drug can be administered via various routes and the specific route chosen largely depends on the urgency to achieve the desired effect in a given clinical circumstance. In our review of pediatric psychopharmacology, we are mainly concerned with the oral route. Once ingested, the drug is absorbed from the gastrointestinal tract. The extent of drug absorption is influenced by many factors ( Table 1 ). Orally ingested drugs will undergo the first pass effect before reaching the circulation. The extent to which a drug is available at its site of action is referred to as the bioavailability of the drug.

Controlled-release preparations have been available for several psychotropic drugs, especially the stimulants. The basis for such a preparation is to control the rate of dissolution of the solid form of the drug in the gastrointestinal tract. The advantages of such preparations include a steady therapeutic level of the drug owing to the elimination of peaks and troughs in drug concentrations and reduced frequency of administration (typically once daily). The interindividual variability of serum concentrations achieved is greater with controlled release preparations compared with immediate release forms; also failure of the dosage form may result in the release of the entire dose with consequent undesirable effects (dose dumping). Generally, controlled release forms are more appropriate for drugs with short half-lives. Another route that is developed for some psychopharmacologic agents is the transdermal route using a patch (eg, nicotine, methylphenidate, clonidine). The skin acts as lipid membrane and drug absorption depends on the surface area exposed to drug, duration of exposure, and its lipid solubility.

For the drug to exert its effect, it has to reach a specific site of action and to do that the drug first needs to be transported across various cell membranes ( Table 2 ). The molecular size and shape of the drug, degree of ionization, solubility at site of absorption, and protein binding are some of the factors that influence the drug’s ability to cross cellular membranes and reach the target sites of action. Crushing of the solid form and mixing it with food or liquids to make it more appropriate and palatable for children may also influence the absorption. Variation in transit time is of particular relevance for sustained release preparations.

Distribution

Once absorbed, the drug reaches the blood stream and is distributed to interstitial and intracellular fluids. In the blood, many psychopharmacologic agents circulate bound to plasma protein (mainly albumin, alpha-1-glycoprotein, and lipoproteins). The extent of plasma protein binding is influenced by the concentration of drug in the blood, its affinity to the binding sites, and number of available binding sites. Extensive protein binding has the potential to lead to decreased glomerular filtration but not tubular secretion or metabolism. Such plasma protein binding is nonselective and another agent can potentially compete for the same binding sites and displace each other, changing the concentration of the unbound drug in the blood. The unbound drug is the only one available for its action. A change in the concentration of the unbound drug could lead to an increase or decrease in the effect of that drug. This is more likely to be significant for drugs that have a narrow therapeutic window. Some drugs may also be stored in tissues, for example, the storage and accumulation of lipid soluble drugs in the adipose tissue.

Unlike the distribution of the drug in various interstitial and intracellular fluids, the distribution of a drug into the central nervous system requires it to first cross the blood brain barrier. In the central nervous system, the capillary endothelial cells form continuous tight junctions and along with the pericapillary glial cells constitute the blood-brain barrier. Thus, to reach the central nervous system, the drug must traverse across the endothelial cells and perivascular cell membranes. Similarly at the choroid plexus, epithelial cells form tight junctions. Therefore, lipid solubility or the lipophilic property of the drug is an important factor that facilitates its transport across the blood brain barrier.

The apparent volume of distribution of a drug is defined as that volume of body fluid required to contain the entire amount of the drug in the body at the same measured concentration in the blood or the plasma. In other words, it correlates the total amount of drug in the body to its concentration in the blood or plasma. The volume of drug distribution thus is a measure of its amount present in the extravascular tissues.

Volume of distribution value can be useful in determining the loading dose or dose needed to achieve the desired serum concentration of the drug (Loading dose = desired serum concentration of the drug [mg/L] × volume of distribution [L/kg] × patient’s weight [kg]). The volume of distribution of a given drug can vary significantly among children, adolescents, and adults, and between genders, because of differences in body composition. Other factors that influence such variability include age-related differences in protein-binding capacity, cellular membrane permeability, hemodynamic factors, and concurrent disease states.

Metabolism

Metabolism of a drug or its biotransformation generally converts it into a more water-soluble polar compound easy to excrete by the kidneys. The drug is converted into its inactive or active metabolites. Although liver is the primary site for metabolism of drugs, biotransformation can also occur to a lesser extent at other sites including the skin, lungs, intestine, and kidneys. Once ingested, some of the drug may be metabolized in the intestinal epithelium or the liver into its inactive metabolites, thereby reducing the amount of drug that reaches the circulation ( the first pass effect ). Bioavailability of the drug refers to the drug that is available at its site of action and the fraction of the administered dose that is actually absorbed without undergoing the first pass effect.

In the liver, various enzyme systems metabolize drugs by 2 major pathways. Phase I biotransformation reactions typically involve hydrolysis, oxidation, reduction, and hydroxylation by enzyme systems on the endoplasmic reticulum, whereas phase II reactions involve conjugation with glucuronic acid (or glutathione, sulfate, or acetate) by enzyme systems in the cytoplasm. The cytochrome P450 (CYP450) enzymes, which are involved in Phase I oxidative reactions, play an important role in the biotransformation of drugs with wide-ranging therapeutic and drug interaction implications. The genetic variability in CYP450 enzymes can account for clinically significant interindividual variability in drug effects. Other factors affecting biotransformation include concurrent disease states, age, and the presence of other drugs. These factors have the potential to increase the effect of a drug, decrease its efficacy, or increase its toxicity. Specific updated sources ( http://www.medicine.iupui.edu/flockhart/ ; http://www.genetest.com/human_p450_database/index.html.p450+ ; www.mhc.com/Cytochromes/index.html ) should be consulted to check for the possibility of such effects and drug-drug interactions related to CYP450 system. Manufacturer’s product information should also be reviewed to check for drug-drug interactions ( http://www.epocrates.com and http://www.pdr.net ).

When there is saturation of the protein-binding sites, the capacity of the liver to further metabolize the drug or the capacity of the kidneys to excrete the drug follows the principles of nonlinear pharmacokinetics . Overall, children metabolize drugs that use hepatic pathways more efficiently and therefore need a higher dose and more frequent daily dosing.

Excretion

Polar (hydrophilic) compounds are excreted more efficiently by the kidneys. Some drugs may be excreted unchanged, whereas others, particularly the lipid-soluble drugs, are first metabolized to more polar water-soluble compounds before being excreted by the kidneys. Renal excretion may vary depending on the age of the patient and the efficiency of the renal function. Children have more efficient renal elimination of drugs compared with adults.

Clearance of a drug is a measure of body’s efficiency in eliminating the drug. A steady state concentration of drug is reached when the rate of drug elimination equals the rate of drug administration. Thus, the dosing rate is the product of clearance and steady state concentration of the drug. The rate of clearance of a given drug remains constant over a range of its measured blood (body fluid) concentrations. When a constant fraction of drug in the body is eliminated per unit of time, it is said to follow first-order kinetics . In first-order kinetics, the elimination rate is proportional to the concentration of the drug in the plasma. When the metabolic system for drug elimination is saturated, a fixed amount of drug is eliminated per unit of time and it is said to follow zero-order kinetics . In zero-order kinetics, clearance will vary with the drug concentration.

The half-life of a drug is defined as the time it takes for the plasma concentration (or the amount of drug in the body) to be reduced by 50% and it varies depending on the clearance and volume of distribution of the drug. Generally, half-life is a clinically useful indicator of the time required for the drug to reach steady state (∼4 half-lives), the time that will be required to eliminate the drug from the body, and a mechanism by which to estimate the dosing interval.

Drug Dosing and Therapeutic Drug Monitoring

The knowledge of the pharmacokinetic parameters of a drug is applied clinically in determining the appropriate dose and dose interval for a drug to achieve desired concentration and realize its therapeutic effect. For many drugs, a relationship exists between the measured level of the drug in the body fluid and its therapeutic effects; whereas, for many others such a relationship is not clear. Some of the pharmacokinetic concepts useful in designing the optimum dosing regimen and therapeutic drug monitoring include clearance, apparent volume of distribution, elimination half-life, and bioavailability of the drug, reviewed previously.

A drug’s concentration in the body that is within a range that provides optimal efficacy without undue side effects or toxicity, defines the therapeutic window for that drug. The strategy for dosage determination of drug based on the relationship between its serum or plasma concentration and desired therapeutic effects (or toxic effects) is referred to as the target concentration strategy .

To maintain a desired therapeutic level or the steady state concentration, the drug should be administered at a rate that equals its rate of elimination. A drug dose and dosing interval can be calculated based on the desired concentration of the drug, its clearance, and bioavailability. A loading dose is typically reserved for cases where a rapid action of the drug is desired. A large loading dose may be associated with undesirable toxicity in some patients, and for drugs with long half-lives it will take a long time for the drug to clear from the body.

It is important to understand that most recommended dosage ranges are designed for an average patient with a given disorder and there is considerable interindividual (genetic) variability in pharmacokinetics and pharmacodynamics; pharmacokinetics is also affected by any associated disease states. Because of lack of sufficient clinical trials and data, the drug dosage of many agents used in children and adolescents are extrapolated based on studies in adult subjects. Therefore, individualization of the dosage is the most prudent approach starting with a low dose and gradually titrating up to achieve the desired effects.

Not all drugs have a clear correlation between their measured concentration in blood (or body fluid) and the desired therapeutic effects; however, in many instances therapeutic drug monitoring can be useful to guide the treatment. The drug concentration just before the next dose is due (ie, the trough level) is the most useful to guide any adjustment of the dose during the initiation as well as the maintenance phase of therapy. When the same dose of the drug is given at the same dosage intervals, a steady state is reached after 4 half-lives. In cases when no loading dose is given and a drug has a narrow therapeutic window with concern for toxicity, the initial drug concentration should be measured after at least 2 half-lives so as to assess the need to adjust the dose. Another level should then be measured after 2 more half-lives (that is after a total of 4 half-lives). A pharmacokinetic consultation is valuable where available for appropriate individualization of the dosage regimen. Given the difficulties with therapeutic monitoring of drugs, it is neither necessary nor useful in all cases; rather individualization based on regular clinical assessment is more useful and desirable in most cases.