Basic pharmacokinetics and the potential effect of physical therapy interventions on pharmacokinetic variables.

[Ciccone CD. Basic pharmacokinetics and the potential effect of physical therapy interventions on pharmacokinetic variables. Phys Ther. 1995; 75:343-351]

Key Words: Exercise, general, Pharmacokinetics, Pharmacology.

A fundamental concept in pharmacology is that a drug must reach specific tissues in the body at a sufficient concentration to exert therapeutic effects without causing excessive harmful or toxic effects. Pharmacokinetics is the basic area of pharmacology that deals with drug administration, absorption, distribution, tissue binding, metabolism, and excretion.[1] Pharmacokinetic properties of a medication need to be known so that an appropriate amount of the drug can be administered to reach target tissues and produce therapeutic responses in a fairly predictable and timely manner.

Pharmacokinetic variables are determined for therapeutic drugs to provide an idea of how each drug is absorbed, distributed, metabolized, and so on. These variables are typically examined during drug testing in asymptomatic volunteers or in patients who have diseases that will not directly affect the pharmacokinetic variables. There are a number of factors, however, that can alter drug disposition, thus altering the normal pharmacokinetic profile for a drug. Factors such as disease, age, diet, genetic variations, and drug interactions have all been noted to cause changes in the way specific drugs are dealt with in the body.[2-4] In addition, there may be interventions used by physical therapists that can change pharmacokinetic effects and alter the response to certain drugs. The purpose of this article is to review some basic pharmacokinetic principles that describe how drugs are absorbed, distributed, and eliminated from the body. The possible effects that interventions such as exercise, physical agents, and manual techniqqes may have on these variables will be addressed.

Pharmacokinetic Variables

Pharmacokinetics involves the complex interaction of multiple factors, including drug administration, absorption, distribution, and elimination.[3] The interrelationships among these variables are illustrated schematically in the Figure. It is beyond the scope of this article to address each of these factors independently. There are, however, three primary variables that can be used to describe the pharmacokinetic profile of a certain drug. These variables are bioavailability, volume of distribution (Vd), and clearance. Each of these primary variables is described here.

[Figure and ILLUSTRATION OMITTED]

Bioavailability

Bioavailability is commonly defined as the fraction or percentage of active medication that reaches the systemic circulation following administration by any route.[5] Drugs that are administered intravenously are considered 100% bioavailable because they are delivered directly into the bloodstream. This concept, therefore, is not very useful for describing the bioavailability of drugs administered intravenously. Bioavailability is more helpful in accounting for the absorption of drugs that are administered by other routes, especially those administered orally. A drug administered orally, for example, would be considered 500/o bioavailable if a 100-mg oral dose results in 50 mg of the drug actually reaching the bloodstream.

The Table lists values for bioavailability of some common medications following oral administration in asymptomatic adults. Bioavailability of drugs administered by other routes, including transdermal administration and subcutaneous and intramuscular injections, can also be calculated depending on how much of the drug ultimately reaches the systemic circulation. Regardless of the route of administration, the bioavailability of any medication can be altered by factors that increase or decrease the amount of drug that is absorbed from the administration site and transported to the bloodstream. This fact can necessitate altering the dosage or route of administration to avoid untoward effects because of changes in the plasma levels of the drug.

[TABULAR DATA OMITTED]

Bioavailability of orally administered drugs may increase, for example, in patients with liver disease.[5] Drugs absorbed from the gastrointestinal tract pass through the liver before reaching the systemic circulation (first-pass effect), and a portion of the administered dose is normally destroyed by hepatic first-pass metabolism. If the liver is damaged, bioavailability will increase because a relatively greater portion of the dose will reach the systemic circulation, and lower dosages may be needed to offset this increased bioavailability. Likewise, bioavadabdity may be increased if drugs are injected into or near exercising muscle.[6] Exercise may cause increased absorption from an intramuscular or subcutaneous injection site, resulting in increased appearance of the drug in the systemic circulation. The implications of increased bioavailability are explored in more detail later in this article.

Volume of Distribution

Volume of distribution is used to indicate how a systemic dose of a medication is ultimately dispersed throughout the body.[5] Volume of distribution is determined by the ratio of how much drug appears in the plasma relative to the total amount of drug administered. This ratio is calculated as follows:

(1) [V.sub.d] = Amount of drug administered/Plasma concentration

Calculation of Vd yields a parameter that is compared with total body water. A typical 70-kg person has a total body water of approximately 42 L. If the calculated Vd is approximately equal to 42, the drug is distributed uniformly throughout the body tissues. A Vd that is substantially less than 42 indicates that the drug is retained in the bloodstream. This typically occurs when the drug binds to some intravascular constituent such as albumin or other plasma proteins. A [V.sub.d] that is substantially greater than 42 indicates that the drug is sequestered outside of the vascular compartment by binding to some extravascular tissue such as skeletal muscle.

Values for Vd of some common medications are listed in the Table. Again, factors that affect Vd can have important implications on the amount of drug that reaches the target tissue. A reduction in plasma proteins, for instance, can have dramatic effects on a drug with a small Vd that is normally retained in the bloodstream. Nonsteroidal anti-inflammatory drugs (aspirin, ibuprofen, and so on) typically have a low Vd because these drugs bind extensively to plasma proteins such as albumin. A reduction in plasma proteins secondary to liver disease or nutritional deficits would increase the Vd of these drugs because the drug would not be retained in the circulation and would be distributed more extensively throughout the body. This greater distribution would also result in larger quantities of the drug reaching the extravascular tissues, which could produce harmful effects if these concentrations reach toxic levels.

Clearance

Clearance is the rate at which the active form of the drug is removed or eliminated from the body. Elimination typically occurs by the combined processes of drug metabolism (which takes place primarily in the liver) and drug excretion (which takes place primarily in the kidneys).[3] Elimination by other organs, including the lungs, skin, and gastrointestinal tract, can also contribute to drug clearance. Systemic clearance, therefore, is the cumulative ability of the liver, kidneys, and various other tissues to eliminate a drug from the body.

Clearance of a drug by a specific organ ([CL.sub.organ]) can be calculated as follows:

(2) [CL.sub.organ] = QX [C.sub.i-[C.sub.o]/[C.sub.i]

where Q is the blood flow to the organ, [C.sub.i] is the concentration of drug entering the organ, and [C.sub.o] is the concentration of drug exiting the organ.

The ratio created by the difference between [C.sub.i] and [C.sub.o] divided by [C.sub.i] is also termed the extraction ratio (ER) because this parameter indicates how well the organ can remove the drug from the bloodstream. Hence, this equation illustrates that the ability of an organ to clear a drug from the body is dependent on two primary factors: the amount of blood reaching the organ (Q) and the ability of the organ to extract the drug from the bloodstream (ER). Factors that alter either Q or ER will affect the clearance of a drug.

Drugs can also be classified as high-extraction or low-extraction drugs depending on how they are cleared by the primary organ responsible for clearing each drug, usually the liver.[5] High-extraction drugs have a high ER in a particular organ and undergo extensive elimination by that organ. Clearance of high-extraction drugs is also said to be flow-dependent because the rate-limiting factor in elimination is the amount of blood flow that delivers the drug to the organ. Low-extraction drugs have a smaller ER because the organ is less able to clear the drug from the bloodstream. Clearance of these drugs is less sensitive to changes in organ perfusion, but any further reduction in the organ's metabolic capacity due to disease or the presence of other drugs can cause dramatic changes in clearance of low-extraction drugs. The relevance of high-extraction and low-extraction drugs during specific interventions such as exercise will be discussed later in this article.

Effect of Exercise on Pharmacokinetics

Exercise can produce dramatic changes in the pharmacokinetic variables of certain drugs, resulting in altered clinical responses because the amount of drug reaching the bloodstream and ultimately reaching target tissues is excessively high or excessively low.[6,7] The magnitude of these changes is dependent on factors that pertain to the characteristics of each drug as well as exercise-related factors such as exercise intensity, mode, and duration. Only the effects of an exercise bout on pharmacokinetics are reviewed here because the changes produced by a single exercise bout can cause sudden changes in pharmacokinetics that may have an immediate impact on patients who are exercising during physical therapy. Exercise training can also produce changes in pharmacokinetics, but these changes tend to occur over a longer period of time and cause a slower and fairly predictable change in the patient's response to certain medications. For more information about the effects of exercise training, the reader is referred to a review on this topic by Dossing.[8]

Effect on Exercise on Bioavailability

Exercise can affect bioavailability by altering drug absorption at the site of drug administration. Exercise can affect absorption in two primary ways. First, increased tissue heat during exercise will increase kinetic molecular movement and thus increase diffusion of drug molecules across biological membranes. Second, drug dispersion away from the drug delivery site can be increased or decreased, depending on whether exercise increases or decreases blood flow to the site of drug administration. These two factors, therefore, must be considered along with the drug administration route to determine whether an exercise bout will increase or decrease bioavailability. Exercise may produce opposing effects on absorption of orally administered drugs, for instance, because the increased kinetic movement of the drug across the gastrointestinal mucosa may be offset by the reduction in splanchnic blood flow commonly seen during moderate- to high-intensity exercise.[9]

Studies that have examined the effect of exercise on bioavailability following oral drug administration have produced conflicting results. In a study of 10 patients with Parkinson s disease, a dose of levodopa was administered orally during a bout of exercise on a cycle ergometer.[10] Levodopa absorption was delayed in 5 patients, was increased in 3 patients, and was unchanged in 2 patients. Another study examined the effects of the absorption of midazolam (a sedative-hypnotic agent) during 50 minutes of treadmill running in 16 asymptomatic volunteers.[11] The authors stated that midazolam absorption was impaired during exercise because the amount of drug appearing in the plasma (peak plasma concentration) was significantly lower than during a control, nonexercise period. In that same study, the pharmacokinetics of ephedrine (a decongestant/bronchodilator) were not significantly affected by the exercise bout. Peak plasma concentrations of three different antibacterial drugs (sulfamethizole, tetracycline, and doxycycline) were all significantly increased in asymptomatic volunteers undergoing 4 hours of moderate exercise,[12] and the absorption of digoxin (a cardiac glycoside used to treat heart failure) was reported to increase during 8 hours of intermittent cycling exercise performed at moderate intensity.[13] Conversely, 3 hours of moderate, intermittent exercise (5 minutes of exercise, 5 minutes of rest) did not alter the plasma concentration of quinidine (an antiarrhythmic), salicylate (an anti-inflammatory/analgesic), or sulfadimidine (an antibacterial).[14] Hence, exercise can produce variable effects on bioavailability following oral administration, and these effects are probably dependent on the characteristics of the drug and the intensity, duration, and type of exercise bout.

The effect of exercise on systemic bioavailability following subcutaneous or intramuscular injection is somewhat more predictable. Absorption is generally increased when drugs are injected into or near actively exercising muscles.[6] This observation may be explained by the fact that transmembrane diffusion and blood flow are both increased in exercising tissues and the drug is absorbed more quickly and dispersed more rapidly away from the injection site and into the systemic circulation. There is also some evidence that absorption of subcutaneously administered drugs may be increased without a concomitant increase in subcutaneous blood flow, suggesting that the exercising tissues may contribute a mechanical or massage-like effect that helps increase drug absorption.[15] The opposite effect may occur if drugs are injected into nonexercising tissues, and absorption may be delayed if blood is shunted away from the site of injection and redistributed to more active tissues.6

The increased bioavailability of injected drugs can have important clinical implications because the injected drug may reach the systemic circulation too rapidly during the exercise bout. This occurrence has been well-documented with insulin administration in patients with diabetes mellitus.[15-17] Exercise involving an extremity that has served as the site for insulin injection generally increases the absorption from the injection site and thus increases systemic bioavailability by increasing plasma insulin levels.[15-17] A sudden increase in plasma insulin may be harmful because blood glucose may fall precipitously, thus causing a hypoglycemic event. This is especially true during exercise because exercise works synergistically with insulin to reduce blood glucose more than either factor working independently.[18,19] Patients should therefore select injection sites that are not in the exercising tissues (eg, inject insulin into the arms or abdomen during leg exercise), or therapists may have to alter the exercise regimen so that the exercising tissues do not involve injection sites.

Exercise may also affect bioavailability of drugs that are administered transdermally. Exercise will typically increase transdermal absorption because of increased skin temperature and increased skin hydration secondary to sweating.[6] Absorption will also be enhanced if exercise causes an increase in cutaneous blood flow, although the amount of cutaneous vasodilation is variable and cutaneous dilation may actually decrease at higher exercise work loads or in people who are hypovolemic and exercising in extreme heat.[20,21]

The clinical implications of increased transdermal administration are numerous, especially considering that more and more drugs are being administered through transdermal patches. Plasma concentrations of medications such as nitroglycerin have been observed to increase as much as threefold in asymptomatic volunteers undergoing cycling exercise while wearing a nitroglycerin patch.[20,21] This occurrence could have beneficial effects if the increased plasma nitroglycerin concentration helps offset an increased tendency for exercise-induced anginal attacks. Conversely, negative effects would be seen if the increased plasma nitroglycerin potentiates exercise-induced vasodilation, thus leading to excessive hypotension. Additional research is needed to determine the potential effects of changes in systemic bioavailability caused by exercise in patients receiving nitroglycerin and other medications (estrogen, nicotine) through transdermal patches.

The effect of exercise on transdermal bioavailability also has implications for drugs administered through iontophoresis and phonophoresis. Exercise involving the administration site could theoretically increase the amount of drug delivery if exercise is performed immediately before or after iontophoretic or phonophoretic treatment. No studies are available, however, to document this phenomenon. Likewise, increased blood flow to the site of delivery may be counterproductive if the goal of transdermal administration is to focus drug delivery to a specific structure such as a tendon or bursa. Increased regional blood flow may cause the drug to be dispersed away from the delivery site, thus negating the desired local effect. Again, the lack of research in this area makes it difficult to determine whether exercise would have a counterproductive effect on local drug disposition because of an increased washout from the site of application.

Finally, exercise can increase the rate of absorption and bioavailability of drugs that are administered by inhalation, including antiasthmatics/bronchodilators such as terbutaline. One study noted that inhalation of terbutaline just prior to a bout of stationary cycling caused an increase in the rate of appearance of the drug in the plasma and an increase in peak plasma concentrations of this drug.[24] This effect was attributed to a concomitant increase in pulmonary blood flow and increased movement of drug across the alveolar membranes. This effect might be advantageous because the moderate increase in plasma drug levels seen during exercise could offset an increase in the tendency for exercise to initiate an asthma attack. More research is needed to determine whether the increased bioavailability of inhaled antiasthmatic drugs during exercise is clinically beneficial as evidenced by a decrease in exercise-induced asthma.

Effect of Exercise on Drug Distribution

Exercise has been reported to cause a decrease in the Vd of certain medications, indicating that the plasma concentration of the drug is increased.[6] An exercise-induced decrease in Vd has been observed for several orally administered drugs such as the calcium channel blocker verapamil,[25] the cardiac beta-blocker propranolol,[25-27] the antiasthmatic agent theophylline,[28] and the central nervous system stimulant caffeine.[29] Exercise also decreased the Vd of atropine (an anticholinergic agent) when this drug was administered by intramuscular injection.[30,31]

The observed decrease in Vd seen with these drugs may be caused to some extent by the effect of exercise on other pharmacokinetic variables. For instance, an increase in bioavailibility combined with a decrease in drug clearance could account for increased plasma drug levels, thus decreasing Vd. This fact would be especially true for drugs that tend to be retained in the plasma, that is, drugs that tend to have a low Vd under normal (nonexercise) conditions. The decrease in Vd seen with certain drugs may also be caused by the redistribution of blood flow and plasma volume that occurs during an exercise bout. Plasma volume may decrease by as much as 12% to 180/o during exercise,[32,33] and this decrease will cause a relative increase in the concentration of drugs located in the bloodstream. The decrease in Vd of some drugs, however, is not fully explained by changes in plasma volume, and the rapid decrease in Vd observed for drugs such as propranolol has been attributed to other factors, such as increased entry of the drug into the bloodstream after the drug is displaced from extravascular binding sites.[34] Regardless of the exact mechanism, exercise can cause a relative increase in intravascular concentration of certain drugs, as evidenced by a decrease in the Vd of these agents.

Conversely, Vd may increase for some drugs during exercise, indicating that more of the drug is drawn out of the bloodstream and into extravascular tissues. The most common example is digoxin, which binds to the cell membrane of skeletal muscle.[35,36] Exercise appears to increase the affinity of skeletal muscle binding sites for digoxin, thus causing plasma digoxin concentration to decrease and muscle concentration to increase.[35,37]

Volume of distribution for a given drug can increase or decrease, depending on a number of factors such as the binding properties of the drug and concomitant changes in other pharmacokinetic variables during exercise. The intensity and duration of the exercise bout are also factors that can influence Vd, as evidenced by the fact that the Vd for propranolol and verapamil was not altered during prolonged (7-hour), intermittent submaximal exercise.[38,39]

If Vd does change during exercise, the clinical implications of these changes are often unclear. A decrease in the Vd could mean that more drug is being sequestered in the bloodstream and less drug is available to reach extravascular target tissues. Aspirin and similar nonsteroidal anti-inflammatory drugs, for instance, would be less effective if they are retained excessively in the vascular compartment and are not able to reach peripheral tissues such as an arthritic joint. Conversely, an increase in Vd could mean that drugs reach the peripheral tissues more extensively than expected, and this fact could precipitate adverse effects if drug concentrations at the target tissues are excessively high. Increased digoxin concentrations could reach the myocardium, for example, thus increasing the possibility of cardiotoxic effects. Thus, exercise clearly can affect the distribution of certain medications, but it remains to be seen whether these particular pharmacokinetic changes ultimately cause clinical problems.

Effect of Exercise on Drug Clearance

Exercise produces transient changes in liver function that could potentially alter hepatic drug clearance. Hepatic blood flow decreases progressively as exercise intensity increases, with hepatic perfusion being reduced by as much as 50% when exercise intensity approaches 70% of maximal oxygen uptake.[9] A decrease in hepatic perfusion during exercise can potentially decrease the clearance of drugs that are metabolized in the liver, especially high-extraction drugs.[8] Recall that metabolism of high-extraction drugs is essentially dependent on delivery of the drug via the bloodstream; hence, clearance of these drugs should be decreased if hepatic perfusion decreases during exercise. Low-extraction drugs will probably not be affected as greatly during exercise because clearance of these drugs is dependent on the metabolic capacity of the liver rather than on hepatic blood flow.[8]

Given the rather pronounced effect of exercise on hepatic perfusion, exercise should produce predictable declines in the clearance of drugs that undergo extensive hepatic metabolism. Only a limited number of studies have investigated this phenomenon, however, and these studies have generally failed to discern any dramatic reduction in hepatic clearance even with high-extraction drugs such as verapamil and propranolol.[38,39] It is not clear how hepatic clearance can remain unchanged during exercise, although a decrease in hepatic clearance may be masked during exercise by other factors such as increased nonhepatic clearance and changes in other pharmacokinetic variables (absorption and distribution). Nonetheless, additional research is needed to determine conclusively whether exercise produces changes in the hepatic clearance of various medications, especially high-extraction drugs.

The kidney also undergoes transient changes during exercise that can affect drug clearance. Renal blood flow and glomerular filtration rate decrease by as much as 65% and 30%, respectively, at higher exercise intensities.[40-42] Clearance of drugs that undergo flow-dependent elimination by the kidneys (high-extraction drugs), therefore, can be decreased during exercise because less of the drug is reaching the nephron.[6] Other changes in renal function, including decreased secretion of drugs into the renal tubule and increased reabsorption of acidic drugs from the tubule, can contribute to an exercise-induced decrease in renal drug clearance.[6]

A limited number of studies have investigated the effects of exercise on renal drug clearance, and these studies have typically shown reductions in renal clearance ranging from 8% to 84% depending on the particular drug and the mode and intensity of the exercise bout.[43-45] Thus, an exercise-induced decrease in renal elimination seems fairly predictable and consistent with what would be expected considering the changes in renal hemodynamics and filtration that are known to occur during exercise. Still, additional research is needed to determine the extent that these decreases in renal drug clearance can cause subsequent alterations in the clinical response to specific drugs.

Summary of Exercise Effects

Exercise produces complex changes in the pharmacokinetics of certain drugs, which can alter the amount of drug reaching the target tissue and thus alter the patient's response to the medication. These changes, however, are highly variable, depending on factors such as the chemical properties of each drug; the route of drug administration; and the intensity, duration, and mode of the exercise bout. It is difficult, therefore, to make general statements about how an exercise bout will influence the disposition and subsequent clinical response to various types of drugs. An exception, perhaps, is the fact that absorption and bioavailability of drugs administered by local injection (intramuscular, intravenous) or by local transdermal application (patches, iontophoresis/ phonophoresis) will typically be increased if the site of administration is actively involved in the exercise bout. Nonetheless, the potential pharmacokinetic changes that can occur with all drugs should be considered if any variation in the clinical response is noticed during or after an exercise bout.

Effects of Physical Agents on Pharmacokinetics

Various physical agents have the potential to modify the pharmacokinetics of systemically administered drugs by affecting factors such as local blood flow and tissue metabolic activity. Thermal agents that increase regional blood flow can potentially increase delivery of a drug to a specific tissue site (tendon, muscle, bursa, and so on). Conversely, cold can restrict drug delivery by causing vasoconstriction at the cryotherapy site. Although drug delivery can theoretically be altered by thermal agents, there are few studies that have documented whether these changes have any clinical relevance. Still, heating and cooling agents have been shown to produce changes in local blood flow, and it seems reasonable to assume that delivery of systemically administered drugs to the tissues treated with thermal agents will be increased or decreased by regional vasodilation or vasoconstriction, respectively.

Thermal agents may also have an effect on drugs that are administered locally by intramuscular or subcutaneous injection. Application of local heat to the site of drug administration will almost certainly increase dispersion of the drug away from the delivery site, This increased dispersion may cause untoward effects because the drug is delivered too rapidly into the systemic circulation and the plasma concentration increases more rapidly than would occur without heating. Application of heat over the site of subcutaneous insulin injection, for example, would accelerate absorption into the bloodstream, thus potentially causing excessive insulin effects and hypoglycemia. Application of heat over the site of these types of injection should probably be avoided, although there are really no definitive research studies that support this belief.

Locally applied heat and cold also have the potential to alter transdermal drug kinetics, but these effects are poorly understood. it has been shown that systemic absorption of iontophoretically administered drugs can be increased or decreased in the presence of drugs that produce local vasodilation or vasoconstriction, respectively.[46] It seems reasonable, therefore, that thermal agents that produce similar vasoactive effects will also influence absorption of drugs applied by iontophoresis or phonophoresis. Application of local heat, for instance, could be used to intentionally increase the systemic absorption of locally applied drugs if the desired effect is to increase the systemic bioavailability of these medications.

Anecdotal reports have also suggested that applying heat after iontophoresis or phonophoresis may be beneficial because the drug will be dispersed more readily within the subcutaneous tissues due to increased local blood flow. This rationale seems questionable, however, if the goal of transdermal application is to focus the drug to a specific subcutaneous tissue or structure. Increasing local tissue perfusion would cause a washout of the drug from the administration site, thus negating the benefit of local transdermal delivery. Again, there is no experimental research to document the positive or negative effects of local heat following transdermal delivery, but the potential washout effect should certainly be considered if local heat is applied directly after transdermal delivery.

The effects of other physical agents such as electrotherapeutic devices on pharmacokinetics are not known. Certain types of electrical stimulation of skeletal muscle will increase local heat and blood flow, and this effect can potentially increase drug delivery to the stimulated muscle. Again, it is not known whether this effect is sufficient to cause a meaningful increase in local drug delivery. Conversely, a washout effect may be caused if the stimulated muscle was used as a site for depot injection of a slow-release drug formulation, and stimulation of the injected muscle should probably be avoided.

Effects of Manual Techniques on Pharmacokinetics

Manual techniques, including massage, can increase drug absorption from local subcutaneous injection sites. This effect has been documented with insulin absorption, where external massage has been shown to increase the disappearance of insulin from the injection site and thus increase plasma insulin concentration.[47] Interestingly, this effect has been observed in the absence of any simultaneous increase in subcutaneous blood flow, suggesting that massage increases insulin absorption through some type of mechanical effect on local tissues.[48] The increased absorption produced by massage can have clinical implications if plasma drug levels are increased to the point where untoward effects (eg, hypoglycemia) begin to occur.

The effect of massage on delivery of systemically administered drugs to local tissues is not known. Massage could conceivably increase drug delivery to the massaged tissues by increasing local blood flow or by some type of mechanical "milking" effect. The extent to which massage can increase delivery to specific tissues and whether this has any clinical relevance is unclear.

Summary

Pharmacokinetics involves the processes that affect drug disposition within the body. Certain pharmacokinetic variables such as bioavailability, Vd, and clearance must be known to estimate the proper dosing regimen that will enable a drug to reach its target tissue at an appropriate therapeutic concentration. Certain physical therapy interventions have the potential to produce transient changes in the pharmacokinetic profile of certain drugs so that the clinical response to the drug is altered. In particular, exercise, thermal agents, and massage can affect the disposition of certain agents by altering one or more pharmacokinetic variables. This seems especially true for drugs that are administered locally by transdermal techniques or by subcutaneous or intramuscular injection. Exercise, local heat, or massage of the administration site can potentially increase absorption of a drug, causing a relative increase in systemic bioavailability. This increased bioavailability can increase the incidence of side effects, because the plasma concentrations may increase more quickly and to a greater extent than expected.

Clinicians, therefore, should be aware of the need to modify certain treatments so that the effect on local drug absorption, distribution, and metabolism is minimized. Likewise, exercise and other physical therapy intervention can cause physiological changes that could alter the disposition of systemically administered drugs, and the possibility that these interventions may have an impact on pharmacokinetics should always be considered when a patient exhibits any untoward drug response.

References

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CD Ciccone, PhD, PT, is Associate Professor, Department of Physical Therapy, School of Health Science and Human Performance, Ithaca College, Ithaca, NY,