Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Pharmacokinetic Mechanisms of Drug Interactions Donald S. Robinson To cite this article: Donald S. Robinson (1975) Pharmacokinetic Mechanisms of Drug Interactions, Postgraduate Medicine, 57:2, 55-62, DOI: 10.1080/00325481.1975.11713963 To link to this article: http://dx.doi.org/10.1080/00325481.1975.11713963
Published online: 07 Jul 2016.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Australian Catholic University]
Date: 22 August 2017, At: 05:10
DONALD S. ROBINSON, MD
Downloaded by [Australian Catholic University] at 05:10 22 August 2017
University of Vermont College of Medicine Burlington
Pharmacokinetic Mechanisms of Drug Interactions Every physician has a responsibility to become familiar with certain fundamental principles of drug interaction. The administration of several drugs to a patient is frequently medically justifiable, but evidence suggests that often the number of drugs a patient receives far exceeds the optimal. This situation arises in part from a failure to recognize or appreciate the untoward effects of drugs, both singly and in combination. Studies 1 •2 have shown that the probability of an adverse drug reaction is directly proportional to the number of drugs a patient is receiving. Therefore, every effort should be made to limit the number of drugs prescribed and, when more than one drug is indicated, to guard against interactions. Knowledge of certain pharmacokinetic principles3-5 enables the physician to anticipate and prevent undesired interactions without resort purely to memory or cumbersome drug lists. Behavior of any drug within the body is governed by the same basic pharmacokinetic steps: ( 1) absorption, usually from the gastrointestinal
Vol. 57 • No. 2 • February 1975 • POSTGRADUATE MEDICINE
Physicians can predict the way in which many drugs will interact if they differentiate between acidic and basic drugs and learn a few pharmacokinetic processes common to all drugs. This will enable them not only to anticipate serious and life-threatening reactions but also to maximize the beneficial effects of multiple-drug therapy. tract, (2) distribution, mainly via the bloodstream, (3) metabolism, usually in liver but in some cases in other organs, and (4) excretion, usually by the kidneys but sometimes via the biliary tract or other routes (figure 1). While the drug is undergoing these processes, some fraction of it is reaching receptor sites in the target organ as well. Here the pharmacologic effect often results from conformation of drug molecule to macromolecular receptor site, with the intensity of response proportional to drug concentration. Many drug interactions resulting from competition between two or more drugs during the pharmacokinetic processes are predictable. Drug interactions can also occur at the receptor site level, but knowledge of pharmacokinetic properties of drugs is less useful in predicting such interactions because of their diversity. Ionization of Drug Molecules
Drug molecules holding a positive or negative electrical charge (polar, or ionized) behave
55
Downloaded by [Australian Catholic University] at 05:10 22 August 2017
differently from uncharged drug molecules (nonpolar, or nonionized). Since most drugs are either weak acids or weak bases, in solution they may ionize, depending on the pH of the fluid or tissue. Weak acids tend to dissociate at an alkaline pH, so that the drug becomes anionic (negatively charged) (figure 2)_ Weak-acid drugs are often predominantly polar in the slightly alkaline environment of plasma or small bowel, whereas in the acidic environment of stomach or urine, they tend to be nonpolar. The reverse is true for weak-base drugs. The ability of lipid-soluble weak acids and bases to diffuse across membranes is governed by their state of ionization, since polar compounds cross cell membranes poorly. Thus, weak-acid drugs often are readily absorbed directly from the stomach, since they are nonpolar in the acidic gastric environment, whereas weak-base drugs are not significantly absorbed until they reach the alkaline environment of the small boweL Perhaps more important, the likelihood of drug interaction is greater if two concurrently administered drugs are both acids or both bases_ Table 1 categorizes some common drugs and drug classes as to their acidic or basic natures. Absorption
Figure 1. Pharmacokinetic processes governing drug interactions.
Drug type
Acid (low pH) medium
Alkaline (high pH) medium
Weak acid
R-COOH
R-cooO
Weak base
R-NH,O
R-NH,
+
H
Figure 2. The influence of pH on polarity (ionization) of weak-acid and weak-base drugs.
56
Since most drugs are administered orally, it is particularly important for the physician to be familiar with interactions in the gastrointestinal tract affecting absorption_ Drugs are best absorbed in their most lipid-soluble (nonpolar) state_ Many drugs are normally only partially absorbed because of bioavailability factors related to manufacturing methods, inherently low lipid solubility, high degree of ionization in the bowel, or tendency to bind to foods and other drugs. Drugs that are not completely absorbed are often especially susceptible to interactions within the bowel. Alterations in any of the bioavailability factors may cause an increase or decrease in the fraction of drug absorbed. For example, drugs affecting gastric and intestinal motility influence both retention time within the stomach and transit time through the small bowel, where the predominant part of drug absorption normally occurs because of the enormous surface area of the mucosa_ Thus, by in-
POSTGRADUATE MEDICINE • February 1975 • Vol. 57 • No. 2
Downloaded by [Australian Catholic University] at 05:10 22 August 2017
creasing gastric retention time, anticholinergic drugs could delay the onset of action of basic drugs, which are not absorbed significantly until they pass from the stomach into the small bowel. However, paradoxically, the longer intestinal transit time resulting from the anticholinergic effect could also result in a larger fraction of a given dose being ultimately absorbed. Significant alterations in digoxin absorption have been shown to occur with either propantheline (Pro-Banthine), an anticolinergic drug that decreases gastrointestinal motility and prolongs transit time, or metoclopramide (Sinemet•), a drug that increases motility. 6 The former can increase and the latter can decrease serum digoxin levels, presumably by changing the contact time within the bowel for digoxin, a drug that is not completely absorbed. A similar decrease in digoxin absorption might be anticipated with cathartics, laxatives, or cholinergic drugs such as bethanechol (Urecholine). Another mechanism of impaired drug absorption is physical or chemical bonding to foods or interacting drugs. For example, both iron and the penicillins bind significantly to food substances. To avoid binding, many drugs should be taken one hour before or three hours after a meal. Potent chelators such as the tetracycline antibiotics form insoluble complexes with divalent cations contained in iron and antacid preparations and in dairy products (calcium). Obviously, the concurrent administration of a third drug that alters gastrointestinal motility, such as an anticholinergic, could further complicate the picture by increasing the contact time for interfering foods and drugs. Drugs also can bind significantly to antacids and to kaolin products because the large surface areas of these substances favor nonspecific adsorption. Thus, antacids decrease the absorption of acidic drugs such as phenylbutazone (Butazolidin), nitrofurantoin (Furadantin), nalidixic acid (NegGram), certain sulfonamides, and the oral anticoagulant dicumaroP This may be due to the tendency of these drugs to be anionic in the alkaline environment of the small bowel, thereby favoring adsorption to suspensions such •Nor marketed in the United Stares.
Vol. 57 • No. 2 • February 1975 • POITIIRADUATI: MEDICINE
TABLE 1. COMMON ACIDIC AND BASIC DRUGS AND DRUG CLASSES Weak Acids
Weak Bases
Barbiturates
Opiates (codeine, etc)
Salicylates
Antihistamines
Penicillins and cephalosporins
Major tranqu i I izers (phenothiazines)
Anticoagulants (warfarin)
Tricyclic antidepressants (imipramine)
Phenylbutazone (Butazol id in) and oxyphenbutazone (Tandearil) Sulfonamides and derivatives (thiazide diuretics and sulfonylurea hypoglycemic agents)
Erythromycin Quinidine Amphetamines Guanethidine (lsmelin)
Diphenylhydantoin (Dilantin) Clofibrate (Atromid·S)
as antacids or kaolin. The absorption of the antibiotic lincomycin (Lincocin) is impaired by the concurrent ingestion of kaolin mixtures. 7 The phenothiazine tranquilizers, such as chlorpromazine (Thorazine), are also bound by antacid suspensions in the bowel and can lose their effectiveness with chronic antacid ingestion.8 In summary, both the speed of absorption and the amount of drug absorbed are influenced in part by the drug's state of ionization. Drugs that affect intestinal motility, alter gastric or intestinal pH, or have large surface areas available for adsorption have a potential for clinically significant interactions. Thus, the number of drugs administered orally to a patient should be kept to a minimum. Timing of doses in relation to meals and the schedule for other drugs always should be considered and appropriate precautions taken. Distribution and Transport
Drug interaction related to drug distribution results from competition for plasma-proteinbinding sites. Most drugs are reversibly bound
57
Downloaded by [Australian Catholic University] at 05:10 22 August 2017
Figure 3. Drug distribution by transport in blood bound to plasma albumin. Bound fraction is inactive reservoir of drug.
Figure 4. Competition for protein-binding sites. Drug 8, with higher binding affinity, tends to displace drug A at shared binding sites, resulting in 3% absolute but 100% relative increase in concentration of free (active) form of drug A.
Figure 5. Some commonly used acidic drugs whose potentiation by another drug with high affinity may produce toxic effects.
Figure&. Hepatic drug metabolism. Drug molecules become more polar, favoring urinary excretion.
58
POSTGRADUATE MEDICINE • February 1975 • Vol. 57 • No. 2
Downloaded by [Australian Catholic University] at 05:10 22 August 2017
to plasma albumin to varying degrees (figure 3). Molecules of two different drugs, especially those bearing a similar electrical charge, can compete for shared binding sites. The fraction of bound drug is pharmacologically inactive, serving as a reservoir of drug, while the unbound fraction of drug is free to diffuse throughout the tissues and to exert its pharmacologic effect. Since drugs have varying affinities for these shared binding sites, one drug may tend to displace another with a lower affinity, thereby increasing the free (unbound) fraction and potentiating the pharmacologic effect of the second drug. Thus, the concentration of the active form of a drug may be doubled by as small an absolute change as 3% in binding equilibrium (figure 4). Since acidic drugs tend to be anionic in the alkaline environment of plasma, they compete for common binding sites on plasma protein. Figure 5 lists some clinically important acidic drugs that have been shown to interact. Of these, the sulfonylurea hypoglycemic agents and oral anticoagulants have the most serious potentiating interactions with other drugs. I recently observed a prolonged hypoglycemic reaction with coma (blood sugar
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Pharmacokinetic Mechanisms of Drug Interactions Donald S. Robinson To cite this article: Donald S. Robinson (1975) Pharmacokinetic Mechanisms of Drug Interactions, Postgraduate Medicine, 57:2, 55-62, DOI: 10.1080/00325481.1975.11713963 To link to this article: http://dx.doi.org/10.1080/00325481.1975.11713963
Published online: 07 Jul 2016.
Submit your article to this journal
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Australian Catholic University]
Date: 22 August 2017, At: 05:10
DONALD S. ROBINSON, MD
Downloaded by [Australian Catholic University] at 05:10 22 August 2017
University of Vermont College of Medicine Burlington
Pharmacokinetic Mechanisms of Drug Interactions Every physician has a responsibility to become familiar with certain fundamental principles of drug interaction. The administration of several drugs to a patient is frequently medically justifiable, but evidence suggests that often the number of drugs a patient receives far exceeds the optimal. This situation arises in part from a failure to recognize or appreciate the untoward effects of drugs, both singly and in combination. Studies 1 •2 have shown that the probability of an adverse drug reaction is directly proportional to the number of drugs a patient is receiving. Therefore, every effort should be made to limit the number of drugs prescribed and, when more than one drug is indicated, to guard against interactions. Knowledge of certain pharmacokinetic principles3-5 enables the physician to anticipate and prevent undesired interactions without resort purely to memory or cumbersome drug lists. Behavior of any drug within the body is governed by the same basic pharmacokinetic steps: ( 1) absorption, usually from the gastrointestinal
Vol. 57 • No. 2 • February 1975 • POSTGRADUATE MEDICINE
Physicians can predict the way in which many drugs will interact if they differentiate between acidic and basic drugs and learn a few pharmacokinetic processes common to all drugs. This will enable them not only to anticipate serious and life-threatening reactions but also to maximize the beneficial effects of multiple-drug therapy. tract, (2) distribution, mainly via the bloodstream, (3) metabolism, usually in liver but in some cases in other organs, and (4) excretion, usually by the kidneys but sometimes via the biliary tract or other routes (figure 1). While the drug is undergoing these processes, some fraction of it is reaching receptor sites in the target organ as well. Here the pharmacologic effect often results from conformation of drug molecule to macromolecular receptor site, with the intensity of response proportional to drug concentration. Many drug interactions resulting from competition between two or more drugs during the pharmacokinetic processes are predictable. Drug interactions can also occur at the receptor site level, but knowledge of pharmacokinetic properties of drugs is less useful in predicting such interactions because of their diversity. Ionization of Drug Molecules
Drug molecules holding a positive or negative electrical charge (polar, or ionized) behave
55
Downloaded by [Australian Catholic University] at 05:10 22 August 2017
differently from uncharged drug molecules (nonpolar, or nonionized). Since most drugs are either weak acids or weak bases, in solution they may ionize, depending on the pH of the fluid or tissue. Weak acids tend to dissociate at an alkaline pH, so that the drug becomes anionic (negatively charged) (figure 2)_ Weak-acid drugs are often predominantly polar in the slightly alkaline environment of plasma or small bowel, whereas in the acidic environment of stomach or urine, they tend to be nonpolar. The reverse is true for weak-base drugs. The ability of lipid-soluble weak acids and bases to diffuse across membranes is governed by their state of ionization, since polar compounds cross cell membranes poorly. Thus, weak-acid drugs often are readily absorbed directly from the stomach, since they are nonpolar in the acidic gastric environment, whereas weak-base drugs are not significantly absorbed until they reach the alkaline environment of the small boweL Perhaps more important, the likelihood of drug interaction is greater if two concurrently administered drugs are both acids or both bases_ Table 1 categorizes some common drugs and drug classes as to their acidic or basic natures. Absorption
Figure 1. Pharmacokinetic processes governing drug interactions.
Drug type
Acid (low pH) medium
Alkaline (high pH) medium
Weak acid
R-COOH
R-cooO
Weak base
R-NH,O
R-NH,
+
H
Figure 2. The influence of pH on polarity (ionization) of weak-acid and weak-base drugs.
56
Since most drugs are administered orally, it is particularly important for the physician to be familiar with interactions in the gastrointestinal tract affecting absorption_ Drugs are best absorbed in their most lipid-soluble (nonpolar) state_ Many drugs are normally only partially absorbed because of bioavailability factors related to manufacturing methods, inherently low lipid solubility, high degree of ionization in the bowel, or tendency to bind to foods and other drugs. Drugs that are not completely absorbed are often especially susceptible to interactions within the bowel. Alterations in any of the bioavailability factors may cause an increase or decrease in the fraction of drug absorbed. For example, drugs affecting gastric and intestinal motility influence both retention time within the stomach and transit time through the small bowel, where the predominant part of drug absorption normally occurs because of the enormous surface area of the mucosa_ Thus, by in-
POSTGRADUATE MEDICINE • February 1975 • Vol. 57 • No. 2
Downloaded by [Australian Catholic University] at 05:10 22 August 2017
creasing gastric retention time, anticholinergic drugs could delay the onset of action of basic drugs, which are not absorbed significantly until they pass from the stomach into the small bowel. However, paradoxically, the longer intestinal transit time resulting from the anticholinergic effect could also result in a larger fraction of a given dose being ultimately absorbed. Significant alterations in digoxin absorption have been shown to occur with either propantheline (Pro-Banthine), an anticolinergic drug that decreases gastrointestinal motility and prolongs transit time, or metoclopramide (Sinemet•), a drug that increases motility. 6 The former can increase and the latter can decrease serum digoxin levels, presumably by changing the contact time within the bowel for digoxin, a drug that is not completely absorbed. A similar decrease in digoxin absorption might be anticipated with cathartics, laxatives, or cholinergic drugs such as bethanechol (Urecholine). Another mechanism of impaired drug absorption is physical or chemical bonding to foods or interacting drugs. For example, both iron and the penicillins bind significantly to food substances. To avoid binding, many drugs should be taken one hour before or three hours after a meal. Potent chelators such as the tetracycline antibiotics form insoluble complexes with divalent cations contained in iron and antacid preparations and in dairy products (calcium). Obviously, the concurrent administration of a third drug that alters gastrointestinal motility, such as an anticholinergic, could further complicate the picture by increasing the contact time for interfering foods and drugs. Drugs also can bind significantly to antacids and to kaolin products because the large surface areas of these substances favor nonspecific adsorption. Thus, antacids decrease the absorption of acidic drugs such as phenylbutazone (Butazolidin), nitrofurantoin (Furadantin), nalidixic acid (NegGram), certain sulfonamides, and the oral anticoagulant dicumaroP This may be due to the tendency of these drugs to be anionic in the alkaline environment of the small bowel, thereby favoring adsorption to suspensions such •Nor marketed in the United Stares.
Vol. 57 • No. 2 • February 1975 • POITIIRADUATI: MEDICINE
TABLE 1. COMMON ACIDIC AND BASIC DRUGS AND DRUG CLASSES Weak Acids
Weak Bases
Barbiturates
Opiates (codeine, etc)
Salicylates
Antihistamines
Penicillins and cephalosporins
Major tranqu i I izers (phenothiazines)
Anticoagulants (warfarin)
Tricyclic antidepressants (imipramine)
Phenylbutazone (Butazol id in) and oxyphenbutazone (Tandearil) Sulfonamides and derivatives (thiazide diuretics and sulfonylurea hypoglycemic agents)
Erythromycin Quinidine Amphetamines Guanethidine (lsmelin)
Diphenylhydantoin (Dilantin) Clofibrate (Atromid·S)
as antacids or kaolin. The absorption of the antibiotic lincomycin (Lincocin) is impaired by the concurrent ingestion of kaolin mixtures. 7 The phenothiazine tranquilizers, such as chlorpromazine (Thorazine), are also bound by antacid suspensions in the bowel and can lose their effectiveness with chronic antacid ingestion.8 In summary, both the speed of absorption and the amount of drug absorbed are influenced in part by the drug's state of ionization. Drugs that affect intestinal motility, alter gastric or intestinal pH, or have large surface areas available for adsorption have a potential for clinically significant interactions. Thus, the number of drugs administered orally to a patient should be kept to a minimum. Timing of doses in relation to meals and the schedule for other drugs always should be considered and appropriate precautions taken. Distribution and Transport
Drug interaction related to drug distribution results from competition for plasma-proteinbinding sites. Most drugs are reversibly bound
57
Downloaded by [Australian Catholic University] at 05:10 22 August 2017
Figure 3. Drug distribution by transport in blood bound to plasma albumin. Bound fraction is inactive reservoir of drug.
Figure 4. Competition for protein-binding sites. Drug 8, with higher binding affinity, tends to displace drug A at shared binding sites, resulting in 3% absolute but 100% relative increase in concentration of free (active) form of drug A.
Figure 5. Some commonly used acidic drugs whose potentiation by another drug with high affinity may produce toxic effects.
Figure&. Hepatic drug metabolism. Drug molecules become more polar, favoring urinary excretion.
58
POSTGRADUATE MEDICINE • February 1975 • Vol. 57 • No. 2
Downloaded by [Australian Catholic University] at 05:10 22 August 2017
to plasma albumin to varying degrees (figure 3). Molecules of two different drugs, especially those bearing a similar electrical charge, can compete for shared binding sites. The fraction of bound drug is pharmacologically inactive, serving as a reservoir of drug, while the unbound fraction of drug is free to diffuse throughout the tissues and to exert its pharmacologic effect. Since drugs have varying affinities for these shared binding sites, one drug may tend to displace another with a lower affinity, thereby increasing the free (unbound) fraction and potentiating the pharmacologic effect of the second drug. Thus, the concentration of the active form of a drug may be doubled by as small an absolute change as 3% in binding equilibrium (figure 4). Since acidic drugs tend to be anionic in the alkaline environment of plasma, they compete for common binding sites on plasma protein. Figure 5 lists some clinically important acidic drugs that have been shown to interact. Of these, the sulfonylurea hypoglycemic agents and oral anticoagulants have the most serious potentiating interactions with other drugs. I recently observed a prolonged hypoglycemic reaction with coma (blood sugar
