CLINICAL PHARMACOI,OGY and
THERAPEU'l'ICS volume 26
number 5
November, 1979
Commentaries How much is enough?
Jean Sice, Ph.D. Denver, Colo,
, , . improper dosage with the proper drug is probably as commoll a calise ofIailure ill (hemp), as the lise o{ all improper drug. e
A distinguished clinician, when recently asked to elaborate on this quotation, offered some provocative comments. First, he said, this statement either has not received the attention that it deserves, or those who recognize its importance do not know what to do about it. Second, he added, improper dosages have probably become a far greater cause of error in therapy than is the prescription of inappropriate drugs. But in all fairness, he concluded, let us not forget that determining the dose required by a particular patient is more difficult than selecting the drug indicated in the treatment of his illness. After all, he remarked, we now have several authoritative compendia that list the drug or drugs known to be the most effective against all types of diseases. But few of these texts go beyond recommending ranges of doses which often are so wide that one does not know where to start and where to stop. Reprint requests to: Dr. Jean Sice, 866 Adams, Denver, CO 80206.
Before these opmlOns are accepted or rejected, their reliability should be examined. Unfortunately, such a test could present formidable problems of data collection. Few investigators of drug reactions, for instance, have tried to establish causal relationships between adverse effects and dosages, although most have been able to identify the drugs which elicited these effects. An outstanding exception is that of the Veterans Administration Cooperative Urological Research Group which was able to relate, in men treated for prostatic carcinoma, the incidence of cardiovascular complications with estrogen dosage.' Circumstantial evidence, however, can be adduced in support of the epigraph. Casual observation of prescribing practices reveals that some physicians seldom adjust dosages. This practice has been verified with the administration of a fixed 0.25 mg dose of digoxin daily to all patients. 3 Others use dosages which, for no apparent reason, are beneath recommended ranges for adults, such as 25 mg imipramine daily in endogenous depression, or
0009-9236/79/110537+03$00.30/0 © 1979 The C. V. Mosby Co.
537
538
Sid
2 gm sulfisoxazole daily for eradication of urinary infections. Similar dose-shy prescriptions are not uncommon in the management of essential hypertension; in such cases, however, practitioners usually order excessively low doses of two or more drugs although the desired response can be obtained with a moderate dose of a single product. The same phenomenon has been observed in several efficacy trials, the protocols of which specified that dosages should be adjusted according to the therapeutic results. Few clinicians, and often none, ordered the highest allowable doses of investigational drugs, even though full therapeutic responses were not secured. Such prudence, incidentally, could not always have been due to manifestations of adverse effects, because the same investigators also did not advance placebos to the highest allowed levels. It is of some interest to note that dosage problems are seldom encountered with anesthetists. To them, the proposition of giving fixed amounts of thiopental, curare, or gas would be ludicrous. Perhaps the major reason for that remarkable exception is that anesthetists immediately and continuously monitor the effects of their pharmacologic interventions, because they must induce effects precisely. Although their position certainly gives them an advantage that few other clinicians can experience, when it comes to controlling patients responses their operational principle in this respect represents a model of effective drug use. Informal discussions of the reason for excessively low dosages with their prescribers suggest that these clinicians would rather risk incomplete therapeutic successes than adverse reactions. They feel that in the present safetyconscious climate, errors of omission are more acceptable than errors of commission. This reasoning, however, overlooks the fact that a number of drug reactions are not dose dependent. It also implies the questionable belief that administration of small doses of several drugs is safer than giving adequate doses of a single product. Low dosage prescribers might thus be overreacting to the flood of warnings against the potential adverse effects of almost any medication. But in doing so they obey an indiscriminate fear, whereas they should selectively avoid
Clin. Pharmacal. Ther. November 1979
the particular hazards presented by certain therapeutic maneuvers. Adverse drug effects, after all, have many causes which can be classified, for the purpose of this discussion, into 6 broad categories. The first includes excessive doses, as was not uncommon with digitalis until recently, and as happened with phenylbutazone or hydralazine shortly after these drugs became available. The second includes excessive duration of administration; phenylbutazone again provides an example of a product which can be safely used for a short period, but can become dangerous if taken for too long a time. The third category includes the administration of improper drugs. This condition can have more complex consequences than the others because failure to treat the primary illness, or drug-induced aggravation of the disease, adds to the risk of adverse drug effects. Examples of such mistreatment are the administration of antibiotics in viral infections, of digitalis in myocarditis, or of analgesic doses of aspirin in gout. Wanton polypharmacy is probably responsible for a large number of adverse effects in this category. The fourth includes the use of drugs which are appropriate to an illness but improper for the patient because of certain genetic, anatomic, physiologic, immunologic, or pathologic characteristics, or previous adverse reactions to drugs of the same class. The fifth category includes the use of drugs which cause frequent anomalies, such as elevation of ANA titer with procainamide, or life-threatening reactions, as with chloramphenicol. The sixth includes all the rare or unexpected effects which can occur at any time in any patient, and often at any dose level, not to mention delayed, yet unknown effects, such as carcinogenicity. Of these 6 categories, only the first includes reactions that can be attributed to excessive doses. All the others, which now probably account for most drug reactions, are not. Routine administration of inadequate doses of the proper drugs, therefore, cannot correct the evils of all other therapeutic mishaps or errors, including polypharmacy, and might even do more harm than good. How can we solve the posology problem? Preclinical pharmacology can and must play an active role in this endeavor,4 but not be reviving
Volume 26 Number 5
rote memorization of dosages. Instead, students should be alerted to the fact that there is more to dose-response relationship than the hallowed semi logarithmic plot. The importance of dosage in therapeutic management should be stressed. Factors which affect drug efficacy and safety should be discussed in depth with characteristic examples, rather than just listed. The principle should be firmly established that monitoring drug actions is the keystone of sound therapeutic management. This over view should be reinforced during the study of drugs such as digoxin in tachyarrhythmias and congestive failure, and aspirin in analgesia, rheumatoid arthritis, and rheumatic fever, that call for different dosages in different conditions. Similarly, the study of antihypertensive agents could provide concrete examples of the need for dosage adjustment in the treatment of chronic diseases.
How much is enough?
539
These principles should be reiterated, and their application illustrated to students, interns, and physicians. The rationale and procedures for selecting initial dosage and adjusting maintenance doses should be discussed in specific cases. Techniques of monitoring drug responses should be demonstrated in hospitalized and ambulatory patients.
References I. Coune A: Carcinoma of the prostate, ill Staquet MJ, editor: Randomized trials in cancer, a critical review by sites. New York, 1978. Raven Press, Inc., pp. 389-409. 2. Dosage recommendations, ill AMA drug evaluations, ed. 3. Littleton, Mass, 1977, Publishing Sciences Group. pp. xxi-xxii. 3. Editorial: Digoxin, more problems than solutions. Lancet 2:1288-1290,1978. 4. Sice J: Objectives of pharmacological education. J Med Educ 50:773-778, 1975.
THERAPEU'l'ICS volume 26
number 5
November, 1979
Commentaries How much is enough?
Jean Sice, Ph.D. Denver, Colo,
, , . improper dosage with the proper drug is probably as commoll a calise ofIailure ill (hemp), as the lise o{ all improper drug. e
A distinguished clinician, when recently asked to elaborate on this quotation, offered some provocative comments. First, he said, this statement either has not received the attention that it deserves, or those who recognize its importance do not know what to do about it. Second, he added, improper dosages have probably become a far greater cause of error in therapy than is the prescription of inappropriate drugs. But in all fairness, he concluded, let us not forget that determining the dose required by a particular patient is more difficult than selecting the drug indicated in the treatment of his illness. After all, he remarked, we now have several authoritative compendia that list the drug or drugs known to be the most effective against all types of diseases. But few of these texts go beyond recommending ranges of doses which often are so wide that one does not know where to start and where to stop. Reprint requests to: Dr. Jean Sice, 866 Adams, Denver, CO 80206.
Before these opmlOns are accepted or rejected, their reliability should be examined. Unfortunately, such a test could present formidable problems of data collection. Few investigators of drug reactions, for instance, have tried to establish causal relationships between adverse effects and dosages, although most have been able to identify the drugs which elicited these effects. An outstanding exception is that of the Veterans Administration Cooperative Urological Research Group which was able to relate, in men treated for prostatic carcinoma, the incidence of cardiovascular complications with estrogen dosage.' Circumstantial evidence, however, can be adduced in support of the epigraph. Casual observation of prescribing practices reveals that some physicians seldom adjust dosages. This practice has been verified with the administration of a fixed 0.25 mg dose of digoxin daily to all patients. 3 Others use dosages which, for no apparent reason, are beneath recommended ranges for adults, such as 25 mg imipramine daily in endogenous depression, or
0009-9236/79/110537+03$00.30/0 © 1979 The C. V. Mosby Co.
537
538
Sid
2 gm sulfisoxazole daily for eradication of urinary infections. Similar dose-shy prescriptions are not uncommon in the management of essential hypertension; in such cases, however, practitioners usually order excessively low doses of two or more drugs although the desired response can be obtained with a moderate dose of a single product. The same phenomenon has been observed in several efficacy trials, the protocols of which specified that dosages should be adjusted according to the therapeutic results. Few clinicians, and often none, ordered the highest allowable doses of investigational drugs, even though full therapeutic responses were not secured. Such prudence, incidentally, could not always have been due to manifestations of adverse effects, because the same investigators also did not advance placebos to the highest allowed levels. It is of some interest to note that dosage problems are seldom encountered with anesthetists. To them, the proposition of giving fixed amounts of thiopental, curare, or gas would be ludicrous. Perhaps the major reason for that remarkable exception is that anesthetists immediately and continuously monitor the effects of their pharmacologic interventions, because they must induce effects precisely. Although their position certainly gives them an advantage that few other clinicians can experience, when it comes to controlling patients responses their operational principle in this respect represents a model of effective drug use. Informal discussions of the reason for excessively low dosages with their prescribers suggest that these clinicians would rather risk incomplete therapeutic successes than adverse reactions. They feel that in the present safetyconscious climate, errors of omission are more acceptable than errors of commission. This reasoning, however, overlooks the fact that a number of drug reactions are not dose dependent. It also implies the questionable belief that administration of small doses of several drugs is safer than giving adequate doses of a single product. Low dosage prescribers might thus be overreacting to the flood of warnings against the potential adverse effects of almost any medication. But in doing so they obey an indiscriminate fear, whereas they should selectively avoid
Clin. Pharmacal. Ther. November 1979
the particular hazards presented by certain therapeutic maneuvers. Adverse drug effects, after all, have many causes which can be classified, for the purpose of this discussion, into 6 broad categories. The first includes excessive doses, as was not uncommon with digitalis until recently, and as happened with phenylbutazone or hydralazine shortly after these drugs became available. The second includes excessive duration of administration; phenylbutazone again provides an example of a product which can be safely used for a short period, but can become dangerous if taken for too long a time. The third category includes the administration of improper drugs. This condition can have more complex consequences than the others because failure to treat the primary illness, or drug-induced aggravation of the disease, adds to the risk of adverse drug effects. Examples of such mistreatment are the administration of antibiotics in viral infections, of digitalis in myocarditis, or of analgesic doses of aspirin in gout. Wanton polypharmacy is probably responsible for a large number of adverse effects in this category. The fourth includes the use of drugs which are appropriate to an illness but improper for the patient because of certain genetic, anatomic, physiologic, immunologic, or pathologic characteristics, or previous adverse reactions to drugs of the same class. The fifth category includes the use of drugs which cause frequent anomalies, such as elevation of ANA titer with procainamide, or life-threatening reactions, as with chloramphenicol. The sixth includes all the rare or unexpected effects which can occur at any time in any patient, and often at any dose level, not to mention delayed, yet unknown effects, such as carcinogenicity. Of these 6 categories, only the first includes reactions that can be attributed to excessive doses. All the others, which now probably account for most drug reactions, are not. Routine administration of inadequate doses of the proper drugs, therefore, cannot correct the evils of all other therapeutic mishaps or errors, including polypharmacy, and might even do more harm than good. How can we solve the posology problem? Preclinical pharmacology can and must play an active role in this endeavor,4 but not be reviving
Volume 26 Number 5
rote memorization of dosages. Instead, students should be alerted to the fact that there is more to dose-response relationship than the hallowed semi logarithmic plot. The importance of dosage in therapeutic management should be stressed. Factors which affect drug efficacy and safety should be discussed in depth with characteristic examples, rather than just listed. The principle should be firmly established that monitoring drug actions is the keystone of sound therapeutic management. This over view should be reinforced during the study of drugs such as digoxin in tachyarrhythmias and congestive failure, and aspirin in analgesia, rheumatoid arthritis, and rheumatic fever, that call for different dosages in different conditions. Similarly, the study of antihypertensive agents could provide concrete examples of the need for dosage adjustment in the treatment of chronic diseases.
How much is enough?
539
These principles should be reiterated, and their application illustrated to students, interns, and physicians. The rationale and procedures for selecting initial dosage and adjusting maintenance doses should be discussed in specific cases. Techniques of monitoring drug responses should be demonstrated in hospitalized and ambulatory patients.
References I. Coune A: Carcinoma of the prostate, ill Staquet MJ, editor: Randomized trials in cancer, a critical review by sites. New York, 1978. Raven Press, Inc., pp. 389-409. 2. Dosage recommendations, ill AMA drug evaluations, ed. 3. Littleton, Mass, 1977, Publishing Sciences Group. pp. xxi-xxii. 3. Editorial: Digoxin, more problems than solutions. Lancet 2:1288-1290,1978. 4. Sice J: Objectives of pharmacological education. J Med Educ 50:773-778, 1975.
