Clin Biochem, Vol. 23, pp. 73-77, 1990 Printed in Canada. All rights reserved.
0009-9120/90 $3.00 + .00 Copyright c 1990 The Canadian SOciety of Clinical Chemists.
Toxic Risks of Inappropriate Therapy M. J. STEWART Drug Investigation Unit, Institute of Biochemistry, Royal Infirmary, Glasgow G40SF, Scotland, UK Drug therapy may produce toxicity. Patient individuality or drug interactions account for many cases of poisoning, but other factors such as genetic predisposition, drug contamination or human e r r o r a r e also known causes. Examples of various types of drug poisoning a r e given, illustrating the role of the clinical chemist in minimizing or studying drug toxicity.
KEY WORDS: drug interactions; medication errors; poisoning.
Introduction ll drugs have some side effects some of which are minor while others lead to severe acute illness, permanent disability or death (1,2). Iatrogenic poisoning, the ill effects of drugs prescribed with good intent, has a long history (3). This review deals with those areas of drug toxicity to which the clinical chemist can contribute in diagnosis or prevention.
A
Patient individuality Drugs are usually prescribed to patients on a dose per weight basis, assuming a standard response. Statistically this means that 5% of patients will show toxicity if given the standard dose. The reasons for individual variability are many. Since most drugs are eliminated from the body by a combination of hepatic and renal clearance, patients with hepatic or renal disease require lower doses than the healthy. Similarly patients with low body weight, or with little fat, may have reduced volumes of distribution for some drugs, making them more susceptible to toxicity. Compared with young adults, the elderly and neonates may also show different rates of metabolism. The individualization of drug therapy presents a difficult problem (4). Some patients show an idiosyncratic reaction to drugs; penicillin allergy and many other anaphylactic reactions fall into this category (5). Halothane, for example, although tolerated by a large percentage of patients may be unacceptable to some (6). Correspondence: Dr. M. J. Stewart, Drug Investigation Unit, Institute of Biochemistry, Royal Infirmary, Glasgow G4 OSF, Scotland, UK. Manuscript received February 3, 1989; revised July 17, 1989; accepted July 31, 1989. CLINICAL BIOCHEMISTRY, VOLUME 23, FEBRUARY 1990
There are also genetic polymorphisms which predispose patients to toxicity with some drugs. Scoline may produce apnoea in some individuals with cholinesterase variants (7). Among a population, there are genetically determined fast and slow acetylators (8), and the phenotype may affect how the individual metabolizes drugs such as isoniazid.
Drug interactions Interactions between drugs are well documented, and may result from various causes, including interactions at absorption or receptor sites or within common metabolic pathways (9). An example of one drug affecting the metabolism of another is the inhibition of parahydroxylation of phenytoin by isoniazid. This generally occurs in those individuals who acetylate isoniazid slowly (10). Figure 1 shows changes in serum urea and phenytoin in a patient who was maintained on phenytoin. He developed tuberculosis and was prescribed isoniazid and paraaminosalicylate. The interaction between isoniazid and phenytoin led to a doubling of his plasma phenytoin concentration which resulted in severe toxicity with mental derangement. Although the phenytoin dose was then halved, the plasma concentration continued to rise. This was due not to drug interaction but dehydration resulting from hyperthermia and hyperventi!ation. The patient improved when both phenytoin and isoniazid were stopped.
Contaminated, outdated or incorrectly dispensed drugs The problem of contaminated drugs is illustrated by the case of parenteral albumin preparations in which the levels of aluminum were sufficiently high as to give rise to bone disease in some patients (11). Decomposition of a drug prior to its administration may produce toxic products. In our studies on methotrexate (MTX), a drug used for the treatment of Hodgkin's lymphoma and other cancers, we observed in three patients the presence in urine of deoxyaminopteroic acid (DAMPA), a derivative of MTX which is thought to be as toxic as the parent compound. Comparison of serum levels of 7-hydroxy MTX, the main metabotite of MTX, and of DAMPA showed significant differences (Figure 2). During the 6 h infusion the levels of MTX and DAMPA ran 73
STEWART
IsoniazidandPhenytoin slopped Phenytoin~ 50mgti~ / /
400'
380' 360' 340' 320' o
E
300 280 260 240 220
2OO 180 160 140 120 100 80 60 4O 2O 0
100
100
L.D. a g e 90
80
A .J
o E
':,=or Ph~.y,o!. I
1/ j,.1-/
\\\
70
X
60 E 50
4O 2
4
6
8
10
12
14
16
18
20
22
24
Time(Days) Figure 1--The course of serum phenytoin (e) and urea (©) concentrations in a patient taking both phenytoin and isoniazid. Dotted lines indicate the therapeutic range for phenytoin.
Errors in d o s a g e Errors in dosage may be caused by failure to identify the units in which drugs are dispensed. Hence errors of 10,000 and 1,000 fold occur when, for example, adult preparations are used for treatment of small babies, or preparations designed for intravenous use are used for intrathecal injections, e.g., methotrexate. In one series the antidote for paracetamol poisoning, N-acetylcysteine, was given at 10 times the correct dose to 20 patients, all of whom developed toxicity and two of whom died (14). Failure to recognise the wide range in bioavailability has led to toxicity, an example being a recent case in which an oral digoxin dose of 0.25 mg was given intravenously. Since the absorption of digoxin taken orally in tablet form is only 60-85% (15), the intravenous administration of the same dose led to severe toxicity. When drug levels are being monitored, it is a relatively simple matter to obtain an estimate of the dose actually given (Figure 3). Our laboratory detected a large increase in plasma netilmicin concentration in a patient after a stated dose of 50 mg. The
74
COURSE
2
A c, E z O I,< nlZ l.U
10
\ \ \
1
\ \ \ \
Z Q
k
X I--
\
0,1
\ \
\
0009-9120/90 $3.00 + .00 Copyright c 1990 The Canadian SOciety of Clinical Chemists.
Toxic Risks of Inappropriate Therapy M. J. STEWART Drug Investigation Unit, Institute of Biochemistry, Royal Infirmary, Glasgow G40SF, Scotland, UK Drug therapy may produce toxicity. Patient individuality or drug interactions account for many cases of poisoning, but other factors such as genetic predisposition, drug contamination or human e r r o r a r e also known causes. Examples of various types of drug poisoning a r e given, illustrating the role of the clinical chemist in minimizing or studying drug toxicity.
KEY WORDS: drug interactions; medication errors; poisoning.
Introduction ll drugs have some side effects some of which are minor while others lead to severe acute illness, permanent disability or death (1,2). Iatrogenic poisoning, the ill effects of drugs prescribed with good intent, has a long history (3). This review deals with those areas of drug toxicity to which the clinical chemist can contribute in diagnosis or prevention.
A
Patient individuality Drugs are usually prescribed to patients on a dose per weight basis, assuming a standard response. Statistically this means that 5% of patients will show toxicity if given the standard dose. The reasons for individual variability are many. Since most drugs are eliminated from the body by a combination of hepatic and renal clearance, patients with hepatic or renal disease require lower doses than the healthy. Similarly patients with low body weight, or with little fat, may have reduced volumes of distribution for some drugs, making them more susceptible to toxicity. Compared with young adults, the elderly and neonates may also show different rates of metabolism. The individualization of drug therapy presents a difficult problem (4). Some patients show an idiosyncratic reaction to drugs; penicillin allergy and many other anaphylactic reactions fall into this category (5). Halothane, for example, although tolerated by a large percentage of patients may be unacceptable to some (6). Correspondence: Dr. M. J. Stewart, Drug Investigation Unit, Institute of Biochemistry, Royal Infirmary, Glasgow G4 OSF, Scotland, UK. Manuscript received February 3, 1989; revised July 17, 1989; accepted July 31, 1989. CLINICAL BIOCHEMISTRY, VOLUME 23, FEBRUARY 1990
There are also genetic polymorphisms which predispose patients to toxicity with some drugs. Scoline may produce apnoea in some individuals with cholinesterase variants (7). Among a population, there are genetically determined fast and slow acetylators (8), and the phenotype may affect how the individual metabolizes drugs such as isoniazid.
Drug interactions Interactions between drugs are well documented, and may result from various causes, including interactions at absorption or receptor sites or within common metabolic pathways (9). An example of one drug affecting the metabolism of another is the inhibition of parahydroxylation of phenytoin by isoniazid. This generally occurs in those individuals who acetylate isoniazid slowly (10). Figure 1 shows changes in serum urea and phenytoin in a patient who was maintained on phenytoin. He developed tuberculosis and was prescribed isoniazid and paraaminosalicylate. The interaction between isoniazid and phenytoin led to a doubling of his plasma phenytoin concentration which resulted in severe toxicity with mental derangement. Although the phenytoin dose was then halved, the plasma concentration continued to rise. This was due not to drug interaction but dehydration resulting from hyperthermia and hyperventi!ation. The patient improved when both phenytoin and isoniazid were stopped.
Contaminated, outdated or incorrectly dispensed drugs The problem of contaminated drugs is illustrated by the case of parenteral albumin preparations in which the levels of aluminum were sufficiently high as to give rise to bone disease in some patients (11). Decomposition of a drug prior to its administration may produce toxic products. In our studies on methotrexate (MTX), a drug used for the treatment of Hodgkin's lymphoma and other cancers, we observed in three patients the presence in urine of deoxyaminopteroic acid (DAMPA), a derivative of MTX which is thought to be as toxic as the parent compound. Comparison of serum levels of 7-hydroxy MTX, the main metabotite of MTX, and of DAMPA showed significant differences (Figure 2). During the 6 h infusion the levels of MTX and DAMPA ran 73
STEWART
IsoniazidandPhenytoin slopped Phenytoin~ 50mgti~ / /
400'
380' 360' 340' 320' o
E
300 280 260 240 220
2OO 180 160 140 120 100 80 60 4O 2O 0
100
100
L.D. a g e 90
80
A .J
o E
':,=or Ph~.y,o!. I
1/ j,.1-/
\\\
70
X
60 E 50
4O 2
4
6
8
10
12
14
16
18
20
22
24
Time(Days) Figure 1--The course of serum phenytoin (e) and urea (©) concentrations in a patient taking both phenytoin and isoniazid. Dotted lines indicate the therapeutic range for phenytoin.
Errors in d o s a g e Errors in dosage may be caused by failure to identify the units in which drugs are dispensed. Hence errors of 10,000 and 1,000 fold occur when, for example, adult preparations are used for treatment of small babies, or preparations designed for intravenous use are used for intrathecal injections, e.g., methotrexate. In one series the antidote for paracetamol poisoning, N-acetylcysteine, was given at 10 times the correct dose to 20 patients, all of whom developed toxicity and two of whom died (14). Failure to recognise the wide range in bioavailability has led to toxicity, an example being a recent case in which an oral digoxin dose of 0.25 mg was given intravenously. Since the absorption of digoxin taken orally in tablet form is only 60-85% (15), the intravenous administration of the same dose led to severe toxicity. When drug levels are being monitored, it is a relatively simple matter to obtain an estimate of the dose actually given (Figure 3). Our laboratory detected a large increase in plasma netilmicin concentration in a patient after a stated dose of 50 mg. The
74
COURSE
2
A c, E z O I,< nlZ l.U
10
\ \ \
1
\ \ \ \
Z Q
k
X I--
\
0,1
\ \
\
