Drug Experience
Drug Safety 5 (6): 421-435, 1990 0114-5916/90/0011-0421/$07.50/0 © Adis International Limited All rights reserved. MEDT03318
Adverse Drug Reactions
An Overview of Special Considerations in the Management of the Elderly Patient
L.A. Brawn and CM. Cast/eden Department of Medicine for the Elderly, Leicester General Hospital, Leicester, England
Contents
Summary .................................................................................................................................... 422 I. Adverse Drug Reactions in the Elderly .............................................................................. .422 1.1 Definition ........................................................................................................................ 422 1.2 Incidence ..........................................................................................................................422 1.2.1 Hospital-Based ................................................................................................ _.. 422 1.2.2 Community"Based ..................................................................................................423 1.3 Drugs Implicated ............................................................................................................. 423 1.3.1 Types of Drug ........ ................................................................................................ 424 1.3.2 Numbers of Drugs ................................................................................................ .424 1.3.3 Concomitant Disease Processes ............................................................................ 426 2. Drug Handling in the Elderly ............................................................................................. .426 2.1 Pharmacokinetics ............................................................................................................ 426 2.1.1 Renal Clearance ..................................................................................................... 426 2.1.2 Hepatic Clearance .................................................................................................. 426 2. 1.3 Body Coinposition ......................................................................... v ._ ; .... . . . .. .. ... ....427 2.1.4 Protein Binding ...................................................................................................... 427 2.1.5 Absorption .............................................................................................................427 2.2 Pharmacodynamics .........................................................................................................· 427 3. Prescribing for the Elderly Patient ...................................................................................... 428 3.1 Diuretics .......................................................................................................................... 428 3.1.1 Potassium-Losing Diuretics ................................................................................... 428 3.1.2 Potassium-Sparing Diuretics ................................................................................ 428 3.J.3 Potassium Supplements .........................................................................................429 3.2 Antihypertensive Drugs .................................................................................................. 429 3.2.1 Precautions for the Elderly Hypertensive ............................................................ 429 3.2.2 P-Blockers and Calcium Antagonists ....................................................................430 3.2.3 Angiotensin-Converting Enzyme Inhibitors ........................................................ 430 3.3 Analgesics and NSAIDs .................................................................................................430 3.3.1 Precautions in the Elderly ..................... ................................................................ 431 3.4 Digoxin ............................................................................................................................ 431 n ••
Drug Safety 5 (6) 1990
422
3.5 Anti-Parkinsonian Drugs ................................................................................................ 432 3.5.1 Idiopathic Parkinson's Disease ............................................................................ .432 3.5.2 Drug-Induced Parkinsonism ................................................................................. 432 3.6 Anticoagulants ................................................................................................................. 432
Summary
The incidence of adverse drug reactions increases with aging, and the elderly are more likely to suffer serious or fatal reactions. Thus, morbidity and mortality are considerable in old patients, with 15% of those in hospital suffering a reaction, and many admitted as a consequence of one. The greater propensity of older patients for adverse drug reactions largely reflects the prescription of drugs to them, although over-the-counter purchases must also playa part. The elderly take more drugs per se (which is a reflection of mUltiple pathology), and more drugs with a narrow therapeutic index associated with a high risk of dangerous adverse reactions and drug interactions. They also have a reduced ability to withstand any reactions due to concomi.tant disease, and an altered pharmacokinetic and -dynamic response which tends to increase drug effects. The recommendation must be to use fewer drugs in older patients, perhaps trying alternative medicine first in nonacute conditions. Starting doses can often be reduced in the elderly, and clinical and therapeutic monitoring of effect is mandatory. The use of diuretics, antihypertensives, anti-Parkinsonian drugs and anticoagulants emphasise these points, and is discussed in detail together with digoxin, analgesics and nonsteroidal anti-inflammatory drugs. Clear guidelines are given for the use of each of these classes of drug.
As to diseases, make a habit of two things - to help, or at least to do no harm. - Epidemics. Hippocrates
1. Adverse Drug Reactions in the Elderly 1.1 Definition
The World Health Organization classifies any unintended reaction to a drug as an adverse drug reaction, whereas the Boston Collaborative Drug Surveillance Programme states that adverse drug reactions are clinically important drug effects which are unintended or undesired (Miller 1973).
l.2 Incidence
1.2.1 Hospital-Based The incidence of adverse drug reactions in the elderly has been studied most extensively in hospital inpatients (Caranasos et al. 1974; Hurwitz & Wade 1969; Seidl et al. 1966; Williamson & Chopin 1980). Individuals in this elderly population
are more likely to have multiple pathology and be frailer than their community-dwelling counterparts. Hurwitz (1969) studied 1160 admissions to hospital in Great Britain and found that 10.2% of patients had adverse drug reactions. The admissions were made to all hospital wards, and patients were kept under surveillance during their stay. Of the reactions identified, 5% were thought responsible for the admission. Patients who developed adverse reactions were significantly older than those who did not, an incidence of 15.4% in patients >60 years old compared with 6.3% in those younger than 60. The ages of the patients admitted ranged from II to 93 years. Patients over 60 years old, although only 22% of the total admissions, represented 42.5% of the prescribed-drug takers. A later multicentre study of 1998 consecutive admissions to geriatric departments found adverse drug reactions in 248 patients, representing an incidence of 15.5% in 1624 prescribed-drug takers. The drug reaction was thought to have contributed
423
Adverse Drug Reactions in the Elderly
to the need for admission in 209 of these patients. Although the lower end of the age range was not stated, there was no significant difference in the incidences of reactions whether the patient was over or under 75 years of age. However, approximately three-quarters of the population studied were over 75, and this represented 73% of prescribed-drug takers (Williamson & Chopin I 980). In the United States the use of hospital-based epidemiological surveillance programmes has contributed greatly to our knowledge of adverse reactions in inpatients. The Boston Program reported that these events occurred in 28% of all patients, 10.5% being of major severity (Miller 1973). The reaction had caused or strongly influenced the reason for hospital admission in 3.7% of patients. The rate did rise with age, but not so prominently as in the Hurwitz study. Seidl et al. (1966) found a more marked rate of adverse drug reaction with increasing age, with a rate of 24% in those aged 81 or over.
1.2.2 Community-Based Community-based surveys have not been so numerous, and are highly selective with the exception of that by Cartwright and Smith (1988). These authors looked at 800 elderly people and found that 60% were taking drugs, with 20% taking 3 or more. Law and Chah;ners (l976) had found earlier that those over 74 years of age took about 3 times the number of drugs prescribed for the general population, and women took twice as many drugs regularly as men (Law & Chalmers 1976). Prescribing habits are known to vary enormously between doctors but overall the numbers of prescription items written in England for the years 1979 to 1984 rose steadily for those over the age of65, from 12.5 items per annum per head in 1979 to 14.2 per annum in 1989. At the same time the number prescribed for younger patients remained steady at about 5.2 items per annum (Weber & Griffin 1986). This is particularly disturbing in view of Martys' (1979) report of a higher incidence of adverse effects in his general practice survey compared with other, hospitalbased, surveys. Kellaway and McCrae (l973) also found that the incidence of adverse drug reactions
was considerably higher in outpatients than inpatients. They confirmed the higher rate in those over 60 and particularly those over 70 years of age. More recently, in Great Britain a large study of 36 500 patients in general practice showed that 0.6% of consultations involved a suspected adverse drug reaction in the 0 to 20 age group. This rose to 1.3% in those aged 21 to 50, years, and to 2.7% in those over 50 years of age (Lumley et al. 1986). A major problem with any of these surveys is that adverse drug reactions may be under-reported by both patients and physicians. Klein et al. (1984) interviewed 299 randomly selected medical outpatients, of whom 30% identified at least 1 medication as causing an undesirable symptom; however, patients aged 65 or older attributed a lower mean number of adverse symptoms to their medications than did younger subjects. Practitiollers themselves are known to under-report adverse drug reactions to the Committee on Safety of Medicines: only 6% of 638 suspected drug reactions were found to have been reported from general practice (Lumley et al. 1986). In an attempt to assess objectively the incidence of serious adverse drug reactions in the elderly, Castleden and Pickles (1988) compared the numbers of reports to the Committee on Safety of Medicines from 1965 to 1983 and the age-related prescription data available from the Drug Surveillance Research Unit in Southampton. The proportion of suspected adverse reactions for patients over 65 had risen from 24% in 1965 to 35% in 1983, with a concurrent rise of I % in the proportion of the elderly population. When this was compared with prescription figures for fenbufen and 'Osmosin' (indomethacin) the increase in reactions correlated with increased prescribing in that age group. Such correlations did not hold for all adverse drug reactions. The shortcomings of this study have been highlighted by Pickles herself, in that prescription data are often inaccurate in this age group (Pickles 1986). 1.3 Drugs Implicated The increased number ofadverse drug reactions in the elderly are due to a combination of factors (table I).
424
Table I. Factors contributing to adverse drug reactions in the elderly
Types of drugs used Number of drugs prescribed Concomitant disease processes Drug-drug interactions Altered pharmacokinetics Altered pharmacodynamics
1.3.1 Types of Drug Certain drugs are particularly implicated in adverse reactions or important drug interactions. Such drugs largely have a narrow therapeutic index (e.g. hypotensives, hypoglycaemics, anticoagulants and chemotherapeutic agents). Hurwitz and Wade (1969) reported that 19.8% of patients receiving digoxin preparations had reactions, and the risk was increased if the patients were also taking diuretics. The Boston Collaborative Drug Surveillance Program again emphasised the dangers of digoxin but also found high levels of adverse reactions with heparin, prednisolone, spironolactone, hydrochlorothiazide and neomycin (Miller 1973). Williamson and Chopin, in their study of elderly patients, reported the greatest risk of reactions with hypotensive drugs, anti-Parkinsonian therapy and ps¥chotropics (Williamson & Chopin 1980) [fig. 1]. In many studies, drugs not necessarily associated with a narrow therapeutic index (such as antibiotics, diuretics and analgesics) have been found to be common causes of adverse reactions. This reflects the numbers of prescriptions given (see below) and not primarily a high risk of reaction with such drugs. For example, Lumley et al. (1986) reported that the majority of suspected adverse reactions were associated with cardiovascular drugs, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics and anti-infectives. The problem for elderly patients is that they are more likely to be suffering from chronic conditions which require therapy known to have a high risk of adverse drug reaction (Castleden & George 1984). Castleden and Pickles (1988) found that there were certain drugs to which the elderly were particularly sensitive; examples are blood dyscrasias
Drug Safety 5 (6) 1990
in patients on phenylbutazone (Inman 1977), cotrimoxazole (trimethoprim plus sulfamethoxazole) [Committe on Safety of Medicines 1985] and serious gastrointestinal bleeding in patients receiving NSAIDs.
1.3.2 Numbers of Drugs It is now widely reported and accepted that adverse drug reactions are related to the number of drugs prescribed. The elderly often have multiple pathology and therefore may need several items of medication for therapeutic effect. Drug interaction and individual drug reaction may each cause an adverse effect. Weber and Griffin (1986) calculated the numbers of suspected adverse reaction reports for men and women over 65 and compared these with corresponding prescription totals. They found that those over 65 years of age were not subject to more reports than those under 65 at identical prescription totals, and concluded that the high level of prescribing for patients over the age of 65 was the cause of their disproportionate share of adverse drug reaction reports (Weber & Griffin 1986). Such data did not support an increase in overall susceptibility. Castleden and Pickles (1988), using a similar database, agreed that in general the number of adverse reactions reported in the elderly may be proportional to their drug use, for example aten0101, alprazolam, zomepirac, benoxaprofen, fenbufen and indomethacin. Inappropriate prescribing in the elderly is another important factor. A recent survey of prescriptions for elderly patients attending an emergency department found that 4.8% of patients were taking drugs contraindicated for their medical diagnosis (Adams et al. 1987). A further 4.4% were taking drugs contraindicated on the basis of subsequent laboratory tests. Over-the-Counter Prescribing The contribution of self-prescribing to adverse drug reactions is also difficult to assess. Nevertheless, if reports of reactions are related to the number of drugs taken, then over-the-counter purchasing must be contributing to the rate. This is particularly worrying in view of the tendency to-
Adverse Drug Reactions in the Elderly
60
425
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c: ,2
Drug Safety 5 (6): 421-435, 1990 0114-5916/90/0011-0421/$07.50/0 © Adis International Limited All rights reserved. MEDT03318
Adverse Drug Reactions
An Overview of Special Considerations in the Management of the Elderly Patient
L.A. Brawn and CM. Cast/eden Department of Medicine for the Elderly, Leicester General Hospital, Leicester, England
Contents
Summary .................................................................................................................................... 422 I. Adverse Drug Reactions in the Elderly .............................................................................. .422 1.1 Definition ........................................................................................................................ 422 1.2 Incidence ..........................................................................................................................422 1.2.1 Hospital-Based ................................................................................................ _.. 422 1.2.2 Community"Based ..................................................................................................423 1.3 Drugs Implicated ............................................................................................................. 423 1.3.1 Types of Drug ........ ................................................................................................ 424 1.3.2 Numbers of Drugs ................................................................................................ .424 1.3.3 Concomitant Disease Processes ............................................................................ 426 2. Drug Handling in the Elderly ............................................................................................. .426 2.1 Pharmacokinetics ............................................................................................................ 426 2.1.1 Renal Clearance ..................................................................................................... 426 2.1.2 Hepatic Clearance .................................................................................................. 426 2. 1.3 Body Coinposition ......................................................................... v ._ ; .... . . . .. .. ... ....427 2.1.4 Protein Binding ...................................................................................................... 427 2.1.5 Absorption .............................................................................................................427 2.2 Pharmacodynamics .........................................................................................................· 427 3. Prescribing for the Elderly Patient ...................................................................................... 428 3.1 Diuretics .......................................................................................................................... 428 3.1.1 Potassium-Losing Diuretics ................................................................................... 428 3.1.2 Potassium-Sparing Diuretics ................................................................................ 428 3.J.3 Potassium Supplements .........................................................................................429 3.2 Antihypertensive Drugs .................................................................................................. 429 3.2.1 Precautions for the Elderly Hypertensive ............................................................ 429 3.2.2 P-Blockers and Calcium Antagonists ....................................................................430 3.2.3 Angiotensin-Converting Enzyme Inhibitors ........................................................ 430 3.3 Analgesics and NSAIDs .................................................................................................430 3.3.1 Precautions in the Elderly ..................... ................................................................ 431 3.4 Digoxin ............................................................................................................................ 431 n ••
Drug Safety 5 (6) 1990
422
3.5 Anti-Parkinsonian Drugs ................................................................................................ 432 3.5.1 Idiopathic Parkinson's Disease ............................................................................ .432 3.5.2 Drug-Induced Parkinsonism ................................................................................. 432 3.6 Anticoagulants ................................................................................................................. 432
Summary
The incidence of adverse drug reactions increases with aging, and the elderly are more likely to suffer serious or fatal reactions. Thus, morbidity and mortality are considerable in old patients, with 15% of those in hospital suffering a reaction, and many admitted as a consequence of one. The greater propensity of older patients for adverse drug reactions largely reflects the prescription of drugs to them, although over-the-counter purchases must also playa part. The elderly take more drugs per se (which is a reflection of mUltiple pathology), and more drugs with a narrow therapeutic index associated with a high risk of dangerous adverse reactions and drug interactions. They also have a reduced ability to withstand any reactions due to concomi.tant disease, and an altered pharmacokinetic and -dynamic response which tends to increase drug effects. The recommendation must be to use fewer drugs in older patients, perhaps trying alternative medicine first in nonacute conditions. Starting doses can often be reduced in the elderly, and clinical and therapeutic monitoring of effect is mandatory. The use of diuretics, antihypertensives, anti-Parkinsonian drugs and anticoagulants emphasise these points, and is discussed in detail together with digoxin, analgesics and nonsteroidal anti-inflammatory drugs. Clear guidelines are given for the use of each of these classes of drug.
As to diseases, make a habit of two things - to help, or at least to do no harm. - Epidemics. Hippocrates
1. Adverse Drug Reactions in the Elderly 1.1 Definition
The World Health Organization classifies any unintended reaction to a drug as an adverse drug reaction, whereas the Boston Collaborative Drug Surveillance Programme states that adverse drug reactions are clinically important drug effects which are unintended or undesired (Miller 1973).
l.2 Incidence
1.2.1 Hospital-Based The incidence of adverse drug reactions in the elderly has been studied most extensively in hospital inpatients (Caranasos et al. 1974; Hurwitz & Wade 1969; Seidl et al. 1966; Williamson & Chopin 1980). Individuals in this elderly population
are more likely to have multiple pathology and be frailer than their community-dwelling counterparts. Hurwitz (1969) studied 1160 admissions to hospital in Great Britain and found that 10.2% of patients had adverse drug reactions. The admissions were made to all hospital wards, and patients were kept under surveillance during their stay. Of the reactions identified, 5% were thought responsible for the admission. Patients who developed adverse reactions were significantly older than those who did not, an incidence of 15.4% in patients >60 years old compared with 6.3% in those younger than 60. The ages of the patients admitted ranged from II to 93 years. Patients over 60 years old, although only 22% of the total admissions, represented 42.5% of the prescribed-drug takers. A later multicentre study of 1998 consecutive admissions to geriatric departments found adverse drug reactions in 248 patients, representing an incidence of 15.5% in 1624 prescribed-drug takers. The drug reaction was thought to have contributed
423
Adverse Drug Reactions in the Elderly
to the need for admission in 209 of these patients. Although the lower end of the age range was not stated, there was no significant difference in the incidences of reactions whether the patient was over or under 75 years of age. However, approximately three-quarters of the population studied were over 75, and this represented 73% of prescribed-drug takers (Williamson & Chopin I 980). In the United States the use of hospital-based epidemiological surveillance programmes has contributed greatly to our knowledge of adverse reactions in inpatients. The Boston Program reported that these events occurred in 28% of all patients, 10.5% being of major severity (Miller 1973). The reaction had caused or strongly influenced the reason for hospital admission in 3.7% of patients. The rate did rise with age, but not so prominently as in the Hurwitz study. Seidl et al. (1966) found a more marked rate of adverse drug reaction with increasing age, with a rate of 24% in those aged 81 or over.
1.2.2 Community-Based Community-based surveys have not been so numerous, and are highly selective with the exception of that by Cartwright and Smith (1988). These authors looked at 800 elderly people and found that 60% were taking drugs, with 20% taking 3 or more. Law and Chah;ners (l976) had found earlier that those over 74 years of age took about 3 times the number of drugs prescribed for the general population, and women took twice as many drugs regularly as men (Law & Chalmers 1976). Prescribing habits are known to vary enormously between doctors but overall the numbers of prescription items written in England for the years 1979 to 1984 rose steadily for those over the age of65, from 12.5 items per annum per head in 1979 to 14.2 per annum in 1989. At the same time the number prescribed for younger patients remained steady at about 5.2 items per annum (Weber & Griffin 1986). This is particularly disturbing in view of Martys' (1979) report of a higher incidence of adverse effects in his general practice survey compared with other, hospitalbased, surveys. Kellaway and McCrae (l973) also found that the incidence of adverse drug reactions
was considerably higher in outpatients than inpatients. They confirmed the higher rate in those over 60 and particularly those over 70 years of age. More recently, in Great Britain a large study of 36 500 patients in general practice showed that 0.6% of consultations involved a suspected adverse drug reaction in the 0 to 20 age group. This rose to 1.3% in those aged 21 to 50, years, and to 2.7% in those over 50 years of age (Lumley et al. 1986). A major problem with any of these surveys is that adverse drug reactions may be under-reported by both patients and physicians. Klein et al. (1984) interviewed 299 randomly selected medical outpatients, of whom 30% identified at least 1 medication as causing an undesirable symptom; however, patients aged 65 or older attributed a lower mean number of adverse symptoms to their medications than did younger subjects. Practitiollers themselves are known to under-report adverse drug reactions to the Committee on Safety of Medicines: only 6% of 638 suspected drug reactions were found to have been reported from general practice (Lumley et al. 1986). In an attempt to assess objectively the incidence of serious adverse drug reactions in the elderly, Castleden and Pickles (1988) compared the numbers of reports to the Committee on Safety of Medicines from 1965 to 1983 and the age-related prescription data available from the Drug Surveillance Research Unit in Southampton. The proportion of suspected adverse reactions for patients over 65 had risen from 24% in 1965 to 35% in 1983, with a concurrent rise of I % in the proportion of the elderly population. When this was compared with prescription figures for fenbufen and 'Osmosin' (indomethacin) the increase in reactions correlated with increased prescribing in that age group. Such correlations did not hold for all adverse drug reactions. The shortcomings of this study have been highlighted by Pickles herself, in that prescription data are often inaccurate in this age group (Pickles 1986). 1.3 Drugs Implicated The increased number ofadverse drug reactions in the elderly are due to a combination of factors (table I).
424
Table I. Factors contributing to adverse drug reactions in the elderly
Types of drugs used Number of drugs prescribed Concomitant disease processes Drug-drug interactions Altered pharmacokinetics Altered pharmacodynamics
1.3.1 Types of Drug Certain drugs are particularly implicated in adverse reactions or important drug interactions. Such drugs largely have a narrow therapeutic index (e.g. hypotensives, hypoglycaemics, anticoagulants and chemotherapeutic agents). Hurwitz and Wade (1969) reported that 19.8% of patients receiving digoxin preparations had reactions, and the risk was increased if the patients were also taking diuretics. The Boston Collaborative Drug Surveillance Program again emphasised the dangers of digoxin but also found high levels of adverse reactions with heparin, prednisolone, spironolactone, hydrochlorothiazide and neomycin (Miller 1973). Williamson and Chopin, in their study of elderly patients, reported the greatest risk of reactions with hypotensive drugs, anti-Parkinsonian therapy and ps¥chotropics (Williamson & Chopin 1980) [fig. 1]. In many studies, drugs not necessarily associated with a narrow therapeutic index (such as antibiotics, diuretics and analgesics) have been found to be common causes of adverse reactions. This reflects the numbers of prescriptions given (see below) and not primarily a high risk of reaction with such drugs. For example, Lumley et al. (1986) reported that the majority of suspected adverse reactions were associated with cardiovascular drugs, diuretics, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics and anti-infectives. The problem for elderly patients is that they are more likely to be suffering from chronic conditions which require therapy known to have a high risk of adverse drug reaction (Castleden & George 1984). Castleden and Pickles (1988) found that there were certain drugs to which the elderly were particularly sensitive; examples are blood dyscrasias
Drug Safety 5 (6) 1990
in patients on phenylbutazone (Inman 1977), cotrimoxazole (trimethoprim plus sulfamethoxazole) [Committe on Safety of Medicines 1985] and serious gastrointestinal bleeding in patients receiving NSAIDs.
1.3.2 Numbers of Drugs It is now widely reported and accepted that adverse drug reactions are related to the number of drugs prescribed. The elderly often have multiple pathology and therefore may need several items of medication for therapeutic effect. Drug interaction and individual drug reaction may each cause an adverse effect. Weber and Griffin (1986) calculated the numbers of suspected adverse reaction reports for men and women over 65 and compared these with corresponding prescription totals. They found that those over 65 years of age were not subject to more reports than those under 65 at identical prescription totals, and concluded that the high level of prescribing for patients over the age of 65 was the cause of their disproportionate share of adverse drug reaction reports (Weber & Griffin 1986). Such data did not support an increase in overall susceptibility. Castleden and Pickles (1988), using a similar database, agreed that in general the number of adverse reactions reported in the elderly may be proportional to their drug use, for example aten0101, alprazolam, zomepirac, benoxaprofen, fenbufen and indomethacin. Inappropriate prescribing in the elderly is another important factor. A recent survey of prescriptions for elderly patients attending an emergency department found that 4.8% of patients were taking drugs contraindicated for their medical diagnosis (Adams et al. 1987). A further 4.4% were taking drugs contraindicated on the basis of subsequent laboratory tests. Over-the-Counter Prescribing The contribution of self-prescribing to adverse drug reactions is also difficult to assess. Nevertheless, if reports of reactions are related to the number of drugs taken, then over-the-counter purchasing must be contributing to the rate. This is particularly worrying in view of the tendency to-
Adverse Drug Reactions in the Elderly
60
425
r--r---
~
401-
en
c: ,2
