CENTRAL NERVOUS SYSTEM
Cerebral function in old people is easily disturbed, resulting in disorientation and confusion. Drugs are one of the factors that contribute to this state; sedatives and hypnotics can easily precipitate a loss of awareness and clouding of consciousness.
NIGHT SEDATION
The elderly do not sleep as well as the young. They sleep for a shorter time, their sleep is more likely to be broken and they are more easily aroused. This is quite normal, and old people should not have the expectations of the young as far as sleep is con- cerned. Before hypnotics are commenced, other possible factors should be considered and treated if possible. These include:
1. pain, which may be due to such causes as arthritis;
2. constipation – the discomfort of a loaded rectum;
3. urinary frequency;
4. depression;
5. anxiety;
58 DRUGS IN THE ELDERLY
6. left ventricular failure;
7. dementia;
8. nocturnal xanthine alkaloids, e.g. caffeine in tea, theophylline.
A little more exercise may help, and ‘catnapping’ in the day reduced to a minimum and regularized (as in Mediterranen cultures).
The prescription of hypnotics (see Chapter 18) should be minimized and restricted to short-term use.
ANTIDEPRESSANTS
Although depression is common in old age and may indeed need drug treatment, this is not without risk. Tricyclic anti- depressants (see Chapter 20) can cause constipation, urinary retention and glaucoma (due to their muscarinic blocking action which is less marked in the case of lofepraminethan other drugs of this class), and also drowsiness, confusion, pos- tural hypotension and cardiac dysrhythmias. Tricyclic antide- pressants can produce worthwhile remissions of depression but should be started at very low dosage.
Selective 5-hydroxytryptamine reuptake inhibitors (e.g.
fluoxetine) are as effective as the tricyclics and have a distinct side-effect profile (see chapter 20). They are generally well tolerated by the elderly, although hyponatraemia has been reported more frequently than with other antidepressants.
ANTI-PARKINSONIAN DRUGS
The anticholinergic group of anti-parkinsonian drugs (e.g.
trihexyphenidyl,orphenadrine) commonly cause side effects in the elderly. Urinary retention is common in men. Glaucoma may be precipitated or aggravated and confusion may occur with quite small doses. Levodopacombined with a peripheral dopa decarboxylase inhibitor such as carbidopacan be effec- tive, but it is particularly important to start with a small dose, which can be increased gradually as needed. In patients with dementia, the use of antimuscarinics, levodopaoramantidine may produce adverse cerebral stimulation and/or hallucin- ations, leading to decompensation of cerebral functioning, with excitement and inability to cope.
CARDIOVASCULAR SYSTEM
HYPERTENSION
There is excellent evidence that treating hypertension in the elderly reduces both morbidity and mortality. The agents used (starting with a C or D drug) are described in Chapter 28. It is important to start with a low dose and monitor carefully.
Some adverse effects (e.g. hyponatraemia from diuretics) are much more common in the elderly, who are also much more likely to suffer severe consequences, such as falls/fractures from common effects like postural hypotension. Alpha- blockers in particular should be used as little as possible.
Methyldopamight be expected to be problematic in this age group but was in fact surprisingly well tolerated when used as add-on therapy in a trial by the European Working Party on Hypertension in the Elderly (EWPHE).
Key points
Pharmacodynamic changes in the elderly include:
• increased sensitivity to central nervous system (CNS) effects (e.g. benzodiazepines, cimetidine);
• increased incidence of postural hypotension (e.g.
phenothiazines, beta-blockers, tricyclic antidepressants, diuretics);
• reduced clotting factor synthesis, reduced warfarin for anticoagulation;
• increased toxicity from NSAIDs;
• increased incidence of allergic reactions to drugs.
antagonists, tricyclic antidepressants and diuretics is increased in elderly patients. The QT interval is longer in the elderly, which may predispose to drug-induced ventricular tachy- dysrhythmias. Clotting factor synthesis by the liver is reduced in the elderly, and old people often require lower warfarin doses for effective anticoagulation than younger adults.
DIGOXIN
Digoxintoxicity is common in the elderly because of decreased renal elimination and reduced apparent volume of distribution.
Confusion, nausea and vomiting, altered vision and an acute abdominal syndrome resembling mesenteric artery obstruction are all more common features of digoxintoxicity in the elderly than in the young. Hypokalaemia due to decreased potassium intake (potassium-rich foods are often expensive), faulty homeo- static mechanisms resulting in increased renal loss and the con- comitant use of diuretics is more common in the elderly, and is a contributory factor in some patients. Digoxinis sometimes prescribed when there is no indication for it (e.g. for an irregu- lar pulse which is due to multiple ectopic beats rather than atrial fibrillation). At other times, the indications for initiation of treatment are correct but the situation is never reviewed. In one series of geriatric patients on digoxin, the drug was withdrawn in 78% of cases without detrimental effects.
DIURETICS
Diuretics are more likely to cause adverse effects (e.g. postural hypotension, glucose intolerance and electrolyte disturbances) in elderly patients. Too vigorous a diuresis may result in urin- ary retention in an old man with an enlarged prostate, and necessitate bladder catheterization with its attendant risks.
Brisk diuresis in patients with mental impairment or reduced mobility can result in incontinence. For many patients, a thia- zide diuretic, such as bendroflumethiazide, is adequate. Loop diuretics, such as furosemide, should be used in acute heart failure or in the lowest effective dose for maintenance treatment of chronic heart failure. Clinically important hypokalaemia is uncommon with low doses of diuretics, but plasma potassium should be checked after starting treatment. If clinically important hypokalaemia develops, a thiazide plus potassium-retaining diuretic (amilorideortriamterene) can be considered, but there is a risk of hyperkalaemia due to renal impairment, especially if an ACE inhibitor and/or angiotensin receptor antagonist and aldosterone antagonist are given together with the diuretic for hypertension or heart failure. Thiazide-induced gout and glucose intolerance are important side effects.
ISCHAEMIC HEART DISEASE This is covered in Chapter 29.
ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACEI) AND ANGIOTENSIN RECEPTOR BLOCKERS (ARB) These drugs plays an important part in the treatment of chronic heart failure, as well as hypertension (see Chapters 28 and 31), and are effective and usually well tolerated in the elderly.
However, hypotension, hyperkalaemia and renal failure are more common in this age group. The possibility of atheroma- tous renal artery stenosis should be borne in mind and serum creatinine levels checked before and after starting treatment.
Potassium-retaining diuretics should be co-administered only with extreme caution, because of the reduced GFR and plasma potassium levels monitored. Despite differences in their phar- macology, ACEI and ARB appear similar in efficacy, but ARB do not cause the dry cough that is common with ACEI. The
EFFECT OFDRUGS ONSOMEMAJORORGANSYSTEMS INTHEELDERLY 59 question of whether co-administration of ACEI with ARB has much to add remains controversial; in elderly patients with reduced GFR, the safety of such combined therapy is an impor- tant consideration.
ORAL HYPOGLYCAEMIC AGENTS
Diabetes is common in the elderly and many patients are treated with oral hypoglycaemic drugs (see Chapter 37). It is best for elderly patients to be managed with diet if at all possi- ble. In obese elderly diabetics who remain symptomatic on diet, metformin should be considered, but coexisting renal, heart or lung disease may preclude its use. Short-acting sulphonylureas (e.g. gliclazide) are preferred to longer-acting drugs because of the risk of hypoglycaemia: chlorpropamide (half-life 36 hours) can cause prolonged hypoglycaemia and is specifically contraindicated in this age group, glibenclamide should also be avoided. Insulinmay be needed, but impaired visual and cognitive skills must be considered on an individual basis, and the potential need for dose reduction with advanc- ing age and progressive renal impairment taken into account.
ANTIBIOTICS
The decline in renal function must be borne in mind when an antibiotic that is renally excreted is prescribed, especially if it is nephrotoxic (e.g. an aminoglycoside or tetracycline). Appendix 3 of the British National Formulary is an invaluable practical guide.
Over-prescription of antibiotics is a threat to all age groups, but especially in the elderly. Broad-spectrum drugs including cephalosporins and other beta-lactams, and fluoroquinones are common precursors of Clostridium difficileinfection which has a high mortality rate in the elderly. Amoxicillinis the most com- mon cause of drug rash in the elderly. Flucloxacillin induced cholestatic jaundice and hepatitis is more common in the elderly.
Case history
An 80-year-old retired publican was referred with ‘congest- ive cardiac failure and acute retention of urine’. His wife said his symptoms of ankle swelling and breathlessness had gradually increased over a period of six months despite the GP doubling the water tablet (co-amilozide) which he was taking for high blood pressure. Over the previous week he had become mildly confused and restless at night, for which the GP had prescribed chlorpromazine. His other medication included ketoprofen for osteoarthritis and fre- quent magnesium trisilicate mixture for indigestion. He had been getting up nearly ten times most nights for a year to pass urine. During the day, he frequently passed small amounts of urine. Over the previous 24 hours, he had been unable to pass urine. His wife thought most of his problems were due to the fact that he drank two pints of beer each day since his retirement seven years previously.
On physical examination he was clinically anaemic, but not cyanosed. Findings were consistent with congestive cardiac failure. His bladder was palpable up to his umbili- cus. Rectal examination revealed an enlarged, symmetrical prostate and black tarry faeces. Fundoscopy revealed a grade II hypertensive retinopathy.
60 DRUGS IN THE ELDERLY
4 .Use the fewest possible number of drugs the patient needs.
5. Consider the potential for drug interactions and co-morbidity on drug response.
6. Drugs should seldom be used to treat symptoms without first discovering the cause of the symptoms (i.e. first diagnosis, then treatment).
7. Drugs should not be withheld because of old age, but it should be remembered that there is no cure for old age either.
8. A drug should not be continued if it is no longer necessary.
9. Do not use a drug if the symptoms it causes are worse than those it is intended to relieve.
10. It is seldom sensible to treat the side effects of one drug by prescribing another.
In the elderly, it is often important to pay attention to mat- ters such as the formulation of the drug to be used – many old people tolerate elixirs and liquid medicines better than tablets or capsules. Supervision of drug taking may be necessary, as an elderly person with a serious physical or mental disability cannot be expected to comply with any but the simplest drug regimen. Containers require especially clear labelling, and should be easy to open – child-proof containers are often also grandparent-proof!
RESEARCH
Despite their disproportionate consumption of medicines, the elderly are often under-represented in clinical trials. This may result in the data being extrapolated to an elderly population inappropriately, or the exclusion of elderly patients from new treatments from which they might benefit. It is essential that, both during a drug’s development and after it has been licensed, subgroup analysis of elderly populations is carefully examined both for efficacy and for predisposition to adverse effects.
Initial laboratory results revealed that the patient had acute on chronic renal failure, dangerously high potassium levels (7.6 mmol/L) and anaemia (Hb 7.4 g/dL). Emergency treatment included calcium chloride, dextrose and insulin, urinary catheterization, furosemide and haemodialysis.
Gastroscopy revealed a bleeding gastric ulcer. The patient was discharged two weeks later, when he was symptomat- ically well. His discharge medication consisted of regular doxazosin and ranitidine, and paracetamol as required.
Question
Describe how each of this patient’s drugs prescribed before admission may have contributed to his clinical condition.
Answer
Co-amilozide – hyperkalaemia: amiloride, exacerbation of prostatic symptoms: thiazide
Chlorpromazine – urinary retention
Ketoprofen – gastric ulcer, antagonism of thiazide diuretic, salt retention, possibly interstitial nephritis
Magnesium trisilicate mixture – additional sodium load (6 mmol Na/10 mL).
Comment
Iatrogenic disease due to multiple drug therapy is common in the elderly. The use of amiloride in renal impairment leads to hyperkalaemia. This patient’s confusion and rest- lessness were most probably related to his renal failure.
Chlorpromazine may mask some of the symptoms/signs and delay treatment of the reversible organic disease. The anal- gesic of choice in osteoarthritis is paracetamol, due to its much better tolerance than NSAID. The sodium content of some antacids can adversely affect cardiac and renal failure.
NON-STEROIDAL ANTI-INFLAMMATORY DRUGS The elderly are particularly susceptible to non-steroidal anti- inflammatory drug (NSAID)-induced peptic ulceration, gastro- intestinal irritation and fluid retention. An NSAID is frequently prescribed inappropriately for osteoarthritis before physical and functional interventions and oral paracetamolhave been adequately utilized. If an NSAID is required as adjunctive therapy, the lowest effective dose should be used. Ibuprofen is probably the NSAID of choice in terms of minimizing gas- tro-intestinal side effects. A proton pump inhibitor should be considered as prophylaxis against upper gastro-intestinal complications in those most at risk.
PRACTICAL ASPECTS OF PRESCRIBING FOR THE ELDERLY
Improper prescription of drugs is a common cause of morbid- ity in elderly people. Common-sense rules for prescribing do not apply only to the elderly, but are especially important in this vulnerable group.
1. Take a full drug history (see Chapter 1), which should include any adverse reactions and use of over-the-counter drugs.
2. Know the pharmacological action of the drug employed.
3. Use the lowest effective dose.
Case history
A previously mentally alert and well-orientated 90-year-old woman became acutely confused two nights after hospital admission for bronchial asthma which, on the basis of peak flow and blood gases, had responded well to inhaled salbu- tamol and oral prednisolone. Her other medication was cimetidine (for dyspepsia), digoxin (for an isolated episode of atrial fibrillation two years earlier) and nitrazepam (for night sedation).
Question
Which drugs may be related to the acute confusion?
Answer
Prednisolone, cimetidine, digoxin and nitrazepam.
Comment
If an H2-antagonist is necessary, ranitidine is preferred in the elderly. It is likely that the patient no longer requires digoxin (which accumulates in the elderly). Benzodiazepines should not be used for sedation in elderly (or young) asthmatics.
They may also accumulate in the elderly. The elderly tend to be more sensitive to adverse drug effects on the central ner- vous system (CNS).
RESEARCH 61
FURTHER READING
Dhesi JK, Allain TJ, Mangoni AA, Jackson SHD. The implications of a growing evidence base for drug use in elderly patients. Part 4.
Vitamin D and bisphosphonates for fractures and osteoporosis.
British Journal of Clinical Pharmacology2006;61: 520–8.
Hanratty CG, McGlinchey P, Johnston GD, Passmore AP. Differential pharmacokinetics of digoxin in elderly patients. Drugs and Aging 2000;17: 353–62.
Mangoni AA, Jackson SHD. The implications of a growing evidence base for drug use in elderly patients. Part 1. Statins for primary and secondary cardiovascular prevention. British Journal of Clinical Pharmacology2006;61: 494–501.
Mangoni AA, Jackson SHD. The implications of a growing evidence base for drug use in elderly patients. Part 2. ACE inhibitors and angiotensin receptor blockers in heart failure and high cardiovas- cular risk patients. British Journal of Clinical Pharmacology2006;61:
502–12.
Mangoni AA, Jackson SHD. The implications of a growing evidence base for drug use in elderly patients. Part 3. β-adrenoceptor block- ers in heart failure and thrombolytics in acute myocardial infarc- tion.British Journal of Clinical Pharmacology2006;61: 513–20.
Sproule BA, Hardy BG, Shulman KI. Differential pharmacokinetics in elderly patients. Drugs and Aging2000;16: 165–77.
●Introduction 62
●Identification of the drug at fault 63
●Adverse drug reaction monitoring/surveillance
(pharmacovigilance) 63
●Allergic adverse drug reactions 66
●Prevention of allergic drug reactions 67
●Examples of allergic and other adverse
drug reactions 68
CHAPTER 12