di
Anna Giulia Cattaneo, M.D.
University of Insubria, DBSF, via J-H. Dunant, 3 - 21100 Varese.

The problem of treating old people with drugs is a major challenge both for the complexity, and for the social cost of the treatment. Elderly is a main cause of poverty in developed countries, and many individuals reaching the retirement age must cope with their increased physical frailty, added to substantial reduction of financial resources. These facts are frequently superimposed to a background of depression and lack of inner drive, decreased ability of self care, abandonment or incapability to understand from the family, and need for multiple drugs intake associated with reduced tolerance to many of them. Attempts of auto-medication and unauthorized discontinuation of the right therapy, and sometimes overmedication and medical malpractice have the obvious consequence of increased morbidity and possibly serious side effects.

In this Editorial a summary of most important factors leading to a poor compliance with drug therapy in the oldest subjects is presented. The pharmacokinetics of an antiarrhythmic agent is presented, as an example.

Factors affecting the safety of drug therapy in aged individuals.

The severity of the impact of aging on the quality of life in older individuals is mainly determined not only by the patient himself and the entity of aging process, but even by the taking care (physicians, nurses, family members, others).

The patient could experience:
1. Increased morbidity when age increases, leading to increased need for drug therapy and reduced autonomy.
2. Abandonment, poor ability of self-care (impaired motility and economical support, visual or intellectual decline) leading to frequent misuse of therapy.
3. Increased depression, leading to reduce determination in following therapeutic protocols and even in seeking help for physical disabilities.
The care taking (professional, or a family member) must face difficulties, like those listed below:
1. Impaired ability to eat and swallow medicines, complain for gastric discomfort, leading to difficulties in correctly following the therapeutic schedules.
2. Reduced muscle mass, leading to difficulties in administering parenteral therapy
3. Unapparent or confusing symptoms, hostile or poorly co-operative habit of the old subject, leading to delay in reporting possible side reaction of drugs to the physician.
The physician must be an expert manager of the frail body of elderly patients, and be aware that:
1. Multiple drug assumption required for multi-systemic affecting diseases lead to increased risk of adverse side reactions
2. More frequent occasions for use and misuse of antimicrobial agents lead to enhanced infective episodes with resistant organisms
3. Symptoms unapparent or misunderstood lead to poorly diagnosed side reaction of drugs or of counteracting diseases.
4. Altered physiology and reduced renal, hepatic and cardiovascular function lead to altered clearance and distribution of drugs into body compartment.
5. Erroneous eating habits and aging of metabolic organs lead to malabsorption, low content of protein in plasma, reduced (or relatively augmented, in comparison with muscles) fat body pads and altered body compartments, in a word erratic pharmacokinetics.

Prevention of malpractice and poor compliance.

a. Pharmacovigilance.
Post marketing pharmacovigilance is the main preventive measure in this field. It can be extended to the aged population of a town, a region or a country, or be limited to representative samples, sized according to the epidemiological protocols. Data should be inserted into a national database, as recently auspicated by the Italian Group for Pharmaco-epidemiology in the Aged (Gruppo Italiano di Farmacoepidemiologia dell'Anziano, GIFA), and discussed in the 49° Congress of the Italian Society of Geriatrics and Gerontology (SIGG), held in November, 3rd - 7 th, 2004.
Large populations can be analysed in this way, and a great number of data can be collected and validated using adequate statistical tools. Patient's symptoms, before, during and after drug therapy, compliance with therapy itself, type and timing of drug assumed can be evaluated by questionnaires in addition to supervision. Mental and physical condition, economical an social status of individuals entered in the study can be evaluated in the same way. A new field of interest, increasingly important, is pharmacogenetics, which could be improved by the creation of databases of genetic profile of populations: genotypes related to abnormal drug sensitivity, or associated with diseases and other clinical conditions could be taken into account. However, at the present state of practical knowledge, these kind of data seem to be a target for a not near future, at least when general screening of the old population is taken into account. The existence in the sampled population of sub samples (women vs. men, subjects living at home vs. those living in nursing homes, and others) should be evident if the study has been well planned. This classification can simplify the result analysis, and help to adopt effective preventive measures against complaint, side effects and jatrogenic diseases.
WHO has online published the guidelines for efficaciously report drug side effects (file .pdf, 288 kb). The need to develop post marketing pharmacovigilance services active in this area should be of great interest.

b. Admission to results
The possibility to have free access to evidences on drug toxicity and counteracting effects of drugs in old population, from the local or national databases could be of importance for the practitioner that must cope with a rare, or not before experienced side effect of drug in an aged patient, perhaps unable to correctly report his distress. The online access to rapid and clear review, eventually organised as an alphabetic list of compounds, or as a net of causes of toxic signs and symptoms, is in my opinion a powerful mean to counteract malpractice or at least drugs misuse, especially when the state of knowledge is regularly updated by non-profit organisms.
A comprehensive search motor is furnished form the Food and Drug Administration (FDA). Another useful tool is maintained in a self-claimed non-for-profit web site (The Drug Monitor). The site offers free accession to a calculator for several variables (like the anion gap, the glomerular filtrate, etc.) involved in drug clearance: corrections for age, gender and body features are included. A similar tool, devoted to problems concerning aging and maintained by public institution or scientific societies, should be very useful.

c. Improved training in geriatrics in medical schools
The world population is aging: the WHO and other organisms strongly advocates that all future medical doctors should be well trained in care of the older persons, that will represent an increasing part of their patients in daily practice. Documents on global survey on geriatrics in medical curriculum are freely accessible at the web site of the American Geriatrics Society and of WHO (document .pdf, 630 kb, published in 2002). The first institute auspicate special training in geriatrics for medical specialists. On the basis of aging process in the world population, with special focus on developing countries, the WHO predicts that an epidemiological transition should be expected, and strongly advocates that future doctors will be trained at the best in care of older persons. Results from a worldwide study (TeGeME, carried out in 2000) are presented: an inter-countries comparison index (GERIND) has been calculated on the basis of a set of qualitative and quantitative characteristics of rules and facilities for teaching and practicing geriatrics in medical schools. The analysis of 34 participants (Italy was not included) permits to divide countries into three groups: A) high proportion of older persons among the population and insufficient geriatric education; B) low, but steadily rising older population segment and insufficient geriatric education; C) high segment of older persons among the population and good training of medical students in geriatric medicine. Predictions for 2025 are done: no substantial variation of the quality of teaching should be expected, in association with a shift on the left (older ages in population) in all groups.
Geriatrics must be considered as a discipline requiring multidisciplinary approach: the need to have good knowledge and skills in medical disciplines, as well as in psychiatry and surgical practice, is mandatory to avoid the feeling of disorientation that could disturb the beginner at its first contact with patients suffering from loss of consciousness, memory, and presenting the physical sequels of aging. Pharmacovigilance and pharmacokinetics must be familiar to the physician involved in this kind of care.

A brief discussion of recent trials
Recent studies underline old and new fundamentals in pharmacologically care for older patients. The most important among them can be shortly summarized as follows:
1. Reach an accurate diagnosis before starting treatment
2. Attempt to correct or ameliorate symptoms with adequate modifications of live stile (drinking alcohols, smoking, eating habits, exercise, adequate fluid intake) to avoid or minimize prescriptions
3. Evaluate the integrity of most important district for pharmacokinetics/dynamics (kidney and liver function, plasma carriers of drugs, mainly albumin and other proteins, body mass index and body surface, evaluation of subcutaneous fat pad, muscle mass and the entity of eventual dehydration or oedema)
4. Record accurately all drug used by the subjects, keeping in mind the possibility of auto medication even with agents not considered as active drugs by subjects (like herbal preparations)
5. Evaluate the real adherence to the therapy
6. Maintain an accurate and actual knowledge of all the possible counteracting effects and of their underlying causes
Older subjects are at risk of overmedications: it is generally better to avoid prescribing antiobesity drugs, analeptics, vasodilators, drugs claimed to improve mental, physical or sexual fitness. The most frequently used drugs in the elderly seems to be sedatives/hypnotics, diuretics, cardiac therapy agents, and minor analgesics and antipyretics: remember that sedatives and diuretics can enhance the risk of nocturnal falls, aspirin and glucocorticoids agents seems to be associated with increased risk for developing dementia in particular genotypes, involving apoE epsilon4 allele, and cardiac glycosides can cause complex side effects, involving the CNS (also with behavioural modifications) in addition to the cardiovascular systems.

Pharmacokinetics of antiarrhythmic drugs: the case of disopyramide

In a study involving 300 subjects treated with antiarrhythmic drugs, 40% of patients showing drug-induced side effects were treated with disopyramide (Vigreux P et al, Terapie, 1995, 50:413-8).
This molecule, while not widely used, appears to be interesting for the purposes of this paper, because its complex pharmacokinetics is altered in aging and in age-related pathologic conditions, because it is not a drug at risk of auto prescription, and because its administration schedule is relatively simple (oral administration, once or twice daily).
The metabolic fate of disopyramide follows a hepatic pathway of dealkilation, controlled by inducible enzymes. The pathway is stereo selective: the drug in pharmaceutical preparations is a mix of two isomers, only one of which is easily metabolised for unclear reasons.
It is uncertain if the major metabolite retain some antiarrhythmic effect and/or enhanced side-effects in humans, however it competes with the parent molecule for the saturable (non-linear) binding to plasma protein, namely to a1 -acid glycoprotein. This is an acute-phase reactant, increased in aging, IMA, CRF and renal transplant recipients.
The excretion is 80% urinary (mainly as active, free drug), both by glomerular filtration and tubular secretion, and 15% faecal (ca.1/3 as active drug). Total clearance is a function of total drug concentration; renal clearance is a function of free (unbound) drug concentration (30% from tubular excretion).

Measured parameters during long-term therapy:
1. Oral absorption >90%
2. Vd at the steady state (l/Kg, range) = ca 0,5 (total); ca 1,5 (free drug)
3. Total concentration in plasma: range: 2 -8 mg/l (after 400 - 600 mg/day)
4. Plasma to tissues or fluids concentration: 1: 7 up to 1: 15 in fat, liver, spleen; 1: 0,3 in brain; 1: 0,8-1.51 in saliva.
5. Metabolite concentration: up to 30 % of active drug.
6. t1/2 = 5-9 hours.

Factors related to the aging that can alter pharmacokinetics:
Aging, alone or associated to cardiac ischemia,

• Increases: binding to protein and the level of the binding protein (by 50%), volume of distribution (Vd) (x 2), steady-state concentration of the free drug in plasma (by 25%), half-life (x 3)
• Decreases total clearance (by 30%)

Other conditions more frequent in aged individuals and able to modify the kinetics of this drug are renal and liver failure, Acute Myocardial Infarct (AMI) (only in acute phase, not in convalescent state), Congestive Hearth Failure (CHF), and chronic inflammatory diseases. These conditions act on absorption, binding to protein, metabolism, clearance and half-life, distribution volume and absorption, often with a random effect.

Multiple drug assumption can lead to multiple effects on liver metabolism (rifampicin, phenytoin) and to competitive binding with a1 -acid glycoprotein.

Conclusive remarks
Better training in geriatrics in medical schools, both for specialists and for general physicians, wider access to well planned and updated tools both for pharmacovigilance and pharmacokinetics, and improved personal skills seems to be highly recommended.
Final targets of these efforts will be a better compliance with therapy, improved wellness and reduced wasting of economical resources due to approximate or inadequate treatments.
When keeping in mind that the older patients represent an increasing part of the near future patients in daily clinical practice, all over the world, the importance of the cited aspects appears to be self-imposing.

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