2.1 CHARACTERISTICS OF DISEASE IN OLDAGE
2.1.2 DRUG BIOA V AILABILITY AND AGEING
2.1.2.2 PHARMACOKINETICS
TeAs; antihistamines; opiods.
Drugs aggravating urinary retention- anticholinergics.
Therapeutic doses of certain products attain higher blood levels, and have a longer active period in the elderly patient than in the younger patient. The effect of absorption, distribution, metabolism, elimination and half-life on drugs in the elderly will be reviewed next.
2.1.2.2.1 Drug absorption in the elderly
Drug absorption is theoretically reduced in the elderly as loss of mucosal intestinal surface, reduced gastric acid secretion, decreased mesenteric blood flow and a decrease in active transport mechanisms occur with ageing. However, while nutrient absorption (calcium, iron and thiamine) is known to be compromised by age, there are few examples of specific drug absorption problems of demonstrable clinical significance. More commonly co-existing disease and drug-related causes of reduced
Drug related problems among geriatric out-patients at a public sector hospital: An intervention study
gastric emptying, such as reduced gastric emptying, decreased gastrointestinal motility produced by anticholingeric agents, are likely to affect the rate rather than the extent of drug absorption. Drugs undergoing high first pass metabolism (such as propranolol) may have a higher bioavailability in the elderly due to changes in liver blood flow and hepatic function (Hudson and Boyter, 1997).
While the rate and extent of drug absorption from the gastro-intestinal tract is usually minimally affected, there are some changes in gastric pH and gut wall metabolism that can affect the bioavailability of some agents. For example, with levodopa there tends to be an increase in the bioavailability in the elderly patient because of reduced levels of the enzyme dopa-decarboxylase in the stomach. However, there may be a decrease in patients with delayed gastric emptying due to loss through metabolism. It has been found that the net effect of all these factors is relatively small with most drugs not being predictably influenced by differences in absorption in the elderly.
Other factors that need to be considered are the effects of food, pathological conditions, surgical alterations to the gut, as well as the administration of concurrent medication.
Drug interactions, however, may affect absorption of drugs in all patients. For example, the anticholinergic effects of drugs such as antidepressants and antihistamines may delay gastric emptying, which will affect absorption of other drugs (Merck Manual, 1992).
2.1.2.2.2 Drug distribution in elderly
Drug distribution is affected by the changes in body composition associated with ageing, particularly the increase in adiposity, which rises from 18 per cent in young adults to 36 per cent in elderly men and 48 per cent in women. The volume of distribution for lipid soluble drugs tends to increase, leading to prolonged half-life of drugs such as with psychotropic agents, particularly, benzodiazepines. Increased body fat, for example, can retard the excretion of fat-soluble drugs such as diazepam and nitrazepam, so that these drugs will be accumulated and their actions prolonged (Merck Manual, 1992).
Drug reloted problems among geriatric out-patients at a public sector hospital: An intervention study
Total body water can decrease by up to 15 per cent in older patients and the volume of distribution of water-soluble drugs may consequently be decreased, leading to higher plasma concentrations of polar drugs such as lithium, cimetidine and many antibiotics. The use of diuretics further exacerbates this problem.
Since the elderly have a decreased lean body mass, the volume of distribution of drugs that are highly bound to muscle, notably digoxin is reduced and plasma concentrations increased. Changes in volume of distribution alone tend to affect the loading doses of drugs and dose intervals rather than overall total daily maintenance doses. (Hudson and Boyter, 1997; Merck Manual, 1992). Loading doses of water soluble drugs or those with a small volume of distribution should be based on ideal body weight while the loading dose of drugs which are fat soluble and have a large volume of distribution should be based on total body weight.
Important biochemical changes in geriatrics include reduction in plasma albumin of as much as 25 per cent exacerbated by many chronic disease states. These results in a higher free ( active) concentration of drug for highly protein bound agents, which can produce either therapeutic or toxic effects. Examples include, most benzodiazepines (increased sedation), warfarin (increased anti-coagulation, therefore possible bleeding), and phenytoin (increased toxicity). Other highly protein-bound drugs frequently used by elderly patients include digoxin, non-steriodal anti-inflammatory and sulphonylurea hypoglycaemic preparations. Such cases may remain undetected by therapeutic drug monitoring in which both the free and the bound drug concentrations are routinely measured (Hudson and Boyter, 1997; Merck Manual, 1992).
2.1.2.2.3 Drug metabolism in the elderly
With advancing age there is a loss of liver mass (and therefore the number of functioning hepatocytes), reduction of hepatic microsomal enzyme activity, and hepatic blood flow, resulting in a general decrease in the ability to biotransform and inactivate drugs. Phase 1 metabolic pathways, such as microsomal oxidation and reduction, are more susceptible to age-related change than phase 2 conjugation pathways. Potentially those drugs whose liver metabolism is blood flow dependent, such as propranolol, morphine, and phenothiazines. may be susceptible to increases in bioavailability due to reduced first pass metabolism (Hudson and Boyter, 1997;
Drug reloted problems anwng geriatric out-patients at a public sector hospital: An intervention study
Ouslander, 1981).
The slow acetylator group also tends to increase in the elderly. Many drugs, e.g.
diazepam, amobarbital, propranolol and paracetamol, have an increased half-life and therefore a prolonged clearance. Phenytoin, however, is cleared more rapidly. There is no change in metabolism of isoniazid and ethanol. However, the clinical significance of age on drug handling by the liver is difficult to judge and the effects of concomitant disease make age-related changes in hepatic function unpredictable.
Changes in liver function vary from patient to patient, making it difficult to predict accurately the changes in dose that may be required. It is thought that smoking and alcohol consumption have more influence on hepatic metabolism of drugs than does aging. Poor nutrition may also adversely affect metabolism ( Hudson and Boyter, 1997; Merck Manual, 1992).
2.1.2.2.4 Renal elimination in the elderly patient
Renal function steadily deteriorates with age, and may be one of the most important physiological variables in the disposition of drugs (Bressler, 1981). Acute illness, dehydration and hypotension aggravate this. Kidney function in the elderly is often impaired, although there is a large inter-patient variability. In the kidney, there are decreases in renal blood flow, renal tubular secretion and glomerular filtration rate.
The body's ability to excrete water-soluble drugs is therefore diminished. Many of these drugs have a narrow therapeutic range, and toxic blood levels may be rapidly attained (Merck Manual, 1992; Ouslander, 1981; Scott, 1997).
Renal elimination is more predictably affected by ageing. Glomerular filtration rate (GFR, normally 100-140mllmin) declines by 1 per cent per year from age 40. On average, the glomerular filtration rate is reduced by 35% in those patients over the age of 65 years. This is accentuated in those patients who have other disease affecting the kidneys directly or indirectly through renal blood flow such as heart disease, renal disease, diabetes, and hypertension (Scott, 1997). Creatinine clearance (Clcr) is a suitable indicator of GFR. In practice, creatinine clearance is more often estimated from serum creatinine rather than measured from urinary output in the elderly, who have a reduced muscle mass, serum creatinine concentrations within the normal range are compatible with marked renal function impairment.
Drug relllted problems among geriatric out-patients at a public sector hospital: An intervention study
Table 2.3 illustrates some of the potentially serious problems associated with the excretion· of certain drugs.
Table 2.3 Potentially serious problems associated with altered excretion of drugs
DRUG PROBLEMS
Lithium Renal toxicity, manifested by weight gain, lethargy, nausea, vomiting
Central nervous system toxicity, manifested by drowsiness, giddiness, lack of co-ordination, convulsions.
Muscle weakness Blurred vision
Gastrointestinal disturbances, e.g. vomitting, diarrhoea.
Digoxin Cardiac toxicity, e.g. low or high pulse, palpitations Confusion
Nausea and vomiting Cimetidine Sedation
Gynaecomastia Confusion
Tetracyclines Renal toxicity (as for lithium)
(Osman, 1996, Pg. 49).
2.1.2.2.5 Half-life of drugs in the elderly
The 1t12 may be prolonged in the elderly and this should be considered when determining dosage intervals. Dosage adjustments are often necessary.