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I.R.F. / Aging news / Diseases / 03061301

Drug Uptake in Aging
Posted on: June 13, 2003

Depression in the elderly is nowadays a predominant health care problem, mainly due to the progressive aging of the population. It results from psychosocial stress, polypathology, as well as some biochemical changes which occur in the aged brain and can lead to cognitive impairments, increased symptoms from medical illness, higher utilization of health care services and increased rates of suicide and non-suicide mortality.

A number of hypotheses have been made, focusing that mood disturbances are probably linked to a disturbed central metabolism of neurotransmitters; however most of this knowledge is derived from animal models. Parkinson's and Alzheimer's diseases are age-related diseases associated to decreased activity or brain lesions in the orbital frontal cortex and basal ganglia. These observations lead to the hypothesis that the dysfunctions of one or more of the cortical basal ganglia-thalamic neuronal loops are involved in the pathophysiology of primary and secondary depression.

Depression may be also caused by a various number of drugs (Table 1) currently administered; this is remarkable especially in elderly people, where polypathology is often associated with polypharmacotherapy.

Table 1

Use of psychotropic drugs in the aged population needs caution, when depression is readily diagnosed and treated; quality of life is clearly improved. A reduced compliance is often observed in the elderly, probably due to cognitive disturbances, lack of understanding of the disease, presence of side effects preceding the clinical response. Age-related changes in pharmacokinetics and pharmacodynamics have also to be taken into account, since they may cause an increase in adverse drug reactions in elderly persons. In fact, aging causes a number of changes in drug absorption, distribution, biotransformation and elimination. Drug pharmacokinetics may change with age as a consequence of living habits in elderly subjects, such as diet, alcohol consumption, smoking, concomitant use of other drugs and genetic polymorphism of hepatic enzymes, diseases, etc. (Fig. 1).

In the elderly some drugs may exert different pharmacological effects than in the young for various reasons, including changes in the number of receptors and in binding affinity, and the deficits in homeostatic mechanisms, such as hormonal, biochemical and nervous compensatory reflexes limiting a drug effect. For example, an old individual may have an orthostatic hypotension following administration of an antihypertensive drug, due to reduced autonomic functions.

Factors, that influence the effects of a drug

Pharmacotherapy is fundamental in the group of patients, whose age-related physiological changes, concomitant diseases and drug treatment may alter the metabolic profile of antidepressant drugs. The chronic administration of an antidepressant shows a β-adrenergic post-synaptic receptor desensitization and a decrease in receptor density for 5-HT (neurotransmitter); this evidence suggests that depression might be linked to a receptor supersensitivity, due to the increase of receptors and of their sensitivity and therefore antidepressants might act to promote a receptor down-regulation.

Mood disturbances are probably linked to a disturbed central metabolism of neurotransmitters - monoamines 5-hydroxytryptamine (5-HT), noradrenaline (NA) and dopamine (DA) - as found in demented patients. Moreover, a close relationship was observed between depression and some concomitant physical diseases such as myocardial infarction, Cushing's syndrome, hypothyroidism, neoplasia. Deficiency in vitamin B12 and folate are linked to depressive disorders and can also influence the treatment response to electroconvulsive therapy, antidepressants and tryptophan.

For example, a number of Parkinson's disease studies have shown that selective autoreceptor block may induce the activation of dopaminergic neurotransmission, thereby having an antidepressant action. Amysulpride is a selective blocker of dopamine receptors, which at low doses inhibits autoreceptors and enhances dopaminergic transmission. Therefore, all the drugs that inhibit dopamine reuptake (bupropion, nomifensine) or increase its intrasynaptic availability (amysulpride, raclopride), have an antidepressant action. Even the effects of cocaine and other psychostimulating drugs may be due to dopaminergic transmission enhancement; in fact, cocaine inhibits dopamine reuptake, whilst amphetamines inhibit vesicular reuptake of dopamine and increase its release.

It is thought that changes in levels of monoamines and their receptors reduce cerebral blood flow in some age-related diseases such as Parkinson's and Alzheimer's. Alterations in cerebrovascular and neuroendocrine function may therefore explain the onset of depression in the elderly. Development of novel approaches such as dynamic brain imaging methods, together with indirect knowledge coming from the effects of new antidepressants, will increase the understanding of neurochemistry of depression in old age.

Source: Pietro Gareri, Pasquale De Fazio, Giovambattista De Sarro; Neuropharmacology of depression in aging and age-related diseases; Ageing Research Reviews; 1 (2002) 113-134;
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