Fifty-five studies of cognitive side effects of beta-blockers were reviewed. Many of the studies were limited by small sample size, use of drugs out of the range of normal administration, failure to control for known confounders for neuropsychological evaluation, or lack of a crossover design. As a result, one needs caution in drawing conclusions on this topic. Nevertheless, given the widespread use of beta-blockers and the frequent allegations about their relative side effect profiles, it is appropriate to summarize the results of these disparate studies. Across all beta-blockers and all cognitive domains, the drugs led to improved functioning in 16% of observations and worsened functioning in 17%, with no significant effect in the rest. Memory, learning, and abstraction have been studied less frequently. The perceptual motor cognitive domain was the most widely studied and was frequently affected by these drugs. There was no consistent evidence of a trend for lipophilic drugs to impair this domain more than lipophobic drugs. There is some evidence that these drugs have a positive effect on complex task performance. The drugs also seem to increase sedation; however, in these studies there was no evidence for a differential effect across lipophilic vs lipophobic drugs.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=intemed&articleId=611263&pdfFileName=archinte_149_3_005.pdf

Neuropsychological side effects of beta-blockers.

Alzheimer's disease is the most prevalent and common form of cognitive impairment, ie, dementia, in the elderly followed in second place by vascular dementia due to the microangiopathy associated with poorly-controlled hypertension. Besides blood pressure elevation, advancing age is the strongest risk factor for dementia. Deterioration of intellectual function and cognitive skills that leads to the elderly patient becoming more and more dependent in his, her, activities of daily living, ie, bathing, dressing, feeding self, locomotion, and personal hygiene. It has been known and demonstrated for many years that lowering of blood pressure from a previous hypertensive point can result in stroke prevention yet lowering of blood pressure does not prevent the microangiopathy that leads to white matter demyelinization which when combined with the clinical cognitive deterioration is compatible with a diagnosis of vascular dementia. It is known from many large studies, ie, SHEP, SCOPE, and HOPE, that lowering of blood pressure gradually will not and should not worsen the cognitive impairment. However, if the pressure is uncontrolled a stroke which might consequently occur would further worsen their cognitive derangement. So an attempt at slow reduction of blood pressure since cerebral autoregulation is slower as age increases is in the patient's best interest. It is also important to stress that control of blood glucose can also be seen as an attempt to prevent vascular dementia from uncontrolled hyperglycemia. Vascular dementia is not considered one of the reversible causes of dementia. Reversible causes of cognitive impairment are over medication with centrally acting drugs such as sedatives, hypnotics, antidepressants, and antipsychotics, electrolyte imbalance such as hyponatremia, azotemia, chronic liver disease, and poor controlled chronic congestive heart failure. Criteria for the clinical diagnosis of vascular dementia include cognitive decline in regards to preceding functionally higher level characterized by alterations in memory and in two or more superior cortical functions that include orientation, attention, verbal linguistic capacities, visual spacial skills, calculation, executive functioning, motor control, abstraction and judgment. Patients with disturbances of consciousness, delirium (acute confusional states), psychosis, serious aphasia, or sensory-motor alterations that preclude proper execution of neuro-psychological testing are also considered to have probably vascular dementia. Furthermore, these are ten of the other essential cerebral or systematic pathologies present that would be able to produce a dementia syndrome.

Hypertension and Cognitive Function in the Elderly

The central effects of atenolol, a cardioselective beta-adrenoceptor antagonist, were investigated in six healthy men. Two flash-fusion threshold (2FFT), simple reaction time (SRT), digital copying (DCT), symbol-digit modalities (SDMT), and Gibson's spiral maze tests (GSMT) and mood rating scales for tension, alertness, depression, detachment, and anxiety were used. Each subject took 50, 100, 200, and 400 mg atenolol and identical placebo orally in a randomized, double-blind, crossover study and the psychomotor tests were performed at 0, 2, 3, 5, and 8 hr. 2FFT was prolonged at 3 hr after all doses and at 2 and 5 hr with 100, 200, and 400 mg. The maximum effect was achieved with 200 mg and mean 2FFT correlated with mean plasma atenolol concentration. SRTs were prolonged after all doses at between 2 and 5 hr. The DCT and the retest gain of the SDMT were both lower than after placebo at 2 hr with 100, 200, and 400 mg. The time taken to perform the GSMT was not altered by active drug, but the number of errors was lower at 2 hr with 100 and 200 mg. The self-rating mood scales showed a subjective decrease in tension 2 hr after 400 mg. The results show that atenolol exerts central effects in man.

Central effects of beta-adrenoceptor antagonists

The development during the 1960s of drugs which specifically antagonise β-adrenoceptors has led to the introduction of a new class of therapeutic agents of established value in the treatment of a variety of cardiovascular diseases, including angina, cardiac arrhythmia and hypertension. It has been assumed that these effects are mediated primarily by the antagonism of the effects of noradrenaline at receptor sites within the peripheral autonomic nervous system. In hypertension, however, the mode of action is by no means certain, and evidence has been put forward in support of a centrally mediated component (Day and Roach, 1973). Various central nervous system effects have been noted in both animals and man, and these effects may provide a basis for the claimed therapeutic benefits seen in some psychiatric and neurological disorders. The mechanisms underlying these therapeutic claims are poorly understood, since β-adrenoceptor antagonists have pharmacological actions other than at β-adrenoceptors and the role of the latter in the CNS is unknown.

Central Nervous Actions of Beta-Adrenoceptor Antagonists

Beta-adrenoceptor antagonists in psychiatry and neurology

Measurement of the excretion of catecholamines appears to provide an indirect but objective measure of pain which may be useful in the assessment of analgesic drugs. There is a large individual variation and the method is likely to be useful only in crossover trials when the patient provides his own control. The differences in treated and untreated patients are not large and urine collections for at least three days are likely to be required to detect them. In a previous experiment, there were no significant differences in treated and untreated patients with urine collected for three 12 h periods overnight. In this study, a variety of treatments was used and in all cases there was a good response to treatment. Less marked pain relief might be undetectable or require longer periods of collection. The findings of this study could also be explained by a direct action of analgesic and anti-inflammatory drugs on some aspect of catecholamine metabolism, which must be considered when the method is applied to individual compounds. It is perhaps surprising that changes in noradrenaline were comparable to those of adrenaline, but stress appears to increase the excretion of both catecholamines (Levi, 1968). Because noradrenaline is excreted in much larger amounts, it is likely to provide the more useful measurement of pain.

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P.C. Bryan

Papers

Propranolol on tests of visual function and central nervous activity.