Влияние физической активности на фармакокинетику лекарственных средств

Physical activity produces many positive physiological changes. Some of these physiological changes, however, can adversely affect the absorption, distribution, metabolism, and/or excretion of certain medications when taken concurrently. Blood flow distribution is fundamental to the study of pharmacokinetics and can vary dramatically during rest compared with exercise. The liver and the kidney play significant roles in calculating the pharmacokinetic parameters of medications. Blood flow to these organs is significant at rest but decreases during exercise. These changes in blood flow, as well as other physiological changes during exercise, have shown to alter the pharmacokinetics of some drugs. Medications that require extra therapeutic monitoring may be affected by this drug-exercise interaction. Health care professionals and patients should be aware of these potential drug-exercise interactions.

Pharmacokinetic Drug Interactions with Physical Activity

Маниакальная симптоматика ассоциированная с приступами мигрени

This is a case report of a previously diagnosed "treatment-refractory bipolar" patient whose successful treatment of atypical migraine resulted in the questioning of any psychiatric diagnosis.

A 47-year-old man was referred to the Mood Disorders Clinic for severe migraine associated with mood, "psychic," and neurologic symptoms. He had first presented to Psychiatry 8 years earlier, for acute "mania" with agitation, extreme lability, intense anger, and religiosity necessitating hospitalization. Subsequently, he had recurrences of similar manic "crises" followed by a "depressive" states consisting of cognitive dysfunction, avolition, and anhedonia. He also experienced severe headache and nonspecific neurological symptoms. A diagnosis of migraine was suspected, and a thorough neurological work-up did not yield other diagnoses. Medical history revealed multiple recurrent migraine-equivalents since childhood (particularly, abdominal pain).

Each psychiatric "crisis" was preceded by weeks of increasingly frequent, severe, early morning migraine attacks, with subsequent sleep deprivation, and intensification of migraine symptoms, including aura, with disorganized speech and thinking and bizarre behavior. A prolonged period of complete rest would break the cycle of migraine, accompanied by complete resolution of psychiatric symptoms.

Previous treatments included lithium, buproprion, as well as nortriptyline, stemetil, valproic acid, and quetiapine, none of which were helpful. Family history was positive for migraine and negative for psychiatric disorders. On referral, his medications were propranolol 40 mg twice daily, valproic acid 500 mg twice daily, and lamotrigine 100 mg twice daily. Valproic acid level was therapeutic. A diagnosis of mood disorder, bipolar type secondary to severe migraine was made.

Discussion

This case illustrates the importance of inquiry of neurological symptoms, in particular headache, in patients with bipolar disorder. Patients with bipolar disorder have a greater-than-twofold risk of having migraine, as compared with the general population.1 Treatment for migraine, irrespective of mood disorder, includes amitriptyline, valproate, topiramate, and beta-blockers.2 In patients with bipolar disorder and migraine, judicious use of treatments for both disorders should be considered. Lamotrigine was used for this patient because valproate, although approved for both disorders,3 did not ameliorate the migraine symptoms. For bipolar disorder, lamotrigine is efficacious in the prevention of depressive episodes and, possibly, rapid-cycling type.4 Less evidence supports its use in acute depression or mania.4 For migraine, lamotrigine was not beneficial in a placebo-controlled trial, but had some effectiveness in two open pilot studies for the treatment and prevention of migraine aura.2

Lamotrigine is generally well tolerated, with an acceptable side-effects profile (mainly dizziness, nausea, and insomnia), and may be considered for a patient with aura nonresponsive to other medication. Slow and low dose increase is recommended for side-effects monitoring, especially for severe rashes and Steven's Johnson syndrome. In our patient, lamotrigine was increased to 200 mg twice daily. Use of lamotrigine with valproate may increase lamotrigine concentrations by up to 200% because of increased lamotrigine clearance inhibition,3,5 and valproate levels may also decrease.3 The patient's headache duration eventually decreased to 1 hour nightly, and he returned to work full-time with a 45-minute nap.

Atypical Migraine Manifesting as Mania

Пропранолол в профилактике рецидивов зависимостей

However, the research also suggests that treatment with the β-blocker propranolol can block stress-induced impairment in decision-making in these individuals, potentially reducing the risk for stress-related relapse.

Beta-Blocker May Prevent Stress-Related Relapse in Addicts

Пропранолол при ПТСР

The β-blocker propranolol may interrupt reconsolidation of traumatic memories through protein synthesis inhibition, presenting a promising treatment option for posttraumatic stress disorder (PTSD), 2 new studies suggests.
Propranolol blocks β-adrenergic receptors and, if administered after subjects have actively recalled their memory, may have a 6-hour window to interrupt memory reconsolidation.

Propranolol a Promising Treatment for PTSD

Бета-блокаторы и депрессия

Beta-Blockers and Depression
Glen L. Xiong, M.D., Jane P. Gagliardi, M.D., and Wei Jiang, M.D.

Sacramento, Calif.
Durham, N.C.

To the Editor: We read with great interest the thought-provoking Clinical Case Conference by Laura K. Kent, M.D., et al., published in the August 2009 issue of the Journal, which described the finding of takotsubo cardiomyopathy after ECT (1). We hope to expand on the discussion regarding the role of beta-blockers in the course of depression treatment, an issue frequently raised by colleagues and trainees. We have searched the medical literature over time and have not found conclusive evidence to support a clear causal role of beta-blockers in depression.

Since Dr. Stoudemire et al. (2) posed, in 1984, that there is very little evidence to link propranolol with mood disturbance, subsequent studies have consistently challenged the dogma that beta-blockers cause depression. A meta-analysis (3) examined 15 randomized, controlled studies involving 35,000 subjects taking beta-blockers for the treatment of myocardial infarction, heart failure, or hypertension and demonstrated no statistical difference between beta-blockers and placebo with respect to depression, although beta-blockers were associated with increased incidence of fatigue and sexual dysfunction. The absolute incidence of depressive symptoms was six per 1,000 subjects (95% confidence interval=–7 to 19). A prospective multicenter trial (4) of 254 subjects taking beta-blockers and 127 comparison subjects measured serial Beck Depression Inventory scores. This study showed no significant difference between groups in the rate of depression at 3, 6, and 12 months, even with an alpha set at <0.10. Dr. Kent et al. suggested that beta-blockers may cause depression more often in women than men. However, Crane et al. (5) examined a cross-sectional sample of 84 women (>65 years old) 6 to 12 months after myocardial infarction and did not find any elevated risk of depression (using the Geriatric Depression Scale) among women who were taking beta-blockers (5).

The aforementioned studies teach us that it is important to distinguish fatigue from depression, that a temporal association between beta-blocker use and depression does not seem to exist (up to 12 months), and that there is no evidence to support a gender difference. When the preponderance of evidence does not support a long-held belief, it is the responsibility of the medical community to adopt a new clinical paradigm. It may be time to change the prevailing wisdom in our field so as not to prevent our patients from receiving beta-blockers for cardiovascular benefits. We support the decision to continue the beta-blocker for the patient discussed in the Clinical Case Conference.

Dr. Kent Replies
Laura Kent, M.D.

New York, N.Y.

To the Editor: We thank Dr. Xiong et al. for their thoughtful response to our article. They make the point that studies on beta blockade have distinguished fatigue from depression, have highlighted that there does not seem to be a temporal association between beta-blocker use and depression (up to 12 months), and that there is no evidence to support a gender difference.

Dr. Xiong et al. state that while we suggested that depression in the setting of beta-blockade use is seen more frequently in women, Crane et al. (1) examined 84 women and found no difference in depression symptoms between women who did and did not use beta-blockers. Although that study suggested that the use of beta-blockade does not cause depression in women, the study had several limitations, including its cross-sectional design, making it difficult to identify causation (even though this is more of an issue when an association is found). We also wish to make the point that very large doses of beta-blockade were used in our case study relative to the doses administered to women in the Crane et al. study, who were post-myocardial infarction and received only conventional doses, thus limiting comparability.

We agree that Van Melle et al. (2) showed no significant difference between groups in the rate of depression at 3, 6, and 12 months. However, the vast majority of these subjects were men (78% in both non-beta-blocker and beta-blocker groups), and thus it is hard to comment on the effect on women.

Beta-blockade is a critical state-of-the-art component of cardiac care, and thus further discussion and research on this topic are of paramount importance, especially given the equivocal nature of the preponderance of evidence to date.

Beta-Blockers and Depression
Dr. Kent Replies

Кортизол и память

В Лейденском университете защищена диссертация на тему ''Ускользающее из памяти'' (ориг. на англ. ''Fading memories''). Автор работы - M.Tollenaar (ф-т социальных наук). Исследование посвящено непосредственным и долговременным эффектам гормонов стресса на способность вспомнить что-либо. Исследовательница изучала прежде всего гормоны стресс: кортизол и (нор)адреналин. Диссертация показывает, что стресс или добавление кортизола приводят к ухудшению памяти. Эти эффекты лучше всего просматривались при попытке воспроизведения заученных слов, но практически не затрагивали личные воспоминания. Если под воздействием только стресса люди затруднялись припомнить менее эмоциональные слова, то при добавлении кортизола они уже хуже справлялись с задачей припоминания нейтральных слов. Самым важной новой находкой является то, что острый стресс в сочетании с некоторой дозой кортизола производит также долговременный эффект в части воспоминания нейтральных и эмоциональных слов. Автор не обнаружила воздействия стресса и кортизола на эмоциональные переживания воспоминаний. Исследовательница планирует в будущем исследовать эффекты гормонов стресса на автобиографические воспоминания. Это позволит лучше понять применение кортизола и пропранолола в клинической практике.

МНИИП

Миртазапин в качестве корректора акатизии вызванной антипсихотиками

OBJECTIVE: To evaluate the role of mirtazapine in the treatment of antipsychotic-induced akathisia. DATA SOURCES: MEDLINE (1966-February 2008) and PsycINFO (1967-February 2008) were searched using the terms akathisia and mirtazapine. A bibliographic search was conducted as well. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the search were evaluated. All primary literature was included in the review. DATA SYNTHESIS: Antipsychotic-induced akathisia can be difficult to manage and may respond to mirtazapine based on its antagonist activity at the serotonin 5-HT(2A)/5-HT(2C) receptors. Three case reports (N = 9 pts.), 1 placebo-controlled trial (N = 26), and 1 placebo- and propranolol-controlled study (N = 90) that evaluated mirtazapine for antipsychotic-induced akathisia have been published. Mirtazapine demonstrated a response rate of 53.8% compared with a 7.7% response rate for placebo, based on at least a 2-point reduction on the Barnes Akathisia Scale (global subscale; p = 0.004). Using the same criterion, mirtazapine and propranolol demonstrated efficacy based on response rates of 43.3% and 30.0% compared with placebo (6.7%; p = 0.0051). Mirtazapine was better tolerated than propranolol. In both studies, drowsiness was the most common adverse event associated with mirtazapine. CONCLUSIONS: Mirtazapine may be considered a treatment option for antipsychotic-induced akathisia. It may be especially useful for patients with contraindications or intolerability to beta-blockers and for those with comorbid depression or negative symptoms. Additional studies should be conducted to provide further evidence of mirtazapine's effectiveness in treating akathisia.

pubmed

Антипсихотические свойства пропранолола

Propranolol in psychiatric illness.

Propranolol in chronic schizophrenia: a controlled study in neuroleptic-treated patients.

Propranolol in schizophrenia: a double blind, placebo controlled trial of propranolol as an adjunct to neuroleptic medication.

Does propranolol have an antipsychotic effect? A placebo-controlled study in acute schizophrenia.