blocking drugs: the role of ancillary properties

Among the side effects commonly reported with the use of /3-blockers are symptoms related to the central nervous system (CNS). In this study we compared the effects of four /3-blockers with different ancillary properties (atenolol, metoprolol, propranolol, and pindolol) and placebo on objective and subjective measures of CNS function in 30 healthy male subjects. All subjects were randomly assigned to a double-blind, placebo controlled, Latin-square design study in which five 1 week periods of drug or placebo administration were separated by 2 week washout periods. Laboratory evaluations were conducted at the end of each treatment period, and included multistage exercise stress testing; questionnaire assessments of mood state, sexual function, and sleep habits; tests of psychomotor function; and overnight polysomnographic measures of sleep. Significant effects on sleep continuity were observed for each of the lipophilic drugs, as reflected in the number of awakenings (pindolol = 6.4 + 5.0; propranolol = 6.3 + 3.2; metoprolol = 7.2 + 4.7; atenolol = 3.6 + 2.9; placebo = 3.9 + 2.7) and time of wakefulness (pindolol = 20.6 27.0 min; propranolol = 15.5 ± 23.0 min; metoprolol = 19.5 ± 24.3 min; atenolol 10.2 11.6 min; placebo = 9.2 + 74.5 min). Only pindolol significantly affected rapid eye movement (REM) sleep time (pindolol = 54.5 + 21.9 min; placebo = 74.5 ± 74.5 min) and REM latency (pindolol = 175.0 60.7 min; placebo 95.4 43.8 min). Subjective reports of sleep similarly indicated increased wakefulness and greater restlessness with lipophilic /3-blockers. Although higher depression scores were observed in association with pindolol and propranolol, other measures of psychomotor and sexual function failed to show a consistent pattern of results. Exercise stress test results indicated that during exercise all /3-blockers depressed heart rate to equivalent degrees. These results provide strong evidence that CNS effects of /3blockers are modulated by the ancillary properties (e.g., lipophilicity, intrinsic sympathomimetic activity) of the drugs. Circulation 75, No. 1, 204-212, 1987. ,B-ADRENERGIC-BLOCKING DRUGS have found wide clinical application in the treatment of hypertension, angina, arrhythmias, and other noncardiovascular conditions.1 Eight /8-blockers are currently marketed in the United States and many others are in various stages of clinical investigation. In addition to their ability to block the /8-receptor, these drugs possess ancillary properties such as /31-selectivity, lipophilicity, intrinsic sympathomimetic activity, and membrane-stabilizing activity.'' The physician faced with a large array of available agents may use these ancillary properties to match the pharmacologic agent to the clinical condition of the individual patient. Among the side effects commonly reported with the From UMDNJ-Rutgers Medical School, New Brunswick, NJ. Address for correspondence: John B. Kostis, M.D., Professor of Medicine and Chief, Division of Cardiovascular Diseases and Hypertension, UMDNJ-Rutgers Medical School, CN19, New Brunswick, NJ 08903. Received May 30, 1986; revision accepted Sept. 18, 1986. use of /8-blockers are symptoms related to the central nervous system (CNS).i9 Tiredness, fatigue, lethargy, and related symptoms are among the most troublesome side effects associated with the use of /3-blockers, are reported by up to 40% of patients, and are a primary reason for withdrawal of drug therapy in hypertensive patients.'0' ` There are numerous case reports of clinical effects on mood state, including occasionally severe depression, in persons using /l-blockers, although this is not common. 1-4 In addition, it may be difficult to distinguish clinical depression from a pseudodepressive state resulting from fatigue, weakness, and psychomotor retardation.'5 Disturbances of sleep, including difficulty in falling asleep and vivid dreams, are reported by patients. 16 17 Objective studies have found equivocal effects on rapid eye movement (REM) and non-REM sleep, and deleterious effects on sleep apnea have been reported.'8' ` CIRCULATION 204 by gest on N ovem er 8, 2017 http://ciajournals.org/ D ow nladed from THERAPY AND PREVENTION-f-BLOCKADE Sexual dysfunction has been reported in 5% to 50% of patients using fl-blockers, depending on the agent used, the dose and duration of treatment, population under study, and the means of evaluation (i.e., specifically assessing sexual function vs recording spontaneous patient complaints).2`22 However, none of the studies conducted to date have included laboratory assessment by objective techniques, such as nocturnal penile tumescence. Although there are many case reports and retrospective studies, few placebo-controlled, comparative studies of CNS effects of different fl-blockers are available. The purpose of this article is to report on a double-blind, placebo-controlled study of the CNS effects associated with four fl-blockers with different ancillary properties, with the use of both subjective and objective measures. Materials and methods Study design. This was a placebo-controlled, Latin-square design, double-blind study with five treatment periods of 1 week each separated by 2 week drug-free washout periods. The following medications were administered: 100 mg atenolol at 8:00 A.M. and placebo at 7:00 P.M., 100 mg metoprolol at 8:00 A.M. and 100 mg at 7:00 P.M., 10 mg pindolol at 8:00 A.M. and 10 mg at 7:00 P.M., 80 mg propranolol at 8:00 A.M. and 80 mg at 7:00 P.M., and placebo both at 8:00 A.M. and at 7:00 P.M. Atenolol is a hydrophilic PI-selective blocker, metoprolol is a lipophilic fl1-selective blocker, and propranolol is a lipophilic nonselective fl-blocker. Pindolol is a nonselective lipophilic ,fblocker that also possesses intrinsic sympathomimetic activity. The patients were instructed to take the medications for 7 days from prepackaged blind blister cards. Laboratory evaluations were performed at the end of the seventh day of administration of drug (14 tablets ingested), beginning 1 hr after the ingestion of the 7:00 P.M. dose. After each 7 day treatment period with the active medication or placebo in the fashion described above, the subjects entered a drug-free washout period for 14 days. Patient compliance was ascertained by pill count of the blister cards and was verified by the time of the ingestion of each dose that was entered in the daily logs that the patients kept. Patients had strict instructions to contact the study coordinator or, in his absence, an investigator with any questions or difficulties in taking the medication. According to these measures of compliance only one of 1050 tablets was missed, and no tablet was missed on a sleep study day. Subjects. Thirty healthy men from 23 to 40 years old (mean ± SD, 29.4 ± 4.3) were enrolled in the study. All subjects were screened for one or more of the following exclusion criteria: any acute illness or chronic disease, acute or chronic alcoholism, psychiatric disorders, chronic use of any prescribed and unprescribed medications or drugs, sinus bradycardia (pulse 60 beats/min), heart block greater than first degree, cardiac failure, bronQhospastic disease, diabetes, ischemic heart disease, impaired renal function, a history of adverse reaction to f-blocking drugs, evidence of noncompliance, and failure to provide written informed consent. Subjects with significant abnormalities on laboratory tests (routine blood chemistry [14 tests], complete blood count, and urinalysis) or psychologic or sexual dysfunction that was discovered on interview with a psychologist were also excluded. Dependent measures. Drug effects were evaluated by means of both objective and subjective measures as follows. Daily questionnaires for sleep, mood, and sexual activity were completed during each of the drug periods. More extensive questionnaires pertaining to sexual activity, sleep, and mood were administered at the end of each treatment period before the objective testing in the laboratory. Measures of mood included standardized instruments such as the Depression Adjective Check List (DACL),23 the Profile of Mood States (PoMS),24 and the Spielberger Anxiety Inventory (STAI).25 In addition, the Tyrer self-rating scales26 were obtained both at the laboratory visit and in an abbreviated version on the daily questionnaires. Tests of auditory reaction time and visual reaction time and a coding vigilance test27 were also administered during the laboratory visit. An evaluation of subjective side effects (e.g., faintness, blacking out, blurred vision, hallucinations, nausea, constipation, cold hands and feet, flushing, dry mouth, and feeling better) was also included. Multistage exercise stress testing on a bicycle was performed at around 9:00 P.M. approximately 2 hr after the ingestion of the evening dose of the study medication as follows: 50 W for 3 min, 75 W for 3 min, 100 W for 3 min, 125 W for 3 min, and 150 W for 3 min. The bicycle was calibrated by means of kilogram weights. Heart rate and systolic and diastolic blood pressure were measured in subjects at supine rest, sitting, at each exercise level, and immediately on completion of the exercise test. The suppression of exercise heart rate (heart rate during exercise at 125 W) compared with that after placebo was used as an indirect measure of efficacy of the f8-blockers. Sleep laboratory (polysomnographic) evaluation. After administration of the questionnaire instruments, psychomotor assessment, and exercise testing, subjects were prepared for overnight sleep laboratory assessment. All sleep studies were conducted in a sound-proofed and electrically shielded chamber, and standardized sleep laboratory techniques were used for the recording and scoring of all sleep records. Specific measures included the following. Electroencephalogram (EEG). Electrode sites for bilateral recording of the EEG were standard C4-C3, with A1-A2 reference sites. Gold-plated cup electrodes were secured by means of collodion, and signals were displayed on a Beckman type RM polygraph. Electrooculogram. Recordings of eye movement were obtained by means of monopolar silver chloride electrodes placed over the outer canthi of the right and left eye and referenced to A2. Eye movements during REM sleep and phasic REM activity were scored according to the Pittsburgh method.28 Electromyogram (EMG). Two silver chloride electrodes were attached to the subject's chin for continuous recording of the EMG. Reduction in electromyographic levels was used as an additional criterion for the onset of REM sleep. Electrocardiogram. Recordings were obtained by placement of three self-adhesive electrodes on the precordium to obtain "modified lead V5." In addition, a cardiotachometer was used to convert electrocardiographic signals into heart rate. Nocturnal penile tumescence (NPT). The NPT recording was obtained by means of a mercury-in-rubber strain gauge placed midway on the penile shaft. The tumescence gauge was connected to the polygraph, and was calibrated for millimeters of increase in penile circumference. Subjective sleep reports. On awakening in the laboratory, all subjects were required to complete a brief sleep questionnaire. This included the Stanford Sleepiness Scale, subjective ratings of dream content and quality, and subjective reports of erection. Sleep stage scoring. All sleep records were scored according to the standard method of Rechtschaffen and Kales,29 including identification of REM and stages 1 through 4 of non-REM sleep. Sleep onset was scored from the appearance of the first Vol. 75, No. 1, January 1987 205 by gest on N ovem er 8, 2017 http://ciajournals.org/ D ow nladed from