Clinical Evaluation of Atenololin Hypertensive Patients

M. MOHSEN IBRAHIM, MB., B.CH., M.D., AND RAGAA MOSSALLAM, M.B., B.CH., D.M.

SUMMARY Atenolol, a cardioselective jl-adrenergic blocking agent, was given as the sole hypotensive drugfor 8-12 weeks to 20 patients with hypertension of varying degrees of severity. Initial systolic blood pressureranged from 162-238 mm Hg (mean ± SEM 196 4 5.5 mm Hg) and diastolic blood pressure ranged from 105-143 mm Hg (118 ± 2.5 mm Hg). Three patients had accelerated hypertension, six had cardiomegaly with re-cent exertional dyspnea and three were diabetics. Atenolol, 100-300 mg once daily, controlled both the supineand standing blood pressure and markedly attenuated the initial hypertensive response to severe exercise. In 17patients (85%), atenolol therapy reduced blood pressure more than 20/10 mm Hg; however, adequate bloodpressure control was not achieved in severe hypertension. A significant hypotensive action developed within 2weeks of treatment, and control of hypertension was maintained for 2 weeks after sudden interruption oftherapy. No patient had postural or postexercise hypotension. The drug appeared to exert its maximum hypo-tensive effect at the 100-mg dosage. The magnitude of the hypotensive response was related to the initialsystolic blood pressure (r = 0.77,p < 0.01) and the degree of inhibition of exercise tachycardia (r = 0.66,p <0.01). The atenolol plasma level and its hypotensive action were not related. Except for impairment of glucosetolerance in diabetic patients, atenolol had minimal side effects.

THE EFFICACY of f-adrenergic blocking drugs forthe treatment of hypertension has been well estab-lished,'~" but most such drugs lack cardioselectivityand their use has been generally restricted to patientswithout associated respiratory or peripheral vasculardiseases. Atenolol (Tenormin) is a new cardio-selective 3-adrenergic blocking agent that has no in-trinsic sympathomimetic properties and, unlikepropranolol, has no membrane-stabilizing action.4Preliminary reports indicate that atenolol may exert amarked antihvpertensive action in man.5-8 However,previous trials with atenolol were limited to mild ormoderate uncomplicated forms of hypertension. Thepresent study was designed to assess the efficacy andsafety of this new cardioselective drug in the treat-ment of varying degrees of hypertension, particularlysevere, complicated forms and those associated withcardiomegaly. Some of the factors that might in-fluence the magnitude of the hypotensive action wereexamined.

Methods

Patients

Twenty male patients who were attending the CairoTransport Organization Hospital Hypertension Clinicwere studied. Patients with a diastolic blood pressureof at least 105 mm Hg were entered into the trial.

Clinical evaluation and routine investigations wereperformed as previously described.3 These includedhematologic, chest x-ray examination, electro-cardiography, fundus examination, serum creatinine

From the Cardiac Department, Cairo University and GeneralTransport Hospital, Cairo, Egypt.

Address for correspondence: M. Mohsen Ibrahim, M.D., 1, El-Sherifein Street, Cairo, Egypt.

Received January 31, 1980; revision accepted November 12,1980.

Circulation 64, No. 2, 1981.

and creatinine clearance, blood sugar, urinary cate-cholamines and vanillyl mandelic acid estimations andi.v. pyelography, if necessary.

All patients were employed as bus drivers or con-ductors at the Cairo Transport Organization. Theywere 30-64 years old (mean age 49.9 ± 1.64 years[± SEM]). Their body surface area ranged from1.60-2.12 m2 (mean 1.93 ± 0.03 in2). Three patientshad recently discovered hypertension, while the othershad known hypertension ranging from 1-15 years(mean 5.41 ± 0.95 years). Optic fundi (Keith-Wagner-Barker classification) were normal in only twopatients; nine patients had grade I, six patients hadgrade II, and three had grade III hypertensive retinop-athy (hemorrhages and exudates - accelerated hyper-tension). Six patients had radiologic evidence of car-diac enlargement (cardiothoracic ratio greater than0.5). Seven patients had electrocardiographic evi-dence of left ventricular hypertrophy (criteria ofSokolow and Lyon" and McPhie10). Eleven patientshad other electrocardiographic abnormalities in theform of ST-segment, T-wave changes and intraven-tricular conduction defects. Six patients had a historyof classic angina of effort documented by electrocar-diographic evidence of myocardial ischemia. Threepatients had diabetes mellitus (one patient was insulin-dependent), and one patient had chest wheezes andasthmatic bronchitis. Six patients had a recent his-tory of exertional dyspnea and radiologic evidence ofcardiomegaly.Serum creatinine ranged from 1.1-1.6 mg% (mean

1.3 mg%). All but four patients were receiving variousantihypertensive medications when admitted to thetrial. Except for nine patients who were hospitalizedand limiting their activities for varying periodsbecause of severe hypertension and/or symptoms ofdyspnea and chest pain, the rest of patients were am-bulatory and doing their routine work. All patientswere advised to avoid excess salt in the diet. Eachpatient volunteered for the study.

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Design of the Study

The duration of the study was 16-20 weeks per

patient. The study comprised four phases, and in fourpatients, an additional fifth phase. The first phase wasa 4-week placebo run-in period during which all pre-vious therapy was discontinued. This phase was can-

celed in patients with accelerated hypertension, andthe drug was introduced immediately without an ini-tial placebo period. The second phase was 4 weeks of asingle daily morning dose of 100 mg of atenolol; thethird phase was either a continuation of the 100-mgdose or doubling it to 200 mg, depending on thepatient's blood pressure response at the end of the sec-ond phase. Patients with blood pressure greater than170/100 mm Hg were given the 200-mg dosage inphase 3. In the fourth phase, atenolol was discon-tinued and replaced by a placebo for the second timefor a 4-week period. In four patients with resistant hy-pertension (blood pressure greater than 180/110 mmHg) a fifth phase of 300 mg of atenolol in a single dailydose was given for 4 weeks, replacing phase 4,followed by the final 4-week placebo period.

Electrocardiographic studies, examination of opticfundi and serum creatinine measurements were madebefore and 8 weeks after atenolol treatment.

Patients were asked to take atenolol tablets at7-7:30 a.m. Ambulant patients were seen every 2weeks and blood pressure was recorded with a stan-dard cuff sphygmomanometer under standard condi-tions between 10 and 1 1:30 a.m. by the same observer.The mean of three blood pressure readings (same arm)after 10 minutes resting supine and 2-3 minutes stand-ing was recorded. The diastolic pressure was recordedat phase 5 Korotkoff sounds. Heart rate was checkedat the same time. Then every patient was asked to per-form a maximal physical exercise of climbing stairs tothe point of maximal tolerance (near exhaustion) or tothe development of chest pain in anginal patients. Thenumber of stairs and the time taken by each patientwere recorded in each visit. Blood pressure and pulserate were measured within 1 minute of completion ofexercise and also 5 minutes later. Hospitalized pa-tients were seen and had their blood pressures checkedevery day. However, for the purpose of the studydesign and to make results comparable with otherpatients, data of blood pressure readings every 2weeks only were included in this paper.

Tablet counts and body weight were checked ateach visit. Initial weight averaged 76 kg. Questionswere directed to specific items such as general well-being, dizziness, headaches, shortness of breath, chestpain, wheezes, palpitations, insomnia, cold extremi-ties, nightmares and depression. Patient compliancewas confirmed by tablet counts.

Atenolol plasma level was determined in 18 patientsusing the gas-liquid chromatography technique"' bythe Imperial Chemical Industries Laboratories.Determinations were made after 2 and 6 weeks ofatenolol therapy. Blood pressure was measured at thesame time of blood sampling. In 15 patients, blood

samples were taken 24 hours after atenolol intake andin three patients, 2 hours after administration of thedrug.

ResultsBlood Pressure

Atenolol reduced both supine and standing arterialpressures in all patients. Table 1 and figure 1 show theblood pressure readings during the various phases ofthe trial. A significant reduction in blood pressure was

achieved by the end of the second week of therapy. Atthe end of the eighth week, the decrease in systolicblood pressure ranged from 7-58 mm Hg and indiastolic blood pressure, from 5-38 mm Hg. In 85% ofpatients atenolol therapy reduced blood pressuregreater than 20/10 mm Hg. The magnitude of thehypotensive response was related to the level of initialpressure (fig. 2). There was a positive correlationbetween the reduction in systolic blood pressure andthe initial systolic blood pressure (r = 0.77, p < 0.01).This relationship did not hold for diastolic bloodpressure.Sudden interruption of treatment produced a grad-

ual rise in blood pressure (table 1, fig. 1).In all nine patients with mild-to-moderate hyper-

tension (supine blood pressure less than 200/120 mmHg, normal or grade I retinopathy and absence of car-

diac hypertrophy), blood pressure was adequately con-trolled and it decreased from 175/112 ± 3.7/1.5 mmHg to 148/93 ± 1.8 mm Hg. On the other hand, sevenpatients in the whole group (35%) failed to achieve a

blood pressure of 150/90 mm Hg. These patients werecharacterized by an initially high blood pressure (aver-age 220/129 mm Hg), six had electrocardiographicabnormalities, four had cardiomegaly and three hadaccelerated hypertension. Doubling the atenololdosage in 12 patients to 200 mg/day did not signifi-

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cantly reduce blood pressure further. In four patients,the dose of atenolol was increased to 300 mg/day. In-creasing the dosage had minimal effect on bloodpressure (fig. 3). Each dose was given for 4 weeks. Thesomewhat greater fall in blood pressure on the higherdosage is probably primarily because the high dosewas always given after the lower dose and would bene-fit from the progressive decrease in blood pressurewith time (fig. 1). Eight patients receiving a single dose(100 mg/day) for 8 weeks had a progressive reductionin blood pressure. However, readings at the end of thefourth and eighth weeks of treatment did not differsignificantly.

Blood pressure measurements taken 24 hours afteratenolol at the time of blood sampling for atenololplasma level, did not differ significantly from meas-urements made 3-4 hours after atenolol.

In six patients with cardiomegaly and recent exer-tional dyspnea, blood pressure decreased from219/127 ± 7.1/5.7 mm Hg to 170/106 ± 5.6/5.8 mmHg. No patient showed clinical evidence of deteriora-tion in cardiac function; in five patients shortness ofbreath was relieved and exercise tolerance improved.

Heart Rate

Atenolol produced a progressive slowing of theheart rate both in the supine and standing positions(table 1, fig. 4). Changes were significant after 2 weeksof treatment (p < 0.025). Continuation of therapyproduced more slowing of the heart rate; however, thedifferences between changes at the second and eighthweeks were not significant.

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Postural tachycardia was attenuated with atenolol;the supine and standing cardiac rates were similar dur-ing therapy (fig. 4).

Increasing the atenolol dosage from 100 to 200mg/day caused a decrease in supine heart rate of 7beats/min (p < 0.05).

Muscular Exercise

Except for two patients who developed angina, allpatients tolerated the maximal exercise test well.Patients were not acquainted with the procedure dur-ing the first trial, so some had difficulty in achievingthe desirable maximal effort. Therefore, the bloodpressure and heart rate measurements during the firstadmission exercise were excluded. When patients wereon placebo, blood pressure rose from 196/118 ±5.5/2.5 mm Hg to 225/129 ± 5.1/2.7 mm Hg within 1minute after maximal exercise. At the end of theeighth week of atenolol therapy, blood pressure in-creased from 161/99 ± 3.6/2.7 mm Hg to 179/106 ±4.0/2.1 mm Hg. Figure 5 shows the marked reduc-tion of blood pressure at 1 and 5 minutes after exer-cise during treatment.

Figure 6 shows the changes in the exercise heart rateproduced by atenolol. Before treatment, heart rate in-creased by 36 beats/min (42%) within 1 minute ofmaximal exercise. After treatment, the heart rate in-creased by 19 beats/min (26%). The drug produced a

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reduction of 29 beats/min (24%) in the maximal exer-cise heart rate. The slowing of exercise heart rate (1minute) by atenolol was related to the degree of reduc-tion in supine systolic blood pressure (r = 0.66, p <0.01) (fig. 7).

Atenolol Plasma Level

Twenty-eight determinations of atenolol plasmalevel were made in 18 patients. Blood pressure wasmeasured at time of blood sampling. Twenty-fivedeterminations were made 24 hours after intake of thetablet (table 2). In three patients, determinations weremade 2 hours after atenolol intake (100 mg); in thesepatients plasma levels were 0.20, 0.35 and 0.52 ,g/ml.The limit of detection in these analyses was about 0.01,g/ml. There was marked variability in plasma levelafter atenolol administration (table 2). However,atenolol level and the hypotensive effect were notrelated. In six determinations, nothing was detected inplasma despite the presence of hypotensive action.The duration of therapy did not influence the plasmalevel, but an increase in dosage produced higheratenolol concentrations in the blood (able 2).

Effect on ECG, Fundi and Serum Creatinine

ST-segment and T-wave abnormalities were nor-malized in four of 13 patients; however, electrocar-diographic left ventricular hypertrophy did not regressafter therapy. Abnormalities in optic fundi improvedin the majority of patients: grade I reverted to normalin three of eight and grade II regressed to grade I inthree of six and to normal in one patient. The threepatients with grade III regressed to grade II. Serumcreatinine decreased from 1.3 to 1.1 mg/100 ml.

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Side Effects

All patients completed the trial. None of the sideeffects was severe enough to warrant interruption ofatenolol therapy. Four patients complained of cold ex-tremities. Three patients complained of tiredness andfatigue. These two complaints were present predom-inantly at the start of the treatment by atenolol; how-ever, they subsided and greatly ameliorated with con-tinuation of therapy, especially in the last 2 weeks.Two patients complained of insomnia, one patientcomplained of dizziness and one of dyspepsia.

Diabetic patients tolerated atenolol as well as theother patients did. However, the insulin requirementshad to be increased in the patient with insulin-dependent diabetes. The three diabetic patients hadmore impairment in the 3-hour glucose tolerancecurve, with more hyperglycemic changes. Broncho-spasm and asthmatic bronchitis did not worsen withatenolol therapy. Body weight did not change duringtreatment.

TABLE 2. Atenolol Plasma LevelDuration

Atenolol of No. of Atenolol plasmadose therapy determi- level (,ug/ml)

(mg/day) (weeks) nations Range Mean ± SD100 2 12 ND to 0.29 0.09 ± 0.09100 6 6 ND to 0.18 0.08 ± 0.07200 6 7 ND to 0.50 0.18 ±0.17Abbreviation: ND = nothing detected (limit of detection

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Discussion

Previous trials with f3-adrenergic blocking agents asthe sole hypotensive agents were usually limited toselected groups of patients with mild-to-moderate un-complicated hypertension. The present study wasdesigned to examine the efficacy and safety ofatenolol, a cardioselective 0-adrenergic blocking drug,in a heterogeneous group of hypertensive patients, in-cluding patients with mild, moderate, and severe,accelerated hypertension. The drug was given to com-plicated cases - patients with cardiomegaly, dia-betics and a patient with bronchial asthma. Previousstudies have shown atenolol to be effective in treatingmild and moderate hypertension.7 8, 12-14 However, itsuse in severe, complicated cases has not beendescribed. The cardioselectivity of atenolol could beexpected to reduce the risk of obstructive respiratorysymptoms. Moreover, as vascular f2 receptors are leftunblocked by atenolol, it seems probable that acuterises of blood pressure, e.g., due to stress-inducedrelease of circulating catecholamines, would be lessmarked than f0- and f2-receptor blocking agents (non-cardioselective).'8 The lack of sympathomimetic effectof atenolol would be expected to be an advantage, atleast in the treatment of severe hypertension, as hasbeen claimed for propranolol.'6The results of the present study demonstrate that

atenolol lowers arterial pressure in all grades of hy-pertension with minimal side effects. Patients withmild-to-moderate hypertension showed the best thera-peutic response; blood pressure was adequately con-trolled in all nine patients in this group. A signifi-cant hypotensive action developed within 2 weeks oftherapy, and control of hypertension was maintainedfor 2 weeks after sudden interruption of treatment.The return of blood pressure to the initial placebolevel was gradual and took more than 4 weeks (fig. 1).Atenolol controlled both the supine and the standingblood pressure and markedly attenuated the initialhypertensive response to severe exercise. There wasneither postural hypotension nor postexercise hypo-tension. The present study did provide evidence thatatenolol was effective over 24 hours. Blood pressurewas measured at time of blood sampling for atenololplasma level 24 hours after drug intake. These meas-urements and those taken 3-4 hours after administra-tion of atenolol were the same. The persistence of a.hypotensive action for 2 weeks after discontinuationof treatment (table 1, fig. 1) was an additional indica-tion of prolonged effectiveness of atenolol. Previousstudies showed that once-daily dosing with atenololcontrolled blood pressure for at least 24 hours.8' 18

Atenolol was given once daily in a single dose of100-300 mg. The drug appeared to exert its maxi-mum hypotensive effect at the 100-mg/day dosage.This observation is in agreement with the preliminaryfindings of Amery et al.6 and Myers et al.,7 which alsoshowed a flat dose-response relationship between in-creasing doses of atenolol and changes in arterialpressure. We found that an increase in atenolol dosagefrom 100 to 200 mg had no significant additional

hypotensive effect; it only produced more slowing ofthe heart rate. An increase in dosage to 300 mg/daywas tried in four resistant cases (blood pressure of180/1 10 mm Hg) in an effort to achieve better controlof hypertension. This increase in dosage decreasedblood pressure by an average of 13/8 mm Hg (range0-22/0-14 mm Hg) (fig. 3). However, one must con-sider that the somewhat greater fall in blood pressureon the higher dose of atenolol is probably because thehigh dose was always given after the lower dose andwould possibly benefit from the progressive decreasein blood pressure with time.

The magnitude of the hypotensive response wasrelated to the initial systolic blood pressure (fig. 2).There was a positive correlation between the reduc-tion in systolic blood pressure and the initial systolicblood pressure (r = 0.77, p < 0.01). Such a relation-ship has been described with propranolol.'7 Themechanism of this correlation is not clear from thepresent study.

Atenolol was given to six patients with cardio-megaly and recent exertional dyspnea. The drug waseffective and safe. In five patients, shortness of breathwas relieved and exercise tolerance markedly im-proved. Studies in animals have shown that atenololhas no negative inotropic effect.'8 Hemodynamicstudies in man have shown that during supine rest, thestroke volume was higher after therapy than before"9and that myocardial contractility was not depressed.20Control of hypertension would relieve the pressureafterload, and the bradycardia would allow better fill-ing of the heart.One objective of this study was to examine some of

the factors that might influence the magnitude of thehypotensive action of atenolol. Previous studies failedto show a clear relationship between cardiac f, block-ade and the antihypertensive effect of ,B-blockingagents.2" 22 To assess the degree of the blockade of in-trinsic B-sympathetic drive, exercise was used becauseit offers a reproducible physiologic adrenergic stimu-lation. We found a positive correlation between theslowing of the exercise heart rate by atenolol and thedegree of reduction in supine systolic blood pressure (r= 0.66, p < 0.01) (fig. 7). This finding suggests thatpart of the hypotensive action of atenolol was relatedto cardiac fl blockade. However, the atenolol plasmalevel and its hypotensive effect were not related. Theplasma level was not influenced by the duration oftherapy, but by the dose given (table 2). Large inter-individual differences in the plasma concentrationwere found. This was in agreement with the observa-tions on other a blockers.2' 24The antihypertensive effect of atenolol was not in-

fluenced by the age of the patient, the duration ofhypertension, the initial heart rate or the presence oftarget organ damage. However, the drug was mosteffective in patients with mild-to-moderate hyperten-sion.

Thus, atenolol is an effective antihypertensiveagent. It can be used in the treatment of hypertensionof varying degrees of severity, whether complicated ornot, although atenolol therapy did not control blood

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pressure in severe hypertension. The only side effectthat should be carefully considered is the impairmentof glucose tolerance in diabetic patients.

AcknowledgmentThe authors express their sincere gratitude to Dr. S. Heshmat

Gadoo, Director General of the Medical Department of the CairoTransport Organization, for his help and for allowing the study tobe carried in his hospital. Also, we are grateful to Dr. Hassan Negmand the Imperial Chemical Industries Laboratories for providingthe atenolol (Tenormin) and placebo tablets and for doing plasmaatenolol estimations and to Mostafa Abdel Mohaymen for hissecretarial assistance and his help in typing the manuscript.

References1. Prichard BNC, Dillam PMS: Treatment of hypertension with

propranolol. Br Med J 1: 7, 19692. Lohmoller G, Frohlich ED: A comparison of timolol and

propranolol in essential hypertension. Am Heart J 89: 437,1975

3. Ibrahim MM, Mossallam R: Pindolol in the treatment of mildand moderately severe hypertension. Med J Cairo University46: 129, 1978

4. Barrett AM, Carter J, Fitzgerald JD, Hull L, LeCount D: Anew type of cardioselective adrenoceptive blocking drug. Br JPharmacol 48: 340, 1973

5. Aberg H: Plasma renin activity after the use of a new beta-adrenergic blocking agent (I.C.I. 66082). Int J Clin Pharmacol9: 98, 1974

6. Amery A, Billiet L, Fagard R: Beta receptors and renin re-lease. N Engl J Med 290: 284, 1974

7. Myers MG, Lewis GRJ, Steiner J, Dollery CT: Atenolol in es-sential hypertension. Clin Pharmacol Ther 19: 502, 1976

8. Douglas-Jones AP, Cruickshank JM: Once-daily dosing withatenolol in patients with mild or moderate hypertension. BrMed J 1: 990, 1976

9. Sokolow M, Lyon TP: The ventricular complex in left ven-tricular hypertrophy as obtained by unipolar precordial andlimb leads. Am Heart J 37: 161, 1949

10. McPhie J: Left ventricular hypertrophy: electrocardiographicdiagnosis. Aust Ann Med 7: 317, 1958

11. Scales B, Copsey PB: The gas chromatographic determinationof atenolol in biological samples. J Pharm Pharmacol 27: 430,1975

12. Petrie JC, Galloway DB, Webster J, Simpson WT, Lewis JA:Atenolol and bendrofluazide in hypertension. Br Med J 4: 133,1975

13. Castleden CM, Dathan JRE, George CF: A comparison ofonce and twice daily atenolol in hypertension. Postgrad Med J53: 679, 1977

14. Webster J, Jeffers TA, Galloway DB, Petrie JC, Barker NP:Atenolol, methyldopa and chlorthalidone in moderate hyper-tension. Br Med J 1: 76, 1977

15. Hansson L, Karlberg BE, Aberg H, Westerlund A, Jameson S,Heningsen NC: Long term hypotensive effect of atenolol (ICI66.082), a new beta adrenergic blocking drug. Acta Med Scand199: 257, 1976

16. Kincaid-Smith P: Management of severe hypertension. Am JCardiol 32: 575, 1973

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M M Ibrahim and R MossallamClinical evaluation of atenolol in hypertensive patients.

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