TENORMIN (atenolol)

TENORMIN
(atenolol)
Tablets, 50 mg and 100 mg

THERAPEUTIC CLASSIFICATION
Beta-adrenergic receptor blocking agent
ACTIONS AND CLINICAL PHARMACOLOGY
TENORMIN (atenolol) is a beta1-selective, beta adrenergic blocking agent, devoid of
membrane stabilizing or intrinsic sympathomimetic (partial agonist) activities. It is a racemic
mixture and the beta1 properties reside in the S(-) enantiomer. Beta1-selectivity decreases
with increasing dose.
The mechanism of the antihypertensive effect has not been established. Among the factors
that may be involved are:
(a) competitive ability to antagonize catecholamine-induced tachycardia at the beta-
receptor sites in the heart, thus decreasing cardiac output
(b) inhibition of renin release by the kidneys
(c) inhibition of the vasomotor centres
The mechanism of the anti-anginal effect is also uncertain. An important factor may be the
reduction of myocardial oxygen requirements by blocking catecholamine-induced increases in
heart rate, systolic blood pressure, and the velocity and extent of myocardial contraction.
In man atenolol reduces both isoproterenol- and exercise-induced increases in heart rate over
the dose range of 50 to 200 mg. At an oral dose of 100 mg the beta1 blocking effects persist
for at least 24 hours; the reduction in exercise-induced heart rate increase being about 32%
and 13%, 2 and 24 hours after dosing, respectively. The logarithm of the plasma atenolol
level correlates with the degree of beta1 blockade but not with the antihypertensive effect.

Pharmacokinetics

Approximately 40 to 50% of an oral dose of atenolol is absorbed from the gastrointestinal
tract, the remainder being excreted unchanged in the feces. Peak plasma concentrations occur
2-4 hours after dosing and are subject to a 4-fold variability. The plasma levels are
proportional to dose over the range 50-400 mg and 6 to 16% of atenolol is bound to plasma
proteins. The mean peak plasma concentrations of atenolol were approximately 300 and 700
nanogram/mL following 50 and 100 mg, respectively. The plasma half-life is approximately
6-7 hours. Atenolol is extensively distributed to extravascular tissues, but only a small
amount is found in the central nervous system.
There is no significant hepatic metabolism of atenolol in man and more than 90% of the
absorbed dose reaches the systemic circulation unaltered. Small quantities of a hydroxy
metabolite and a glucuronide are produced but neither has major pharmacological activity. As
a consequence no accumulation occurs in patients with liver disease and no dosage adjustment
is required. Approximately 47 and 53% of the oral dose is eliminated in the urine and feces,
respectively. Recovery is complete after 72 hours.
Atenolol is primarily eliminated by the kidney, predominantly by glomerular filtration. The
normal elimination half-life may increase in severe renal impairment but no significant
accumulation occurs in patients who have creatinine clearance greater than 35 mL/min. The
oral dose should be reduced in patients with a creatinine clearance less than 35 mL/min (see
DOSAGE and ADMINISTRATION).
Following intravenous administration, peak plasma levels were reached within 5 minutes.
Declines from peak plasma levels are rapid (5- to 10-fold) during the first 7 hours; thereafter,
plasma levels decay with a half-life similar to that of orally administered drug. Over 85% of
an intravenous dose is excreted in urine within 24 hours.
Atenolol is excreted in human breast milk and crosses the placental barrier - the maternal to
cord blood ratio being about unity.

INDICATIONS AND CLINICAL USE
Hypertension
TENORMIN (atenolol) tablets are indicated in patients with mild or moderate hypertension.
It is usually used in combination with other drugs, particularly a thiazide diuretic. However, it
may be tried alone as an initial agent in those patients in whom, in the judgement of the
physician, treatment should be started with a beta-blocker rather than a diuretic. TENORMIN
may be used in combination with diuretics and/or vasodilators to treat severe hypertension.
The combination of TENORMIN with a diuretic or peripheral vasodilator has been found to
be compatible. Limited experience with other antihypertensive agents has not shown evidence
of incompatibility with TENORMIN.

TENORMIN is not recommended for the emergency treatment of hypertensive crises.

Angina Pectoris
TENORMIN tablets are indicated in the long-term management of patients with angina
pectoris due to ischemic heart disease.
CONTRAINDICATIONS
TENORMIN (atenolol) should not be used in the presence of:
1. sinus bradycardia, or bradycardia of other origin
2. second and third degree A-V block
3. sick sinus syndrome
4. right ventricular failure secondary to pulmonary hypertension
5. uncontrolled heart failure
6. cardiogenic shock
7. hypotension
8. severe peripheral arterial disorders
9. anesthesia with agents that produce myocardial depression
10. pheochromocytoma, in the absence of alpha-blockade
11. metabolic acidosis
12. known hypersensitivity to the product
WARNINGS
a) Cardiac Failure
Special caution should be exercised when administering TENORMIN (atenolol) to patients
with a history of heart failure. Sympathetic stimulation is a vital component supporting
circulatory function in congestive heart failure and inhibition with beta blockade always
carries the potential hazard of further depressing myocardial contractility and precipitating
cardiac failure. TENORMIN acts selectively without abolishing the inotropic action of
digitalis on the heart muscle. However, the positive inotropic action of digitalis may be
reduced by the negative inotropic effect of TENORMIN when the two drugs are used
concomitantly. The effects of beta-blockers and digitalis are additive in depressing A-V
conduction. In patients without a history of cardiac failure, continued depression of the
myocardium over a period of time can, in some cases, lead to cardiac failure. Therefore, at the
first sign or symptom of impending cardiac failure, patients should be fully digitalised and/or
given a diuretic and the response observed closely. If cardiac failure continues, despite
adequate digitalisation and diuretic therapy, TENORMIN therapy should be immediately
withdrawn.
b) Abrupt Cessation of Therapy with TENORMIN
Patients with angina should be warned against abrupt discontinuation of TENORMIN. There
have been reports of severe exacerbation of angina and of myocardial infarction or ventricular
arrhythmias occurring in patients with angina pectoris, following abrupt discontinuation of
beta-blocker therapy. The last two complications may occur with or without preceding
exacerbation of angina pectoris. Therefore, when discontinuation of TENORMIN is planned
in patients with angina pectoris, the dosage should be gradually reduced over a period of about
two weeks and the patient should be carefully observed and advised to limit physical activity
to a minimum. The same frequency of administration should be maintained. In situations of
greater urgency, TENORMIN should be discontinued stepwise over a shorter time and under
closer observation. If angina markedly worsens or acute coronary insufficiency develops, it is
recommended that treatment with TENORMIN be reinstituted promptly, at least temporarily.
c) Oculomucocutaneous Syndrome
Various skin rashes and conjunctival xerosis have been reported with beta-blockers, including
TENORMIN. A severe syndrome (oculomucocutaneous syndrome) whose signs include
conjunctivitis sicca and psoriasiform rashes, otitis, and sclerosing serositis has occurred with
the chronic use of one beta-adrenergic blocking agent (practolol). This syndrome has not been
observed with TENORMIN or any other such agent. However, physicians should be alert to
the possibility of such reactions and should discontinue treatment in the event that they occur.
d) Prinzmetal's Angina
TENORMIN may increase the number and duration of angina attacks in patients with
Prinzmetal's angina due to unopposed alpha-receptor mediated coronary artery
vasoconstriction. TENORMIN, therefore, should only be used in these patients with the
utmost care.
e) Sinus Bradycardia
Severe sinus bradycardia may occur with the use of TENORMIN from unopposed vagal
activity remaining after blockade of beta1-adrenergic receptors; in such cases, dosage should
be reduced.
f) Thyrotoxicosis
In patients with thyrotoxicosis, possible deleterious effects from long-term use of
TENORMIN have not been adequately appraised. Beta-blockade may mask the clinical signs
of continuing hyperthyroidism or its complications and give a false impression of
improvement. Therefore, abrupt withdrawal of TENORMIN may be followed by an
exacerbation of the symptoms of hyperthyroidism, including thyroid storm.
g) Pregnancy
Atenolol can cause fetal harm when administered to a pregnant woman. Atenolol crosses the
placental barrier and appears in the cord blood.
No studies have been performed on the use of atenolol in the first trimester and the possibility
of fetal injury cannot be excluded. Administration of atenolol, starting in the second trimester
of pregnancy, has been associated with the birth of infants that are small for gestational age.
Studies in humans have shown that transplacental passage of atenolol does occur in pregnant
women, with fetal drug serum levels equal to those of the mother. In a limited number of
patients who were given the drug during the last trimester of pregnancy, low birth weight,
neonatal hypoglycemia, bradycardia in the fetus/newborn, and placental insufficiency were
observed.
Neonates born to mothers who are receiving TENORMIN at parturition or breast-feeding may
be at risk for hypoglycemia and bradycardia. Caution should be exercised when TENORMIN
is administered during pregnancy or to a woman who is breast-feeding. (See
PRECAUTIONS, Use in Lactating Women.)
Atenolol has been shown to produce a dose-related increase in embryo/fetal resorptions in rats
at doses equal to or greater than 50 mg/kg/day or 25 or more times the maximum
recommended human dose.
PRECAUTIONS
a) Bronchospastic Disorders
Patients with bronchospastic diseases should, in general, not receive beta-blockers. Due to the
relative beta1-selectivity of TENORMIN, TENORMIN may be used with caution in patients
with bronchospastic disease who do not respond to, or cannot tolerate, other antihypertensive
treatment. Since beta1-selectivity is not absolute, a beta2-stimulating agent should be
administered concomitantly, the lowest possible dose of TENORMIN should be used.
Despite these precautions, the respiratory status of some patients may worsen, and, in such
cases, TENORMIN should be withdrawn.
b) First Degree Heart Block
Due to its negative effect on A-V conduction time, TENORMIN should be used with caution
in patients with first degree block.
c) Peripheral Arterial Circulatory Disorders
TENORMIN may aggravate less severe peripheral arterial circulatory disorders (see
CONTRAINDICATIONS).
d) Anaphylaxis - Epinephrine and Beta-Blockers
There may be increased difficulty in treating an allergic type reaction in patients on beta
blockers. In these patients, the reaction may be more severe due to pharmacological effects of
beta-blockers and problems with fluid changes. Epinephrine should be administered with
caution since it may not have its usual effects in the treatment of anaphylaxis. On the one
hand, larger doses of epinephrine may be needed to overcome the bronchospasm, while on the
other, these doses can be associated with excessive alpha adrenergic stimulation with
consequent hypertension, reflex bradycardia and heart-block and possible potentiation of
bronchospasm. Alternatives to the use of large doses of epinephrine included vigorous
supportive care such as fluids and the use of beta agonists including parenteral salbutamol or
isoproterenol to overcome bronchospasm, and norepinephrine to overcome hypotension.
e) Diabetes and Patients Subject to Hypoglycemia
TENORMIN should be administered with caution to patients subject to spontaneous
hypoglycemia, or to diabetic patients (especially those with labile diabetes) who are receiving
insulin or oral hypoglycemic agents. Beta-adrenergic blockers may mask the premonitory
signs (e.g. tachycardia) and symptoms of acute hypoglycemia.
f) Impaired Renal Function
TENORMIN should be used with caution in patients with impaired renal function (see
DOSAGE AND ADMINISTRATION).
When renal function is impaired, clearance of atenolol is closely related to the glomerular
filtration rate; however, significant accumulation does not occur until the creatinine clearance
falls below 35 mL/min/1.73 m2
.
g) Elective or Emergency Surgery
It is not advisable to withdraw beta-adrenoceptor blocking drugs prior to surgery in the
majority of patients. However, care should be taken when using TENORMIN with
anaesthetic agents such as those which may depress the myocardium. Vagal dominance, if it
occurs, may be corrected with atropine (1-2 mg i.v.).
Some patients receiving beta-adrenergic blocking agents have been subject to protracted
severe hypotension during anesthesia. Difficulty in restarting and maintaining the heartbeat
has also been reported.
In emergency surgery, since atenolol is a competitive inhibitor of beta-adrenergic receptor
agonists, its effects may be reversed, if necessary, by sufficient doses of such agonists as
isoproterenol or norepinephrine.
h) Ethnic Populations
TENORMIN appears to be effective and well-tolerated in most ethnic populations, although
the responses may be less in black patients than in Caucasians.
i) Use in Lactating Women
In humans, there is a significant accumulation of atenolol in the breast milk of lactating
women. Neonates born to mothers who are breastfeeding may be at risk for hypoglycemia
and bradycardia. If the use of TENORMIN is considered essential, then mothers should stop
nursing.
j) Use in Children
There is no experience with TENORMIN in the treatment of pediatric age groups.
k) Activities Requiring Mental Alertness
Use of TENORMIN is unlikely to result in any impairment of the ability of patients to drive or
operate machinery. However, it should be taken into account that dizziness or fatigue may
occur.
l) Geriatric Use
Clinical studies of TENORMIN did not include sufficient numbers of subjects aged 65 and
over to determine whether they respond differently from younger subjects. Other reported
clinical experience has not identified differences in responses between elderly and younger
patients. In general, dose selection for an elderly patient should be cautious, usually starting
at the low end of the dosing range, reflecting the greater frequency of decreased hepatic renal,
or cardiac function, and concomitant diseases or other drug therapy.
m) Drug Interactions
Clonidine
Beta-blockers may exacerbate the rebound hypertension which can follow the withdrawal of
clonidine. If the two drugs are co-administered, the beta-blocker should be withdrawn several
days before discontinuing clonidine. If replacing clonidine by beta-blocker therapy, the
introduction of beta-blockers should be delayed for several days after clonidine administration
has stopped. (Also see prescribing information for clonidine).
Reserpine or Guanethidine
Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be
closely monitored because the added beta-adrenergic blocking action of TENORMIN may
produce an excessive reduction of sympathetic activity. TENORMIN should not be combined
with other beta-blockers.
Antiarrhythmic Agents
Class I anti-arrhythmic drugs (e.g. disopyramide) and amiodarone may have potentiating
effect on atrial-conduction time and induce negative inotropic effect.
Calcium Channel Blockers
Combined use of beta-blockers and calcium channel blockers with negative inotropic effects
can lead to prolongation of S-A and A-V conduction, particularly in patients with impaired
ventricular function, conduction abnormalities, or diminished cardiac output. This may result
in severe hypotension, bradycardia and cardiac failure. Concomitant therapy with
dihydropyridines, e.g., nifedipine, may increase the risk of hypotension, and cardiac failure
may occur in patients with latent cardiac insufficiency.
Digitalis Glycosides
Digitalis glycosides may potentiate the bradycardia of beta1-blockade.
Non-Steroidal Anti-Inflammatory Agents
The concomitant use of non-steroidal anti-inflammatory agents may blunt the antihypertensive
effects of beta-blockers.
Anaesthetic Agents
Anaesthetics can produce a hypotensive state with associated reflex tachycardia. Since beta-
blockade will inhibit reflex tachycardia, the hypotensive potential of anaesthetic agents is
increased with concomitant use of TENORMIN. The anaesthetist should be informed and the
choice of anaesthetic should be an agent with as little negative inotropic activity as possible
(see CONTRAINDICATIONS and PRECAUTIONS, Elective or Emergency Surgery).
Fingolimod
Concomitant use of fingolimod with beta blockers may potentiate bradycardic effects and is
not recommended. Where such co-administration is considered necessary, appropriate
monitoring at treatment initiation, i.e. at least overnight monitoring, is recommended.
ADVERSE REACTIONS
The most serious adverse reactions encountered are congestive heart failure, A-V block and
bronchospasm. Bronchospasm may occur in patients with bronchial asthma or a history of
asthmatic complaints.
The most common adverse reactions reported in clinical trials with oral TENORMIN
(atenolol) in 2500 patients are bradycardia (3%), dizziness (3%), vertigo (2%), fatigue (3%),
diarrhea (2%) and nausea (3%).
Adverse reactions occuring with an incidence of less than 1%, grouped by system, are as
follows:
Cardiovascular
Heart failure deterioration (see WARNINGS)
Heart block
Palpitations
Lengthening of P-R interval
Chest pain
Lightheadedness
Postural hypotension which may be associated with syncope
Raynaud's phenomenon
Intermittent claudication, or worsening of pre-existing intermittent claudication
Leg pain and cold extremities
Edema
Respiratory
Dyspnea, wheeziness
Cough
Bronchospasm
Central Nervous System
Faintness
Ataxia
Tiredness
Lethargy
Nervousness
Depression
Drowsiness
Vivid dreams
Insomnia
Paresthesia
Headache
Tinnitus
Mood Changes
Visual disturbances
Psychoses and hallucinations
Gastrointestinal
Constipation
Anorexia
Abdominal discomfort, indigestion
Miscellaneous
Skin rash
Itchy and/or dry eyes
Psoriasiform skin reactions
Exacerbation of psoriasis
Decreased exercise tolerance
Alopecia
Epistaxis
Flushes
Impotence, decreased libido
Sweating
General body aches
Thrombocytopenia and purpura
POST MARKETING EXPERIENCE
During the post-marketing experience with TENORMIN, cold extremities, gastrointestinal
disturbances and fatigue were commonly reported. The following have been reported in
temporal relationship to the use of the drug: elevated liver enzymes and/or bilirubin, headache,
confusion, nightmares, impotence, Peyronie's disease, psoriasiform rash or exacerbation of
psoriasis, purpura, reversible alopecia and thrombocytopenia. Rare cases of hepatic toxicity including intrahepatic cholestasis have been reported. TENORMIN, like other beta blockers,
has been associated with the development of antinuclear antibodies (ANA) and lupus
syndrome.
In a long-term, well-controlled trial of 1,627 elderly patients with systolic hypertension, the
incidence of dry mouth was significantly higher in patients taking atenolol (12.2%).
Potential Adverse Reactions
The following adverse reactions have occurred with other beta-blockers but have not been
reported with TENORMIN:
Cardiovascular: pulmonary edema, cardiac enlargement, hot flushes and sinus
arrest
Central Nervous System: aggressiveness, anxiety, short term memory loss, and emotional
lability with slightly clouded sensorium
Allergic: laryngospasm, status asthmaticus and fever combined with
aching and sore throat
Dermatological: exfoliative dermatitis
Ophthalmological: blurred vision, burning, and grittiness
Hematological: agranulocytosis
Gastrointestinal: mesenteric arterial thrombosis and ischemic colitis
SYMPTOMS AND TREATMENT OF OVERDOSAGE
Limited information is available with regard to overdosage with TENORMIN (atenolol) in
humans. Overdosage with atenolol has been reported with patients surviving acute doses as
high as 5 g. One death was reported in a man who may have taken as much as 10 g acutely.
The predominant symptoms reported following atenolol overdosage are lethargy, disorder of
respiratory drive, wheezing, sinus pause, and bradycardia. Additionally, common effects
associated with overdosage of any beta-adrenergic blocking agent are congestive heart failure,
hypotension, bronchospasm, and/or hypoglycemia.
Treatment should be symptomatic and supportive and directed to the removal of any
unabsorbed drug by induced emesis, or administration of activated charcoal. Atenolol can be
removed from the general circulation by hemodialysis. Further consideration should be given
to dehydration, electrolyte imbalance and hypotension by established procedures.

Other treatment modalities should be employed at the physician's discretion and may include:
BRADYCARDIA: Atropine 1-2 mg intravenously. If there is no
response to vagal blockade, give isoproterenol
cautiously. In refractory cases, a transvenous cardiac
pacemaker may be indicated. Glucagon in a 10 mg
intravenous bolus has been reported to be useful. If
required, this may be repeated or followed by an
intravenous infusion of glucagon 1-10 mg/h
depending on response. If no response to glucagon
occurs or if glucagon is unavailable, a beta-
adrenoceptor stimulant such as dobutamine 2.5 to 10
micrograms/kg/minute by intravenous infusion or
isoproterenol 10 to 25 micrograms given as an
infusion at a rate not exceeding 5 micrograms/minute
may be given, although larger doses may be required.
HEART BLOCK:
(second or third degree)
Isoproterenol, or transvenous pacemaker.
CONGESTIVE HEART FAILURE: Digitalize the patient and administer a diuretic.
Glucagon has been reported to be useful.
HYPOTENSION: Vasopressors such as dopamine or norepinephrine.
Monitor blood pressure continuously.
BRONCHOSPASM: A beta2-stimulant such as isoproterenol or terbutaline
and/or intravenous aminophylline.
HYPOGLYCEMIA: Intravenous glucose.
Based on the severity of symptoms, management may require intensive support care and
facilities for applying cardiac and respiratory support.
DOSAGE AND ADMINISTRATION
Hypertension
TENORMIN (atenolol) is usually used in conjunction with other antihypertensive agents,
particularly a thiazide diuretic, but may be used alone (see INDICATIONS).
The dose of TENORMIN should be administered in accordance with individual patient's
needs.
The following guidelines are recommended:
The initial dose of TENORMIN is 50 mg administered as one tablet a day either added to
diuretic therapy or alone. The full effect of this dose will usually be seen within one to two
weeks. If an adequate response is not achieved, the dose should be increased to TENORMIN
100 mg once daily. Increasing the dose beyond 100 mg a day is unlikely to produce any
further benefit.
If further lowering of the blood pressure is required, another antihypertensive agent should be
added to the regimen.
Angina Pectoris
The initial dose of TENORMIN is 50 mg given as one tablet a day. The full effect of this
dose will usually be seen within one to two weeks. If an optimal response is not achieved
within one week, the dosage should be increased to TENORMIN 100 mg given as one tablet a
day or 50 mg twice daily. Some patients may require a dosage of 200 mg a day for optimal
effect.
Patients with Renal Impairment
Since atenolol is eliminated predominantly via the kidneys, dosage should be adjusted in
patients with severe renal impairment. Significant accumulation of atenolol occurs when
creatinine clearance falls below 35 mL/min/1.73m2
(normal range is 100-150
mL/min/1.73m2
).
The following maximum dosages are recommended for patients with renal impairment:
Creatinine
Clearance(mL/min/1.73m2
)
Atenolol Elimination Half-
Life(hr)
Maximum Dosage
15-35 16-27 50 mg daily
<15 >27 50 mg every other day
Patients on hemodialysis should be given 50 mg after each dialysis; this should be done under
hospital supervision as marked falls in blood pressure can occur.
Dosage requirements may be reduced in the elderly, especially in patients with impaired renal
function.
PHARMACEUTICAL INFORMATION
Drug Substance
Proper name Atenolol
Chemical Name 4-[2'-hydroxy-3'-[(1-methylethyl) amino] propoxy]-
benzeneacetamide
Molecular Formula C14H22N2O3
Structural Formula
Molecular Weight
(free base)
266.34
Description Atenolol is a white or almost white crystalline powder. It is a
relatively polar hydrophilic compound with a water solubility of 26.5
mg/mL at 37°C and a log partition coefficient (octanol/water) of 0.23.
Atenolol is freely soluble in 1N HCl (300 mg/mL at 25°C) and less
soluble in chloroform (3 mg/mL at 25°C). The melting point for
atenolol is 152.0°C to 155.0°C
Composition
In addition to the active ingredient atenolol, each tablet contains the following inactive
ingredients: maize starch, heavy magnesium carbonate, gelatin, sodium lauryl sulphate,
magnesium stearate, hydroxypropyl methylcellulose, glycerol and titanium dioxide.
Storage Recommendations
TENORMIN Tablets should be stored between 15 and 25°C, protected from light and
moisture.
AVAILABILITY OF DOSAGE FORMS
50 mg tablets – white, round biconvex, film-coated tablets embossed with 50 on one face and
bisected on the reverse, in calendar packs of 30 tablets.
100 mg tablets – white, round biconvex, film-coated tablets embossed with 100 on one face
and bisected on the reverse, in calendar packs of 30 tablets.
PHARMACOLOGY
Animal Studies
Chronic studies performed in animals have revealed the occurrence of vacuolation of
epithelial cells of Brunner's glands in the duodenum of both male and female dogs at all tested
dose levels of atenolol (starting at 15 mg/kg/day or 7.5 times the maximum recommended
human dose) and an increased incidence of atrial degeneration of hearts of male rats at 300 but
not 150 mg atenolol/kg/day (150 and 75 times the maximum recommended human dose,
respectively).
Effect on the Cardiovascular System
In anesthetized cats, atenolol infusion reduces the chronotropic response to isoproterenol and
right cardiac sympathetic nerve stimulation.
In anesthetized dogs, atenolol 0.03 mg/kg i.v. depresses the heart rate by 22%, cardiac
contractile force by 16% and diastolic blood pressure by 11%.
Studies in rats showed that atenolol was devoid of intrinsic sympathomimetic activity.
Atenolol in concentrations up to 10 mg/mL had no local anesthetic effect on the isolated
sciatic nerve of the frog.
Atenolol (5-20 mg/kg i.v.) was without effect on the ventricular tachycardia produced by toxic
levels of ouabain in anesthetized dogs. Atenolol (0.2 mg/kg i.v.) protected coronary ligated
dogs from the arrhythmogenic activity of adrenaline on the fourth day after ligation (when the
cardiac rhythm was predominantly sinus).
Single oral doses of 100 mg atenolol given to volunteers reduced exercise-induced tachycardia
by 31% at 4 hours and by 15% at 24 hours after administration. The maximal suppression of
the systolic blood pressure response to exercise was 21% at 4 hours.
Effects on Plasma Renin Activity
Studies in hypertensive patients have shown that the antihypertensive effect of atenolol is
associated with a decrease in plasma renin activity.
Effects on Pulmonary Function
The effects of a single 100 mg dose of atenolol on forced expiratory volume (FEV1) and
airways resistance (AWR) were assessed in ten patients with labile asthma. The
cardioselective agents tested in this comparative trial, including atenolol, usually had a lesser
dose-related effect on airway function than non-selective beta-blockers. Atenolol produced a smaller decrease in FEV1 than did the non-selective agents and did not inhibit the
bronchodilator response to isoprenaline. The decrease in FEV1 was 8-9%. Other studies in
asthmatic patients have reported similar decreases in FEV1 with atenolol. Dose-effect
comparisons with cardioselective agents have shown a fall in FEV1 values at the higher doses,
indicating some beta2-blocking effect.
Metabolic Effects
TENORMIN did not potentiate the hypoglycemic effects of insulin in 12 patients with
diabetes.
TOXICOLOGY
Acute Toxicity
Species Sex Concentration Route LD50 (mg/kg)
Mouse M/F 20% (1) Oral >2000
Mouse M/F 0.8-1.2% (2) i.v. 100
Rat M/F 30% (1) Oral >3000
Rat Male 21.3% (3) Oral 4960
Rat Female 21.3% (3) Oral 6600
Rat M/F 1.0-4.0% (2) i.v. 50-60
Rat Male 0.5% (2) i.v. 129(25)
Rat Female 0.5% (2) i.v. 114(30)
Rhesus Monkey M/F Variable (1) Oral >6000
(1) Suspension (2) Solution (3) Formulated Tablet
Toxic signs in rats were: depression, ataxia, labored respiration, cyanosis, tremors and
convulsions. Effects occurred within 5 minutes following intravenous administration and
surviving rats appeared normal after 2 hours. Effects following oral administration occurred
within 1 hour and some persisted through 48 hours. Surviving rats appeared normal within 72
hours.
Following intravenous administration, all mice convulsed immediately and those animals
dying did so within 5 minutes.
Toxic signs in monkeys following oral administration were emesis, lethargy, slight mydriasis,
occasional ptosis, salivation and decreased respiration. Surviving monkeys appeared normal
within 24 hours.