Atenolol

Atenolol is an antihypertensive agent belonging to the beta-blocker class.It is approved for treating hypertension, angina pectoris due to coronary atherosclerosis, and acute myocardial infarction.

Atenolol is a hydrophilic beta-receptor blocker mostly excreted by the kidneys; the liver is only involved in the metabolism of roughly 5% of the drug. About 50% of the beta-blocker is finally bioavailable after oral treatment since Atenolol is only partially absorbed from the colon. Only 3% of Atenolol in plasma is linked to proteins.

The common side effects of Atenolol include feeling sleepy, tired or dizzy, cold fingers or toes, nausea, vomiting, diarrhea, stomach pain, etc.

Atenolol is available in the form of Tablets and Injections.

Atenolol is available in Australia, Belgium, Canada, Hong Kong, Ireland, and India.

Atenolol, a cardioselective beta-1-adrenergic antagonist, blocks the positive inotropic and chronotropic actions of endogenous catecholamines like isoproterenol, norepinephrine, and epinephrine, preventing sympathetic stimulation. These catecholamines include isoproterenol, norepinephrine, and epinephrine. Through this activity, heart rate, blood pressure, and myocardial contractility are all reduced.

The onset of action of Atenolol occurs in 1 hour for oral administration and within 5 minutes for IV administration, and the peak effect at about 2-4 hours. The activity persists for approximately 24 hours.Atenolol peak plasma concentration i.e. Tmax (600 ng/ml), was discovered 3 hours after the initial dose was administered, and detectable levels (50–70 ng/ml) were discovered 24 hours later and Cmax of 0.49 µg/ml.

•  Atenolol comes as a tablet. As directed by a physician, the regular Tablet is often taken once or twice daily.
•  Atenolol injection is given as an infusion into a vein by the physician.
•  Atenolol is available in various dosage forms like- tablets and injections.

Atenolol can be used in the treatment of :

• High Blood pressure
• Angina Pectoris due to coronary atherosclerosis,
• Acute Myocardial Infraction

Atenolol is used to treat high blood pressure alone or in combination with other drugs.It works by blocking the action of certain natural chemicals in the body, such as epinephrine, on the heart and blood vessels. This effect lowers the heart rate, blood pressure, and strain on the heart. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. This medication is also used to treat chest pain (angina) and to improve survival after a heart attack. 

Atenolol is approved for use in the following clinical indications:

•  High Blood Pressure:

To treat hypertension and reduce blood pressure, Atenolol is prescribed. Lowering the blood pressure lowers the risk of fatal and non-fatal cardiovascular events, including strokes and myocardial infarctions.It can be utilized either on its own or in combination with other antihypertensive medications, notably a thiazide-type diuretic.

• Angina Pectoris Due to Coronary Atherosclerosis:

Atenolol is helpful in the long-term therapy of angina pectoris because it lowers the oxygen demands of the heart at any given amount of effort.

• Acute Myocardial Infarction:

In patients with definite or suspected acute myocardial infarction, treatment with Atenolol I.V. Injection should be used as soon as possible after the patient's arrival in the hospital and after eligibility is established. Such treatment should be initiated in a coronary care or similar unit immediately after the patient's hemodynamic condition has been stabilized.

As mentioned above, some subgroups, such as elderly people with systolic blood pressure < 120 mm Hg, appeared to be less likely to benefit.

Off-label indications include treatment of arrhythmias, migraine prophylaxis, paroxysmal supraventricular tachycardia, alcohol withdrawal, thyrotoxicosis, and prophylaxis against secondary myocardial infarction.

•  Arrhythmias:

Atenolol causes the heart to beat more slowly and gently by inhibiting the actions of epinephrine on beta-1 receptors found in cardiac tissue. This reduces heart rate.

•  Thyrotoxicosis:

The principal mechanism of action of beta blockers in hyperthyroidism is to antagonize beta-receptor-mediated effects of catecholamines. Beta Blockers are effective in treating hypermetabolic symptoms in a variety of hyperthyroid states. Used alone, they offer significant symptomatic relief.

Atenolol is available in Tablet and injections. The method of administration of Atenolol for various treatment are as follows:

•  High Blood Pressure: Atenolol initial dose is one 50 mg tablet taken daily, either on its own or in combination with the use of diuretics.

Usually, it takes one to two weeks for this dose to take full action. If the intended outcome is not achieved, the dosage should be increased to Atenolol 100 mg delivered as one Tablet daily. The dosage is unlikely to offer any further benefits if taken above 100 mg per day. Atenolol is an antihypertensive drug that can be used alone or in combination with other antihypertensive drugs such as hydralazine, alpha-methyldopa, prazosin, thiazide-type diuretics, and hydralazine.

• Angina pectoris: The initial dosage in hypertension is 50mg night and morning, increasing to 100 or 200 mg per dose depending on the response. (The treating physician's clinical judgment should guide the dosage and length of the course of treatment.)Giving doses greater than necessary to achieve an immediate maximal effect enables 24-hour control with once-daily dosing. However, at these dosages, the effect at 24 hours is diminished, averaging around 50% to 75% of that reported with once-daily oral doses of 200 mg. The maximum early effect on the exercise tolerance occurs with 50 to 100 mg doses.
• Acute Myocardial Infarction: As soon as the patient arrives at the hospital and once eligibility has been confirmed, treatment with Atenolol I.V. Injection should begin in patients with a confirmed or suspected acute myocardial infarction. Once the patient's hemodynamic situation has stabilized, such treatment should be started in a coronary care or comparable unit. The first 5 minutes of treatment should be spent injecting 5 milligrams of Atenolol intravenously, followed by another 5 mg injection 10 minutes later.
• Atenolol I.V. Injection: It should only be given under extremely controlled circumstances, including regular monitoring of ECG, heart rate, and blood pressure. It is possible to utilize Atenolol I.V. Injection diluted with Sodium Chloride Injection USP, Dextrose Injection USP, Sodium Chloride and Dextrose Injection. For 48 hours, these admixtures remain constant.Patients who respond well to the full intravenous dose (10 mg) should start taking Atenolol Tablets 50 mg 10 minutes after the previous intravenous dose, and another 50 mg oral dose should be taken 12 hours later. Following that, Atenolol can be taken by mouth in dosages of either 100 mg once daily or 50 mg twice daily for an additional 6–9 days or until being released from the hospital. Atenolol should be stopped if bradycardia, hypotension that needs treatment, or any other undesirable symptoms appear.

Atenolol should be used in the treatment of high blood pressure, angina pectoris, migraine and acute myocardial infraction, along with appropriate dietary restrictions.

•  High Blood Pressure: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable
• Angina Pectoris: Avoid foods high in saturated fat and hydrogenated or partially hydrogenated fats. Reduce the intake of dairy products, including cheese, cream, and eggs.
• Acute Myocardial infarction: No more than 25 to 35 percent of the daily calories should come from total fat (including saturated fat).The risk of fatal and non-fatal cardiovascular event, such as strokes and myocardial infarctions, is reduced by lowering blood pressure.Avoid trans fats and Consume less than 200 milligrams a day of dietary cholesterol.

The dietary restriction should be individualized as per patient requirements.

The contraindications of Atenolol are as follows:

• Sinus bradycardia, second or third-degree heart blocks, cardiogenic shock, heart failure, severe peripheral arterial disease, metabolic acidosis, and pheochromocytoma are also contraindications of Atenolol. If there is no other option, it may be used combined with a bronchodilator in individuals who have a history of asthma, bronchospasm, or other obstructive airway conditions.
• When prescribing to diabetic or thyroid patients, caution is required because the drug's actions could conceal the signs of hypoglycemia and thyrotoxicosis; also, abrupt discontinuation could trigger a thyroid storm.
• Atenolol is contraindicated in those patients with a history of hypersensitivity to Atenolol or any of the drug product's components.

For using Atenolol following warnings and precautions must be taken.The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

•  Cardiac Failure

In congestive heart failure, sympathetic activation is required to support circulatory function, and beta-blocking presents the potential risk of further decreasing myocardial contractility and triggering more severe failure. A contraindication to beta-blocker therapy in individuals with acute myocardial infarction is cardiac failure that is not quickly and successfully treated by 80 mg of intravenous furosemide or comparable therapy.

•  Bronchospastic Diseases

Beta-blockers should, in general, not be given to patients with bronchospastic disease. However, due to its relative beta 1 selectivity, Atenolol should only be used caution in bronchospastic patients who have not responded to and are unable to tolerate other antihypertensive medications. The lowest effective dose of Atenolol should be administered with therapy starting at 50 mg, and a beta2-stimulating drug (bronchodilator) should be made accessible because beta 1 selectivity is not always present. If the dosage must be raised, splitting the dose may be an option to reduce peak blood levels.

•  Diabetes and Hypoglycemia

If a beta-blocking medication is required, diabetic people should use Atenolol with caution. Beta-blockers may conceal tachycardia brought on by hypoglycemia, but they might not have a substantial impact on other symptoms like perspiration and vertigo. Atenolol, unlike nonselective beta-blockers, does not aggravate insulin-induced hypoglycemia when taken at the authorised doses. It also does not postpone the return of blood glucose to normal levels.

Precautions:

General:

Before giving Atenolol, patients taking a beta-blocker need to be carefully assessed. Atenolol dosages can be decreased initially and moving forward based on clinical data such as blood pressure and pulse.Peripheral arterial circulation problems may become worse with Atenolol.

Impaired Renal Function:

The drug should be used with caution in the patients with impaired renal function.

•  When compared to the concentration in plasma, Atenolol is eliminated from the body in human breast milk at a ratio of 1.5 to 6.8. When administering Atenolol to a nursing mother, caution should be taken. There have been cases of clinically severe bradycardia in breastfeed babies. Infants who are premature or have compromised renal function may be more susceptible to negative consequences.
• In newborns to women who are taking Atenolol at the time of parturition or who are breastfeeding their children, there is a risk of hypoglycemia and bradycardia. When Atenolol is delivered to a pregnant or nursing woman, caution should be taken.

• When given to a pregnant woman, Atenolol can harm the fetus. Cord blood contains Atenolol because it has crossed the placental barrier.
• Atenolol use, beginning in the second trimester of pregnancy, has been linked to the delivery of babies that are undersized for gestational age.
• Atenolol use during the first trimester hasn't been studied, and it's impossible to rule out the chance of fetal harm.
• Patients should be made aware of any potential risks to the fetus if this medication is used during pregnancy or if they become pregnant while taking it.

The food warning while consuming Atenolol that should be taken in concentrations while its consumption are:-

•  Grapefruit Juice: Grapefruit juice inhibits the activity of liver enzymes which inactivate several drugs. Intake of grapefruit juice with Atenolol may increase the level of Atenolol in the blood.
• Sodium-rich foods: Foods rich in sodium content may reduce the blood pressure-lowering effect of Atenolol.

The Adverse Reaction of Atenolol for various treatment can be categorised as:

• Allergic: Fever, combined with aching and sore throat, laryngospasm, and respiratory distress.
• Common Adverse effects: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by disorientation of time and place; short-term memory loss; emotional lability with slightly clouded sensorium; and decreased performance on neuropsychometrist.
• Infrequent adverse effect : Mesenteric arterial thrombosis, ischemic colitis.
• Rare adverse effect: Erythematous rash.
• Miscellaneous: There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking drugs.

The clinically relevant drug interactions of Atenolol are briefly summarized as follows:

Mental health drugs

Reserpine and monoamine oxidase inhibitors (MAOIs) may increase or add to the effects of atenolol. They may also increase lightheadedness or slow the heart rate more.MAOIs can continue to interact with atenolol for up to 14 days after taking them. Examples of MAOIs include:

• Isocarboxazid
• Phenelzine
• Selegiline
• Tranylcypromine

Heart rhythm drugs

Taking certain heart drugs with atenolol can slow down the heart rate too much. Examples of these drugs include:

• Digitalis
• Amiodarone
• Disopyramide

Calcium channel blockers

Like atenolol, these drugs are used to treat high blood pressure and several other heart problems. If combined with atenolol, they may reduce the contractions of heart and slow it down more. Examples of these drugs include:

• Amlodipine
• Diltiazem
• Felodipine
• Isradipine
• Nicardipine
• Nifedipine
• Nimodipine
• Nisoldipine
• Verapamil

Alpha blockers

Alpha blockers lower blood pressure. They may decrease blood pressure too much when combined with atenolol. Examples of these drugs include:

• Methyldopa
• Prazosin
• Clonidine

Clonidine must be carefully managed if it’s combined with atenolol. Suddenly stopping the drug while also taking atenolol can cause a big jump in blood pressure.

Pain killers

Taking indomethacin with atenolol can reduce the blood pressure-lowering effects of atenolol.

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 overdose are lethargy, wheezing, sinus pause and bradycardia. Additionally, common effects associated with overdosage of any beta-adrenergic blocking agent and which might also be expected in Atenolol overdose are congestive heart failure, hypotension, bronchospasm and/or hypoglycemia.

Treatment of overdose should be directed to the removal of any unabsorbed drug by induced emesis, gastric lavage, or administration of activated charcoal. Atenolol can be removed from the general circulation by hemodialysis. Other treatment modalities should be employed at the physician's discretion and may include:

• Bradycardia: Atropine intravenously. If there is no response to vagal blockade, give isoproterenol cautiously. In refractory cases, a transvenous cardiac pacemaker may be indicated.
•  Heart block (second or third degree): Isoproterenol or transvenous cardiac pacemaker.

• Cardiac failure: Digitalize the patient and administer a diuretic. Glucagon has been reported to be useful.
• Hypotension: Vasopressors such as dopamine or norepinephrine (levarterenol). Monitor blood pressure continuously.
• Bronchospasm: A beta2 stimulant such as isoproterenol or terbutaline and/or aminophylline.
• Hypoglycemia: Intravenous glucose. Based on the severity of symptoms, management may require intensive support care and facilities for applying cardiac and respiratory support.

Pharmacodynamics

• The majority of Atenolol effects are primarily felt by the heart because it is a cardio-selective beta-blocker. It functions as a sympathetic innervation antagonist and inhibits the release of norepinephrine from the peripheral nervous system, which reduces heart rate, electrical conductivity, and contractility in the heart. Together, contractility and rate declines cause a drop in cardiac output, which in turn causes a short-term rise in peripheral vascular resistance as a form of compensation. With long-term usage of Atenolol, this reaction later returns to baseline. More importantly, this decrease in the strain placed on the myocardial also results in a decrease in oxygen demand, which has therapeutic benefits by lessening the imbalance between oxygen supply and demand in conditions where coronary blood flow is restricted, such as coronary atherosclerosis.
•  Reducing oxygen demand, especially as a result of activity, might lessen the frequency of angina pectoris symptoms and may even increase the likelihood that the myocardium that is still healthy would survive a myocardial infarction. By regulating the rate of action potential generation and enabling more efficient coordinated contractions, the blockade of adrenergic beta receptors has been shown to be beneficial in arrhythmic conditions like atrial fibrillation. This is because it slows the movement of potentials through the atrioventricular node and reduces the frequency of ectopic potentials. Since maintaining cardiac function necessitates some sympathetic activity, Atenolol diminished contractility may cause or exacerbate heart failure, particularly during volume overload.
• Due to its reduced capacity to pass the blood-brain barrier, Atenolol has CNS effects similar to those of other beta-blockers, although to a lesser extent. It may result in sleep difficulties including nightmares or sleeplessness, as well as exhaustion, depression, and other mental health issues. However, compared to nonselective beta-blockers, Atenolol effects on the respiratory system are substantially less significant. By inhibiting the relaxation of bronchial smooth muscle mediated by the sympathetic nervous system, interaction with two receptors in the airways can cause bronchoconstriction.
• In both asthma and chronic obstructive pulmonary disease, the same effect can interfere with -agonist treatments.
•  Atenolol doesn't have an intrinsic sympathomimetic or membrane stabilising effect, and it also doesn't affect glycemic control as certain other beta-blockers works.

Pharmacokinetics

• Absorption: Oral medication is quickly and consistently absorbed, but not completely. An oral dose is absorbed from the gastrointestinal tract about 50% of the time, while the remaining 50% is eliminated intact in the stool. Two to four hours after administration, peak blood levels are reached.
• Distribution: In addition to two peripheral compartments with a total volume of 51–95 L, Atenolol distributes into a central volume that is 12.8–17.5 L in size. For the center compartment, distribution takes around 3 hours; for the shallower peripheral compartment, 4 hours; and for the deeper peripheral compartment, 5 to 6 hours.
•  Metabolism: Hepatic metabolism is very low. The hydroxylation process between the amide and benzene groups at the carbon results in the solitary non-conjugated metabolite. The glucuronide conjugate is the only additional metabolite that has been verified. These metabolites account for 8% and 2%, respectively, of the really excreted dosage, with 87–90% of the medication remaining unaltered. The beta-blocking action of the hydroxylated metabolite is one-tenth that of Atenolol.
•  Elimination: Oral Atenolol has an elimination half-life of roughly 6 to 7 hours, and chronic treatment has little effect on the drug's kinetic profile.Unlike its other beta-1-blocking counterparts, there is little hepatic metabolism of atenolol - it is primarily renally excreted. Therefore, while no hepatic dosage adjustment is needed, it is imperative to assess the renal function before starting treatment, with regular monitoring throughout the duration of treatment. In addition, impaired glomerular function results in significant accumulation of the drug in the body; therefore, patients with creatinine clearance under 35 mL/min should receive much lower doses.

Patients with a history of obstructive airway disease should have regular lung function tests, and patients with the diabetes should monitor blood glucose levels.

There are some clinical studies mentioned below for atenolol:

1. Hansson L, Karlberg BE, Aberg H, et al. Clinical evaluation of atenolol in hypertension. Clinical Science and Molecular medicine. Supplement. 1976 Dec 1;3:513s-5s. DOI :https://doi.org/10.1042/cs051513s

2. Pfisterer M, Cox JL, et al. Atenolol use and clinical outcomes after thrombolysis for acute myocardial infarction: the GUSTO-I experience. Journal of the American College of Cardiology. 1998 Sep;32(3):634-40.DOI : https://www.jacc.org/doi/abs/10.1016/S0735-1097(98)00279-4

3. Elliott WJ, Hewkin AC, et al. A drug dose model for predicting clinical outcomes in hypertensive coronary disease patients. The Journal of Clinical Hypertension. 2005 Nov;7(11):654-63.Nonclinical toxicology DOI :https://doi.org/10.1111/j.1524-6175.2005.04800.x

1. https://go.drugbank.com/drugs/DB00335

2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/018240s031lbl.pdf

3. https://www.nhs.uk/medicines/atenolol/side-effects-of-atenolol/

4. DailyMed - atenolol- atenolol tablet. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f36d4ed3-dcbb-4465-9fa6-1da811f555e6