Amlodipine + Atenolol

Amlodipine + Atenolol is the combination of an antihypertensive Agent belonging to the "Calcium Channel Blocker (CCB)" and "Beta-blocker class."

Amlodipine + Atenolol is a combination drug approved for treating Hypertension in adults, a condition characterized by high blood pressure levels. Amlodipine relaxes blood vessels, while Atenolol slows the heart rate, effectively lowering blood pressure and reducing the risk of cardiovascular complications.

Amlodipine is rapidly absorbed, with a half-life of 30-50 hours, reaching peak blood levels in 6-12 hours. Approximately 50% of the beta-blocker is bioavailable orally due to partial colon absorption. Only 3% of Atenolol in plasma binds to proteins. About 5% is processed in the liver and is primarily eliminated by the kidneys. The common side effects of Amlodipine + Atenolol include headache, ankle swelling, slow heart rate, and nausea. Amlodipine + Atenolol is available as a tablet for convenient administration.

Amlodipine + Atenolol is available in the United States, Canada, the United Kingdom, India and Australia.

Amlodipine + Atenolol is the combination of an antihypertensive Agent belonging to the "Calcium Channel Blocker (CCB)" and "Beta-blocker class."

Amlodipine: Amlodipine primarily affects the smooth muscle of the arteries, lowering peripheral vascular resistance by preventing calcium ion inflow. According to experimental data, Amlodipine interacts with specific membrane binding sites. It mainly exerts its therapeutic effects by dilating peripheral arterioles, which lowers cardiac workload and oxygen consumption, and by promoting coronary artery dilation, which improves oxygen supply. It is beneficial in conditions like variant angina and mitigates coronary vasoconstriction. These two distinct mechanisms prove Amlodipine's effectiveness in treating angina and Hypertension.

The Onset of action of Amlodipine is not clinically established.

The Duration of Action for Amlodipine in the body is approximately 24 hours.

The Tmax was found within 6-12 hours following the administration of Amlodipine.

Vd: 21 L/kg

Half-life: 30-50 hr

Clearance: 25 L/hr

Atenolol: Atenolol, a cardioselective beta-1-adrenergic antagonist, prevents sympathetic activation by blocking the positive inotropic and chronotropic activities of endogenous catecholamines such as isoproterenol, norepinephrine, and epinephrine. Isoproterenol, norepinephrine, and epinephrine are examples of catecholamines. This activity lowers heart rate, blood pressure, and myocardial contractility.

The onset of action of Atenolol is 1 hour for oral administration and 5 minutes for IV administration, with the maximal effect occurring between 2-4 hours. The activity will last around 24 hours. Tmax (600 ng/ml) of Atenolol was identified 3 hours after the primary dose was administered, and measurable levels (50-70 ng/ml) were detected 24 hours later, with a Cmax of 0.49 g/ml.

Synergistic Benefits: Amlodipine + Atenolol combines the benefits of a Beta blocker (Atenolol) with a calcium channel blocker (Amlodipine) to successfully treat Hypertension (high blood pressure). Both medications in this combination work synergistically to lower blood pressure through distinct mechanisms.

Amlodipine, a calcium channel blocker, relaxes blood arteries, lowering blood pressure. Atenolol, a beta-blocker, reduces heart rate and cardiac output. Thus resulting in effective blood pressure control. This combination minimizes the heart's workload and reduces the risk of side effects associated with high doses of a single medication.

When one medication fails to regulate your blood pressure, these medications are combined.

Data Onset of action of Amlodipine + Atenolol is shown within a few hours of post-administration.

Data duration of action of Amlodipine + Atenolol typically lasts about 24 hours.

The Data of Tmax of Amlodipine + Atenolol typically takes 6-12 hours, whereas Atenolol reaches Tmax in around 1-2 hours after delivery.

The Data of Cmax of Amlodipine + Atenolol combination is typically achieved within 6-12 hours.

Amlodipine and Atenolol are available in tablets.

As the physician recommends, take the medication orally once daily, generally with or without a meal.

Treatment of Hypertension (high blood pressure) in adults and angina pectoris (heart-related chest pain).

Amlodipine + Atenolol is the combination of an antihypertensive Agent belonging to the "Calcium Channel Blocker (CCB)" and "Beta-blocker class."

Amlodipine: It prevents calcium ions from entering "slow channels" or particular voltage-sensitive regions of the myocardium and vascular smooth muscle during depolarization, resulting in relaxation of the latter and coronary vasodilation; it also increases myocardial oxygen delivery in people with vasospastic angina. Amlodipine directly affects vascular smooth muscle to cause peripheral arterial vasodilation, which lowers blood pressure and peripheral vascular resistance.

Atenolol: Atenolol is used to treat high blood pressure which is either used alone or in combination with other medications. It prevents certain chemical substances in the body, such as epinephrine, on the heart and blood arteries. This effect reduces heart rate, blood pressure, and cardiac strain. Lowering blood pressure also helps prevent strokes, heart attacks, and kidney disorders. This medicine is also used to treat angina (chest pain) and to enhance survival after a heart attack.

Amlodipine and Atenolol work together, inducing vasodilation, heart rate reduction, and increased cardiac efficiency, resulting in lower blood pressure levels. Controlling blood pressure lowers the risk of heart attacks, strokes, and renal problems drastically. To ensure the medication's effectiveness, following the prescribed regimen and taking it consistently as directed by the doctor or other medical professional is critical. This allows individuals to stay healthier for a more extended period. Immediate benefits from taking this medication may not be noticed, but it will keep you healthy in the longer term.

• The combination of Atenolol and Amlodipine is indicated to treat Hypertension. Amlodipine relaxes blood arteries, whereas Atenolol slows the heart rate, leading to helpful blood pressure control. Lowering blood pressure also minimizes the risk of cardiovascular complications such as heart attacks, strokes, and renal disease.
• Amlodipine + Atenolol can rapidly decrease blood pressure and prevent complications when blood pressure is extremely high and may cause organ damage.
• Amlodipine + Atenolol may also be indicated to treat angina pectoris. This condition is characterized by chest pain or discomfort caused by decreased blood flow to the heart muscles. The vasodilatory effect of Amlodipine improves blood supply to the heart, while Atenolol lowers heart rate and workload, reducing angina symptoms.

Orally: Amlodipine + Atenolol is available as a tablet that can be taken orally. Amlodipine and Atenolol should be taken on an empty stomach or with food. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Amlodipine + Atenolol has various strengths, such as 5mg+ 25 mg, 5mg +50mg, 10mg+100 mg,

Dosage Adjustment for Adult Patients

Chronic stable angina, Hypertension

Adults: Each tablet includes atenolol 25 or 50 mg and Amlodipine (as besylate) 5 mg: 1 tab once daily, possibly increasing to 2 tablets if necessary.

Elderly: Each tablet includes 25 mg of Atenolol and 5 mg of Amlodipine (besylate). Start with a single tablet every day.

Amlodipine + Atenolol is available in the form of Oral tablets.

Amlodipine and Atenolol should be used in treating Hypertension, along with appropriate nutritional restrictions.

While taking this combination, it is advised to maintain a rich, heart-healthy diet and consume plenty of vegetables, whole grains, fruits, and lean proteins. Avoid excessive consumption of caffeine, grapefruit, grapefruit juice, and food rich in potassium or alcohol, as it may interact with the medication.

Regular exercise, weight reduction, and a balanced diet will help you control your blood pressure.

The dietary restriction should be individualized as per patient requirements.

Amlodipine + Atenolol may be contraindicated in patients with the following conditions:-

• Hypersensitivity (to the drug or any of its components)
• Pregnancy
• Severe Renal impairment
• Severe Liver Impairment (Active liver disease or unexplained elevated transaminases)
• Hypotension
• Uncontrolled heart failure
• Sinus bradycardia (<45 bpm)
• 2nd & 3rd degrees of heart block
• Cardiogenic shock
• Acute congestive failure,
• Reduced LV function
• Metabolic acidosis
• Untreated Pheochromocytoma
• Severe peripheral arterial circulatory

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• Amlodipine

Hypotension

Particularly in individuals with severe aortic stenosis, symptomatic hypotension is possible. Acute hypotension is rare because of the action's delayed onset.

Angina and/or myocardial infarction are increasing

Particularly in individuals with severe obstructive coronary artery disease, worsening angina and sudden myocardial infarction might occur after initiating or increasing the dose of Amlodipine.

Removing Beta-Blockers

Amlodipine is not a beta-blocker and does not provide protection against the risks of abrupt beta-blocker withdrawal; any such withdrawal should be accomplished by gradually lowering the dose of beta-blocker.

Hepatic failure patients

Titrate carefully when giving Amlodipine to individuals with significant hepatic impairment since the liver substantially metabolizes the drug, and the plasma elimination half-life (t1/2) is 56 hours in those patients with impaired hepatic function.

• Atenolol

Failure of the Heart

Congestive heart failure needs sympathetic activation to sustain circulatory function, and beta-blocking can further reduce myocardial contractility and lead to more severe failure. If 80 mg of intravenous furosemide or an equivalent medication cannot be used to treat cardiac failure rapidly and effectively in patients with acute myocardial infarction, beta-blocker treatment is contraindicated.

Diseases Caused by Bronchospasm

Patients with bronchospastic disease should typically avoid using beta-blockers. If other antihypertensive medications are not tolerated, Atenolol may be taken cautiously with its relative beta1 selectivity. Due to possible beta2 effects, start with the lowest effective dosage (50 mg) and provide a bronchodilator. Consider splitting the dose to lower the peak blood levels when increasing the dosage.

Diabetes and Hypoglycemia

Diabetic patients should take Atenolol cautiously if a beta-blocking drug is necessary. Beta-blockers could mask hypoglycemic tachycardia, but they might not have much of an effect on symptoms like sweat and dizziness. When used at the recommended levels, Atenolol, unlike nonselective beta-blockers, does not worsen insulin-induced hypoglycemia. Additionally, it doesn't delay the recovery of blood glucose to normal ranges.

Precautions:

General: Be cautious when standing up, especially if you experience dizziness or lightheadedness. Amlodipine and Atenolol can cause orthostatic hypotension, which may increase the risk of falls.

Patients on beta-blockers must be thoroughly evaluated before being given Atenolol. Based on clinical information like blood pressure and pulse, atenolol doses can be gradually reduced over time. Atenolol may make peripheral arterial circulation issues worse.

Impairment in Renal Function: The medication should be cautiously administered in individuals with compromised renal function.

It is unsafe to consume alcohol with Amlodipine and Atenolol

It is not recommended to use during breastfeeding. However, there's no sufficient scientific evidence traceable regarding the use and safety of Amlodipine + Atenolol for breastfeeding populations.

 Avoid use during pregnancy.

Avoid or minimize the consumption of caffeine, grapefruit or grapefruit juice. Caution should be taken while consuming potassium-rich foods.

The adverse reactions related to Amlodipine + Atenolol can be categorized as

• Common: Peripheral oedema (swelling in the legs and ankles), dizziness or lightheadedness, headache and fatigue
• Less Common: Shortness of breath, nausea or stomach discomfort, flushing and constipation.
• Rare: Arthralgia, Erythematous rash, thrombocytopenia, severe allergic reactions, Hyperkalemia or Insomnia.

The clinically relevant drug interactions of Amlodipine and Atenolol are briefly summarized here.

• CYP3A4 Inhibitors: Coadministration with CYP3A4 inhibitors, such as fibrates, niacin, cyclosporine, macrolides, and azole antifungals, increases the risk of myopathy; medication should be stopped if myopathy is detected or suspected.
• CYP3A inhibitors (moderate and potent): When Amlodipine is coadministered with CYP3A inhibitors (moderate and potent), systemic exposure to the medication is increased and may necessitate dose reduction; monitor for signs of hypotension and oedema to evaluate whether dose adjustment is necessary.
• Sildenafil: Monitor closely for hypotension when sildenafil is coadministered with Amlodipine.
• Antipsychotic drugs: Reserpine and Monoamine Oxidase Inhibitors (Isocarboxazide, phenelzine, selegiline, tranylcypromine) may enhance or supplement the effects of Atenolol. They may also cause dizziness or slow the heart rate further.MAOIs can interact with Atenolol for up to 14 days after taking them.
• Calcium channel blockers(Amlodipine, diltiazem, felodipine, isradipine, nicardipine): These medications, including Atenolol, treat excessive blood pressure and other heart conditions. When taken with Atenolol, they may lessen cardiac contractions and slow it down even further.
• Alpha blockers: Alpha blockers(Methyldopa, prazosin, clonidine) lower blood pressure. They may significantly decrease blood pressure when combined with Atenolol.
• Pain killers: Taking indomethacin with Atenolol can diminish Atenolol's blood pressure-lowering effects.
• Anti-rhythmic drugs: Taking certain heart drugs like Digitalis, amiodarone, and disopyramide with Atenolol can slow down the heart rate too much.
• Immunosuppressants: It is advised to monitor the trough blood levels of cyclosporine and tacrolimus regularly and to alter the dose as necessary since Amlodipine may enhance the systemic exposure of cyclosporine or tacrolimus when coadministered.
• Simvastatin: Coadministration of simvastatin with Amlodipine raises the systemic exposure of simvastatin. Limit the simvastatin dose in patients on Amlodipine to 20 mg daily.

• Sleepiness
• Headache
• Ankle swollen
• Flushing (a warmed sensation in the cheeks, ears, neck, and trunk)
• Slow heart rate
• Palpitations
• Nausea
• Edema (fluid retention)
• Constipation
• Tiredness
• Extreme cold extremities

Amlodipine + Atenolol should be prudent in the following group of special populations.

• Pregnancy

Amlodipine: Pregnancy Category C; Use with caution if benefits outweigh risks.

There haven't been any controlled studies conducted on pregnant women. Amlodipine should only be used during pregnancy if the benefits exceed the hazards to the developing foetus. Amlodipine maleate was given orally to pregnant rats and rabbits during critical organ development periods at doses up to 10 mg amlodipine/kg/day (8 times and 23 times the maximum recommended human dose of 10 mg on a mg/m2 basis, respectively), and no teratogenicity or other embryo/fetal toxicity was found. The litter size significantly decreased by nearly 50% during mating and gestation in rats receiving 10 mg of amlodipine/kg/day for 14 days before mating. In contrast, intrauterine mortality dramatically increased (about 5-fold). Additionally, the rats' gestation and labour times were prolonged by this dosage.

Amlodipine's postmarketing data lacks info on congenital disabilities or miscarriage risks. Poorly controlled Hypertension during pregnancy poses maternal and fetal risks.

Atenolol: Pregnancy Category D; Use in LIFE-THREATENING situations when no better alternatives are available.

Pregnancy and Fetal Injury.

When given to a pregnant woman, atenolol tablets can damage the foetus. As a result of penetrating the placental barrier, Atenolol is found in cord blood. Small-for-gestational-age newborns have been reported to be born when the combination is administered beginning in the second trimester of pregnancy. The use of the combination in the first trimester has not been studied, and it is impossible to rule out the risk of foetal harm. The patient should be informed of the possible risk to the foetus if this medication is used during pregnancy or if the patient accidentally gets pregnant while taking this medication.

The risk of hypoglycemia and bradycardia exists in newborns born to mothers who take Atenolol at the time of parturition or while breastfeeding. When giving Atenolol to a woman expecting a baby or nursing, caution should be used.

At dosages equivalent to or higher than 50 mg/kg/day, or 25 or more times the maximum advised human antihypertensive dose, Atenolol has been demonstrated to cause a dose-related increase in embryo/foetal resorptions in rats. The substance was not studied in rabbits at doses over 25 mg/kg/day, or 12.5 times the maximum advised human antihypertensive dose*, although equivalent effects were not observed in rabbits.

• Lactating Mothers

There is no data on the drug in human milk or its impact on breastfeeding infants and milk production. It's recommended that nursing mothers avoid breastfeeding while on Atenolol/amlodipine treatment.

Although it has been demonstrated that Amlodipine + Atenolol pass on into human milk and Atenolol is found in rat milk, it is unknown if it is present in human milk.

Amlodipine: Amlodipine may pass into breast milk, however, this is unknown. Nursing should be stopped while Amlodipine is provided if this information is lacking.

Atenolol: Compared to the plasma concentration, Atenolol is eliminated from the body in human breast milk at a ratio of 1.5 to 6.8. When administering Atenolol to a lactating mother, caution should be used. There have been cases of clinically severe bradycardia in breastfed babies. Infants who are premature or have compromised renal function may be more susceptible to negative consequences. Hypoglycemia and bradycardia may occur in newborns whose mothers take Atenolol at the time of parturition or while breastfeeding. Caution should be used when giving Atenolol to pregnant women or breastfeeding mothers.

• Pediatric Use

Dosage Adjustment for Pediatric Patients

Amlodipine: Amlodipine's effect on blood pressure in individuals under six is unknown.

Atenolol: This combination's safety and effectiveness have not been studied in paediatric patients.

• Geriatric Use

Amlodipine: There were insufficient elderly participants in amlodipine clinical trials to ascertain whether their responses differed from younger participants. Other documented clinical experience has not found variations in reactions between senior and younger patients. In general, choosing a dosage for an aged patient should be careful, beginning at the low end of the dosing range, reflecting the increased incidence of reduced hepatic, renal, or cardiac function, concurrent illness, or other pharmacological therapy. A lower starting dosage can be necessary in elderly individuals due to slower amlodipine clearance, which causes a rise in AUC of around 40–60%.

Atenolol:

Angina Pectoris and Hypertension linked to coronary atherosclerosis

There were insufficient elderly individuals included in atenolol clinical research to assess whether their responses differed from those of younger people. According to other published clinical experiences, there are no changes in patient reactions between elderly and younger patients. The selection of dosage for an aged patient should generally be careful, often beginning at the low end of the dosing range, reflecting the higher incidence of reduced hepatic, renal, or cardiac function and the presence of concurrent illness or other medication therapy.

Acute Myocardial Infarction

In the ISIS-1 study, 8,037 suspected acute myocardial infarction patients were randomly assigned to receive Atenolol, and 33% (2,644) of them were 65 years of age or older. Older individuals with systolic blood pressure below 120 mmHg appeared to be less likely to benefit from treatment. Still, it could not find any apparent variations in efficacy and safety between them and younger patients.

Elderly patients should have their doses chosen carefully, often starting at the low end of the dosage range due to the higher likelihood of reduced hepatic, renal, or cardiac function, concurrent illness or other medication therapy. Renal function testing should always be done on individuals with myocardial infarction or high blood pressure.

Dosage Adjustment in Kidney Impairment Patient

Mild to moderate kidney impairment (Cr Clearance 30-60 mL/min): No dose change is usually necessary.

Severe kidney impairment (Cr Clearance less than 30 mL/min): Caution is advised. Atenolol can accumulate, which might result in more severe adverse effects. Atenolol dosage reduction should be taken into consideration.

Renal impairment: Atenolol 25 mg and amlodipine (besylate) 5 mg are present in each tablet. Begin out with one tablet per day.

Dosage Adjustment in Hepatic Impairment Patient

Mild to moderate hepatic impairment: No specific dosage adjustment is typically required.

Severe hepatic impairment: People with significant liver impairment may experience the effects of Atenolol for a more extended period of time. Atenolol dosage reduction should be taken into consideration.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Amlodipine + Atenolol. Overconsumption of Amlodipine + Atenolol could lead to severe hypotension (low blood pressure), bradycardia, dizziness, weakness, and potential cardiac arrhythmias.

There is no specific antidote or treatment for excessive intake of Amlodipine + Atenolol. However, immediate medical attention is essential.

Amlodipine + Atenolol should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Management typically involves supportive measures and symptomatic treatment. Supportive therapy should be given, addressing any symptoms that persist or worsen. Activated charcoal may also be considered if the overdose is detected shortly after ingestion to reduce absorption. Monitoring the patient's vital signs and correcting any electrolyte imbalances is crucial. In severe cases, gastric lavage may be performed if ingestion occurs within the previous hour. Physical treatment might be added if necessary.

Extracorporeal procedures such as hemodialysis or hemoperfusion may be considered in severe cases where standard treatments are insufficient to remove the drug from the bloodstream.

Pharmacodynamic of Amlodipine + Atenolol

• Amlodipine: Amlodipine binds to cell membranes with a high affinity and inhibits specific membrane calcium channels to modulate calcium influx. Long-acting effects and a less frequent dose schedule are made possible by this medication's unique binding qualities.
• Atenolol: Atenolol, a cardio-selective beta-blocker, primarily affects the heart by lowering norepinephrine release and blocking sympathetic innervation. This causes a decrease in heart rate, electrical conductivity, and contractility, resulting in a short-term reduction in cardiac output. Long-term use normalizes these effects, reducing cardiac strain and oxygen consumption, which benefits disorders like coronary atherosclerosis with restricted blood flow.

Atenolol decreases oxygen demand during physical exercise, which may minimize angina symptoms and improve myocardial survival during a heart attack. Decreasing action potentials through the atrioventricular node also helps arrhythmias such as atrial fibrillation. However, in the case of heart failure, the reduced contractility caused by Atenolol's effect may cause difficulties during volume overload.

With low blood-brain barrier penetration, Atenolol has weaker CNS effects than other beta-blockers. It can cause sleep problems, tiredness, sadness, and mental health problems. It has a significantly lower influence on the respiratory system than nonselective beta-blockers, which cause bronchoconstriction by decreasing sympathetic-mediated bronchial smooth muscle relaxation.

The same effect can interfere with -agonist therapy in asthma and chronic obstructive pulmonary disease.

Atenolol does not have an intrinsic sympathomimetic or membrane-stabilizing effect, nor does it alter glycemic control like other beta-blockers do.

Pharmacokinetics of Amlodipine + Atenolol

Absorption:

Amlodipine: Amlodipine is slowly and almost entirely absorbed from the digestive tract. Peak plasma concentrations are reached 6 to 12 hours after oral dosing. Amlodipine's bioavailability is estimated to be between 64 - 90%. After 7-8 days of regular medication, steady-state plasma amlodipine levels are attained. Food does not affect absorption.

Atenolol: Absorption is rapid, constant, but incomplete; approximately half of an oral dose is absorbed in the GI tract and plasma levels peak 2-4 hours after administration.

Distribution

Amlodipine: The plasma protein binding of Amlodipine is approximately 98%.

Atenolol: Besides two peripheral compartments with a total volume of 51-95 L, Atenolol distributes into a 12.8-17.5 L core volume. Distribution takes about 3 hours for the central compartment, 4 hours for the shallower peripheral compartment, and 5 to 6 hours for the deeper peripheral compartment; 6-16% bound to plasma proteins.

Metabolism

Amlodipine: Amlodipine is primarily (approximately 90%) converted to inactive metabolites via hepatic breakdown with 10%(parent compound) and 60% (metabolites).

Atenolol: Hepatic metabolism is limited, with only one non-conjugated metabolite generated via hydroxylation at the carbon between the amide and benzene groups. A glucuronide conjugate has also been identified as a metabolite, accounting for 8% and 2% of the excreted dosage. Most of the medication (87-90%) is excreted unaltered. Notably, the hydroxylated metabolite has just one-tenth the beta-blocking efficacy of Atenolol.

Excretion

Amlodipine: Approximately 10% of a given dose is excreted in the urine.

Atenolol: 50% of the oral dose is eliminated intact in the faeces; absorbed medication is primarily eliminated by renal excretion; the half-life is approximately 6-7 hours.

Therapeutic benefits of a combination of Amlodipine and Atenolol

• Amlodipine (calcium channel blocker)and Atenolol (beta-blocker) work together to reduce blood pressure. Amlodipine relaxes blood arteries, lowering peripheral resistance, while Atenolol slows the heart rate and cardiac output. This combination provides comprehensive blood pressure regulation, making it useful for hypertension management. Lowering blood pressure also significantly reduces the risk of strokes, heart attacks, and other cardiovascular problems.
• Amlodipine + Atenolol is also helpful in treating angina pectoris, a condition marked by chest pain caused by a decrease in oxygen flow to the heart muscle. The vasodilatory effect of Amlodipine increases blood flow to the heart, whereas Atenolol minimizes the pressure of the heart, decreasing oxygen demand.
• Amlodipine and Atenolol are used in combination to improve cardiovascular health. Lowering blood pressure and cholesterol levels relieves cardiac strain and improves healthier circulation. This can result in increased energy, decreased fatigue, and a better quality of life.

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