Acebutolol

Acebutolol is a cardioselective beta-1 adrenergic blocking agent with intrinsic sympathomimetic activity in the beta-blocker class.

Acebutolol is approved to treat hypertension, angina pectoris, and cardiac arrhythmia

Acebutolol is well absorbed from the GI tract. It is subject to extensive first-pass hepatic biotransformation, with an absolute bioavailability of approximately 40% for the parent compound. The major metabolite, N-acetyl derivative (diacetolol), is pharmacologically active. This metabolite is equipotent to Acebutolol and, in cats is more cardioselective than Acebutolol; therefore, this first-pass phenomenon does not attenuate the therapeutic effect of Acebutolol. Food intake does not have a significant effect on the area under the plasma concentration-time curve (AUC) of Acebutolol although the rate of absorption and peak concentration decreased slightly. The plasma elimination half-life of Acebutolol is approximately 3 to 4 hours, while that of its metabolite, diacetolol, is 8 to 13 hours

The common side effects associated with Acebutolol include slower heart rate, diarrhea, weakness, tiredness, dizziness, anxiety, nausea, dry or burning eyes, headache, cold or flu symptoms, etc.

Acebutolol is available in the form of Tablets and Capsules.

The molecule is available in France, Spain, the US, India

• Acebutolol is a selective β1-receptor antagonist. Activation of β1-receptors by epinephrine increases the heart rate and blood pressure, and the heart consumes more oxygen. Acebutolol blocks these receptors, lowering the heart rate and blood pressure. This drug then has the reverse effect of epinephrine. In addition, beta-blockers prevent the release of renin, which is a hormone produced by the kidneys which lead to constriction of blood vessels.
• The onset of action is within 1.5- 3 hours of dosing, Acebutolol reaches its peak plasma concentrations within 3-8 hours.
• Acebutolol peak plasma levels are achieved within Tmax of 2.5 hours and Cmax of 925 ng/ ml was observed after 24 hours.

Acebutolol is available in form of tablets and capsules.

Acebutolol comes as a tablet and capsules. As directed by a physician, the regular tablet or capsule is often taken once or twice a day.

Acebutolol is approved to treat hypertension, angina pectoris and cardiac arrhythmia.

Acebutolol slows down the activity of the heart by stopping messages sent by nerves to heart. It does this by blocking tiny areas (called beta-adrenergic receptors) where the messages are received by the heart. As a result, the heart beats more slowly and with less force. This allows the pressure of blood within the blood vessels to be reduce in high blood pressure (hypertension), and helps to prevent abnormally fast and uneven heartbeats in a heart rhythm disorder (arrhythmia).

Acebutolol is approved for use in the following clinical indications.

• Hypertension :

Acebutolol is indicated for management of the hypertension in adults. It may be used alone or in combination with other antihypertensive agents, especially thiazide-type diuretics.

• Ventricular Arrhythmias :

Acebutolol is indicated in management of ventricular premature beats; it reduces total number of premature beats, as well as number of paired and multiform ventricular ectopic beats, and R-on-T beats.

Although not approved , there have been certain Off label uses documented for Acebutolol .These includes:

• Stable ischemic heart disease : Oral: Initial: 200 mg 3 times daily; titrated to desired heart rate by increasing at weekly intervals by 300 mg/day; maximum dose: 1,200 mg/day.
• Thyrotoxicosis: Oral 200 mg 2 to 3 times daily; treatment period in clinical trials was 7 to 10 days. Additional data may be necessary to further define the role of acebutolol in the treatment of this condition.

Acebutolol is available in the form of tablets.

Hypertension

The initial dosage of Acebutolol in uncomplicated mild-to-moderate hypertension is 400 mg. This can be given as a single daily dose, but in occasional patients twice daily dosing may be required for about 24-hour blood-pressure control. An optimal response is usually achieved with dosages of 400 to 800 mg per day, although some patients have maintained as little as 200 mg per day. Patients with more severe hypertension or who have demonstrated inadequate control may respond to a total of 1200 mg daily (administered b.i.d.), or to the addition of a second antihypertensive agent. Beta-1 selectivity diminishes as the dosage increased.

Ventricular Arrhythmia

The usual initial dose of Acebutolol is 400 mg daily given as 200 mg b.i.d. Dosage should be increased gradually until an optimal clinical response is obtained, generally at 600 to 1200 mg per day. If treatment is to be discontinued, the dosage should be reduced gradually over a period of about two weeks.

Use in Older Patients

Older patients have an approximately 2-fold increase in bioavailability and may require lower maintenance doses. Doses above 800 mg/day should be avoided in the elderly

Acebutolol are available with the dosage strength of 200 mg and 400 mg.

Acebutolol is available in the form of tablet and capsules.

Acebutolol should be used in the treatment of high blood pressure, angina pectoris, and Ventricular arrhythmia 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 that are high in saturated fat and hydrogenated or partially hydrogenated fats. Reduce your intake of dairy products including cheese, cream, and eggs.
• Ventricular arrhythmia: Some foods can negatively affect your heart health and have been shown to increase the risk of heart complications. Diets high in processed foods, such as fast food, and items high in added sugar, like soda and sugary baked goods, have been linked to increased heart disease risk They can also lead to other negative health outcomes like weight gain, diabetes, cognitive decline, and certain cancers.

Less than 7 %of your daily calories should come from saturated fat.

Avoid trans fats and Consume less than 200 milligrams a day of dietary cholesterol.

Acebutolol is contraindicated in patients with

• Heart failure, poor circulation, and low blood pressure.
• Persistent slow heart rate (bradycardia).
• Atrioventricular block (AV block) in the heart.
• Tumor of adrenal gland called pheochromocytoma.
• Diabetes
• Depression
• Myasthenia gravis, a skeletal muscle disorder.
• Breastfeeding patient
• Moderate to severe kidney impairment
• Peripheral arterial occlusive disease

Cardiac Failure Sympathetic stimulation may be essential for the support of the circulation in individuals with diminished myocardial contractility, and its inhibition by β-adrenergic receptor blockade may precipitate more severe failure. Although β-blockers should be avoided in overt cardiac failure, Acebutolol can be used with caution in patients with a history of heart failure who are controlled with digitalis and/or diuretics. Both digitalis and Acebutolol impair AV conduction. If cardiac failure persists, therapy with Acebutolol should be withdrawn.

• In Patients Without a History of Cardiac Failure

In patients with aortic or mitral valve disease or compromised left ventricular function, continued depression of the myocardium with β-blocking agents over a period of time may lead to cardiac failure. At the first signs of failure, patients should be digitalized and/or be given a diuretic and the response observed closely. If cardiac failure continues despite adequate digitalization and/or diuretic, Acebutolol therapy should be withdrawn.

• Exacerbation of Ischemic Heart Disease Following Abrupt Withdrawal

Following abrupt cessation of therapy with certain β-blocking agents in patients with coronary artery disease, exacerbation of angina pectoris and, in some cases, myocardial infarction and death have been reported. Therefore, such patients should be cautioned against interruption of therapy without a physician’s advice. Even in the absence of overt ischemic heart disease, when discontinuation of Acebutolol is planned, the patient should be carefully observed and should be advised to limit physical activity to a minimum while Acebutolol is gradually withdrawn over a period of about two weeks. (If therapy with an alternative β-blocker is desired, the patient may be transferred directly to comparable doses of another agent without interruption of β-blocking therapy.) If an exacerbation of angina pectoris occurs, antianginal therapy should be restarted immediately in full doses and the patient hospitalized until his condition stabilizes.

• Peripheral Vascular Disease

Treatment with β-antagonists reduces cardiac output and can precipitate or aggravate the symptoms of arterial insufficiency in patients with peripheral or mesenteric vascular disease. Caution should be exercised with such patients, and they should be observed closely for evidence of progression of arterial obstruction.

• Bronchospastic Disease

Patients with bronchospastic disease should, in general, not receive a β-blocker. Because of its relative β1-selectivity, however, low doses of Acebutolol may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate alternative treatment. Since β1-selectivity is not absolute and is dose-dependent, the lowest possible dose of Acebutolol should be used initially, preferably in divided doses to avoid the higher plasma levels associated with the longer dose interval. A bronchodilator, such as theophylline or a β2- stimulant, should be made available in advance with instructions concerning its use.

The necessity, or desirability, of withdrawal of β-blocking therapy prior to major surgery is controversial. β-adrenergic receptor blockade impairs the ability of the heart to respond to βadrenergically mediated reflex stimuli. While this might be of benefit in preventing the arrhythmic response, the risk of excessive myocardial depression during general anesthesia may be enhanced and difficulty in restarting and maintaining the heartbeat has been reported with beta-blockers. If treatment is continued, particular care should be taken when using anesthetic agents which depress the myocardium, such as ether, cyclopropane, and trichloroethylene, and it is prudent to use the lowest possible dose of Acebutolol. Acebutolol, like other β-blockers, is a competitive inhibitor of β-receptor agonists, and its effect on the heart can be reversed by cautious administration of such agents (e.g.,dobutamine or isoproterenol ) Manifestations of excessive vagal tone (e.g., profound bradycardia, hypotension) may be corrected with atropine 1 to 3 mg IV in divided doses.

• Diabetes and Hypoglycemia

β-blockers may potentiate insulin-induced hypoglycemia and mask some of its manifestations such as tachycardia; however, dizziness and sweating are usually not significantly affected. Diabetic patients should be warned of the possibility of masked hypoglycemia.

• Thyrotoxicosis

β-adrenergic blockade may mask certain clinical signs (tachycardia) of hyperthyroidism. Abrupt withdrawal of β-blockade may precipitate a thyroid storm; therefore, patients suspected of developing thyrotoxicosis from whom Acebutolol therapy is to be withdrawn should be monitored closely.

PRECAUTIONS

• Risk of Anaphylactic Reaction

While taking beta-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenges, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

• Impaired Renal or Hepatic Function

Studies on the effect of acebutolol in patients with renal insufficiency have not been performed in the U.S. Foreign published experience shows that acebutolol has been used successfully in chronic renal insufficiency. Acebutolol is excreted through the GI tract, but the active metabolite, diacetolol, is eliminated predominantly by the kidney. There is a linear relationship between the renal clearance of diacetolol and creatinine clearance. Therefore, the daily dose of acebutolol should be reduced by 50% when the creatinine clearance is less than 50 mL/min and by 75% when it is less than 25 mL/min. Acebutolol should be used cautiously in patients with impaired hepatic function. Acebutolol has been used successfully and without problems in elderly patients in the U.S. clinical trials without specific adjustment of dosage. However, elderly patients may require lower maintenance doses because the bioavailability of both Acebutolol and its metabolite are approximately doubled in this age group.

Patients, especially those with evidence of coronary artery disease, should be warned against interruption or discontinuation of Acebutolol therapy without a physician's supervision. Although cardiac failure rarely occurs in properly selected patients, those being treated with β-adrenergic blocking agents should be advised to consult a physician if they develop signs or symptoms suggestive of impending CHF or unexplained respiratory symptoms. Patients should also be warned of possible severe hypertensive reactions from the concomitant use of alpha-adrenergic stimulants, such as the nasal decongestants commonly used in OTC cold preparations and nasal drops.

The intake of acebutolol with alcohol can increase the feeling of dizziness or faintness.

Acebutolol also appear in breast milk with a milk:plasma ratio of 7:1. Use in Breastfeeding women is not recommended.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus.

Pregnancy Category B:

Reproduction studies have been performed with Acebutolol in rats (up to 630 mg/kg/day) and rabbits (up to 135 mg/kg/day). These doses are equivalent to approximately 31.5 and 6.8 times the maximum recommended therapeutic dose in a 60-kg human, respectively. The compound was not teratogenic in either species. In the rabbit, however, doses of 135 mg/kg/day caused slight fetal growth retardation; this effect was considered to be a result of maternal toxicity, as evidenced by reduced food intake, a lowered rate of body weight gain, and mortality. Studies have also been performed in these species with diacetolol (at doses of up to 450 mg/kg/day in rabbits and up to 1800 mg/kg/day in rats). Other than a significant elevation in postimplantation loss with 450 mg/kg/day diacetolol, a level at which food consumption and body weight gain were reduced in rabbit female parents and a non statistically significant increase in the incidence of bilateral cataract in rat fetuses from their mother who where treated with 1800 mg/kg/day diacetolol, there was no evidence of harm to the fetus. There are no adequate and well-controlled trials on pregnant women. Because animal teratology studies are not always predictive of the human response, Acebutolol should be used during pregnancy only if the potential benefit justifies the risk to the fetus.

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

• Salt Substitutes: The combination of Acebutolol with foods rich in salts like sodium, calcium, and magnesium may reduce or negate the blood pressure-lowering effect of Acebutolol. It is better to avoid the intake of Acebutolol with salt-rich foods.
• Potassium Rich Foods:  Acebutolol may increase the potassium levels in the blood. Avoid taking potassium-rich foods with Acebutolol.
• Pleurisy Root: Pleurisy root is not recommended with most heart medications due to the cardiac glycoside content of the root.
• Interaction with caffeine: The interaction of caffeine-containing food items and beverages, along with beta-blockers like Acebutolol may decrease the effectiveness of the drug. It is better to avoid tea or coffee while taking Acebutolol.

Most adverse effects have either been mild or transient.

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

• Catecholamine-depleting drugs, such as reserpine, may have an additive effect when given with β-blocking agents.
• Patients treated with Acebutolol catecholamine depletors should, therefore, be observed closely for evidence of marked bradycardia or hypotension, which may present as vertigo, syncope/presyncope, or orthostatic changes in blood pressure without compensatory tachycardia.
• Exaggerated hypertensive responses have been reported from the combined use of β-adrenergic antagonists and alpha-adrenergic stimulants, including those contained in proprietary cold remedies and vasoconstrictive nasal drops.
• Patients receiving β-blockers should be warned of this potential hazard. Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by nonsteroidal anti-inflammatory drugs has been reported.
• No significant interactions with digoxin, hydrochlorothiazide, hydralazine, sulfinpyrazone, oral contraceptives, tolbutamide, or warfarin have been observed. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

• The common side effects of Acebutolol includes headache, feeling tired, insomnia, joint pain, swelling, or cold symptoms such as stuffy nose, runny nose, cough, sore throat.
• Other side effects includes: shortness of breath, slow heart rate, eye pain, vision problems, etc.

Pharmacodynamics

Acebutolol is a beta-adrenoceptor antagonist which is cardioselective, i.e. acts preferentially on beta1 adrenergic receptors in the heart. Its principal effects are to reduce heart rate, especially during exercise, and lower blood pressure in hypertensive subjects. Acebutolol and its active metabolite, diacetolol, have antiarrhythmic activity, the combined plasma half-life of the active drug and metabolite being 7-10 hours. Both have partial agonist activity (PAA), also known as intrinsic sympathomimetic activity (ISA).

This property ensures that some degree of stimulation of beta receptors is maintained. Under conditions of rest, this tends to balance the negative chronotropic and negative inotropic effects. Acebutolol blocks the effects of excessive catecholamine stimulation resulting from stress.

Pharmacokinetics

Absorption

After oral administration, acebutolol is rapidly and almost completely absorbed from the gastrointestinal tract. A maximum plasma concentration of ± 925 ng/ml was observed 2-4 hours after oral administration of 400 mg of acebutolol. Absorption appears to be unaffected by the presence of food in the gut.

Distribution

The plasma protein binding of acebutolol is weak (20%).

Both Acebutolol and diacetolol are hydrophilic and exhibit poor penetration of the CNS.

Biotransformation

There is the rapid formation of a major equi active metabolite, diacetolol, which possesses a similar pharmacological profile to acebutolol. Acebutolol undergoes a significant first-pass metabolism: absolute bioavailability after oral administration is 30% to 51%. Acebutolol is converted into diacetolol in the liver. This metabolite is pharmacologically active, and in a steady state, the plasma concentration of diacetolol is 2.5 times that of Acebutolol.

Elimination

Peak plasma concentrations of active material (i.e., acebutolol plus diacetolol) are achieved within 2-4 hours, and the terminal plasma elimination half-life is around 8-10 hours.

Because of biliary excretion and direct transfer across the gut wall from the systemic circulation to the gut lumen, more than 50% of an oral dose of acebutolol is recovered in the feces with acebutolol and diacetolol in equal proportions; the rest of the dose is recovered in the urine, mainly as diacetolol.

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