Beta receptor Adrenergic blocking agents

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Chapter: Medicinal Chemistry : Adrenergic Blockers

Adrenergic Blockers : Beta receptor blocking agents - Synthesis and Drug Profile - i. Propranolol (Synonym: Inderal, Ipran, Manopralol, Beetacap) ii. Acebutalol (Sectral) iii. Atenolol(Atenex, Aten, Betacard) iv. Metoprolol (Betaloc, Lopresor, Metolar) v. β-Blockers with α-blocking property i. Labetolol (Labesol, Normadate) ii. Carvedilol (Cardivas, Carvedil, Carvipress) - Structure, Properties, uses, Synthesis, Assay, Storage, Dosage forms, Dose | Synthesis and Drug Profile


SYNTHESIS AND DRUG PROFILE


Beta receptor blocking agents


i. Propranolol (Synonym: Inderal, Ipran, Manopralol, Beetacap)


Synthesis


Properties and uses: It is a white or almost white powder, soluble in water and in ethanol. Currently, it is approved for hypertension associated cardiac arrhythmia, angina pectoris, due to coronary atherosclerosis and prophylaxis of migraine headache. It is a nonselective β-adrenergic antagonist and it has equal affinity for β1 and β2 receptors.

Assay: Dissolve the sample in ethanol and titrate with 0.1 M sodium hydroxide. Determine the end point potentiometrically.

Dose: The oral adult dose for arrhythmias is 10 to 30 mg 3 to 4 times/day.

Dosage forms: Prolonged-release propranolol capsules B.P., Propranolol injection B.P., Propranolol tablets B.P.


ii. Acebutalol (Sectral)


Synthesis


Properties and uses: It is a white or almost white crystalline powder, slightly soluble in acetone and methylene chloride, but freely soluble in water and ethanol. It is one of the very few β-blockers with mild ISA and does not cause bradycardia as propranolol does. Acebutalol and betaxolol possess membrane stabilizing activity, but the activity is much weaker than that seen with propranolol.

Assay: Dissolve the sample in ethanol and add 0.1 M hydrochloric acid. Perform potentiometric titration by titrating with 0.1 M sodium hydroxide.

Storage: It should be stored in well-closed airtight containers, protected from light.

Dose: A dose of 400 mg/day given once daily.

Dosage forms: Acebutalol HCl tablets I.P., Acebutolol capsules B.P., Acebutolol tablets B.P.


iii. Atenolol(Atenex, Aten, Betacard)


Synthesis

Route I. From: 2-(4-Hydroxyphenyl) acetic acid


Route II. From: p-Hydroxy phenyl acetamide


Properties and uses: It is a white or almost white powder, sparingly soluble in water, but soluble in ethanol. It is a β1 selective drug with low lipid solubility. Mainly used in the treatment of essential hypertension.

Assay: Dissolve the sample in anhydrous acetic acid and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: The usual dose is 50 mg/day once daily.

Dosage forms: Atenolol tablets I.P.,B.P., Atenolol injection B.P., Atenolol oral solution B.P., Co-tenidone tablets B.P.


iv. Metoprolol (Betaloc, Lopresor, Metolar)


Synthesis

Route I. From: p-(2-Chloroethyl) phenol


Route II: From p-(2-Methoxy ethyl) phenol


Properties and uses: It is white, odourless powder, bitter in taste, soluble in water, alcohol, and chloroform, but insoluble in acetone and ether. It is a β1 selective antagonist used in the treatment of hypertension.

Dose: The usual initial oral dose is 100 mg given preferably once daily.


v. β-Blockers with α-blocking property


i. Labetolol (Labesol, Normadate)


Properties and uses: It is a white or almost white powder, sparingly soluble in water and alcohol, but insoluble in methylene chloride. Labetolol is a phenyl ethanol amine derivative that is a competitive inhibitor at both β1 and β2 adrenergic receptors and at the α1 -adrenergic receptor. It is more potent β antagonist than α antagonist, since it has two asymmetric carbon atoms (1 and 1’), it exists as a mixture of four isomers. It is the mixture that is used clinically in treating hypertension. The different isomers, however, posses different α and β-antagonistic activities.

Assay: Dissolve the sample in a mixture of anhydrous formic acid and acetic anhydride. Titrate with 0.1 M perchloric acid and determine the end point potentiometrically.

Dose: The usual initial dose is 100 or 200 mg twice/day with food.

Dosage forms: Labetalol injection B.P., Labetalol tablets B.P.


ii. Carvedilol (Cardivas, Carvedil, Carvipress)

It acts on both β and α-adrenergic receptors. Only δ isomer is β–blocking, and both enantiomers have α-blocking activity.


Synthesis


Properties and uses: It is a white or almost white crystalline powder, insoluble in water and dilute acids, but soluble in alcohol. It shows polymorphism. Used in treating hypertension and congestive heart failure.

Assay: Dissolve the sample in anhydrous acetic acid and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: For hypertension: Adult: Initially, 12.5 mg once daily increased to 25 mg once daily after 2 days. Alternatively, initial dose of 6.25 mg twice/day increased to 12.5 mg twice/day after 1–2 week, increased further if necessary to 50 mg once daily or in divided doses. For elderly: 12.5 mg once daily.

For angina pectoris: Adult: Initially, 12.5 mg twice/day increased to 25 mg twice/day after 2 days.

For heart failure: Adult: Initially, 3.125 mg twice/day, doubled to 6.25 mg twice/day after 2 weeks, if tolerated.

For left ventricular dysfunction: After myocardial infarction: Adult: Initially: 6.25 mg twice/day, if tolerated, after 3–10 days, increase to 12.5 mg twice/day and then to a target dose of 25 mg twice/day.


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