Calcium channel blockers

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Chapter: Medicinal Chemistry : Antianginals

Antianginals : Calcium channel blockers - Synthesis and Drug Profile - i. Amlodipine (Amlodac, Stamlo, Amlong) ii. Nifedipine (Caclcigard, Nicardia Retard,Depin) iii. Nitrendipine iv. Felodipine (Felogard, Plendil, Renedil) v. Nicardipine vi. Isradipine


SYNTHESIS AND DRUG PROFILE

Calcium channel blockers

Mode of action: Calcium channel blockers act on the Ca2+ channel receptors, block the release of calcium, and, therefore, the calcium interaction with a protein calmodulin to form calcium calmodulin complex is decreased. This leads to the decreased activation of myosin light chain phosphorylation, which promotes muscle contraction by interacting between actin and myosin.

Metabolism: Prehepatic first-pass metabolism by CYP3A4 enzyme occurs with some orally administered calcium channel blockers, especially verapamil, with its low bioavailability of 20%–35%. The bioavailability of dilitiazem is 40%–67%, nicardipine is 35%, nifedipine is 45%–70%; and amlodipine is 64%–90%. Verapamil is metabolized by CYP3A4 N-demethylation to its principal metabolite, norverapamil, which retains approximately 20% of the activity of verapamil, and by O-demethylation (CYP2D6) into inactive metabolities. Dilitazem is metabolized by enzyme hydrolysis of its primary metabolite, diacetyl derivative, which retains approximately 25%–50% of the activity of Diltiazem.

Diltiazem undergoes N-demethylation by CYP3A4 and O-demethylation by CYP2D6. The N-demethylated metabolic pathways results in a mechanism-based inhibition of CYP3A4. The major metabolites are detected after oral and continuous intravenous administration, but not following rapid intravenous administration.


i. Amlodipine (Amlodac, Stamlo, Amlong)


Properties and uses: It is a white or almost white powder, slightly soluble in water, freely soluble in methanol, sparingly soluble in ethanol and 2-propanol. Used as an antianginal and antihypertensive agent

Assay: It is assayed by adopting liquid chromatography technique.

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

Dose: 2.5 to 10 mg/day amlodipine was equal to or superior to 160–320 mg/day verapamil, 50 to 100 mg/day captopril.

Synthesis



ii. Nifedipine (Caclcigard, Nicardia Retard,Depin)


Synthesis (Hantzsch synthesis)

Step I. Preparation of methyl—[2-acetyl-3-(2-nitrophenyl)]-2-propenoate


Step II. Preparation of Methyl-3-amino-2-butenone


Step III. Condensation of Steps I and II products.


Properties and uses: It is a yellow crystalline powder, sparingly soluble in ethanol, insoluble in water, but freely soluble in acetone. It is used in the treatment of vasospastic angina and hypertension.

Assay: Dissolve the sample in a mixture of 2-methyl-2-propanol and perchloric acid solution. Titrate with

0.1 M cerium sulphate using ferroin as indicator. End point is the disappearance of pink colour.

Storage: When exposed to daylight and artificial light of certain wavelengths, it readily converts into a nitrosophenylpyridine derivative. Exposure to ultraviolet light leads to the formation of a nitrophenylpyridine derivative. Hence, it should be stored in well-closed airtight containers and protected from light.

Dose: For angina pectors: Adult: Long-acting preparation: 10–40 mg twice/day or 30–90 mg once daily.

Dosage forms: Nifedipine capsules I.P., B.P, Nifedipine tablets I.P.


iii. Nitrendipine


Synthesis

Step I. Preparation of methyl-[2-acetyl-3-(nitrophenyl)]-2-propenoate


Step II. Preparation of ethyl-3-amino-2-butenone


Step III. Condensation of Steps I and II products


Properties and uses: It is a yellow crystalline powder exhibiting polymorphism, sparingly soluble in ethanol and methanol, insoluble in water, but freely soluble in ethyl acetate. It is used as a vasodilator and also used in the treatment of mild-to-moderate essential hypertension.

Assay: Dissolve the sample with gentle heating if necessary in a mixture of 2-methyl-2-propanol and perchloric acid solution. Titrate with 0.1 M cerium sulphate, using 0.1 ml of ferroin as indicator.

Storage: Exposure to ultraviolet light leads to the formation of a nitrophenylpyridine derivative. Hence, it should be stored in well-closed airtight containers and protected from light.


iv. Felodipine (Felogard, Plendil, Renedil)


Synthesis


Properties and uses: It is a white or light yellow, crystalline powder, practically insoluble in water, freely soluble in acetone, ethanol, methanol, and in methylene chloride. It is used in the treatment of angina and essential hypertension.

Assay: Dissolve the sample in a mixture of 2-methyl-2-propanol and perchloric acid solution. Add ferroin as an indicator and titrate with 0.1 M cerium sulphate until the pink colour disappears.

Dose: 2.5 to 20 mg alone or in combination with beta-blocker or 5 to 10 mg given once daily.

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


v. Nicardipine


Properties and uses: It exists as white crystals and are used in the treatment of angina and essential hypertension.


vi. Isradipine


Properties and uses: It is a yellow crystalline powder, practically insoluble in water, freely soluble in acetone and soluble in methanol. It is used in the treatment of angina.

Assay: It is assayed by adopting liquid chromatography technique.

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

Dosage forms: Isradipine tablets B.P.


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