Synthesis and Mechanism of action of Verapamil

 

Synthesis of Verapamil

Verapamil is a phenylalkylamine calcium channel blocker used primarily to treat cardiovascular conditions like hypertension, angina, and arrhythmias. The synthesis of verapamil involves a multi-step organic reaction, commonly starting with the following key components:

1. Synthesis of the 3,4-dimethoxybenzyl alcohol: The starting material is 3,4-dimethoxybenzaldehyde, which is reduced using a reducing agent like sodium borohydride (NaBH₄) to form the corresponding 3,4-dimethoxybenzyl alcohol.

   $$\text{C₆H₅(OCH₃)₂CHO}+\text{NaBH₄}\to \text{C₆H₅(OCH₃)₂CH₂OH}$$

2. Formation of 3,4-dimethoxybenzyl chloride: The 3,4-dimethoxybenzyl alcohol is then treated with thionyl chloride (SOCl₂), converting the alcohol group into a chloride to yield 3,4-dimethoxybenzyl chloride.

   $$\text{C₆H₅(OCH₃)₂CH₂OH}+\text{SOCl₂}\to \text{C₆H₅(OCH₃)₂CH₂Cl}$$

3. Preparation of the nitrile intermediate: Reaction of the benzyl chloride with potassium cyanide (KCN) in an appropriate solvent (e.g., ethanol) produces the nitrile compound, 3,4-dimethoxyphenylacetonitrile.

   $$\text{C₆H₅(OCH₃)₂CH₂Cl}+\text{KCN}\to \text{C₆H₅(OCH₃)₂CH₂CN}$$

4. Amidation: The nitrile undergoes reduction, typically using lithium aluminum hydride (LiAlH₄), to form 3,4-dimethoxyphenylethylamine.

   $$\text{C₆H₅(OCH₃)₂CH₂CN}+\text{LiAlH₄}\to \text{C₆H₅(OCH₃)₂CH₂CH₂NH₂}$$

5. Coupling with isopropyl chloroformate: The ethylamine derivative is reacted with isopropyl chloroformate to form the final verapamil structure, incorporating the isopropyl ester and dimethylamine moieties.

Mechanism of Action of Verapamil

Verapamil is a calcium channel blocker, more specifically a L-type voltage-gated calcium channel antagonist. Its mechanism of action can be described as follows:

1. Calcium Channel Inhibition: Verapamil binds to L-type calcium channels on the plasma membrane of cardiac and smooth muscle cells, particularly within the heart and blood vessels. These channels are responsible for the influx of calcium ions during the depolarization phase of the action potential.

2. Decreased Intracellular Calcium: By inhibiting calcium influx, verapamil reduces the concentration of intracellular calcium, which is essential for the contraction of both cardiac and smooth muscle.

3. Reduced Cardiac Contractility (Negative Inotropic Effect): In cardiac myocytes, reduced calcium entry decreases the force of contraction (negative inotropy). This makes the heart work less hard, reducing the oxygen demand, which helps in treating angina.

4. Slowed Heart Rate (Negative Chronotropic Effect): Verapamil slows the conduction of electrical impulses through the atrioventricular (AV) node, leading to a slower heart rate (negative chronotropy). This is useful in managing arrhythmias like atrial fibrillation.

5. Vasodilation: In smooth muscle of blood vessels, decreased calcium levels lead to relaxation of the muscle and vasodilation. This reduces peripheral resistance, lowering blood pressure (antihypertensive effect).

Clinical Effects:

• Treatment of Hypertension: Verapamil lowers blood pressure by causing vasodilation and decreasing cardiac output.
• Anti-anginal Effect: It decreases the workload on the heart, reducing myocardial oxygen demand.
• Anti-arrhythmic Effect: By slowing AV node conduction, it helps control arrhythmias like supraventricular tachycardia.

In summary, verapamil's mechanism of action is centered on blocking calcium channels, which leads to reduced calcium-dependent contraction of the heart and smooth muscle, ultimately lowering heart rate, blood pressure, and oxygen demand in the heart.