Synthesis of Amlodipine and mechanism of action

 

Synthesis of Amlodipine

Amlodipine is a dihydropyridine calcium channel blocker used primarily in the treatment of hypertension and angina. The synthesis of amlodipine typically follows these general steps:

1. Condensation Reaction: The process begins with the formation of a dihydropyridine core structure. This involves a Hantzsch reaction, where two moles of an ester (like methyl acetoacetate) react with a nitrogen-containing compound (ammonia or ammonium acetate) and an aldehyde (typically 2-chlorobenzaldehyde).

2. Formation of Dihydropyridine Ring: The resulting condensation leads to the formation of a dihydropyridine ring system, which is central to the amlodipine molecule.

3. Chlorination: In some synthesis pathways, a chlorinating agent is used to incorporate a chlorine atom into the benzene ring, producing a 2-chlorophenyl group at position 4 of the dihydropyridine ring.

4. Substitution with Aminoalkyl Ether: The ester group at the 3 and 5 positions of the dihydropyridine ring undergoes a substitution reaction with a suitable alcohol derivative, such as an aminoalkyl ether, to introduce the desired side chain containing the basic amine group.

5. Purification and Salt Formation: The free amlodipine base is then purified and reacted with besylate (benzene sulfonic acid) to form amlodipine besylate, the common salt form used in pharmaceutical formulations due to its improved stability and solubility.

Mechanism of Action of Amlodipine

Amlodipine is a calcium channel blocker that works by inhibiting the influx of calcium ions into vascular smooth muscle cells and cardiac muscle cells through L-type calcium channels. Here's a breakdown of its mechanism:

1. Inhibition of Calcium Influx: Amlodipine binds to the alpha-1 subunit of L-type calcium channels, inhibiting the flow of calcium ions into the cells. This reduction in intracellular calcium prevents the contraction of smooth muscles, leading to vasodilation.

2. Vasodilation:

   • Arterial Smooth Muscle: By dilating peripheral arterioles, amlodipine reduces systemic vascular resistance (SVR), which lowers blood pressure (antihypertensive effect).
   • Coronary Arteries: Amlodipine dilates the coronary arteries, improving oxygen delivery to the myocardium and preventing coronary artery spasm (anti-anginal effect).

3. Afterload Reduction: By lowering systemic vascular resistance, amlodipine decreases the afterload (the resistance the heart must overcome to pump blood), making it easier for the heart to function, particularly in patients with hypertension or left ventricular hypertrophy.

4. No Effect on Cardiac Contractility: Unlike non-dihydropyridine calcium channel blockers (e.g., verapamil, diltiazem), amlodipine has minimal effects on cardiac contractility and conduction. This makes it safer for patients with heart failure or those who have bradycardia or other conduction issues.

Thus, amlodipine lowers blood pressure and alleviates angina primarily by causing vasodilation and reducing the workload on the heart.