Amlodipine and its Efficiency in Cardioprotection: Review

Hypertension, smoking, diabetes, and abnormal lipid concentrations constitute some of the modifiable risk factors for cardiovascular diseases (2)

Among the risk factors that contributed to DALYs due to cardiovascular diseases in India in 2016, the leading ones included dietary risks (56·4%), high systolic blood pressure (54·6%) air pollution (31·1%), high total cholesterol (29·4%), tobacco use (18·9%), high fasting plasma glucose (16·7%), and high BMI (14·7%), for both sexes combined.(12)

Hypertension is quite a common medical condition whose prevalence increases with age and has very strong evidence for cardiovascular diseases. It is known to cause various cardiovascular diseases including stroke, heart diseases, chronic kidney diseases, and large vessel diseases. If left untreated high blood pressure can lead to ischaemic and hemorrhagic stroke, myocardial infarction, and heart failure and hence treating hypertension is particularly important. Uncontrolled hypertension increases the relative risk from two to four times for various cardiovascular disease complications (5,6).

There are various classes of drugs that can be used to treat Hypertension. Diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, and calcium channel blockers (CCBs) are the first-line drugs used to treat hypertension (7). These drugs are used as monotherapy or in combination to treat hypertension. As per the guidelines by the American Society of Hypertension (ASH) any combination of the ACE inhibitor/calcium channel blocker (CCB), ACE inhibitor/thiazide-type diuretic, angiotensin II receptor blocker (ARB)/CCB, or ARB/thiazide-type diuretic can be used to treat hypertension (8).

The recent guidelines by the Joint National Committee have recommended Calcium channel blockers (CCBs) as the first-line agent to treat hypertension among the various medications (9). Introduced over 35 years for coronary heart disease, these classes of drugs have gained wide recognition for treating high blood pressure.

There are two major categories of calcium channel blockers - non-dihydropyridines and

dihydropyridines. The non-dihydropyridines include verapamil, a phenylalkylamine, and diltiazem, a benzothiazepine. The dihydropyridines include amlodipine, nifedipine, cilnidipine, etc, which block the inward movement of calcium by binding to the L-type "long- acting" voltage-gated calcium channels in the heart, vascular smooth muscle, and pancreas. The non-dihydropyridines have inhibitory effects on the sinoatrial (SA), and atrioventricular (AV) nodes resulting in slowing of cardiac conduction and contractility. The dihydropyridines affecting peripheral vasodilators help to reduce blood pressure (10).

Amlodipine is a long-acting, lipophilic, third-generation dihydropyridine (DHP) Calcium Channel Blocker that exerts its action through inhibition of calcium influx into vascular smooth muscle cells and myocardial cells, thus resulting in decreased peripheral vascular resistance (PVR). Its usage as a once-daily dosing, long half-life, and gradual onset of action favours patient compliance (11).

Various trials in the past like CAMELOT trial, J-ELAN trial, ALLHAT trial, VALUE trial have all investigated the efficacy of amlodipine as a monotherapy and in combination with other drugs.

Further, Lee et al (13) reported the superiority of amlodipine in preventing Cardiovascular diseases, as compared to non-calcium channel blocker (non-CCB) antihypertensive therapy. They found that with amlodipine, there was a significant reduction of 9% for myocardial infarction, 16% for stroke, 10% for all cardiovascular events and total mortality, and comparable risk of heart failure compared with the overall for β-blockers and diuretics.

In 2014, an editorial review published in the Korean Journal of Internal medicine by Chang Gyu Park also analysed whether amlodipine is more cardioprotective than other antihypertensive drug classes

The author noted that Verapamil and Diltiazem which are non-DHP drugs may have an edge over DHPs in post-myocardial infarction patients and diabetic nephropathy as non-DHP CCBs can suppress the heart rate not only at rest but also during exercise. The author also referred a few studies on how short-acting CCBs are hazardous in ischemic heart disease, and increased mortality, while long-acting CCBs like Amlodipine did not. The author further opined that most of the literature in the past took Amlodipine as the standard calcium channel blocker and compared the drug with various other drugs in their studies. But as the various classes of CCBs differ in their chemistry, mode, and site of action the author found it unreasonable to consider most CCBs to have the same efficacy as amlodipine.

Chang Gyu noted that since a major complication in East Asians is dietary sodium-induced hypertension causing stroke as highlighted by Intersalt Study, and that calcium channel blockers (CCBs) played an effective role in stroke prevention, adding that the major complication of hypertension in East Asians is stroke, rather than myocardial infarction.

The authors noted that in general CCBs especially non-DHP are not recommended for patients with, or at high risk for, heart failure due to reduced left ventricular function as previous studies showed increased plasma norepinephrine levels. The author further referred a Diltiazem trial where diltiazem was associated with an increased risk of death in those patients with depressed left ventricular function.

In comparison, amlodipine does not seem to exert unfavourable effects on the clinical course of patients with heart failure, regardless of the presence or absence of underlying CAD. PRAISE- 2 study (16) noted that in chronic heart failure patients, amlodipine was neutral in patients with the ischemic and nonischemic disease.

The author observed that Amlodipine provided superior protection against stroke and myocardial infarction (MI) than angiotensin II receptor blockers and prevented more stroke than angiotensin-converting enzyme inhibitors (ACEis) or any older drug classes. He referred Valsartan Antihypertensive Long-term Use Evaluation study comparing Valsartan and Amlodipine and noted how Amlodipine was significantly effective at reducing Blood Pressure, especially during the early phases of treatment, and added that the blood pressure- lowering ability of Amlodipine reduced the incidence of myocardial infarctions and strokes.

Regarding the blood pressure variability, the author analyzed the superiority of amlodipine in a study where the blood pressure variability with amlodipine was significantly lower than with atenolol or ACEis.

The author also mentioned a few factors which made Amlodipine superior to other calcium channel blockers and possessing more cardioprotective effects. They include:

Finally, to conclude the author has suggested further clinical trials that can compare Amlodipine with other calcium channel blockers, adding that till then.

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13. Lee SA, Choi HM, Park HJ, Ko SK, Lee HY. Amlodipine and cardiovascular outcomes in hypertensive patients: meta-analysis comparing amlodipine-based versus other antihypertensive therapy. Korean J Intern Med 2014;29:315-324.

14. Chang Gyu Park. Is amlodipine more cardioprotective than other antihypertensive drug classes? Korean J Intern Med. 2014;29(3):301-304. Published online April 29, 2014

15. Packer M, Carson P, Elkayam U, et al. Effect of amlodipine on the survival of patients with severe chronic heart failure due to a nonischemic cardiomyopathy: results of the PRAISE-2 study (Prospective Randomized Amlodipine Survival Evaluation 2). JACC Heart Fail 2013;1:308- 314.