1.6.1 DHPR Blocker Treatment is Associated With Increased Risk of Heart Failure
Although chemically diverse, calcium channel blockers (DHPR blockers) share a common property of blocking ICa through DHPRs in the sarcolemma. Since their
introduction nearly two decades ago, DHPR blockers have been shown to be effective in controlling blood pressure and anginal symptoms 14. They were the most frequently prescribed antihypertensive drugs in the United States as recently as 1993 116. In the past a few years, however, the long-term safety of DHPR blockers has been questioned, owing to an association with development of cardiovascular events. Recent large clinical studies report that the use of DHPR blockers, particularly in high doses, was associated with an increased risk of adverse cardiovascular events, especially myocardial infarction and heart failure 14. In 1995, a population-based case-control study of 2655 patients on anti-hypertensive treatment found that the use of short-acting DHPR blockers were associated with a 58% increased risk of myocardial infarction compared to the use of diuretics 17. In 2000, a large meta-analysis, which included nine published trials, eight calcium channel blockers, and a total of 27,743 patients, found that the use of DHPR blockers was associated with a significantly higher risk of myocardial infarction, heart failure, and other major cardiovascular events 56. In 2002, the ALLHAT Trial (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial), a randomized double-blind trial involved 33,357 subjects aged 55 years or older, also found the patients on long-term treatment with amlodipine (a DHPR blocker) had a 38% higher
risk of heart failure and a 35% higher risk of hospitalization/fatal heart failure as compared to patients on chlorthalidone (a diuretic) 117. Similarly, in 2003, the CONVINCE trial (the Controlled Onset Verapamil Investigation of Cardiovascular End Points Trial), which enrolled 16,602 patients, reports long-term using of extended-release verapamil was associated with an increased risk of heart failure compared with atenolol (a β-adrenergic blocker) or hydrochlorothiazide (a diuretic) 18
1.6.2 Deferent Classes of DHPR Blockers Exert Different Pharmacological Effects on Hearts
. Not known are the mechanisms that underlie the increased risk of heart failure associated with chronic treatment with DHPR blockers.
DHPR blockers are categorized into five classes according to their chemical structure: phenylalkylamines, dihydropyridines, benzothiazepines, diphenylpiperazines, and diarylaminopropylamines 14, 118. Although all five classes work by blocking DHPRs, each structurally different class binds at a unique location on DHPRs and varies in tissue selectivity 14, 118, 119. Among them, phenylalkylamines are the most cardiac selective as they preferentially block DHPRs in the myocardium 118, 120. In contrast, dihydropyridines preferentially bind vascular smooth muscle L-type channels and produce the most potent vasodilatory effects of the DHPR blockers thereby indirectly affecting cardiac function by the sympathetic reflex (Table 1.1) 118-120. Verapamil and nifedipine are the prototypes of phenylalkylamines and dihydropyridines respectively. Their tissue selectivity, pharmacological effects and clinical applications are discussed further below.
Table 1.1 Comparison of cardiovascular effects of nifedipine and verapamil in vivo 118, 120 Nifedipine (vascular selective) Verapamil (cardiac selective) Heart
1. suppression of cardiac contractility
0/+ +++
2. suppression of conduction (AV node) 0 +++ 3. suppression of automaticity (SA node) 0 +++ 4. suppression of heart rate 0 ++ 5. cause reflex tachycardia Yes No 6. prescribed for ventricular tachycardia
No Yes
Vessel
1.vasodilatation of peripheral vessel +++ + 2.vasodilatation of coronary vessel +++ ++ 0, no effect; +, mild; ++, moderate; +++, pronounced.
Compared to nifedipine, verapamil preferentially blocks DHPRs in cardiac cells. At clinically used doses, nifedipine does not block DHPRs in the myocardium but verapamil does and produces inotropic and chronotropic effects on the heart in vivo 118, 120
. In contrast, the negative inotropic effect is rarely, if ever, seen in intact animals or patients with nifedipine treatment. Probably because of sympathetic reflex responses to its potent vasodilating effects, hemodynamic studies of the immediate release nifedipine formulation in patients with normal ventricular function have generally found a small increase in cardiac index without major effects on ejection fraction, left ventricular end- diastolic pressure or volume (From Drug Information issued by US Food and Drug Administration; available at Verapamil is an antiarrhythmic drug which is the treatment of choice for idiopathic left ventricular tachycardia (also known as verapamil-sensitive VT) 121, and the
next treatment of choice for terminating sinus node, atrioventricular (AV) node reentry tachycardia after simple vagal maneuvers and adenosine 15. The antiarrhythmic effect is partially due to the ability of verapamil to prolong the effective refractory period within the AV node and slow AV nodal conduction in a rate-related manner in vivo 118. In contrast, nifedipine is not an antiarrhythmic drug 120. In patients with normal conduction systems, nifedipine administered as the immediate release capsule had no tendency to prolong AV nodal conduction or sinus node recovery time, or to slow sinus rate 118
Verapamil is thought to access cardiac DHPRs from the intracellular side and bind to open, depolarized channels
. Nifedipine is commonly prescribed to control high blood pressure and angina symptoms due to its preferential blockade of DHPRs in vascular smooth muscle.
122
. One planar bilayer study reported that verapamil also can directly bind to RyRs in vitro and inhibit the Ca2+ release from the cardiac SR 123. As verapamil is one of the most cardiac selective DHPR blockers 118. Thus treatment with verapamil, but not nifedipine, provides an approach to build up an animal model for chronic and partial blockade of cardiac DHPRs in vivo.