(1)
University of Ottawa The Ottawa Hospital, Ottawa, ON, Canada
There are important, subtle differences among the available calcium antagonists that may affect the choice in treating individual patients. First generation dihydropyridines are short-acting agents that include felodipine, isradipine, nifedipine, and nitrendipine. These rapid-acting vasodilators are powerful antihypertensive agents, but their fast onset of action results in marked vasodilation that causes reflex stimulation of the sympathetic nervous system and hemodynamic adverse effects that include increased heart rate, increased cardiac workload, and an increased incidence of heart failure in patients with left ventricular dysfunction. The short-acting formulations of dihydropyridines, verapamil, and diltiazem are no longer recommended.
Calcium antagonists are the most effective blood pressure-lowering agents currently available and have been proved in randomized clinical trials (RCTs) to decrease cardiovascular disease (CVD) outcomes in patients with hypertension but carry a significant risk for heart failure (HF) in the elderly. Available calcium channel blockers include: amlodipine, diltiazem, felodipine, isradipine lacidipine, lercanidipine hydrochloride, nicardipine hydrochloride nifedipine, nimodipine, and verapamil hydrochloride.
It is important to know when to choose a calcium antagonist for the individual patient and which one to choose.
Recommendations are given after discussion of the mechanism of action.
Mechanism of Action
Calcium antagonists influence the myocardial cells, the cells within the specialized conducting system of the heart, and the cells of vascular smooth muscle. Calcium antagonists act at the plasma membrane to inhibit calcium entry into cells by blocking voltage-dependent calcium channels. They interfere with the inward displacement of calcium ions through the slow channels of active cell membranes. Calcium ions play a vital role in the contraction of all types of muscle: cardiac, skeletal, and smooth. Myoplasmic calcium depends on calcium entry into the cell. Calcium binds to the regulatory protein troponin, removing the inhibitory action of tropomyosin, and in the presence of adenosine triphosphate allows the interaction between myosin and actin with consequent contraction of the muscle cell. During phase 0 of the cardiac action potential, there is a rapid inward current of sodium through so-called fast channels. During phase 2 (the plateau phase), there is a slow inward current of calcium through channels that are 100 times more selective for calcium than for sodium; these channels have been termed slow calcium channels.
Fleckenstein (1977) showed that calcium channels can be selectively blocked by a class of agents he termed calcium antagonists (also called calcium channel blockers, calcium channel antagonists, and calcium entry blockers).
There are at least two types of calcium channels: L and T. L channels are increased in activity by catecholamines. The calcium antagonists available for clinical use are mainly L channel blockers. A second type of channel, termed the T channel, appears at more negative potentials and seems to play a role in the initial depolarization of the sinoatrial (SA) and atrioventricular (AV) nodal tissue. T channels are also present in vascular smooth muscle cells, Purkinje cells, and neurohormonal secretory cells. Mibefradil was touted as a T channel blocker; it caused bradycardia and has a host of adverse effects and interactions. The drug has been withdrawn from the market.
Calcium movement into the cell is mediated by at least seven mechanisms (Braunwald 1982). The slow channels represent two of these mechanisms. Two or more types of slow channels exist:
1.
Voltage-dependent calcium channels are blocked by calcium antagonists.
Nifedipine is one of the most potent calcium antagonists and appears to act by plugging the calcium channels. It causes dilation of coronary arteries and arterioles and considerable peripheral arteriolar dilation. Nifedipine has a small and usually unimportant negative inotropic effect on the heart.
Verapamil and diltiazem cause distortion of calcium channels and also cause coronary artery dilation: there are additional effects on the SA and AV nodes; in addition, these drugs have a negative inotropic effect. Peripheral vasodilation is relatively milder than that noted after nifedipine administration.
2.
Receptor-operated calcium channels are blocked by beta-adrenoceptor blockers. Beta-agonists increase calcium influx through such channels, and this effect is blocked by beta-adrenoceptor blocking agents, which cause the failure of a certain proportion of the calcium channels to open. Beta-adrenergic blockers reduce intracellular levels of cyclic adenosine monophosphate; this, in turn, decreases the number of receptor-operated calcium channels available for calcium influx and thus lowers intracellular calcium and actuates a decrease in heart rate and myocardial contractility. In other words, beta-adrenoceptor blockers have a calcium channel blocking property. In fact, verapamil was first investigated because its action resembled that of the beta-adrenoceptor blocking agents.
A clinical classification of calcium antagonists is given in Table 5-1.
Table 5-1
Clinical classification of calcium antagonists
Group | Characteristics |
|---|---|
I | L channel blockers: no action on SA or AV nodes: no effect |
Dihydropyridines: amlodipine, felodipine, isradipine, nifedipine, nicardipine, niludipine, nimodipine, nisoldipine, nitrendipine, ryosidine | |
II | L channel blockers and probably some T channel blockade: additional action on SA and TV nodes: |
EP effects | |
Phenylalkylamines: verapamil | |
Benzothiazepines: diltiazem | |
III | Mainly T-type channel blocker: mibefradil (Posicor, withdrawn) |
The dihydropyridines (DHPs), phenylalkylamines, and benzothiazepines have vastly different actions (Table 5-2). Their indications are necessarily different, as well as several of their important adverse effects and cautions. They are interchangeable only in the management of coronary artery spasm. For use in other clinical situations (in angina, in hypertension, or in the elderly), care is necessary in their selection. Only amlodipine and felodipine have proved safe in patients with mild left ventricular (LV) dysfunction. (See Table 5-2 for a comparison of cardiac effects and peripheral dilation.)
Table 5-2
Hemodynamic and electrophysiologic effects of calcium antagonists
Nifedipinea | Diltiazem | Verapamil | |
|---|---|---|---|
Coronary dilation | ++ | ++ | + |
Peripheral dilation | ++++ | ++ | +++ |
Negative inotropic | + | ++ | +++ |
AV conduction ↓ | ↔ | +++ | ++++ |
Heart rate | ↑↔ | ↓↔ | ↓↔ |
Blood pressure ↓ | ++++ | ++ | +++ |
Sinus node depression | ↔ | ++ | ++ |
Cardiac output ↑ | ++ | ↔ | ↔ |
The DHPs are discussed first because they were used in clinical practice much before the benzothiazepine diltiazem.
Drug name: | Nifedipine |
Trade names: | Procarida XL, Adalat CC; Adalat XL (C), Adalat LA (UK) |
Supplied: | Procardia XL 30, 60, 90 mg; Adalat XL 30, 60, 90 mg; Adalat LA 30, 60 mg |
Dosage: | Extended release, 30 mg once daily; average maintenance dose 60 mg; max. 90 mg (rarely advisable); short-acting formulations not recommended; see text; avoid grapefruit juice |
Action
Nifedipine is a DHP calcium antagonist. Nifedipine and most DHPs are primarily powerful vasodilators and are effective in all grades of hypertension at all ages. They possess negligible negative inotropic and electrophysiologic effects. In clinical practice, there is virtually no adverse effect on the sinus or AV nodes. The absence of significant electrophysiologic effect renders DHPs ineffective as antiarrhythmic agents.
Caution: Their minimal negative inotropic effect may precipitate pulmonary edema in patients with poor LV function.
Adverse Effects and Interactions for DHPs
Contraindications include the following:
Patients with heart failure or those with poor LV function, ejection fraction (EF) < 30 %, should not be given nifedipine or other calcium antagonists.
Significant aortic stenosis: In severe aortic stenosis, impedance to LV ejection is fixed, and nifedipine, like other arteriolar vasodilators, will not reduce LV afterload. In such patients, the mild negative inotropic effect of nifedipine or DHPs may precipitate pulmonary edema, if the LV end-diastolic pressure is already increased. Nifedipine and DHPs should be avoided in the presence of a fixed obstruction to LV ejection. Other vasodilators are of limited value in this situation, and indeed any of these agents may be harmful when there is dynamic obstruction, as in aortic stenosis or in some patients with hypertrophic cardiomyopathy with severe obstructive features.
Bradycardia: Patients with sick sinus syndrome and second- or third-degree AV block represent relative contraindications. It is preferable to pace such patients before using a DHP, although studies indicate that nifedipine has no electrophysiologic effects, causing no depression of SA or AV node function at conventional doses, 30–60 mg/day (Krikler et al. 1982). It is relatively safe to combine a DHP with beta-blockers, whereas it is necessary to select patients and to be careful when verapamil or diltiazem is added to a beta-blocker because of the tendency for the verapamil and diltiazem to exacerbate bradycardia or HF.
The side effects of nifedipine and verapamil are given in Table 5-3. Further clinical trials from 1984 to 1999 indicate that about 20 % of patients complain of side effects from nifedipine or DHP therapy, and in about 10 %, the agent has to be discontinued. Adverse effects are much less common with extended-release formulations such as Procardia XL, Adalat XL, or Adalat LA. Rapid-release nifedipine capsules are no longer recommended. Flatulence and heartburn may be increased by all calcium antagonists because they cause relaxation of the lower esophageal sphincter. A rebound increase in angina sometimes, but rarely, occurs on sudden discontinuation of nifedipine or other calcium antagonists, especially in patients with coronary artery spasm (Lette et al. 1984). Slow withdrawal with the addition of nitrates is advisable. A similar withdrawal phenomenon has been noted with nisoldipine in patients with stable angina.
Table 5-3
Side effects of dihydropyridines (DHPs) and verapamil
Side effect | DHPs (%) | Verapamil (%) |
|---|---|---|
Dizziness | 3 | 3.6 |
Edema | 15 | 2 |
Headaches | 5 | 1.8 |
Flushing and burning | 8 | 2 |
Hypotension | 0.5 | 2.9 |
Constipation | 2 | 1.5 |
Upper Gl upset | 1.6 | — |
Heart failure | 0.5 | 10 |
Prolonged PR interval | — | 3.2 |
Second-degree AV block | — | 0.4 |
Third-degree AV block | — | 0.8 |
Intraventricular conduction defect | — | 1.2 |
Bradycardia | — | 1.1 |
Need to discontinue the drug because of side effects | 4 | 4 |
Nifedipine, by increasing ventilation–perfusion imbalance, slightly reduces altered oxygen tension at rest and during submaximal exercise in patients with stable angina (Choong et al. 1986). These effects are also observed with diltiazem and verapamil. It may be prudent to administer calcium antagonists with care in patients with compromised respiratory function. Although oral nifedipine significantly reduces airway reactivity in patients with asthma, it also lowers arterial oxygen tension because of a worsening ventilation–perfusion relationship (Ballester et al. 1986). Other very rare side effects of nifedipine and other calcium antagonists include shakiness, jitteriness, depression, psychosis, transient blindness at the peak of plasma level, arthritis, and muscle cramps.
Gingival hyperplasia occurred in 38 % of patients receiving nifedipine compared with 4 % for controls (Steele et al. 1994).< div class='tao-gold-member'>Only gold members can continue reading. Log In or Register to continue
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