Calcium channel blockers controversy: a review of the literature.

Calcium channel blockers (CCBs) are a commonly used cardiovascular drug class. Sales of CCBs have been estimated to be approximately $3.2 billion annually. Clinicians have prescribed calcium channel blockers for the treatment of angina pectoris, hypertension, and cardiac rhythm disturbances since the 1980s (Katzung, 1998). In 2002, the eighth most prescribed drug in the United States was amlodipine, a calcium channel blocker, and several other types of calcium channel blockers are also found among the top 100 prescription drugs (Mosby's Drug Consult, Online). However, the use of calcium channel blockers has not been without controversy. The controversy started with a review written by Psaty et al. in 1995, which showed increased incidence of myocardial infarction in patients taking short acting calcium channel blockers to treat hypertension. In the mid-1990s the popular media sensationalized research that questioned the safety of calcium channel blockers, which resulted in some patients stopping their use of these medications and also spawned lawsuits for libel against some news organizations (Carruthers, 2002).

Calcium channel blockers are used safely by thousands of people, but have also been associated with both adverse effects and poisonings. Calcium channel blocker overdose is one of the most lethal prescription drug ingestions. This paper will examine the actions of calcium channel blockers, how they can be effective in treating certain conditions, their adverse effects in normal (correct) use, and their effects in improper (incorrect) use, such as overdose.

METHODS

Definitions and limitations. A calcium channel blocker (CCB) is a drug that prevents calcium from entering cells and has its chief effects on vascular smooth muscle and the heart. CCBs are also called calcium antagonists and slow channel blockers. Commonly prescribed calcium channel blockers fall into one of three chemical families--dihydropyridine, phenylalkylamine, and benzothiazepine (Lehne, 1998), although newer classes of CCBs are under investigation (Lacolley, Poitevin, Koen, and Levy, 1998).

This paper defines "adverse effects" and "poisoning" according to the International Classification of Diseases, 9th edition, Clinical Modification (ICD-9-CM). An adverse effect occurs when a medication is prescribed and administered properly (i.e., the right patient, drug, time, dose and route), yet the patient still experiences an untoward reaction. A poisoning is the result of improper use of a drug, whether the result of an accidental medication error or of an intentional overdose, as in a suicide attempt (Brown, 2003).

A limitation of this review is that it investigates a sampling of issues related to adverse effects and poisonings due to calcium channel blockers. A comprehensive, in-depth report on every known or suspected adverse effect or poisoning result is beyond the scope of this paper.

Sources. The researchers retrieved articles using various sources, including a search using the abstract and indexing service, MEDLINE, for the years 1996--April 2004. Focusing on the key term, "Calcium Channel Blockers," specifying the subject headings, "adverse effects" and "poisoning" and limiting the search to English language articles dealing with human subjects resulted in a total of 485 articles for this time period. The researchers also utilized the MDConsult database and the search phrases "calcium channel blocker AND adverse effects," which yielded 870 articles from the year 2001 to present, and "calcium channel blocker AND overdose," which found 90 articles from 2001 to present. The author selected articles for inclusion in this paper that provided information related to the usefulness of calcium channel blockers, the potential adverse effects of their use, and the mechanisms and circumstance by which poisoning or overdose of calcium channel blockers cause harm. Textbooks provided general background information.

BODY OF REVIEW

Calcium Channels. Calcium has long been known to plan a diverse and critical role as a mediator of cell function, both as a transmembrane charge carrier and as an intracellular second messenger. Although the cell possesses large stores of calcium, intracellular free calcium is maintained in the submicromolar range. Low intracellular calcium concentration in maintained by pumps or exchange systems which act to transport calcium from the cytoplasm to the outside of the cell. Transient increases in calcium concentration provide a critical link in cellular activation processes such as excitation-contraction and excitation-secretion coupling. Transient increases in intracellular calcium occur by two mechanisms, both presumably involving calcium channels. The first is the release from internal sites such as the endoplasmic reticulum. The second involves channels in the plasma membrane that allow extracellular calcium to pass down a concentration gradient and enter the cell. The plasma membrane calcium channels can be divided into two subtypes. One type is the receptor operated channel, in which calcium influx is directly coupled to a receptor (Miller, 1987). Less is known about the receptor operated channels than about the second subtype of voltage-sensitive channels.

The voltage sensitive calcium channels have been divided into 3 subtypes (L, N, and T) based upon their conductances and sensitivities to voltage (Schwartz et al., 1988; Tsien et al., 1988). Only the L-type channel is sensitive to calcium channel blockers. The calcium channels in smooth muscles, exocrine glands, and skeletal muscle seem to be dihydropyridine sensitive.

Calcium Channel Blockers' Action on Calcium Channels. It is believed that dihydropyridines bind to only the large [[alpha].sub.1] subunit of the calcium channel. Other conventional channel blockers bind to different sites on the L-channel. A recent report by Hering et al. in 2000 showed evidence that the phenylalkylamine class of calcium channel blockers binds to and accesses their receptors from an intracellular site.

In addition to blocking the calcium channel, the dihydropyridines may also inhibit a cyclic nucleotide phosphodiesterases. The increase of serum cyclic nucleotide, in particular adenosine, may also contribute to their greater effects on vascular relaxation than the other classes.

Actions and Uses of Calcium Channel Blockers. Calcium channel blockers have their effects chiefly on the heart (on both the cardiac muscle and the cardiac conduction system) and on vascular smooth muscle. In the heart, the entry of calcium ions into cardiac cells through the slow calcium channels has both inotropic (force of contraction) and chronotropic (rhythm) effects. When calcium ions enter a cardiac muscle cell, this triggers a release of calcium from the sarcoplasmic reticulum, which ultimately allows the actin and myosin cross-bridges needed for contraction of the muscle to form. The fewer the cross-bridges, the more diminished the more diminished the strength of the contraction (negative inotropic effect) (Proano, Chiang, and Wang, 1995; McKenry and Salerno, 1998). With regard to effects on cardiac rhythm, the cells of the sinoatrial (SA) node depolarize spontaneously, generating action potentials at a faster rate than other cardiac muscle cells, thus making this node the natural pacemaker of the heart (Seeley, Stephens, and Tate, 2003). The spontaneous depolarization of the cells of the SA node is linked to the influx of calcium ions into the cells through the slow calcium channels. Therefore, blocking the slow calcium channels decreases the rate of depolarization, which decreases the rate at which the SA node generates impulses. A similar mechanism affects the atrioventricular (AV) node, slowing the rate at which impulses are conducted across the AV junction and ultimately slowing the rate of ventricular contraction (negative chronotopic effect) (McKenry and Salerno, 1998). The overall effect on the heart of blocking calcium channels, then, is to decrease the heart's force of contraction and to slow its rate of contraction.

In a similar fashion, the contractility of vascular smooth muscle is affected by calcium channel blockade. The reduced rate of influx of calcium ions into vascular smooth muscle cells interferes with the action of actin and myosin, thus inhibiting the ability to contract. This results in relaxation and dilation of arteries (McKenry and Salerno, 1998), which can be helpful in the treatment of several diseases.

As previously stated, there are three chemical families containing commonly used calcium channel blockers. There are numerous drugs in the dihydropyridine family, including nifedipine, amlodipine, felodipine, and so on. Each of the other two families contains only one widely available drug--verapamil in the phenylalkylamine family and diltiazem in the benzothiazepine family. Different types of calcium-channel blockers tend to be used to treat different types of diseases. The dihydropyridines have a greater effect on vascular smooth muscle, specifically on arterioles, and do not depress heart action significantly in normal use. Therefore, the dihydropyridines are frequently used to treat angina pectoris and hypertension, because relaxing the arteries allows blood to flow more easily. Improved blood flow would help to relieve anginal pain by improving oxygenation of heart muscle and hypertension by decreasing peripheral circulatory resistance. Drugs used in the treatment of angina are used to treat the pain associated with ischemic heart disease. Basically, they provide symptomatic treatment and do not affect the disease course.

Verapamil and diltiazem, however, affect both the heart and vascular smooth muscle at therapeutic doses. The direct effects of these two drugs in slowing the heart are counteracted by the baroreceptor reflex, which increases heart rate and force of contraction, thus counterbalancing the effects of verapamil and diltiazem on the heart. Like the dihydropyridines, these two drugs are used to treat angina pectoris and hypertension. Additionally, they are useful in treating cardiac dysrhythmias because of their direct affects on the heart (Lehne, 1998; Katzung, 1998).

Several studies have shown the benefits of treatment of certain conditions with CCBs. Wang and Staessen (2002) reviewed the results of eleven clinic trials of various medications for hypertension. Compared to conventional therapy (diuretics and beta blockers), calcium channel blockers were more effective in preventing thickening of the intima and media of the carotid artery and also were more effective in preventing mild renal dysfunction.

Studies comparing different calcium channel blockers have been conducted and newer uses of these drugs have been investigated. One animal study compared nifedipine and amlodipine (dihydropyridines) to mibefradil, which is a new calcium antagonist from benzimidazolyl-substituted tetraline derivatives. Because edema can be an adverse effect of dihydropyridine use, the researchers were interested in learning whether there would be differences in fluid filtration with a new class of drug. Their study found that mibefradil had the same effect as the dihydropyridines in lowering blood pressure, yet with lower fluid filtration, suggesting that mibefradil is not as harmful to vascular permeability in hypertensive rats as dihydropyridines. (Lacolley et al., 1998). Dihydropyridines also have been shown to inhibit platelet aggregation and can be used to prevent the formation of thromboemboli in patients with prosthetic cardiac valves (Chou et al., 1999).

Because of the calcium channel blocker "scare" alluded to in the introduction and described more in depth later, there has been interest in developing more long-acting calcium channel blockers. An example of a study of this nature compared nisoldipine-extended release (ER), a second-generation long-acting dihydropyridine, to the popular drug amlodipine. The result of this clinical trial were that both were effective in reducing blood pressure and increasing exercise time in patients with hypertension and angina pectoris. The investigators' description of the results highlights potential adverse effects (to be discussed later): "Neither drug increased heart rate and both decreased frequency of anginal episodes. Adverse events were infrequent, and typically were vasodilator-related effects (including headache and peripheral edema) that occurred with somewhat higher incidence in the nisoldipine-ER group. Thus, nisoldipine-ER and amlodipine provided comparable antihypertensive and anti-ischemic efficacy, and both were generally well tolerated" (Pepine et al., 2003, p. 274).

Calcium channel blockers have been found to be useful in treating hypertension in patients who also have respiratory problems, such as chronic airway obstruction. CCBs have been found not to cause as many respiratory adverse effects as some other hypertension treatments. For example, coughing may occur with treatment using ACE inhibitors, which may also exacerbate asthma. Although diuretics may be the first choice in treatment of hypertension in patients with airway obstruction, CCBs are recommended if response to diuretics is poor. The effects of CCBs on smooth muscle can in some instances be beneficial to patients with airway obstruction by muting hypersensitivity of the airways (Cazzola et al., 2002).

One investigational use of CCBs is in the treatment of migraine headaches. Certain types of migraine headaches are accompanied by a transient hemiparesis (weakness on one side of the body). When this type of migraine is found in several family members, it is called familial hemiplegic migraine (FHM) and when there is no apparent family history, it is termed sporadic hemiplegic migraine (SHM). Gene mutations affecting the calcium channels were discovered to be associated with FHM and so calcium channel blockade has been investigated as a possible treatment. IV verapamil has been used to stop acute attacks of FHM and case reports have shown both oral and IV verapamil to be effective in treating SHM that was refractory to other treatments (Yu and Horowitz, 2003). Flunarizine, an investigational drug (not yet approved by the FDA for routine prescription in the U.S.), is a calcium channel blocker that has been effective in reducing the severity and preventing recurrences of migraines in early trials. (Katzung, 1998).

Several studies have evaluated the use of calcium channel blockers as a means of managing preterm labor. Because the myometrium of the uterus is comprised of smooth muscle, it stands to reason that CCBs could be effective in suppressing early uterine contractions. (The term, "tocolytic" is applied to an agent that effectively stops uterine contractions.) Researchers at Duke University and the University of North Carolina abstracted data from 75 studies of tocolytic agents and conducted a meta-analysis using 24 studies. Their review showed that calcium channel blockers could be used effectively in tocolytic treatment, prolonging the gestational period and improving birth outcomes. The reviews did uncover a pattern of slight increase in risk for minor cardiovascular harm for patients treated with calcium channel blockers in some of the studies (Berkman et al., 2003).

Pharmacokinetics. The CCBs all have similar pharmacokinetic properties. With the exception of amlodipine and the sustained release products, all are rapidly absorbed following oral administration and generally reach peak concentration in 1-2 hours. Amlodipine reaches peak concentrations in 6-9 hours. Absorption is nearly complete after administration, but the bioavailability is reduced because of first pass metabolism. The liver metabolizes the CCBs almost exclusively. All the CCBs also exhibit significant protein binding (70-90%) (Table 1).

Adverse Effects. Adverse effects that can occur at normal therapeutic dosages of CCBs include vasodilator effects such as facial flushing, dizziness, headache, and peripheral edema. However, some of the newer CCBs, such as lacidipine, appear to be less likely to cause ankle edema (Andresdottir et al., 2000). CCBs may also cause gingival (gum tissue) hyperplasia. Verapamil also tends to cause constipation, which is not as much a problem with diltiazem and the dihydropyridines. However, drugs such as nifedipine sometimes cause reflex tachycardia (increased heart rate in response to lowered blood pressure) (Lehne, 1998).

Controversy arose during the 1990s over the safety of calcium channel blockers when meta-analyses by Furberg, Psaty, and Meyer (1995) and Psaty et al. (1995) indicated that rapid acting nifedipine in moderate to high doses was associated with increased risk of mortality. Their studies suggested that people with high blood pressure who had been taking short acting CCBs had a 60% higher risk of heart attack compared to patients on beta blockers and/or diuretics. A subsequent case control study by Pahor et al. (1995) confirmed their findings in elderly hypertensives. The authors hypothesized that other calcium channel blockers may have similar mortality patterns. The attention that these articles received in the mainstream media generated a firestorm caused by headlines such as this one, which appeared in The Washington Post: "Drugs for Blood Pressure Linked to Heart Attacks: Researchers Fear 6 Million Are Imperiled" (Washington Post, 1995; Messerli, 1995). In Canada, the Canadian Broadcasting Corporation (CBC) aired an investigative report that implied that all calcium channel blockers were dangerous and painted an extremely negative portrait of certain physicians who believed in the safety of CCBs. Six years after the airing of the report, two physicians who had been pilloried in the Canadian media won libel lawsuits against CBC (Carruthers, 2002). A similar panic occurred in 2000 when the New York Times placed a story questioning the safety of CCBs on its front page. Following the 2000 scare, Norman M. Kaplan expressed the concern of many physicians about the effects of unbalanced presentations of such studies in the mass media: "Hypertension is the most common risk factor for cardiovascular diseases that are the most common cause of disability and death in ... all developed societies.... As the 'silent killer,' hypertension will always be difficult to control. It is hard to keep asymptomatic people on daily treatment for life when they recognize no obvious benefit, but rather have adverse effects and often spend large amounts of money for medications.... (W)ide press and media coverage ... provoked a great deal of fear and anxiety among patients taking the calcium channel blockers.... Among patients who abruptly stopped their medications without contacting their physicians (after the 2000 scare), heart attacks and strokes likely occurred, as had been noted after the 1995 scare.... Over the subsequent 5 years, multiple, properly controlled trials have attested to the efficacy and safety of long-acting calcium channel blockers" (2001, pp. 759-760).

The meta-analysis that started the controversy in 1995 was based on short-acting nifedipine, which indeed has been recognized to be unsafe in large doses. However, long-acting calcium channel blockers have been found to be generally safe and effective (Eisenberg, Brox, and Bestawros, 2004). For example, researchers with the Framingham Heart Study found that there were no differences in mortality among subjects with hypertension being treated with CCBs and those who were not using calcium channel blockers (Abascal et al., 1998). More recently, a meta-analysis by Opie and Schall in 2002 found the risk of mortality for CCBs to be about the same as for conventional treatment such as diuretics and beta blockers. Although they found a relative increase in the rate of myocardial infarction with CCBs, this was offset by a decreased incidence of stroke among CCB patients. A study of hypertensive diabetic patients also found calcium antagonists to be safe and effective, "although their use is associated with a lesser reduction of risk of heart failure as compared with other treatments for hypertension" (Grossman and Messerli, 2004, p. 44). We see from this discussion that long-acting CCBs compare favorably with other hypertension treatments with regard to mortality, even though some calcium channel blockers may not decrease the risk of adverse cardiac events as much as some other treatments.

What are the other possible risks or adverse effects of CCBs? Butler et al. (2004) studied patients who were experiencing heart failure, and found an increased incidence of declining renal function among patients receiving CCBs. Another less-commonly reported adverse effect is a photosensitive dermatologic reaction (Silvestre and Albares, 2001; Seggev and Lagstein, 1996). Case reports have also described pulmonary edema as an idiosyncratic reaction to calcium channel blockers (Lee-Chiong and Matthay, 2004). Finally, a single case of acute hypoxemia apparently due to nimodipine provides a reason for physicians to carefully monitor patient oxygenation status when using this CCB (Devlin et al., 2000).

Poisoning. Calcium channel blockers often exert their actions on the L-type of calcium channels that are located primarily in the cardiac and vascular smooth muscle cells. CCBs prevent calcium influx into the cell, resulting in a decrease in vascular tone as well as negative cardiac inotropy and chronotropy. In situations of overdose, patients may experience vasodilation and bradycardia (slow heart rate) leading to shock.

When a calcium channel blocker overdose occurs, exaggeration of the effects of the drug on the heart can create serious problems such as bradycardia, atrioventricular block, cardiac arrest, and congestive heart failure (Katzung, 1998). Other manifestations sometimes occur that are related to the nervous system, including lethargy, confusion, and coma (Zimmerman, 2003). Case reports have also described myoclonus (sudden, brief, irregular involuntary movements) as a manifestation of CCB overdose (Vadlamudi and Wijdicks, 2002). Inhibition of insulin secretion resulting in hyperglycemia has also been reported after CCB overdose (Mokhlesi et al., 2003).

Overdose by short acting agents is characterized by rapid progression to cardiac arrest. Overdose by extended relief formulations result in delayed onset of arrhythmias, shock, sudden cardiac collapse and bowel ischemia. Other physiologic responses to CCB overdose include suppression of insulin release from the pancreas and decreased free fatty acid utilization by the myocardium. These factors produce hyperglycemia, lactic acidosis, and depressed cardiac contractility.

Reports on the frequency of CCB overdose in the U.S. from the American Association of Poison Control Centers (AAPCC) for a four-year period are shown in the table below:

Year  # Cases  # Fatalities  # Major Outcomes

1996  8555     58           225
1997  9077     44           232
1998  8666     61           277
1999  8841     61           243

Approximately 25-28% of cases each year occurred in children under the age of six years (Horowitz, 2004).

Overdose can occur easily in children and so CCBs are rarely prescribed for this population (Barcelona and Cote, 2001). Ingestion of even one tablet by a child can result in vomiting, lethargy, low blood pressure, slow heart rate, and a trip to the emergency department (Abbruzzi and Stork, 2002). Therefore, adults who use calcium channel blockers should be careful to store them safely out of the reach of children.

Of all the calcium channel blockers, verapamil is most commonly associated with serious illness and death when used inappropriately (Zimmerman, 2003). Verapamil has a pronounced negative effect on the force of cardiac contraction, whereas nifedipine has more of a vasodilatory effect. Both verapamil and diltiazem slow the pacemaker and conduction activities of the heart. (Mokhlesi et al., 2003).

Aggressive cardiovascular support is necessary for management of CCB overdose. Although calcium administration may overcome some adverse effects of CCBs, other treatment is generally needed to restore normal cardiovascular status. A number of case reports showed good results from the use of glucagon and inamrinone (Doyon and Roberts, 1993; Fant et al., 1997; Mahr, Valdes, and Lamas, 1997; Stone, May, and Carrol, 1995; Tuncok et al., 1996; Walter et al., 1993). In addition, vasopressor agents are frequently used for adequate resuscitation when hypotension is evident. Recent case reports suggest that the use of high dose insulin, with maintenance of euglycemia by dextrose infusion, may be more efficacious (Yuan et al., 1999; Salhanick and Shannon, 2003; Boyer and Shannon, 2001).

Recommended treatment for overdose of calcium channel blockers includes gastric lavage and wholebowel irrigation for long-acting CCBs. Hypotension and shock are treated with administration of fluids and glucagon (Mokhlesi et al., 2003). Administration of intravenous calcium raises the level of extracellular calcium and the availability of free calcium. Because the T tubules of the sarcoplasmic reticulum are formed by the infolding of the cell membrane, extracellular calcium can enter the T tubules and stimulate the sarcoplasmic reticulum to release calcium, thus improving the contractility of the myocardium (Proano, Chiang, and Wang, 1995). Intravenous calcium has been used to improve the hemodynamic status of patients presenting with CCB overdose without creating further adverse effects (Lam, Tse, and Lau, 2001). However, mortality rates associated with massive CCB overdose are traditionally quite high (Durward et al., 2003).

CRITICAL DISCUSSION AND CONCLUSION

Calcium channel blockers are generally safe and effective when used correctly for treatment of hypertension, angina pectoris, and cardiac dysrhythmias. However, some have noted a pattern of increased cardiac-related mortality compared to other treatments. Others argue that the lower stroke mortality rates in CCB treatment offset the increase in deaths associated with heart problems so that the net increase in mortality compared to other treatments is zero. Achieving good patient compliance with hypertension treatment extends life expectancy and patients are more likely to be compliant if they have confidence in their treatment and if their treatment does not result in adverse effects. Further study of newer calcium channel blockers may bring about approval of medications that inspire greater confidence from patients and result in fewer unpleasant side effects, thus improving compliance and achieving a longer and better quality of life. Also, further study could provide more evidence regarding the effectiveness of calcium channel blockers for nontraditional uses, for example, in treating migraine headaches or patients with cardiac implants. Finally, caution must be exercised to avoid CCB overdose, which can have serious consequences. In summary, while calcium channel blockers are generally safe and effective, further investigation of these drugs can result in refinements that improve their selectivity and decrease their toxicity, thus providing health benefits to many patients diagnosed with circulatory disorders.

Table 1. Calcium Channel Blockers (Pharmokinetics).

Class             Agents       Bioavail-  Onset  Protein   Route of
                               ability    (h)    Binding   metabolism

                  Nifedipine   immediate  0.33    92-98%   Liver
                  Amlodipine   52-88      6       97       Liver
Dihydropyridine   Felodipine   10-25      3-5    >99       Liver
                  Isradipine   15-24      2       97       Liver
                  Nicardipine  35         0.33    89-99.5  Liver
Phenylalkylamine  Verapamil    20-35      0.5     83-92    Liver
Benzothiazepine   Diltiazem    40-67      0.5-1   70-80    Liver

Class             Agents       Route of
                               Excretion

                  Nifedipine   60-80% urine
                  Amlodipine   Bile
Dihydropyridine   Felodipine   70% urine
                               10% feces
                  Isradipine   90% urine
                               10% feces
                  Nicardipine  60% urine
                               35% feces
Phenylalkylamine  Verapamil    70% urine
                               16% feces
Benzothiazepine   Diltiazem    urine

Data compiled from Goodman and Gilman's The Pharmacological Basis of
Therapeutics (8th ed.). Pergamon Press (1990).

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Ann H. Peden and Hamed A. Benghuzzi

University of Mississippi Medical Center Jackson, MS 39216