Calcium channel blockers

See also Individual agents

General information

The calcium channel blockers block the movement of calcium across L-type calcium channels. The main drugs that share this action are verapamil (a phenylalkylamine), diltiazem (a benzthiazepine), and the dihydropyridines, which include amlodipine, darodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, and nitrendipine. Other agents, for example prenylamine and lidoflazine, are now rarely used, and perhexiline, having failed to reach the market at all in some countries, was withdrawn in the UK after continuing concerns about its safety [ ].

Mibefradil blocks T type calcium channels; it was withdrawn within 1 year of marketing because of multiple drug interactions, emphasizing the need for rigorous drug assessment before release and the importance of postmarketing surveillance of new drugs [ ].

The properties of these drugs vary widely [ ]. Nifedipine is said to have little negative inotropic effect and no effect on the atrioventricular node; verapamil is a potent cardiac depressant, with a marked effect on the atrioventricular node; and diltiazem has less cardiac depressant effect but inhibits atrioventricular nodal activity.

Controversy has surrounded the use of calcium channel blockers in the treatment of hypertension [ ] and ischemic heart disease [ ], with evidence for an association with unfavorable coronary outcomes compared with other therapies. Most of the evidence comes from the use of short-acting formulations, especially short-acting nifedipine. The hypothesis put forward to explain these findings was that short-acting formulations cause reflex activation of the sympathetic nervous system [ ]. Further observational studies showed that these drugs were also associated with gastrointestinal hemorrhage [ ] and cancer [ ]. Claims of conflicts of interests amongst authors were published [ ], often amid heated debate. Further evidence against the short-acting calcium channel blockers in hypertension has been forthcoming [ , ] and a worse than expected outcome with respect to coronary outcomes in diabetic patients has fuelled the debate [ ]. Further evidence of gastrointestinal bleeding has been published [ ], but there is evidence against a link with cancer [ ]. All these scares have undoubtedly reduced the standing of this class of drugs in the eyes of physicians.

That calcium channel blockers are effective in relieving the symptoms of angina pectoris is beyond doubt. However, the Angina and Silent Ischemia Study [ ], in which nifedipine, diltiazem, and propranolol were compared with placebo in a crossover study, produced conflicting results. Only diltiazem improved treadmill exercise time and only propranolol convincingly reduced the number of silent ischemic episodes during ambulatory monitoring. These findings are hard to explain [ ]. Beta-blockers may be cardioprotective and therefore preferable to calcium channel blockers [ ]. The clinically significant deterioration seen in patients with impaired left ventricular function taking calcium channel blockers is important, as many patients with angina have previously had a myocardial infarction or have poor left ventricular function. Calcium channel blockers cannot be assumed to be safe second-line drugs for angina in patients with poor cardiac reserve, although newer agents may prove to be safer [ ].

Calcium channel blockers are very effective in controlling variant angina, and are often used during coronary angioplasty and after coronary artery surgery. They are also useful in patients who are intolerant of beta-blockers [ ], or who have a poor response to nitrates, or who have concurrent hypertension.

General adverse effects and adverse reactions

Although they are chemically heterogeneous, many adverse effects and reactions are common to all calcium channel blockers, predictable from their pharmacological actions. Calcium plays a role in the functions of contraction and conduction in the heart and in the smooth muscle of arteries; drugs that interfere with its availability (of which there are many, the calcium channel blockers being the most specific) will therefore act in all these tissues. A few idiosyncratic and hypersensitivity reactions have also been reported with individual calcium channel blockers.

Throbbing headache, facial warmth and flushing, and dizziness are minor complaints associated with the use of calcium channel blockers; these effects are believed to be caused by inhibitory actions on smooth muscle [ ]. Palpitation, muscle cramps, and pedal edema also occur [ ]. Dizziness, facial flushing, leg edema, postural hypotension, and constipation have been reported in up to one-third of patients. They are rarely severe and often abate on continued therapy. More serious adverse effects, mainly those affecting cardiac conduction, are much less common, and only rarely is withdrawal necessary.

Organs and systems

Cardiovascular

Cardiac failure

Although acute hemodynamic studies have suggested that calcium channel blockers can be beneficial in cardiac failure [ ], long-term treatment has been associated with clinical deterioration. Calcium channel blockers should therefore be prescribed with caution for patients with impaired cardiac function, who should be regularly reassessed; treatment should be withdrawn if the signs or symptoms of cardiac failure appear. In some cases heart failure is predictable, as in the case of a patient with aortic stenosis who developed left ventricular failure after treatment with nifedipine [ ]. Increased sympathetic activity can also compensate for the myocardial suppressant effects of calcium channel blockers, and the combination of these drugs (particularly verapamil) with beta-adrenoceptor antagonists has therefore given cause for concern in the past, although this combination is now considered relatively safe for the majority of patients with normal cardiac function [ ].

Myocardial ischemia

There have been many studies of the efficacy of calcium channel blockers in early and late intervention in myocardial infarction [ ]. These studies have failed to show convincing benefits. Indeed, in the nifedipine intervention studies there was a consistent trend towards higher mortality in the treated patients than in those taking placebo. A study in which patients were randomized to placebo or nifedipine within 48 hours of admission was terminated after 1358 patients had been recruited, because mortality at 6 months was 15.4% on nifedipine and 13.3% on placebo [ ].

It has been argued that dihydropyridine calcium channel blockers, which increase heart rate, can all increase the risk of death and reinfarction [ , ]. Early beneficial results with diltiazem in patients with non-Q-wave infarction [ ] were not confirmed in the Multicenter Diltiazem Postinfarction Trial [ ]. In patients with pulmonary congestion, diltiazem was associated with an increase in cardiac events, and there was a similar result in patients with low ejection fractions. However, verapamil does appear to reduce reinfarction [ ], a benefit that is more marked in those without heart failure [ ]. Nifedipine may also have a detrimental effect in unstable angina; it certainly appears to offer no benefit [ ].

A retrospective case–control study [ ] sparked controversy concerning the use of short-acting calcium channel blockers in treating hypertension. The study involved 623 cases of fatal and non-fatal myocardial infarction over a period of 8 years, and 2032 age- and sex-matched controls. The risk of myocardial infarction in patients taking calcium channel blockers was 16 per 1000, compared with 10 per 1000 in patients taking beta-blockers or thiazides. However, this result may have been an example of confounding by indication, since patients exposed to calcium channel blockers will have been more likely to have had peripheral vascular disease, lung disease (a low forced expiratory volume being a risk factor for cardiovascular disease), higher serum cholesterol concentrations, and diabetes mellitus. Careful statistical analysis was carried out in an attempt to control for some of the confounding factors, but such confounding can only be properly controlled for in a randomized study. A meta-analysis of 16 randomized secondary prevention studies in patients with coronary heart disease showed that the use of short-acting nifedipine is associated with an increased mortality in a dose-related manner (dose, risk: 30–50 mg, 1.06; 60 mg, 1.18; 80 mg, 2.83) [ ]. However, the event rates in this study were relatively small. A prospective cohort study in 906 elderly hypertensive patients showed that short-acting nifedipine is associated with a relative mortality risk of 1.7 compared with beta-blockers [ ]. After the publication of these studies, the FDA recommended that short-acting nifedipine should no longer be used in hypertension or unstable angina [ ].

Disturbances of cardiac rhythm

Calcium channel blockers differ in their effects on the myocardial conduction system. Both verapamil and diltiazem have significant inhibitory effects on both sinoatrial and atrioventricular nodal function, whereas nifedipine has little or no effect. Nevertheless, nifedipine can on occasion cause troublesome bradydysrhythmias [ , ].

Severe conduction disturbances can also occur if calcium channel blockers are used in hypertrophic cardiomyopathy [ ], but these drugs are used in this condition [ ].

Hypotension

There have been many case reports of symptomatic hypotension, usually in hypertensive patients treated with large dosages of calcium channel blockers [ , ] or in patients with myocardial infarction [ ]. These may represent injudicious prescribing rather than true adverse drug effects. In the DAVIT II study, 1.9% of the verapamil-treated group versus 1.6% of the placebo-treated group developed hypotension or dizziness [ ]; the frequency of hypotension in a randomized study of diltiazem after infarction was 0.6% in the drug-treated group and 0.2% in the placebo-treated group [ ].

Respiratory

Adverse respiratory effects are uncommon with calcium channel blockers. However, three cases of acute bronchospasm accompanied by urticaria and pruritus have been reported in patients taking verapamil [ ], and a patient with Duchenne-type muscular dystrophy developed respiratory failure during intravenous verapamil therapy for supraventricular tachycardia [ ]. Recurrent exacerbations of asthma occurred in a 66-year-old lady with hypertension and bronchial asthma given modified-release verapamil [ ].

In pulmonary hypertension, both verapamil and nifedipine increase mean right atrial pressure in association with hypotension, chest pain, dyspnea, and hypoxemia; the severe hemodynamic upset resulted in cardiac arrest in two patients after verapamil and death in another after nifedipine [ ]. A patient with pulmonary hypertension also developed pulmonary edema whilst taking nifedipine [ ] and another seems to have developed this as an allergic reaction [ ].

Nervous system

Calcium channel blockers can cause parkinsonism. Of 32 patients with this complication, only three had made a full recovery 18 months after withdrawal; patients under 73 years of age tended to have a better prognosis [ ]. It is not known if these patients would have developed parkinsonism in any case, and whether the drugs merely act as precipitants.

Calcium channel blockers can worsen myasthenic syndromes. Myasthenia gravis can deteriorate with oral verapamil [ ]. A patient with Lambert–Eaton syndrome and a small-cell carcinoma of the lung developed respiratory failure within hours of starting treatment with verapamil for atrial flutter, and required assisted ventilation [ ]. Only after verapamil had been withdrawn did breathing improve. Verapamil affects calcium channels in nerve membranes in animals, but the experimental concentrations used exceeded those found in clinical practice [ ]. Thus, the evidence for a drug-related effect is circumstantial. In another case, diltiazem triggered Lambert–Eaton syndrome, which improved with drug withdrawal [ ].

Sensory systems

Eyes

Painful eyes occurred in 14% of patients taking nifedipine compared with 9% in captopril-treated patients in a postmarketing surveillance study [ ]. The mechanism is unknown but is not via ocular vasodilatation [ ].

Taste

Transient disturbances of taste and smell, without other signs of neurological deficit, have been reported after nifedipine and diltiazem. The time to the onset of symptoms after nifedipine varied from days to months, and symptoms regressed within 24 hours of withdrawal [ ]. With diltiazem the effect gradually abated over 10 weeks, despite continuation of therapy [ ].

Psychiatric

A patient taking diltiazem developed the signs and symptoms of mania [ ] and another developed mania with psychotic features [ ]. There have also been reports that nifedipine can cause agitation, tremor, belligerence, and depression [ ], and that verapamil can cause toxic delirium [ ]. Nightmares and visual hallucinations have been associated with nifedipine [ ]. Depression has been reported as a possible adverse effect of nifedipine [ ].

Some reports have suggested that calcium channel blockers may be associated with an increased incidence of depression or suicide. However, there is a paucity of evidence from large-scale studies. A study of the rates of depression with calcium channel blockers, using data from prescription event monitoring, involved gathering information on symptoms or events in large cohorts of patients after the prescription of lisinopril, enalapril, nicardipine, and diltiazem by general practitioners [ ]. The crude overall rates of depression during treatment were 1.89, 1.92, and 1.62 per 1000 patient-months for the ACE inhibitors, diltiazem, and nicardipine respectively. Using the ACE inhibitors as the reference group, the rate ratios for depression were 1.07 (95% CI = 0.82, 1.40) and 0.86 (0.69, 1.08) for diltiazem and nicardipine respectively. This study does not support the hypothesis that calcium channel blockers are associated with depression.

Endocrine

In six hypertensive patients given nitrendipine 20 mg/day for 30 days, there was inhibition of aldosterone response but no significant change in ACTH secretion in response to corticotrophin-releasing hormone [ ].

The calcium-dependent pathway of aldosterone synthesis in the zona glomerulosa is blocked by calcium channel blockers, producing a negative feedback increase in the pituitary secretion of ACTH, which in turn causes hyperplasia of the zona glomerulosa. This leads to increased production of androgenic steroid intermediate products and subsequently testosterone, which acts on gingival cells and matrix, giving rise to gingival hyperplasia (see the section on Mouth and teeth ).

Metabolism

Calcium transport is essential for insulin secretion, which is therefore inhibited by calcium channel blockers [ ]. Despite this, calcium channel blockers generally have minimal effects on glucose tolerance in both healthy and diabetic subjects. Oral glucose tolerance is not affected by verapamil, and basal blood glucose concentrations were not altered during long-term verapamil administration [ ]. Similarly, neither nifedipine nor nicardipine produced significant hyperglycemic effects in either diabetic or non-diabetic patients [ ]. In 117 hypertensive patients nifedipine caused a significant rise in mean random blood glucose of only 0.3 mmol/l [ ], an effect that was clearly of no clinical relevance. In the Treatment of Mild Hypertension Study, 4 years of monotherapy with amlodipine maleate caused no change compared with placebo in the serum glucose of 114 hypertensive patients [ ]. In a review [ ] it was concluded that in usual dosages calcium channel blockers do not alter glucose handling. However, in a few patients diabetes appeared de novo or worsened considerably on starting nifedipine [ , ], so there may be a small risk in some individuals.

Fluid balance

Edema of the legs is a well-recognized reaction to nifedipine and also occurs with verapamil, diltiazem, and the long-acting dihydropyridines [ , ], suggesting that this is a class effect of calcium channel blockers.

Hematologic

Calcium channel blockers rarely cause hematological effects. A hemorrhagic diathesis, including impaired platelet function, develops in chronic renal insufficiency, in which calcium channel blockers are used widely as antihypertensive agents. In 156 patients with moderate to severe chronic renal insufficiency not on hemodialysis calcium channel blockers prolonged the bleeding time (OR = 3.52; 95% CI = 1.01, 12.3) [ ]. However, despite this effect, there were no clinically serious hemorrhagic events during the study. Among those taking calcium channel blockers, 21 patients with prolonged bleeding times were randomly assigned to two groups; in one group treatment was withdrawn and bleeding time shortened; in those who continued to take the treatment the bleeding time was unchanged.

Nifedipine has been reported to cause agranulocytosis [ ] and leukopenia was attributed to diltiazem; the latter patient had scleroderma, active rheumatoid disease, and pulmonary fibrosis, but the white cell count fell after 3 weeks of diltiazem, recovered on withdrawal, and fell on rechallenge [ ]. Diltiazem has also been reported to cause immune thrombocytopenia in a 68-year-old man with angina [ ].

Mouth and teeth

Gingival hyperplasia, similar to that seen with phenytoin and ciclosporin, is a rare but well-recognized adverse effect of nifedipine [ ]. It has also been reported in patients taking felodipine [ , ], nitrendipine [ ], and verapamil [ ], suggesting that this adverse effect is a class effect. Only one case of gingival hyperplasia related to calcium channel blockers was reported to the Norwegian Adverse Drug Reaction Committee up to 1991, despite their widespread use [ ]. However, subclinical gingival hyperplasia on tissue histology was found in 83% and 74% of patients taking nifedipine and diltiazem respectively [ ]. The reaction generally occurs within a few months of starting treatment, and in some cases drug withdrawal produces marked regression of clinical hyperplasia. The mechanism of this adverse effect is unclear, but has been proposed to involve a hormonal imbalance in the hypothalamic–pituitary–adrenal axis [ ].

Periodontal disease has been assessed in 911 patients taking calcium channel blockers, of whom 442 were taking nifedipine, 181 amlodipine, and 186 diltiazem, and in 102 control subjects [ ]. There was significant gingival overgrowth in 6.3% of the subjects taking nifedipine, while the prevalence induced by amlodipine or diltiazem was not significantly different than in the controls. The severity of overgrowth in the nifedipine group was related to the amount of gingival inflammation and also to sex, men being three times as likely to develop overgrowth than women.

Gastrointestinal

Because of effects on smooth muscle, the calcium channel blockers (particularly verapamil [ ] but also diltiazem) can cause constipation. This may be due to colonic motor activity inhibition [ ]. Gastroesophageal reflux can also occur, and the calcium channel blockers should be avoided in patients with symptoms suggestive of reflux esophagitis [ ]. Calcium channel blockers (verapamil, diltiazem, and nifedipine) can also be associated with an increased incidence of gastrointestinal bleeding, as reported in a prospective cohort study in 1636 older hypertensives, with a relative risk of 1.86 (95% CI = 1.22, 2.82) compared with beta-blockers [ ]. However, this finding was not confirmed in other retrospective studies [ , , ].

Liver

Mild hepatic reactions have been observed in association with verapamil, nifedipine [ ], and diltiazem [ , ]. In some cases fever, chills, and sweating have been associated with right upper quadrant pain, hepatomegaly, and mild increases in serum bilirubin and transaminase activity; in others, patients have remained asymptomatic. One patient had granulomatous hepatitis with diltiazem [ ]; another had a periportal infiltrate rich in eosinophils while taking verapamil [ ]. The increase in liver enzyme activities is generally transient, although mild persistent abnormalities have been seen. Occasionally, extreme increases in hepatic enzyme activities have been reported [ , ]. Their frequency appears to be low, and since the symptoms and signs are mild they could easily be overlooked.

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