Dermatology Online Journal

Calcium antagonists in dermatology: A review of the evidence and research-based studies
Ioulios Palamaras and Kyriakos Kyriakis
Dermatology Online Journal 11 (2): 8

Department of Dermatology, West Attika General Hospital of Athens, Greece. drioulios@hotmail.com

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Abstract

Calcium antagonists (CAs) or calcium-channel blockers are a common group of antihypertensive medications. These drugs have the property of blocking the calcium channels of vascular and cardiac smooth muscle fibers. Some of these drugs may inhibit the growth and proliferation of vascular smooth muscle cells and fibroblasts, and inhibit the synthesis of extracellular-matrix proteins (collagen, fibronectin, proteoglycans). Other CAs also have immunomodulatory or dysregulatory effects on lymphocytes and can suppress superoxide generation and phagocytic action of neutrophils. Moreover mast cell degranulation and platelet aggregation may also be impaired. On account of these properties, calcium antagonists have also been used for the prevention and treatment of various dermatologic diseases such as erythromelalgia, idiopathic- or CREST-related calcinosis cutis, primary and secondary Raynaud phenomenon, chilblains, chronic anal fissures, keloids, and burn scars. They are also used for prevention of skin flap necrosis in experimental models. Calcium antagonists, apart from their well known and established antihypertensive action, should also be considered as possible therapy for several dermatologic diseases.

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Introduction

The drugs classified as calcium antagonists (CAs) or calcium channel blockers (CCBs) are a diverse group of antihypertensive medications introduced into clinical medicine in the 1960s [1]. They possess the property of blocking the transmembrane flow of calcium ions into the cell through voltage-gated channels [1], thus inhibiting the activation of the actin-myosin complex and muscular contraction [2].

Up to the present time there are six different calcium channel subtypes (Table 1) [2]. The L-type has been found in cardiac muscle, vascular smooth muscle (SM) (arteriolar and venous), nonvascular SM (bronchial, gastrointestinal, genitourinary, uterine), noncontractile tissues (pancreas, pituitary, adrenal glands, salivary glands, gastric mucosa, white cells, platelets, and lacrimal tissue) [1].

The structure of the voltage-sensitive calcium channel is composed of the ion-conduction pore α1-subunit, (through which calcium ion passes), and of several accessory subunits designated α2, β, γ, δ. Variations in the α1-subunit account for the differences in voltage and pharmacologic sensitivity between the voltage-sensitive channel subtypes [2]. The α1-subunit itself contains several different functional regions to which the CAs bind; CAs of different classes bind to different regions [1]. The α1-, β-, γ-, and δ-subunits modulate the function of the α1-subunit. Regulation of the entire calcium channel itself is a function of cathecolamines, angiotensin II, endothelin, and hormones [1].

Pharmacologically, CAs are divided into benzothiazepines (diltiazem), phenylalkylamines (verapamil), dihydropyridines (nifedipine) and tetraols (mibefradil) [2]. The current, most useful classification is the one based on receptor binding properties, tissue selectivity and pharmacokinetic profiles proposed by Luscher and Cosentino (adapted and updated in (Table 2) [3].

The CAs that are currently used for the treatment of hypertension, angina, and supraventricular arrhythmias are amlodipine-besilate, barnidipine, bepridil, cilnidipine, diltiazem hydrochloride, efonidipine, felodipine, fendilline, isradipine, lacidipine, lercanidipine, mibefradil, nicardipine, nisoldipine, nitrendipine, nifedipine, and nilvadipine. One CA, nimodipine, is used for the prevention and short-term therapy of neurological deficits from subarachnoid hemorrhage. Only diltiazem hydrochloride, verapamil, nifedipine, and nicardipine are available in intravenous formulation.

Pharmacodynamics

The main effect of CAs is vasodilatation. However, some CAs (amlodipine, diltiazem, nifedipine, isradipine, and verapamil) may inhibit the growth and proliferation of vascular smooth muscle cells and fibroblasts [4, 5, 6, 7]. Others (amlodipine, felodipine, manidipine, verapamil, and diltiazem) may inhibit the synthesis of extracellular matrix proteins (collagen, fibronectin, and proteoglycans) [8]. All these properties appear useful for the treatment of keloids and hypertrophic scars [9, 10, 11, 12, 13, 14].

CAs also have immunomodulatory or dysregulatory effects; in vitro they depress T-cell function and in vivo produce an immune dysfunction. Nifedipine is associated with hyporeactivity in delayed-type hypersensitivity skin tests. A possible mechanism of action could be through the inhibition of potassium efflux in lymphocytes [15, 16].

Other CAs may inhibit mast cell degranulation (verapamil) [17] and platelet aggregation (nifedipine, diltiazem, verapamil, amlodipine, felodipine, isradipine, nitrendipine, nimodipine, lacidipine, nisoldipine, efonidipine), albeit there is an absence of consensus for the latter action [17-33].

Furthermore, verapamil [34-44], gallopamil [44], diltiazem [37, 38, 40, 41, 43], nifedipine [37, 39, 40, 43] felodipine, nimodipine and nisoldipine [36, 42] may also affect neutrophils. These CAs may suppress the neutrophil adhesion and superoxide anion (O^-2) production.

These immunological actions of CAs together with the antiplatelet action seem to be relevant in the treatment of Raynaud phenomenon, chilblains, and chronic anal fissures. These actions may also be relevant for the prevention of necrosis in skin flaps (the latter only in experimental models up to the present time).

Finally, some CAs (verapamil, diltiazem, and nicardipine) may possess analgesic properties that are useful in the treatment of post-herpetic neuralgia when administered alone or in combination with lidocaine by iontophoresis [45]. This action may be explained by the fact that diverse calcium-channel subtypes are responsible for catecholamine and neurotransmitter release (Table 1). Hence, calcium channels may play a role in the pain control mechanism [1, 2, 46, 47, 48]. It is unfortunate that there are no current evidence-based studies to prove this indication.

Side effects

The main adverse effects are related to the pharmacologic actions, vasodilatation, negative inotropic action, and dromotropic action. The adverse effects associated with vasodilatation induced by the dihydropyridines (especially by the immediate-release preparations) appears to be dose related. Symptoms include headache, dizziness, flushing (up to 10 %), and tachycardia [2]. Constipation may occur with verapamil in over 25 percent of patients [1]. Peripheral ankle or pedal edema (up to 30 %) and gingival hyperplasia (up to 21 %) are two unique side effects of CAs. Less common developments are facial or truncal telangiectasia, photosensitivity reactions, new-onset psoriasis (as well as exacerbation of it), purpuric exanthems, pemphigoid manifestations, subacute cutaneous lupus erythematosus, gynecomastia, erythromelalgia, and oral ulcers [49].

Dermatological indications for calcium antagonists

In Dermatology, the calcium antagonists have been used as a first-line option for the treatment of primary and secondary Raynaud phenomenon and chilblains (perniosis). In research-based studies CAs have been used for chronic anal fissures, keloids, burn scars, idiopathic or CREST-related calcinosis cutis (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), and finally for the prevention and treatment of skin flap necrosis in experimental animals (Table 3).

Standard indications for calcium antagonists

Raynaud phenomenon

Raynaud phenomenon refers to the reversible ischemia of peripheral arterioles. Most commonly it is triggered by exposure to cold or stress. However, a variety of other stimuli (e.g., vibration injury, polyvinyl chloride exposure) may also evoke it. Raynaud phenomenon is classified as primary (Raynaud disease) and secondary (Raynaud phenomenon). Raynaud disease is the occurrence of the vasospasm alone with no associated illness. Raynaud phenomenon is vasospasm associated with another illness, most commonly an autoimmune disease. Patients who have vasospasm alone for more than 2 years and who have not developed additional manifestations are at low risk for developing an autoimmune disease. Most of these patients are considered to have (primary) Raynaud disease.

For both Raynaud disease and Raynaud phenomenon (RP), nifedipine [50, 51, 52, 53, 54, 55, 56], amlodipine [50, 57], diltiazem[58, 59], felodipine [60], nisoldipine [61], isradipine[50, 62], nicardipine[50, 63, 64, 65, 66, 67] are effective.

Patients with primary vasospasm are generally easier to treat than those with secondary disease in whom structural damage to the vessel wall is both pronounced and fixed.

Thus, patients with RP (particularly in association with scleroderma) may require more-aggressive therapy and they are less likely to benefit from CAs [68, 69, 70].

A 2001 systematic review of eight randomized controlled, crossover clinical trials with a combined total of 109 patients found all CAs versus placebo to reduce both the frequency (by about 4 per week) and the severity (by 35 %) of the ischemic attacks [71].

Nifedipine

Nifedipine represents the first treatment option. The extended release formulation (Nifedipine SR) should be used continuously; it has fewer adverse effects than the short-acting form. Patients should start with the lowest dose available and titrate up as tolerated to the effective dose (10-20 mg p.o. q.i.d., up to 180 mg/day) [68, 72].

In a randomized controlled clinical trial, double-masked for drug and placebo, involving 313 patients evaluated during 1 winter month, nifedipine SR-treated patients with Raynaud disease had a 66 percent reduction in attacks (p < .001) compared to the placebo group 1 year after initiation of the therapy [51].

For an acute ischemic attack, a rapid acting preparation of nifedipine may be used, starting with a dose of 10 mg p.o. t.i.d.; factors that need to be taken into consideration include cardiovascular risks (acute myocardial infarction, severe systemic hypotension, reflex tachycardia, heart block, sinus arrest, cerebrovascular ischemia), and the possibility of digital ischemia [68, 71, 73]. In fact, in a double-blind, placebo-controlled trial in (n = 21) subjects with RP who received Nifedipine, there was an acute fall in hand perfusion pressure that resulted in a reduced digital blood flow. Hence, caution is warranted in use of this drug in patients with threatened digital ischemia [74].

Amlodipine

A double-blind placebo-controlled crossover trial was performed to assess the efficacy of amlodipine in patients with primary RP. Of twenty-four patients enrolled, twenty completed the trial. The number of episodes of RP per week and the severity of discomfort significantly improved during amlodipine [107]. The suggested dose is 2.5-5 mg/day p.o. up to 10 mg/day p.o. [57, 72].

Diltiazem

Diltiazem is not as effective as the dihydropyridine class of CAs [75]. In a randomized, double-blind, cross-over trial with sixteen patients receiving diltiazem 120 mg and placebo t.i.d. for 2 weeks, there was a statistically significant improvement in patients with primary RP. However, this improvement was not statistically significant for the patients with secondary RD. The proposed dosage is 60-120 mg p.o. b.i.d. or t.i.d for primary RP; wait at least 2 weeks for the therapeutic effect to occur [59, 72]. With diltiazem sustained-release, the dosage is 120-300 mg/day [75].

felodipine

In a single-blind study, ten patients with primary RP were treated with 10 mg felodipine daily for 6 weeks. Two patients became free from Raynaud attacks while in the others, there was a significant reduction in number and trend to shorter duration of attacks (subjective judgement) [60].

nisoldipine

In a controlled double-blind trial, nisoldipine was assessed in nineteen patients with primary RP. Nisoldipine significantly reduced the frequency of attacks, but it did not reduce the severity of attacks. Side effects were uncommon [61]. The suggested initial dose is 10 mg/day p.o., followed by an increase of 10 mg/week (up to 40mg/day) to attain the effective dose [76].

Isradipine

The effect of isradipine was investigated in ten female patients with primary RP in a single-blind dose-response study. After 3 weeks of treatment with 1.25 and 2.5 mg p.o. b.i.d., favorable objective and subjective effects were noticed with no serious adverse effects. The best results were obtained with the higher dose [62]. Taking that into consideration, the dosage may be further increased up to 5 mg b.i.d. [75]

nicardipine

The results regarding the use of nicardipine are controversial. Three randomized, double-blind, crossover, placebo-controlled trials in patients with primary RP (combined n = 110) showed a significant reduction on the frequency of attacks and favorable action on the severity [64, 66]. Another two randomized, double-blind, crossover, placebo-controlled studies showed no statistically significant differences between nicardipine and placebo for number, duration, or severity of the vasospastic attacks [63, 66]. The suggested doses are 20-30 mg p.o. t.i.d. or 30-60 mg p.o. b.i.d. (slow release formulation) [72]. A 3-week interval of treatment is a reasonable time to evaluate for response to therapy.

The mechanism of action of CAs to Raynaud phenomenon is believed to be the induced vasodilatation and possibly the antiplatelet effects, although the beneficial role of the latter is controversial [63, 72, 77, 78].

To conclude, CAs represent the first line treatment in RP. They should be used for up to 6 weeks before assessing benefit.

Chilblains (perniosis)

For the treatment of chilblains, nifedipine represents the first treatment option because it is the only medication tested, albeit in a small controlled trial [79]. The rest of the oral or topical medications have only been used empirically [80].

A double-blind placebo-controlled randomized study (n = 10 patients) and a long term open trial (n = 34) indicate that nifedipine sustained-release (10-20 mg p.o. t.i.d) may be effective in the treatment and prevention of perniosis [79]. The time needed for clearance of the existing lesions was significantly reduced and the development of new chilblains was prevented. The mean time for clearance of the lesions was 8 days for those on the hands (range 7-10 days), 14 days for the thighs (range 10-16 days), 21 days for the hands plus feet (range 5-28 days), and 23 days for those on the feet only (range 6-42 days). Nifedipine was also found to diminish the pain, soreness, and irritation of the lesions. The provoked peripheral arterial vasodilatation and the potential antiplatelet effect may be responsible for the beneficial result.

Research-based indications for CAs

Chronic anal fissures

Some CAs (nifedipine [81, 82, 83], diltiazem[84, 85, 86, 87, 88, 89], lacidipine [90]) have been used for the conservative treatment of chronic anal fissures (CAF). The most consistent finding in typical fissures is spasm of the internal anal sphincter, which is so severe that the pain caused by the fissure is thought to be the result of ischemia of the sphincter. Relief of the spasm has been associated with relief of pain and healing of the fissure [91, 92, 93].

Sphincter contraction depends on an increase in cytoplasmic calcium. The optimal treatment for an anal fissure is to induce a temporary reduction of anal-canal resting pressure with a concurrent improvement of the anal mucosal blood flow to allow healing of the fissure without permanently disrupting normal sphincter function [86, 94]. The immunomodulatory actions of CAs may also play a role in this therapeutic.

Nifedipine

Nifedipine (administered orally or applied topically) has the ability to reduce significantly the internal anal resting pressure [81, 95]. In particular, oral nifedipine (20 mg p.o. b.i.d. for 8 weeks), in two controlled clinical trials with a (combined n = 25 patients) significantly reduced pain scores and healed CAF by 50-60 percent [81, 82]. However, a few side effects occurred (flushing, headache, postural hypotension) [83].

Topical nifedipine gel (0.2 % q.i.d.) [48] was used in a double-blind randomized controlled trial of patients suffering from CAF (n = 52). The end point of the study was healing within 6 months but the treatment was stopped in patients who did not report any amelioration of symptoms within 8 weeks. The topical application appeared to give better healing rates (89 %) with substantial pain relief and fewer systemic adverse effects (5 %). Recurrence occurred in 42 percent of patients after a mean period of 12 ± 4 weeks.

In another double-blind randomized controlled trial (n = 110), the combination of topical nifedipine ointment (0.3 %) and lidocaine ointment (1.5 %), twice daily for 6 weeks healed 94.5 percent of the patients. Recurrence was observed in 5.5 percent of the patients within 1 year of treatment but healing was achieved in 66 percent of them with an additional course of topical therapy [96].

Diltiazem

In a randomized controlled trial of patients with CAF (n = 50), oral administration of diltiazem (60 mg b.i.d. for 8 weeks) gave a complete fissure healing in 38 percent [85]. In the same trial, when it was applied topically (0.7 g of diltiazem gel or ointment 2 % b.i.d. for 8 weeks), healing was achieved in 65 percent of the patients. There has been one recurrence in each group of patients (oral and topical diltiazem), one at 16 weeks and the other at 24 weeks; both of whom responded to further treatment with the preparation originally administered.

Moreover, in a randomized controlled study (n = 43 patients) [88] and in two other clinical trials, one controlled (n = 30 patients) [84] and one open (n = 71 patients) [86], topical application of diltiazem gel (2 % b.i.d. or t.i.d. for 8 weeks) achieved a healing rate of between 67 and 86 percent. The difference in frequency of the applied drug (b.i.d. or t.i.d.), does not seem to change the rate of fissure healing. Regarding the open trial [85], after a median of 32 (range 14-67) weeks' followup after completion of treatment, twenty-seven of forty-one patients available remained symptom free. Six of seven patients with recurrent fissures were treated successfully by further topical treatment.

In addition to that, in an open clinical trial with (n = 47 patients), topical diltiazem (2 % b.i.d. for 8 weeks) appeared to be effective in up to 49 percent of patients with recalcitrant anal fissures that failed to heal with another topical treatment (glyceryl trinitrate 0.2 %) [87]. The side effects reported for this topical treatment included perianal dermatitis and perianal itching (10 %) [89].

Lacidipine

An open clinical trial of Lacidipine (6 mg/day p.o. for 4 weeks) combined with warm sitz baths and stool softeners for the patients with constipation (n = 21) found significantly reduced pain scores and healing in 90.4 percent of the anal fissures [90]. No recurrence was seen at the 2-month followup. Diplopia was one side effect (one out of twenty-one patients).

To summarize, it seems that the topical treatment with Nifedipine ointment (3 %) and lidocaine ointment (1.5 %) b.i.d. gives the better healing rates with the fewer adverse effects than the other CAs. The next best option of these agents is topical diltiazem gel (2 %) b.i.d.

Keloids-burn scars

Hypertrophic scars and keloids are characterized by the overproduction and increased deposition of extracellular-matrix proteins such as laminin, fibronectin, and collagen [8, 9]. The metabolism of cellular calcium ions (i.e., the intracellular concentration) may contribute to this production [9, 11, 12].

Five CAs (amlodipine, felodipine, manidipine, diltiazem, verapamil) significantly decrease collagen deposition in the extracellular matrix and inhibit the expression of various collagens (I, III, IV) in vitro. In addition to that, CAs specifically increase the proteolytic activity of one type of collagenase (IV) [8].

Verapamil

Verapamil has been shown to stimulate procollagenase synthesis in keloid, hypertrophic and normal human cultured fibroblasts, resulting in depolymerization of actin filaments, alteration of their cell shape, and reduction of the fibrous tissue production [13].

In a open-controlled clinical trial (n = 44 patients), verapamil hydrochloride was used for the treatment and prevention of recurrence of keloid and burn scars by local intralesional infiltration [14]. In particular, for stabilized keloids the results are poor compared to topical steroids. However, when verapamil is used following surgical excision of the keloid (2.5 mg/ml with doses ranging from 0.5 to 2.0 ml depending on the size) on postsurgical days 7, 14, 28, and during the second month, and combined with topical silicone layering (without pressure therapy), there was a 54 percent cure (with absence of recurrence at an 18-month followup).

Calcinosis cutis

For the treatment of idiopathic or CREST-related calcinosis cutis (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, telangiectasias), long-term (1-12 years) diltiazem (240-480 mg/day p.o.) was reported in 4 patients [17]. All of them had a reduction or disappearance of the calcified lesions, with striking clinical improvement within 5 years. This therapeutic effect may be related to the fact that CAs diminish intracellular calcium concentration by the antagonism of calcium-sodium pump, thus decreasing the crystal formation [98].

Prevention and treatment of skin-flap necrosis in experimental animals

Nifedipine [17], verapamil [17, 99], nimodipine [100], nitrendipine [101], and diltiazem [101] have been utilized for the prevention and treatment of skin-flap necrosis in rats and rabbits by topical (perilesional) and systemic administration.

The perioperative and postoperative extreme arterial vasoconstriction (vasospasm) is a commonly encountered problem in microvascular surgery. It is attributed to inadequate blood flow that compromises viability of the replanted and revascularized tissues, such us skin flaps [17, 99]. Hence, the use of drugs (i.e., CAs) that have vasodilatative, and antiplatelet action was reported to prevent this vasoconstriction and improve the blood supply in the animal model. Further studies and evidence-based trials on humans is still needed.

Summary

In conclusion, calcium antagonists, apart from their well known and established antihypertensive action, can be used for the prevention and treatment of several dermatologic diseases because of their diverse effects on various kinds of cells of the human organism. Their major indications are for Raynaud phenomenon (better results for primary RP), chilblains, chronic anal fissures, keloids, and burn scars. Additional potential indications may be prevention of skin-flap necrosis and amelioration of post-herpetic neuralgia.

Methods: The literature review for this article was made on the following databases: MEDLINE-1951 to date (MEZZ), MEDLINE -1996 to date (MEDL), EMBASE- 1974 to date (EMZZ), DH-DATA: Health Administration & Medical Toxicology (DHZZ), Allied & Complementary Medicine- 1985 to date (AMED).

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