Diltiazem

Cardiovascular

Diltiazem can be associated with heart block [ , ]. In a randomized trial in patients with non-Q-wave myocardial infarction, 38 of 287 patients who took diltiazem developed some degree of atrioventricular block at some time. Of these episodes, 32 were first-degree, eight were second-degree, and only two were third-degree. In the placebo-treated group there were 10 events in 289 patients; eight were first-degree, two second-degree, and none third-degree.

Atrioventricular block has been reported in three patients taking therapeutic doses of diltiazem; one died [ ].

• A 47-year-old man taking furosemide for hypertension was given diltiazem 300 mg/day to achieve better blood pressure control; 1 month later he developed atrioventricular block, resolved by atropine.

• A 62-year-old hypertensive man with renal artery stenosis, an adrenal adenoma, peripheral artery disease, and an abdominal aortic aneurysm developed a hypertensive crisis with chest pain. He was treated with nitrates, heparin, aspirin, and nicardipine, which were afterwards replaced by diltiazem 200 mg/day, because of persistent chest pain. He developed atrioventricular block 2 hours after the second dose of diltiazem, and was successfully treated with a pacemaker.

• A 59-year-old woman with a previous myocardial infarction, hypertension, diabetes, and uterine cancer developed angina. She was treated with nitrates, aspirin, and heparin; diltiazem 200 mg/day was then added because of persistent chest pain. She developed atrioventricular block 72 hours later, and despite resuscitative efforts died in electromechanical dissociation.

Following the publication of a report of heart block [ ], further cases (junctional bradycardia, sinoatrial block) have been reported [ ].

Nervous system

Paresthesia of the hands and feet has been reported with diltiazem [ ]. Akathisia has been attributed to diltiazem [ ]. Parkinsonism associated with diltiazem has been reported [ ].

• A 53-year-old man with hypertension took diltiazem 60–120 mg/day for 5 years and then developed parkinsonism. His neurological symptoms were treated without success and only after the substitution of diltiazem with an ACE inhibitor did his parkinsonian symptoms begin to regress, with eventual complete recovery.

Mouth and teeth

Gum hyperplasia has been attributed to diltiazem [ ].

• A 49-year-old Afro-Caribbean man with resistant hypertension developed pronounced gum hyperplasia with bleeding, which gradually resolved on withdrawal of amlodipine 20 mg/day. Since the blood pressure was poorly controlled, he was given a non-dihydropyridine calcium channel blocker diltiazem 240 mg/day. The gum hyperplasia recurred 3 months later and slowly resolved after withdrawal of diltiazem.

This case suggests that the well-known adverse reaction of gum hyperplasia is a class effect of calcium channel blockers, not just limited to the dihydropyridines.

Gingival enlargement has been studied in 46 patients taking diltiazem (n = 32) or verapamil (n = 14) compared with 49 cardiovascular controls who had never taken them [ ]. There was more gingival enlargement in the patients taking diltiazem compared with controls: 31% as assessed by the vertical gingival overgrowth index and in 50% as assessed by the horizontal Miranda & Brunet index. The corresponding figures for verapamil were 21% and 36% (not different from controls). The risk of gingival enlargement (odds ratio) associated with diltiazem therapy, adjusted for gingival index values, was 3.5 (1.0–12) the vertical gingival overgrowth index and 6.2 (1.9, 20) for the horizontal Miranda & Brunet index. Verapamil had no significant effect.

Gastrointestinal

Intestinal pseudo-obstruction has been attributed to diltiazem [ ].

• A 74-year-old man with acute myelogenous leukemia and neutropenia was given five doses of intravenous diltiazem 5 mg every 5–10 minutes plus amiodarone for atrial fibrillation, followed by diltiazem 30 mg orally qds and a continuous infusion of amiodarone. Amiodarone was withdrawn after 1 day because of an adverse effect and the dose of diltiazem was increased to 120 mg qds orally by day 14. On day 15, he developed increasing abdominal distention with hyperactive bowel sounds. An abdominal X-ray showed multiple dilated loops in the small and large bowel and diltiazem was withdrawn, after which he recovered.

Medications rarely cause intestinal pseudo-obstruction, but calcium channel blockers cause smooth muscle relaxation, which was probably the causative mechanism in this case.

Urinary tract

Diltiazem was associated with the development of acute renal insufficiency in a patient being treated for severe retrosternal chest pain who had neither primary kidney disease nor urinary tract obstruction [ , ].

Acute interstitial nephritis has been attributed to diltiazem [ ].

• A 53-year-old man was given diltiazem for precordial pain and about 2 hours later developed an erythematous maculopapular rash mainly on the trunk and lower limbs. Four days later he developed abdominal pain radiating to both renal angles, accompanied by dysuria and tenesmus and followed 6 days later by acute renal insufficiency associated with raised liver function test results.

In this case, the self-limiting resolution in 4–5 days without relapse, the presence of the rash, and the liver sequelae suggested a common immunoallergic mechanism. The clinical symptoms, the time relation between drug administration and the occurrence of the syndrome, the inability to explain the syndrome otherwise, and its disappearance on withdrawal of diltiazem support an association with the drug.

A retrospective analysis of postoperative renal function in patients undergoing cardiac operations has been conducted to evaluate whether the use of prophylactic intravenous diltiazem, in order to reduce the incidence of ischemia and dysrhythmias, was associated with increased renal dysfunction [ ]. The incidence of acute renal insufficiency requiring dialysis was 4.4% with diltiazem versus 0.7% in the controls. Logistic regression analysis suggested that the risk of acute renal insufficiency was strongly associated with intravenous diltiazem, age, baseline serum creatinine, the presence of left main coronary disease, and the presence of cerebrovascular disease.

Skin

Skin reactions ranging from exanthems to severe adverse events have been reported in association with diltiazem [ , ]. Three cases of skin reactions (hypersensitivity syndrome reaction, pruritic exanthematous eruption, and acute generalized exanthematous pustulosis) possibly induced by diltiazem have been described and the literature on skin reactions associated with calcium antagonists has been reviewed. The number of diltiazem-induced cutaneous events was significantly greater than those induced by either nifedipine or verapamil. However, there was no difference in the proportion of serious cutaneous adverse events due to any of these three drugs [ ].

Cutaneous vasculitis [ ] and angioedema [ , ] have been reported with diltiazem. In 1988, the Federal German Health Authorities imposed a warning of dermal hypersensitivity reactions (including erythema multiforme) with diltiazem.

• Acute generalized exanthematous pustulosis in an 82-year-old woman was confirmed as being due to diltiazem by a positive patch test [ ].

• Exfoliative dermatitis with fever occurred in a 69-year-old man with ischemic heart disease treated with mexiletine and diltiazem for three weeks; the rash resolved after withdrawal of both drugs and systemic corticosteroid therapy. Patch tests with mexiletine and diltiazem were positive. In addition to this case, 39 cases of drug eruption due to diltiazem have been reported in Japan [ ].

• Lichenoid purpura of 6 months’ duration occurred in a 65-year-old man with hypertension who had taken diltiazem for 1 month. Topical therapy with a very potent glucocorticoid was not effective and the eruption began to regress only after diltiazem withdrawal, after which it disappeared 3 weeks later [ ].

Four cases of photodistributed hyperpigmentation associated with long-term administration of a modified-release formulation of diltiazem hydrochloride have been reported [ ]. All the patients were African-American women, mean age 62 (range 49–72) years. The duration of diltiazem administration before the development of hyperpigmentation was 6–11 months. The hyperpigmentation was slate-gray and reticulated. Phototesting during diltiazem therapy showed a reduced minimal erythema dose to UVA in one patient. Histological examination showed lichenoid dermatitis with prominent pigmentary incontinence. Electron microscopy showed multiple melanosome complexes. Withdrawal of diltiazem resulted in gradual resolution of the hyperpigmentation.

Acute generalized exanthematous pustular dermatitis has been reported after diltiazem [ ].

Skin reactions to calcium channel blockers have been reviewed in the light of a report of three reactions to diltiazem [ ].

• A 54-year-old man developed a generalized erythema-multiforme-like reaction followed by erythrodermia and exfoliative dermatitis after taking diltiazem for 6–7 days.

• An 80-year-old woman had a pruritic exanthematous eruption on her trunk 10 days after taking diltiazem, which evolved to generalized erythrodermia and superficial desquamation; it gradually improved in 10–12 days after withdrawal.

• A 79-year-old man developed erythema and pruritus initially on the back, and then affecting the thorax, limbs, and face after taking diltiazem for 3 days. Diltiazem was withdrawn and the skin improved, but verapamil was started 3 days later and the skin worsened again.

The authors carried out skin tests with different calcium channel blockers. Diltiazem was positive in all three patients; nifedipine was positive in patient 2 and verapamil in patient 3.

Four patients (one man and three women, mean age 60 years) who developed a maculopapular rash at 8–12 days after starting to take diltiazem underwent drug skin tests in order to determine the value of patch tests and cross-reactions among calcium channel blockers [ ]. In all cases patch tests were positive to diltiazem and there were no cross-reactions with nimodipine, nifedipine, nitrendipine, or nicardipine. There was a cross-reaction with diltiazem and verapamil in only one patient.

Photosensitivity reactions associated with diltiazem can cause erythema, pruritus, and/or lichenoid eruptions, which mostly develop soon after exposure to the sun. Photodistributed hyperpigmentation associated with diltiazem has also been reported in four patients with a review of eight other reported cases [ ]. The pigmentary changes developed within 6–24 months. The patient’s ages were 49–77 years; three were men and most were taking diltiazem for hypertension. No other medications causing hyperpigmentation were used. The distribution of hyperpigmentation was on the sun-exposed areas of the face, neck, and forearms, with less pigmentation on the lower chest, back, and shins. To determine the photoabsorption spectrum of diltiazem, photospectrometry analysis was performed. The absorption range of diltiazem was 220–300 nm, within the UV-B spectrum. These results correlated with previous data showing no absorption in the UV-A spectrum. Furthermore, the pattern of photodistributed pigmentation and the history of mild to moderate sun exposure during diltiazem therapy in the four patients also supported a photosensitizing effect. Withdrawal of diltiazem is the most effective way to resolve hyperpigmentation.