Diltiazem

Diltiazem, a benzothiazepine derivative with the molecular formula C22H26N2O4S, belongs to the group of Ca2+ channel blockers(calcium channel antagonist) and is a cationically amphiphilic drug whose positively charged nitrogen is essential for binding to the channel protein. Diltiazem is used to treat heart disease. In the medicinal products it is present as diltiazem hydrochloride.

Diltiazem is subject to a pronounced first pass metabolism, so that the systemic availability is only about 40%. Diltiazem is almost completely metabolised in the liver. In the presence of liver dysfunction a delayed metabolism can be expected. The elimination half-life is 6 hours on average and can be prolonged, especially in patients > 70 years and in patients with liver dysfunction.

As a calcium channel blocker, the substance inhibits the influx of calcium ions through the voltage-dependent L-type calcium channel. This leads to a decrease in peripheral vascular resistance and to vasodilatation and blood pressure reduction. Furthermore, Diltiazem reduces the heart rate, the AV-transition and the contraction strength of the heart muscles. Diltiazem has antiarrhythmic effects. It has a negative dromotropic effect at the AV node and a negative chronotropic effect at the sinus node. Diltiazem is metabolised by CYP3A4. Therefore, simultaneous application with a stronger CYP3A4 inhibitor can lead to an increase in diltiazem plasma levels. Diltiazem is resorbed to a relevant extent when applied locally (Limpongsa E et al. 2008).

CHD: Diltiazem is used in patients with stable angina, unstable angina and especially vasospastic angina (Prinzmetal's angina).

Antiarrhythmic agents: Diltiazem may be used prophylactically for the treatment of paroxysmal supraventricular tachycardia. Furthermore, in atrial fibrillation and atrial flutter in patients without WPW syndrome (to slow the pulse rate).

Hypertension: In the treatment of hypertension, diltiazem is used to lower blood pressure.

Anal fissures: In this case, diltiazem is applied topically, in ointment or cream form.

Oesophageal spasms: Diltiazem is also used in the treatment of diffuse oesophageal spasms. Here it leads to relaxation of the smooth esophageal muscles.

Calcinosis cutis: Rare indications are calcinosis cutis (Jiménez-Gallo D et al. 2015) and erythromelagia (Ljubojević S et al. 2004).

Diltiazem must not be taken during pregnancy and lactation.

Very frequent (≥1/10): peripheral edema

Common (≥ 1/100 - < 1/10) are: headache, dizziness, tiredness, weakness

AV block, ankle or leg edema, flush

gastrointestinal: constipation, dyspepsia, stomach pain, nausea

Allergic skin reactions with itching and flush-like erythema. Also described are severe skin reactions like the "Drug hypersensitivity syndrome" see below. DRESS (Kumari R et al. 2011)

Accommodation/General: Insomnia, hallucinations, depressive moods and potency disorders. In diabetics hyperglycaemia can occur.

Laboratory: liver enzymes Gamma-GT and LDH↑

Diltiazem is metabolised by CYP3A4. In cases of co-administration with a stronger CYP3A4 inhibitor, diltiazem plasma levels may be increased and side effects such as rhabdomyolysis, myositis or hepatitis may occur.

Glucocorticoids (methylprednisolone): Inhibition of the metabolism of methylprednisolone (CYP3A4) and inhibition of P-glycoprotein

Lithium: Risk of increased lithium toxicity

Nitrate derivatives: Enhanced antihypertensive effect and feeling of weakness

Alpha-Antagonists: Hypotension

Amiodarone and digoxin: increased risk of bradycardia

Beta-receptor blockers, antiarrhythmics or cardiac glycosides: Enhancement of effect possible

Diltiazem should not be used with:

• Hypersensitivity to the active substance
• AV block II or III
• SA-block II and III
• Sinus node syndrome, except in patients with pacemakers
• Acute heart attack with complications (bradycardia, pronounced hypotension, left heart failure)
• Manifest heart failure
• Severe bradycardia (resting pulse under 40 beats per minute)
• Simultaneous intravenous administration of dantrolene
• Simultaneous intravenous administration of beta-receptor blockers
• Combination with Ivabradine
• Left heart failure with congestion of the lungs

The following frequency data shall be used for the evaluation of adverse reactions:

• Very frequent: more than 1 treated person out of 10
• Often: 1 to 10 treated from 100
• Occasionally: 1 to 10 treated from 1.000
• Rare: 1 to 10 treated from 10.000
• Very rare: less than 1 treated person per 10.000

1. Jiménez-Gallo D et al (2015) Calcinosis Cutis and Calciphylaxis. Actas Dermosifiliogr 106:785-794.
2. Kumari R et al (2011) Drug hypersensitivity syndrome. Indian J Dermatol Venereol Leprol 77:7-15.
3. Limpongsa E et al (2008) Preparation and evaluation of diltiazem hydrochloride diffusion-controlled transdermal delivery system. AAPS PharmSciTech 9:464-470.
4. Ljubojević S et al. (2004) Erythromelalgia. Acta Dermatovenerol Croat 12:99-105.