It is also an effective preventive medication for migraine. It is a class 3 antianginal drug, and a class IV antiarrhythmic. It is a common adulterant of cocaine seized in the UK, and has been found to reduce cocaine cravings in rats, indicating it may prolong the "high" (see below). It incites minimal reflex sympathetic changes. It is based upon a 1,4-thiazepine ring.
Diltiazem is metabolized by and acts as an inhibitor of the CYP3A4 enzyme.
Diltiazem is a potent vasodilator, increasing blood flow and variably decreasing the heart rate via strong depression of A-V node conduction. Its pharmacological activity is somewhat similar to verapamil.
It is a potent vasodilator of coronary and peripheral vessels, which reduces peripheral resistance and afterload.
Because of its negative inotropic effect, diltiazem causes a modest decrease in heart muscle contractility and reduces myocardium oxygen consumption. Its negative chronotropic effect results in a modest lowering of heart rate, due to slowing of the sinoatrial node. It results in reduced myocardium oxygen consumption.
Because of its negative dromotropic effect, conduction through the AV (atrioventricular) node is slowed, which increases the time needed for each beat. This results in reduced myocardium oxygen consumption.
Nontherapeutic effects and toxicities
A reflex sympathetic response, caused by the peripheral dilation of vessels and the resulting drop in blood pressure, works to counteract the negative inotropic, chronotropic and dromotropic effects of diltiazem. Undesirable effects include hypotension, bradycardia, dizziness, and flushing.
The drug is indicated for angina:
Stable angina (exercise-induced) – diltiazem increases coronary blood flow and decreases myocardial oxygen consumption, secondary to decreased peripheral resistance, heart rate, and contractility.
Variant angina – it is effective owing to its direct effects on coronary dilation.
Unstable angina (preinfarction, crescendo) – diltiazem may be particularly effective if the underlying mechanism is vasospasm.
Because of its vasodilatory effects, diltiazem is useful for treating hypertension. Calcium channel blockers are well tolerated, and especially effective in treating low-renin hypertension.
The dose of diltiazem in supraventricular tachycardias is 0.25 mg/kg, IV bolus push over 2 minutes. Most commonly, a 20 mg IV dose is given to the average-sized patient.
Contraindications and precautions
In congestive heart failure, patients with reduced ventricular function may not be able to counteract the inotropic and chronotropic effects of diltiazem, the result being an even higher compromise of function.
With SA node or AV conduction disturbances, the use of diltiazem should be avoided in patients with SA or AV nodal abnormalities, because of its negative chronotropic and dromotropic effects.
Low blood pressure patients, with systolic blood pressures below 90 mm Hg, should not be treated with diltiazem.
Intravenous diltiazem should be used with caution with beta-blockers because, while the combination is most therapeutically beneficial, there are rare instances of dysrhythmia and AV node block.
Quinidine should not be used concurrently with calcium channel blockers because of reduced clearance of both drugs and potential pharmacodynamic effects at the SA and AV nodes.
Diltiazem and verapamil inhibit hepatic cytochromes CYP3A4, CYP2C9 and CYP2D6, possibly resulting in drug interactions.
Potential future indications
Diltiazem is prescribed off-label by doctors in the US for prophylaxis of cluster migraine. Some research on diltiazem and other calcium channel antagonists in the treatment and prophylaxis of migraine is ongoing.
Diltiazem is also being used in the treatment of anal fissures. It can be taken orally or applied topically with increased effectiveness. When applied topically, it is made into a cream form using either vaseline or Phlojel. Phlojel absorbs the diltiazem into the problem area better than the vaseline base. It has good short term success rates. Like all nonsurgical treatments of anal fissure, it does not address the long term problem of increased basal anal tone and does not decrease the subsequent recurrence rate that can vary between 40 and 60%.
^O'Connor, Stephen E.; Grosset, Alain; Janiak, Philip (1999). "The pharmacological basis and pathophysiological significance of the heart rate-lowering property of diltiazem". Fundamental & Clinical Pharmacology13 (2): 145–53. doi:10.1111/j.1472-8206.1999.tb00333.x. PMID10226758.
^Ramoska, E; Spiller, H; Winter, M; Borys, D (1993). "A one-year evaluation of calcium channel blocker overdoses: Toxicity and treatment". Annals of Emergency Medicine22 (2): 196–200. doi:10.1016/S0196-0644(05)80202-1. PMID8427431.
^Claas, Steven A; Glasser, Stephen P (2005). "Long-acting diltiazem HCL for the chronotherapeutic treatment of hypertension and chronic stable angina pectoris". Expert Opinion on Pharmacotherapy6 (5): 765–76. doi:10.1517/14656518.104.22.1685. PMID15934903.
^Gabrielli, Andrea; Gallagher, T. James; Caruso, Lawrence J.; Bennett, Neil T.; Layon, A. Joseph (2001). "Diltiazem to treat sinus tachycardia in critically ill patients: A four-year experience". Critical Care Medicine29 (10): 1874–9. doi:10.1097/00003246-200110000-00004. PMID11588443.
^Wattanasuwan, N.; Khan, IA; Mehta, NJ; Arora, P; Singh, N; Vasavada, BC; Sacchi, TJ (2001). "Acute Ventricular Rate Control in Atrial Fibrillation : IV Combination of Diltiazem and Digoxin vs IV Diltiazem Alone". Chest119 (2): 502–6. doi:10.1378/chest.119.2.502. PMID11171729.
^Basile, Jan (2004). "The Role of Existing and Newer Calcium Channel Blockers in the Treatment of Hypertension". The Journal of Clinical Hypertension6 (11): 621–29; quiz 630–1. doi:10.1111/j.1524-6175.2004.03683.x.
^Edoute, Yeouda; Nagachandran, Pradeep; Svirski, Boris; Ben-Ami, Haim (2000). "Cardiovascular Adverse Drug Reaction Associated with Combined β-Adrenergic and Calcium Entry-Blocking Agents". Journal of Cardiovascular Pharmacology35 (4): 556–9. doi:10.1097/00005344-200004000-00007. PMID10774785.
^Narimatsu, Akihiro; Norio Taira (August 1976). "Effects on Atrio-Ventricular Conduction of Calcium-Antagonistic Coronary Vasodilators, Local Anaesthetics and Quinidine Injected into the Posterior and the Anterior Septal Artery of the Atrio-Ventricular Node Preparation of the Dog". Archives of Pharmacology294 (2): 169-177. doi:10.1007/bf00507850.
^Ohno, Y; Hisaka, A; Suzuki, H (2007). "General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs". Clinical pharmacokinetics46 (8): 681–96. doi:10.2165/00003088-200746080-00005. PMID17655375.
^Montastruc, JL; Senard, JM (1992). "Médicaments anticalciques et prophylaxie de la migraine" [Calcium channel blockers and prevention of migraine]. Pathologie et Biologie (in French) 40 (4): 381–8. PMID1353873.
^Kim, KE (1991). "Comparative clinical pharmacology of calcium channel blockers". American family physician43 (2): 583–8. PMID1990741.
^Paterna, S; Martino, SG; Campisi, D; Cascio Ingurgio, N; Marsala, BA (1990). "Evaluation of the effects of verapamil, flunarizine, diltiazem, nimodipine and placebo in the prevention of hemicrania. A double-blind randomized cross-over study". La Clinica terapeutica134 (2): 119–25. PMID2147612.
^Peroutka, Stephen J. (1983). "The Pharmacology of Calcium Channel Antagonists: a Novel Class of Anti-migraine Agents?". Headache: the Journal of Head and Face Pain23 (6): 278–83. doi:10.1111/j.1526-4610.1983.hed2306278.x.
^Kishioka, S; Ko, MC; Woods, JH (2000). "Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys". European Journal of Pharmacology397 (1): 85–92. doi:10.1016/S0014-2999(00)00248-X. PMID10844102.
^Verma, V; Mediratta, PK; Sharma, KK (2001). "Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers". Indian journal of experimental biology39 (7): 636–42. PMID12019755.
^Jonas, Marion; Neal, Keith R.; Abercrombie, John F.; Scholefield, John H. (2001). "A randomized trial of oral vs. topical diltiazem for chronic anal fissures". Diseases of the Colon & Rectum44 (8): 1074–8. doi:10.1007/BF02234624.
^Nash, G. F.; Kapoor, K.; Saeb-Parsy, K.; Kunanadam, T.; Dawson, P. M. (2006). "The long-term results of diltiazem treatment for anal fissure". International Journal of Clinical Practice60 (11): 1411–3. doi:10.1111/j.1742-1241.2006.00895.x. PMID16911570.
^Sajid, M. S.; Rimple, J.; Cheek, E.; Baig, M. K. (2007). "The efficacy of diltiazem and glyceryltrinitrate for the medical management of chronic anal fissure: a meta-analysis". International Journal of Colorectal Disease23 (1): 1–6. doi:10.1007/s00384-007-0384-x. PMID17846781.