Diltiazem Explained

Diltiazem, sold under the brand name Cardizem among others, is a nondihydropyridine calcium channel blocker medication used to treat high blood pressure, angina, and certain heart arrhythmias.[1] It may also be used in hyperthyroidism if beta blockers cannot be used.[1] It is taken by mouth or injection into a vein.[1] When given by injection, effects typically begin within a few minutes and last a few hours.[1]

Common side effects include swelling, dizziness, headaches, and low blood pressure.[1] Other severe side effects include an overly slow heart beat, heart failure, liver problems, and allergic reactions.[1] Use is not recommended during pregnancy.[1] It is unclear if use when breastfeeding is safe.

Diltiazem works by relaxing the smooth muscle in the walls of arteries, resulting in them opening and allowing blood to flow more easily.[1] Additionally, it acts on the heart to prolong the period until it can beat again.[2] It does this by blocking the entry of calcium into the cells of the heart and blood vessels.[3] It is a class IV antiarrhythmic.[4]

Diltiazem was approved for medical use in the United States in 1982.[1] It is available as a generic medication.[1] In 2021, it was the 84th most commonly prescribed medication in the United States, with more than 8million prescriptions.[5] [6] An extended release formulation is also available.[1] [7]

Medical uses

Diltiazem is indicated for:

For supraventricular tachycardias (PSVT), diltiazem appears to be as effective as verapamil in treating re-entrant supraventricular tachycardia.[10]

Atrial fibrillation[11] or atrial flutter is another indication. The initial bolus should be 0.25 mg/kg, intravenous (IV).

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.[12]

It is also used as topical application for anal fissures because it promotes healing due to its vasodilatory property.[13]

Contraindications and precautions

Diltiazem is relatively contraindicated in the presence of sick sinus syndrome, atrioventricular node conduction disturbances, bradycardia, impaired left ventricle function, peripheral artery occlusive disease, and chronic obstructive pulmonary disease.

Side effects

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, flushing, fatigue, headaches and edema.[14] Rare side effects are congestive heart failure, myocardial infarction, and hepatotoxicity.[15]

Drug interactions

Because of its inhibition of hepatic cytochromes CYP3A4, CYP2C9 and CYP2D6, there are a number of drug interactions.[16] Some of the more important interactions are listed below.

Beta-blockers

Intravenous diltiazem should be used with caution with beta-blockers because, while the combination is most potent at reducing heart rate, there are rare instances of dysrhythmia and AV node block.[17]

Quinidine

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.[18]

Fentanyl

Concurrent use of fentanyl with diltiazem, or any other CYP3A4 inhibitors, as these medications decrease the breakdown of fentanyl and thus increase its effects.[19]

Mechanism of action

Diltiazem, also known as (2S,3S)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochlorid has a vasodilating activity attributed to the (2S,3S)-isomer.[20] Diltiazem is a potent vasodilator, increasing blood flow and variably decreasing the heart rate via strong depression of A-V node conduction. It binds to the alpha-1 subunit of L-type calcium channels in a fashion somewhat similar to verapamil, another nondihydropyridine (non-DHP) calcium channel blocker.[21] Chemically, it is based upon a 1,4-thiazepine ring, making it a benzothiazepine-type calcium channel blocker.

It is a potent and mild vasodilator of coronary and peripheral vessels, respectively,[22] which reduces peripheral resistance and afterload, though not as potent as the dihydropyridine (DHP) calcium channel blockers. This results in minimal reflexive sympathetic changes.

Diltiazem has negative inotropic, chronotropic, and dromotropic effects. This means diltiazem causes a decrease in heart muscle contractility – how strong the beat is, lowering of heart rate – due to slowing of the sinoatrial node, and a slowing of conduction through the atrioventricular node – increasing the time needed for each beat. Each of these effects results in reduced oxygen consumption by the heart, reducing angina, typically unstable angina, symptoms. These effects also reduce blood pressure by causing less blood to be pumped out.

Research

Diltiazem is prescribed off-label by doctors in the US for prophylaxis of cluster headaches. Some research on diltiazem and other calcium channel antagonists in the treatment and prophylaxis of migraine is ongoing.[8] [23] [24] [25] [26] [27] [28]

Recent research has shown diltiazem may reduce cocaine cravings in drug-addicted rats.[29] This is believed to be due to the effects of calcium blockers on dopaminergic and glutamatergic signaling in the brain.[30] Diltiazem also enhances the analgesic effect of morphine in animal tests, without increasing respiratory depression,[31] and reduces the development of tolerance.[32]

Diltiazem is also being used in the treatment of anal fissures. It can be taken orally or applied topically with increased effectiveness.[33] When applied topically, it is made into a cream form using either petrolatum or Phlojel. Phlojel absorbs the diltiazem into the problem area better than the petrolatum base. It has good short-term success rates.[34] [35]

Notes and References

  1. Web site: Diltiazem Hydrochloride Monograph for Professionals . Drugs.com . AHFS . 28 December 2018 .
  2. Book: Cardiovascular Pharmacotherapeutics . 2011 . Cardiotext Publishing . 978-1-935395-62-1 . 251–52 . 28 December 2018 .
  3. Book: 2010 Nurse's Drug Handbook . 2010 . Jones & Bartlett Learning . 978-0-7637-7900-9 . 320 . registration .
  4. Book: Milne GW . Gardner's Commercially Important Chemicals: Synonyms, Trade Names, and Properties . 2005 . John Wiley & Sons . 978-0-471-73661-5 . 223 . 28 December 2018 .
  5. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  6. Web site: Diltiazem - Drug Usage Statistics . ClinCalc . 14 January 2024.
  7. Web site: Diltiazem hydrochloride – diltiazem hydrochloride extended-release tablets tablet, extended release . DailyMed . 1 April 2019 . 13 April 2020.
  8. Grossman E, Messerli FH . Calcium antagonists . Progress in Cardiovascular Diseases . 47 . 1 . 34–57 . 2004 . 15517514 . 10.1016/j.pcad.2004.04.006 .
  9. Claas SA, Glasser SP . Long-acting diltiazem HCl for the chronotherapeutic treatment of hypertension and chronic stable angina pectoris . Expert Opinion on Pharmacotherapy . 6 . 5 . 765–776 . May 2005 . 15934903 . 10.1517/14656566.6.5.765 . 39272285 .
  10. Gabrielli A, Gallagher TJ, Caruso LJ, Bennett NT, Layon AJ . Diltiazem to treat sinus tachycardia in critically ill patients: a four-year experience . Critical Care Medicine . 29 . 10 . 1874–1879 . October 2001 . 11588443 . 10.1097/00003246-200110000-00004 . 25104288 .
  11. Wattanasuwan N, Khan IA, Mehta NJ, Arora P, Singh N, Vasavada BC, Sacchi TJ . Acute ventricular rate control in atrial fibrillation: IV combination of diltiazem and digoxin vs. IV diltiazem alone . Chest . 119 . 2 . 502–506 . February 2001 . 11171729 . 10.1378/chest.119.2.502 .
  12. Basile J . The role of existing and newer calcium channel blockers in the treatment of hypertension . Journal of Clinical Hypertension . 6 . 11 . 621–629; quiz 630–631 . November 2004 . 15538095 . 10.1111/j.1524-6175.2004.03683.x . 8109670 . 23440538 . free .
  13. Griffin N, Acheson AG, Jonas M, Scholefield JH . The role of topical diltiazem in the treatment of chronic anal fissures that have failed glyceryl trinitrate therapy . Colorectal Disease . 4 . 6 . 430–435 . October 2002 . 12790914 . 10.1046/j.1463-1318.2002.00376.x . 32959944 .
  14. Ramoska EA, Spiller HA, Winter M, Borys D . A one-year evaluation of calcium channel blocker overdoses: toxicity and treatment . Annals of Emergency Medicine . 22 . 2 . 196–200 . February 1993 . 8427431 . 10.1016/S0196-0644(05)80202-1 .
  15. Book: Talreja O, Cassagnol M . Diltiazem . StatPearls . Treasure Island (FL) . StatPearls Publishing . 2019 . 30422532.
  16. Ohno Y, Hisaka A, Suzuki H . General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs . Clinical Pharmacokinetics . 46 . 8 . 681–696 . 2007 . 17655375 . 10.2165/00003088-200746080-00005 . 41343222 .
  17. Edoute Y, Nagachandran P, Svirski B, Ben-Ami H . Cardiovascular adverse drug reaction associated with combined beta-adrenergic and calcium entry-blocking agents . Journal of Cardiovascular Pharmacology . 35 . 4 . 556–559 . April 2000 . 10774785 . 10.1097/00005344-200004000-00007 . free .
  18. Narimatsu A, Taira N . Effects of 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 . Naunyn-Schmiedeberg's Archives of Pharmacology . 294 . 2 . 169–177 . August 1976 . 1012337 . 10.1007/bf00507850 . 21986119 .
  19. Web site: Drug interactions: Interactions between fentanyl and drugs that inhibit CYP3A4 . 26 June 2019 . 3 December 2017 . https://web.archive.org/web/20171203002157/http://www.pharmaceutical-journal.com/learning/learning-article/drug-interactions-interactions-between-fentanyl-and-drugs-that-inhibit-cyp3a4/10039015.article . dead .
  20. Book: Matsumae H, Akatsuka H, Shibatani T . Diltiazem Synthesis . Encyclopedia of Industrial Biotechnology . 2010. 1–20 . 10.1002/9780470054581.eib603 . 978-0-471-79930-6 .
  21. O'Connor SE, Grosset A, Janiak P . The pharmacological basis and pathophysiological significance of the heart rate-lowering property of diltiazem . Fundamental & Clinical Pharmacology . 13 . 2 . 145–153 . 1999 . 10226758 . 10.1111/j.1472-8206.1999.tb00333.x . 20440286 .
  22. Book: Gordon SG, Kittleson MD . Small Animal Clinical Pharmacology . Drugs used in the management of heart disease and cardiac arrhythmias . Elsevier . 2008 . 978-0-7020-2858-8 . 10.1016/b978-070202858-8.50019-1 . 380–457.
  23. Montastruc JL, Senard JM . [Calcium channel blockers and prevention of migraine] . fr . Pathologie-Biologie . 40 . 4 . 381–388 . April 1992 . 1353873 . Calcium channel blockers and prevention of migraine .
  24. Kim KE . Comparative clinical pharmacology of calcium channel blockers . American Family Physician . 43 . 2 . 583–588 . February 1991 . 1990741 .
  25. Andersson KE, Vinge E . Beta-adrenoceptor blockers and calcium antagonists in the prophylaxis and treatment of migraine . Drugs . 39 . 3 . 355–373 . March 1990 . 1970289 . 10.2165/00003495-199039030-00003 . 13621196 .
  26. Paterna S, Martino SG, Campisi D, Cascio Ingurgio N, Marsala BA . [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 Terapeutica . 134 . 2 . 119–125 . July 1990 . 2147612 .
  27. Smith R, Schwartz A . Diltiazem prophylaxis in refractory migraine . The New England Journal of Medicine . 310 . 20 . 1327–1328 . May 1984 . 6144044 . 10.1056/NEJM198405173102015 .
  28. Peroutka SJ . The pharmacology of calcium channel antagonists: a novel class of anti-migraine agents? . Headache . 23 . 6 . 278–283 . November 1983 . 6358127 . 10.1111/j.1526-4610.1983.hed2306278.x . 40215836 .
  29. https://www.sciencedaily.com/releases/2008/02/080227155016.htm Common Heart Drug May Reduce Cocaine Cravings
  30. Mills K, Ansah TA, Ali SF, Mukherjee S, Shockley DC . Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers . Life Sciences . 81 . 7 . 600–608 . July 2007 . 17689567 . 2765982 . 10.1016/j.lfs.2007.06.028 .
  31. Kishioka S, Ko MC, Woods JH . Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys . European Journal of Pharmacology . 397 . 1 . 85–92 . May 2000 . 10844102 . 10.1016/S0014-2999(00)00248-X .
  32. Verma V, Mediratta PK, Sharma KK . Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers . Indian Journal of Experimental Biology . 39 . 7 . 636–642 . July 2001 . 12019755 .
  33. Jonas M, Neal KR, Abercrombie JF, Scholefield JH . A randomized trial of oral vs. topical diltiazem for chronic anal fissures . Diseases of the Colon and Rectum . 44 . 8 . 1074–1078 . August 2001 . 11535842 . 10.1007/BF02234624 . 40406260 .
  34. Nash GF, Kapoor K, Saeb-Parsy K, Kunanadam T, Dawson PM . The long-term results of diltiazem treatment for anal fissure . International Journal of Clinical Practice . 60 . 11 . 1411–1413 . November 2006 . 16911570 . 10.1111/j.1742-1241.2006.00895.x . 23510129 . free .
  35. Sajid MS, Rimple J, Cheek E, Baig MK . The efficacy of diltiazem and glyceryltrinitrate for the medical management of chronic anal fissure: a meta-analysis . International Journal of Colorectal Disease . 23 . 1 . 1–6 . January 2008 . 17846781 . 10.1007/s00384-007-0384-x . 13015745 .

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