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Diltiazem

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Diltiazem
Clinical data
Pronunciation/dɪlˈtaɪəzɛm/
Trade namesCardizem, others
AHFS/Drugs.comMonograph
MedlinePlusa684027
License data
Pregnancy
category
Routes of
administration		By mouth, intravenous
Drug classNondihydropyridine calcium channel blocker
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability40%
MetabolismLiver
Elimination half-life3–4.5 hours
ExcretionKidney
Bile duct
Identifiers
  • cis-(+)-[2-(2-Dimethylaminoethyl)-5-(4-methoxyphenyl)-3-oxo-6-thia-2-azabicyclo[5.4.0]undeca-7,9,11-trien-4-yl]ethanoate
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.050.707 Edit this at Wikidata
Chemical and physical data
FormulaC22H26N2O4S
Molar mass414.52 g·mol−1
3D model (JSmol)
  • O=C2N(c3c(S[C@@H](c1ccc(OC)cc1)[C@H]2OC(=O)C)cccc3)CCN(C)C
  • InChI=1S/C22H26N2O4S/c1-15(25)28-20-21(16-9-11-17(27-4)12-10-16)29-19-8-6-5-7-18(19)24(22(20)26)14-13-23(2)3/h5-12,20-21H,13-14H2,1-4H3/t20-,21+/m1/s1 checkY
  • Key:HSUGRBWQSSZJOP-RTWAWAEBSA-N checkY
  (verify)

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.[9] It may also be used in hyperthyroidism if beta blockers cannot be used.[9] It is taken by mouth or given by injection into a vein.[9] When given by injection, effects typically begin within a few minutes and last a few hours.[9]

Common side effects include swelling, dizziness, headaches, and low blood pressure.[9] Other severe side effects include an overly slow heart beat, heart failure, liver problems, and allergic reactions.[9] Use is not recommended during pregnancy.[9] It is unclear if use when breastfeeding is safe.[1]

Diltiazem works by relaxing the smooth muscle in the walls of arteries, resulting in them opening and allowing blood to flow more easily.[9] Additionally, it acts on the heart to prolong the period until it can beat again.[10] It does this by blocking the entry of calcium into the cells of the heart and blood vessels.[11] It is a class IV antiarrhythmic.[12]

Diltiazem was approved for medical use in the United States in 1982.[9] It is available as a generic medication.[9] In 2022, it was the 100th most commonly prescribed medication in the United States, with more than 6 million prescriptions.[13][14] An extended release formulation is also available.[5][6][9]

Medical uses

[edit]

Diltiazem is indicated for:

For supraventricular tachycardias (PSVT), diltiazem appears to be as effective as verapamil in treating re-entrant supraventricular tachycardia.[17]

Atrial fibrillation[18] 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.[19]

It is also used as topical application for anal fissures because it promotes healing due to its vasodilatory property.[20]

Contraindications and precautions

[edit]

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

[edit]

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.[21] Rare side effects are congestive heart failure, myocardial infarction, and hepatotoxicity.[22]


Drug interactions

[edit]

Because of its inhibition of hepatic cytochromes CYP3A4, CYP2C9 and CYP2D6, there are a number of drug interactions.[23] Some of the more important interactions are listed below.

Beta-blockers

[edit]

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.[24]

Quinidine

[edit]

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.[25]

Fentanyl

[edit]

Concurrent use of fentanyl with diltiazem, or any other CYP3A4 inhibitors, as these medications decrease the breakdown of fentanyl and thus increase its effects.[26]

Mechanism of action

[edit]
180 mg Cardizem capsule

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.[27] 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.[28] 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,[29] which reduces peripheral resistance and afterload, though not as potent as the dihydropyridine (DHP) calcium channel blockers. This results in minimal reflexive sympathetic changes.[citation needed]

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

[edit]

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.[15][30][31][32][33][34][35][needs update]

Recent research[when?] has shown diltiazem may reduce cocaine cravings in drug-addicted rats.[36] This is believed to be due to the effects of calcium blockers on dopaminergic and glutamatergic signaling in the brain.[37] Diltiazem also enhances the analgesic effect of morphine in animal tests, without increasing respiratory depression,[38] and reduces the development of tolerance.[39]

Diltiazem is also being used in the treatment of anal fissures. It can be taken orally or applied topically with increased effectiveness.[40] 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.[41][42]

References

[edit]
  1. ^ a b "Diltiazem Use During Pregnancy". Drugs.com. 4 May 2020. Archived from the original on 31 December 2019. Retrieved 5 May 2020.
  2. ^ "Dilcardia SR 120 mg Prolonged-release hard capsules – Summary of Product Characteristics (SmPC)". emc. 22 March 2018. Archived from the original on 28 August 2021. Retrieved 13 April 2020.
  3. ^ "Angitil SR/XL Capsules – Summary of Product Characteristics (SmPC)". (emc). 7 May 2019. Archived from the original on 28 August 2021. Retrieved 13 April 2020.
  4. ^ "Cardizem–diltiazem hydrochloride tablet, coated". DailyMed. 2 June 2020. Archived from the original on 24 October 2022. Retrieved 23 October 2022.
  5. ^ a b "Cardizem CD–diltiazem hydrochloride capsule, coated, extended release". DailyMed. 30 April 2020. Retrieved 23 October 2022.
  6. ^ a b "Cardizem LA–diltiazem hydrochloride tablet, extended release". DailyMed. 2 May 2019. Archived from the original on 24 October 2022. Retrieved 23 October 2022.
  7. ^ "Cartia XT- diltiazem hydrochloride capsule, extended release". DailyMed. 26 October 2020. Archived from the original on 24 February 2024. Retrieved 30 September 2024.
  8. ^ "Active substance(s): diltiazem" (PDF). European Medicines Agency. 11 January 2018. Archived (PDF) from the original on 24 October 2022. Retrieved 24 October 2022.
  9. ^ a b c d e f g h i j k "Diltiazem Hydrochloride Monograph for Professionals". Drugs.com. AHFS. Archived from the original on 28 December 2018. Retrieved 28 December 2018.
  10. ^ Cardiovascular Pharmacotherapeutics. Cardiotext Publishing. 2011. pp. 251–52. ISBN 978-1-935395-62-1. Retrieved 28 December 2018.
  11. ^ Nurse's Drug Handbook. Jones & Bartlett Learning. 2010. p. 320. ISBN 978-0-7637-7900-9.
  12. ^ Milne GW (2005). Gardner's Commercially Important Chemicals: Synonyms, Trade Names, and Properties. John Wiley & Sons. p. 223. ISBN 978-0-471-73661-5. Retrieved 28 December 2018.
  13. ^ "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
  14. ^ "Diltiazem Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Archived from the original on 1 September 2024. Retrieved 30 August 2024.
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  20. ^ Griffin N, Acheson AG, Jonas M, Scholefield JH (October 2002). "The role of topical diltiazem in the treatment of chronic anal fissures that have failed glyceryl trinitrate therapy". Colorectal Disease. 4 (6): 430–435. doi:10.1046/j.1463-1318.2002.00376.x. PMID 12790914. S2CID 32959944.
  21. ^ Ramoska EA, Spiller HA, Winter M, Borys D (February 1993). "A one-year evaluation of calcium channel blocker overdoses: toxicity and treatment". Annals of Emergency Medicine. 22 (2): 196–200. doi:10.1016/S0196-0644(05)80202-1. PMID 8427431.
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  23. ^ 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 Pharmacokinetics. 46 (8): 681–696. doi:10.2165/00003088-200746080-00005. PMID 17655375. S2CID 41343222.
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  25. ^ Narimatsu A, Taira N (August 1976). "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. doi:10.1007/bf00507850. PMID 1012337. S2CID 21986119.
  26. ^ "Drug interactions: Interactions between fentanyl and drugs that inhibit CYP3A4". Archived from the original on 3 December 2017. Retrieved 26 June 2019.
  27. ^ Matsumae H, Akatsuka H, Shibatani T (2010). "Diltiazem Synthesis". Encyclopedia of Industrial Biotechnology. pp. 1–20. doi:10.1002/9780470054581.eib603. ISBN 978-0-471-79930-6.
  28. ^ O'Connor SE, Grosset A, Janiak P (1999). "The pharmacological basis and pathophysiological significance of the heart rate-lowering property of diltiazem". Fundamental & Clinical Pharmacology. 13 (2): 145–153. doi:10.1111/j.1472-8206.1999.tb00333.x. PMID 10226758. S2CID 20440286.
  29. ^ Gordon SG, Kittleson MD (2008). "Drugs used in the management of heart disease and cardiac arrhythmias". Small Animal Clinical Pharmacology. Elsevier. pp. 380–457. doi:10.1016/b978-070202858-8.50019-1. ISBN 978-0-7020-2858-8.
  30. ^ Montastruc JL, Senard JM (April 1992). "[Calcium channel blockers and prevention of migraine]" [Calcium channel blockers and prevention of migraine]. Pathologie-Biologie (in French). 40 (4): 381–388. PMID 1353873.
  31. ^ Kim KE (February 1991). "Comparative clinical pharmacology of calcium channel blockers". American Family Physician. 43 (2): 583–588. PMID 1990741.
  32. ^ Andersson KE, Vinge E (March 1990). "Beta-adrenoceptor blockers and calcium antagonists in the prophylaxis and treatment of migraine". Drugs. 39 (3): 355–373. doi:10.2165/00003495-199039030-00003. PMID 1970289. S2CID 13621196.
  33. ^ Paterna S, Martino SG, Campisi D, Cascio Ingurgio N, Marsala BA (July 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 Terapeutica. 134 (2): 119–125. PMID 2147612.
  34. ^ Smith R, Schwartz A (May 1984). "Diltiazem prophylaxis in refractory migraine". The New England Journal of Medicine. 310 (20): 1327–1328. doi:10.1056/NEJM198405173102015. PMID 6144044.
  35. ^ Peroutka SJ (November 1983). "The pharmacology of calcium channel antagonists: a novel class of anti-migraine agents?". Headache. 23 (6): 278–283. doi:10.1111/j.1526-4610.1983.hed2306278.x. PMID 6358127. S2CID 40215836.
  36. ^ Common Heart Drug May Reduce Cocaine Cravings Archived 16 June 2018 at the Wayback Machine. Sciencedaily.com (28 February 2008). Retrieved on 21 October 2012.
  37. ^ Mills K, Ansah TA, Ali SF, Mukherjee S, Shockley DC (July 2007). "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. doi:10.1016/j.lfs.2007.06.028. PMC 2765982. PMID 17689567.
  38. ^ Kishioka S, Ko MC, Woods JH (May 2000). "Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys". European Journal of Pharmacology. 397 (1): 85–92. doi:10.1016/S0014-2999(00)00248-X. PMID 10844102.
  39. ^ Verma V, Mediratta PK, Sharma KK (July 2001). "Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers". Indian Journal of Experimental Biology. 39 (7): 636–642. PMID 12019755.
  40. ^ Jonas M, Neal KR, Abercrombie JF, Scholefield JH (August 2001). "A randomized trial of oral vs. topical diltiazem for chronic anal fissures". Diseases of the Colon and Rectum. 44 (8): 1074–1078. doi:10.1007/BF02234624. PMID 11535842. S2CID 40406260.
  41. ^ Nash GF, Kapoor K, Saeb-Parsy K, Kunanadam T, Dawson PM (November 2006). "The long-term results of diltiazem treatment for anal fissure". International Journal of Clinical Practice. 60 (11): 1411–1413. doi:10.1111/j.1742-1241.2006.00895.x. PMID 16911570. S2CID 23510129.
  42. ^ Sajid MS, Rimple J, Cheek E, Baig MK (January 2008). "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. doi:10.1007/s00384-007-0384-x. PMID 17846781. S2CID 13015745.
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