Diltiazem

Diltiazem is indicated for:

• Stable angina (exercise-induced) – diltiazem increases coronary blood flow and decreases myocardial oxygen consumption, secondary to decreased peripheral resistance, heart rate, and contractility.{{cite journal | vauthors = Grossman E, Messerli FH | title = Calcium antagonists | journal = Progress in Cardiovascular Diseases | volume = 47 | issue = 1 | pages = 34–57 | year = 2004 | pmid = 15517514 | doi = 10.1016/j.pcad.2004.04.006 }}{{cite journal | vauthors = Claas SA, Glasser SP | title = Long-acting diltiazem HCl for the chronotherapeutic treatment of hypertension and chronic stable angina pectoris | journal = Expert Opinion on Pharmacotherapy | volume = 6 | issue = 5 | pages = 765–776 | date = May 2005 | pmid = 15934903 | doi = 10.1517/14656566.6.5.765 | s2cid = 39272285 }}
• 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.
• Myocardial bridge

For supraventricular tachycardias (PSVT), diltiazem appears to be as effective as verapamil in treating re-entrant supraventricular tachycardia.{{cite journal | vauthors = Gabrielli A, Gallagher TJ, Caruso LJ, Bennett NT, Layon AJ | title = Diltiazem to treat sinus tachycardia in critically ill patients: a four-year experience | journal = Critical Care Medicine | volume = 29 | issue = 10 | pages = 1874–1879 | date = October 2001 | pmid = 11588443 | doi = 10.1097/00003246-200110000-00004 | s2cid = 25104288 }}

Atrial fibrillation{{cite journal | vauthors = Wattanasuwan N, Khan IA, Mehta NJ, Arora P, Singh N, Vasavada BC, Sacchi TJ | title = Acute ventricular rate control in atrial fibrillation: IV combination of diltiazem and digoxin vs. IV diltiazem alone | journal = Chest | volume = 119 | issue = 2 | pages = 502–506 | date = February 2001 | pmid = 11171729 | doi = 10.1378/chest.119.2.502 }} 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.{{cite journal | vauthors = Basile J | title = The role of existing and newer calcium channel blockers in the treatment of hypertension | journal = Journal of Clinical Hypertension | volume = 6 | issue = 11 | pages = 621–629; quiz 630–631 | date = November 2004 | pmid = 15538095 | doi = 10.1111/j.1524-6175.2004.03683.x | pmc = 8109670 | s2cid = 23440538 | doi-access = free }}

It is also used as topical application for anal fissures because it promotes healing due to its vasodilatory property.{{cite journal | vauthors = Griffin N, Acheson AG, Jonas M, Scholefield JH | title = The role of topical diltiazem in the treatment of chronic anal fissures that have failed glyceryl trinitrate therapy | journal = Colorectal Disease | volume = 4 | issue = 6 | pages = 430–435 | date = October 2002 | pmid = 12790914 | doi = 10.1046/j.1463-1318.2002.00376.x | s2cid = 32959944 }}

• In congestive heart failure, patients with reduced ventricular function may not be able to counteract the negative 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.
• Diltiazem may paradoxically increase ventricular rate in patients with Wolff-Parkinson-White syndrome because of accessory conduction pathways.

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.

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.{{cite journal | vauthors = Ramoska EA, Spiller HA, Winter M, Borys D | title = A one-year evaluation of calcium channel blocker overdoses: toxicity and treatment | journal = Annals of Emergency Medicine | volume = 22 | issue = 2 | pages = 196–200 | date = February 1993 | pmid = 8427431 | doi = 10.1016/S0196-0644(05)80202-1 }} Rare side effects are congestive heart failure, myocardial infarction, and hepatotoxicity.{{cite book | vauthors = Talreja O, Cassagnol M | chapter = Diltiazem | title = StatPearls | location = Treasure Island (FL) | publisher = StatPearls Publishing |date=2019 |pmid=30422532}}

Because of its inhibition of hepatic cytochromes CYP3A4, CYP2C9 and CYP2D6, there are a number of drug interactions.{{cite journal | vauthors = Ohno Y, Hisaka A, Suzuki H | title = General framework for the quantitative prediction of CYP3A4-mediated oral drug interactions based on the AUC increase by coadministration of standard drugs | journal = Clinical Pharmacokinetics | volume = 46 | issue = 8 | pages = 681–696 | year = 2007 | pmid = 17655375 | doi = 10.2165/00003088-200746080-00005 | s2cid = 41343222 }} Some of the more important interactions are listed below.

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.{{cite journal | vauthors = Edoute Y, Nagachandran P, Svirski B, Ben-Ami H | title = Cardiovascular adverse drug reaction associated with combined beta-adrenergic and calcium entry-blocking agents | journal = Journal of Cardiovascular Pharmacology | volume = 35 | issue = 4 | pages = 556–559 | date = April 2000 | pmid = 10774785 | doi = 10.1097/00005344-200004000-00007 | doi-access = free }}

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.{{cite journal | vauthors = Narimatsu A, Taira N | title = 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 | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 294 | issue = 2 | pages = 169–177 | date = August 1976 | pmid = 1012337 | doi = 10.1007/bf00507850 | s2cid = 21986119 }}

Concurrent use of fentanyl with diltiazem, or any other CYP3A4 inhibitors, as these medications decrease the breakdown of fentanyl and thus increase its effects.{{cite web | url=https://www.pharmaceutical-journal.com/learning/learning-article/drug-interactions-interactions-between-fentanyl-and-drugs-that-inhibit-cyp3a4/10039015.article | title=Drug interactions: Interactions between fentanyl and drugs that inhibit CYP3A4 | access-date=26 June 2019 | archive-date=3 December 2017 | archive-url=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 | url-status=dead }}

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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.{{cite book | vauthors =Matsumae H, Akatsuka H, Shibatani T |chapter=Diltiazem Synthesis |title= Encyclopedia of Industrial Biotechnology | year = 2010|pages=1–20 | doi = 10.1002/9780470054581.eib603 |isbn=978-0-471-79930-6 }}

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.{{cite journal | vauthors = O'Connor SE, Grosset A, Janiak P | title = The pharmacological basis and pathophysiological significance of the heart rate-lowering property of diltiazem | journal = Fundamental & Clinical Pharmacology | volume = 13 | issue = 2 | pages = 145–153 | year = 1999 | pmid = 10226758 | doi = 10.1111/j.1472-8206.1999.tb00333.x | s2cid = 20440286 }} 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,{{cite book | vauthors = Gordon SG, Kittleson MD | title=Small Animal Clinical Pharmacology | chapter=Drugs used in the management of heart disease and cardiac arrhythmias | publisher=Elsevier | year=2008 | isbn=978-0-7020-2858-8 | doi=10.1016/b978-070202858-8.50019-1 | pages=380–457}} 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|date=January 2022}}

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.

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.{{cite journal | vauthors = Montastruc JL, Senard JM | title = [Calcium channel blockers and prevention of migraine] | language = fr | journal = Pathologie-Biologie | volume = 40 | issue = 4 | pages = 381–388 | date = April 1992 | pmid = 1353873 | trans-title = Calcium channel blockers and prevention of migraine }}{{cite journal | vauthors = Kim KE | title = Comparative clinical pharmacology of calcium channel blockers | journal = American Family Physician | volume = 43 | issue = 2 | pages = 583–588 | date = February 1991 | pmid = 1990741 }}{{cite journal | vauthors = Andersson KE, Vinge E | title = Beta-adrenoceptor blockers and calcium antagonists in the prophylaxis and treatment of migraine | journal = Drugs | volume = 39 | issue = 3 | pages = 355–373 | date = March 1990 | pmid = 1970289 | doi = 10.2165/00003495-199039030-00003 | s2cid = 13621196 }}{{cite journal | vauthors = Paterna S, Martino SG, Campisi D, Cascio Ingurgio N, Marsala BA | title = [Evaluation of the effects of verapamil, flunarizine, diltiazem, nimodipine and placebo in the prevention of hemicrania. A double-blind randomized cross-over study] | journal = La Clinica Terapeutica | volume = 134 | issue = 2 | pages = 119–125 | date = July 1990 | pmid = 2147612 }}{{cite journal | vauthors = Smith R, Schwartz A | title = Diltiazem prophylaxis in refractory migraine | journal = The New England Journal of Medicine | volume = 310 | issue = 20 | pages = 1327–1328 | date = May 1984 | pmid = 6144044 | doi = 10.1056/NEJM198405173102015 }}{{cite journal | vauthors = Peroutka SJ | title = The pharmacology of calcium channel antagonists: a novel class of anti-migraine agents? | journal = Headache | volume = 23 | issue = 6 | pages = 278–283 | date = November 1983 | pmid = 6358127 | doi = 10.1111/j.1526-4610.1983.hed2306278.x | s2cid = 40215836 }}{{Update inline|date=June 2018}}

Recent research{{when|date=June 2018}} has shown diltiazem may reduce cocaine cravings in drug-addicted rats.[https://www.sciencedaily.com/releases/2008/02/080227155016.htm Common Heart Drug May Reduce Cocaine Cravings] {{Webarchive|url=https://web.archive.org/web/20180616080423/https://www.sciencedaily.com/releases/2008/02/080227155016.htm |date=16 June 2018 }}. Sciencedaily.com (28 February 2008). Retrieved on 21 October 2012. This is believed to be due to the effects of calcium blockers on dopaminergic and glutamatergic signaling in the brain.{{cite journal | vauthors = Mills K, Ansah TA, Ali SF, Mukherjee S, Shockley DC | title = Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers | journal = Life Sciences | volume = 81 | issue = 7 | pages = 600–608 | date = July 2007 | pmid = 17689567 | pmc = 2765982 | doi = 10.1016/j.lfs.2007.06.028 }} Diltiazem also enhances the analgesic effect of morphine in animal tests, without increasing respiratory depression,{{cite journal | vauthors = Kishioka S, Ko MC, Woods JH | title = Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys | journal = European Journal of Pharmacology | volume = 397 | issue = 1 | pages = 85–92 | date = May 2000 | pmid = 10844102 | doi = 10.1016/S0014-2999(00)00248-X }} and reduces the development of tolerance.{{cite journal | vauthors = Verma V, Mediratta PK, Sharma KK | title = Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers | journal = Indian Journal of Experimental Biology | volume = 39 | issue = 7 | pages = 636–642 | date = July 2001 | pmid = 12019755 }}

Diltiazem is also being used in the treatment of anal fissures. It can be taken orally or applied topically with increased effectiveness.{{cite journal | vauthors = Jonas M, Neal KR, Abercrombie JF, Scholefield JH | title = A randomized trial of oral vs. topical diltiazem for chronic anal fissures | journal = Diseases of the Colon and Rectum | volume = 44 | issue = 8 | pages = 1074–1078 | date = August 2001 | pmid = 11535842 | doi = 10.1007/BF02234624 | s2cid = 40406260 }} 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.{{cite journal | vauthors = Nash GF, Kapoor K, Saeb-Parsy K, Kunanadam T, Dawson PM | title = The long-term results of diltiazem treatment for anal fissure | journal = International Journal of Clinical Practice | volume = 60 | issue = 11 | pages = 1411–1413 | date = November 2006 | pmid = 16911570 | doi = 10.1111/j.1742-1241.2006.00895.x | s2cid = 23510129 | doi-access = free }}{{cite journal | vauthors = Sajid MS, Rimple J, Cheek E, Baig MK | title = The efficacy of diltiazem and glyceryltrinitrate for the medical management of chronic anal fissure: a meta-analysis | journal = International Journal of Colorectal Disease | volume = 23 | issue = 1 | pages = 1–6 | date = January 2008 | pmid = 17846781 | doi = 10.1007/s00384-007-0384-x | s2cid = 13015745 }}

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