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Name: Diltiazem
Generic Names: CRD-401[1],[2],[3],[4],[5]
3-Acetoxy-2, 3-dihydro-5-[2-(dimethylamino)ethyl]-2-(p-methoxyphenyl)-1, 5-benzothia zepin-4(5H)-one hydrochloride[6],[5]
(+)-cis-3-(acetyloxy)-5-[2-(dimethylamino)- ethyl] - 2,3 -dihydro -2- (4-methoxyphenyl) - 1,5 - benzothiazepin- 4(5H)one monohydrochloride[7],[2],[3],[4]
Trade Names: Cardizem® tablets[8]
IUPAC name: cis-(+)-[2-(2-dimethylaminoethyl)-5-(4-methoxyphenyl)-3-oxo-6-thia-2-azabicyclo[5,4,0]undeca-7,9,11-trien-4-yl]ethanoate[11]
Molecular Weight: 414 g/mol[12]
Structure: [13],[14],[15],[16],[7], [17],[11]
Functional Group/
Chemical Nature: benzothiazepine derivative[6],[13]
cationic drug[18]
nondihydropyridine calcium channel blocker[19]
& Indications:
Pharmcological Action-
Calcium antagonists[20],[21]
L-type calcium channel blocker[22],[23]
Suggested to have hypotensive effect in man[24],[20],[25]
coronary vasoldilator[2],[26], [6]
weak antiperoxidant[29]
Shown to local anesthetic effects in Guinea pigs[6]
strong anioxidant[30]
very weak antihemolytic[18]
Therapeutic indications:
effective in the treatment of stable, variant and unstable angina pectoris, in terminating supraventricular tachycardia and mild to moderate systemic hypertension[13]
diltiazem is used effectively patients with ischaemic heart disease, systemic hypertension and supraventricular arrhythmias, severe malignant hypertension and to patients with postoperati ve hypertension. long term diltiazem reduced the frequency of spontaneous anginal attacks[13]
effective in treatment of angina, hypertension, and certain heart-rhythm disorders[19]
Preclinical study-
Diltiazem affected mice behaviour, produced relaxing effct on isolated smooth muscles in both normal and potassium depolarised solutions[6]
prolonged the sleeping time in mice induced by thiopental and showed inhibitory action on the convulsion in mice induced by nicotine[6]
Beneficial effect of diltiazem has been suggested in rats during myocardial ischemia[31]
Diltiazem decreases proteinuria and preserves renal structure and function in pregnancy women with chronic renal disease resulting in decreased risk of pre-eclampsia, pre-term delivery and intrauterine fetal growth restriction[32]
oral diltiazem is suggested to be effective as an adjunct therapy for management of chronic malignancy-associated perineal pain, specifically with characteristics of pressure-type pain and tenesmus.[33]
Notes: diltiazem was found to be very stable in plasma at -20oC for a period of at least six weeks[34]
1. Saikawa T, Nagamoto Y, Arita M, Electrophysiologic effects of diltiazem, a new slow channel inhibitor, on canine cardiac fibers. Jpn Heart J. 1977;18(2):235-45.
2. Kohno K et al, Pharmacokinetics and bioavailability of diltiazem (CRD-401) in dog. Arzneimittelforschung. 1977;27(7):1424-8.
3. Nakamura S et al, Metabolic fate of diltiazem. Distribution, excretion and protein binding in rat and dog. Arzneimittelforschung. 1987;37(11):1244-52.
4. Meshi T, Sugihara J, Sato Y, Metabolic fate of d-cis-3-acetoxy-5-(2-(dimethylamino)ethyl)-2,3-dihydro-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride (CRD-401). Chem Pharm Bull (Tokyo). 1971;19(8):1546-56.
5. Sakuma M, Yoshikawa M, Sato Y, The whole body autoradiographic studies on the distribution of 14C-labeled new 1,5-benzothiazepine derivative (14 C-CRD-401) in mice. Chem Pharm Bull (Tokyo). 1971;19(5):995-1005.
6. Nagao T et al, Studies on a new 1,5-benzothiazepine derivative (CRD-401). 3. Effects of optical isomers of CRD-401 on smooth muscle and other pharmacological properties. Jpn J Pharmacol. 1972;22(4):467-78.
7. Clozel JP et al, High-performance liquid chromatographic determination of diltiazem and six of its metabolites in human urine. J Pharm Sci. 1984;73(6):771-3.
8. Caillé G et al, Diltiazem pharmacokinetics in elderly volunteers after single and multiple doses. Eur J Drug Metab Pharmacokinet. 1991 ;16(2):75-80.
9. Pozet N et al, Pharmacokinetics of diltiazem in severe renal failure. Eur J Clin Pharmacol. 1983;24(5):635-8.
10. Argenti D et al, Comparative Pharmacokinetics and Bioavailability of Dilacor XR and Cardizem CD in Healthy Volunteers. Am J Ther. 1995;2(1):20-30.
11. Diltiazem: Calcium channel blockers;In :Pharmacology for anesthetists 3 antihypertensive drugs, edited by Current JD, page no. 214.
12. Yeung PK et al, Pharmacokinetics and metabolism of diltiazem in healthy males and females following a single oral dose. Eur J Drug Metab Pharmacokinet. 1993;18(2):199-206.
13. Buckley MM et al, Diltiazem. A reappraisal of its pharmacological properties and therapeutic use. Drugs. 1990;39(5):757-806.
14. Wood PJ, Hirst DG, Modification of tumour response by calcium antagonists in the SCVII/St tumour implanted at two different sites. Int J Radiat Biol. 1989;56(3):355-67.
15. Montamat SC, Abernethy DR, N-monodesmethyldiltiazem is the predominant metabolite of diltiazem in the plasma of young and elderly hypertensives. Br J Clin Pharmacol. 1987;24(2):185-9
16. Pichard L et al, Identification of the rabbit and human cytochromes P-450IIIA as the major enzymes involved in the N-demethylation of diltiazem. Drug Metab Dispos. 1990 ;18(5):711-9.
17. Zhao P, Lee CA, Kunze KL, Sequential Metabolism Is Responsible for Diltiazem-Induced Time-Dependent Loss of CYP3A. Drug Metab Dispos. 2007;35(5):704-12.
18. Robak J, Duniec Z, Membrane activity, antioxidant, antiaggregatory and antihemolytic properties of four calcium channel blockers. Pharmacol Res Commun. 1986;18(12):1107-17.
19. Diltiazem: Part 2. Compound Articles by Pan Deng; In: Handbook of Metabolic Pathways of Xenobiotics, by Lee P et al, John Wiley & Sons, Ltd, 2014.
20. Hof RP, Calcium antagonist and the peripheral circulation: differences and similarities between PY 108-068, nicardipine, verapamil and diltiazem. Br J Pharmacol. 1983;78(2):375-94.
21. Nakajima H et al, Effect of diltiazem on electrical and mechanical activity of isolated cardiac ventricular muscle of guinea pig. Jpn J Pharmacol. 1975;25(4):383-92.
22. Hockerman GH et al, Molecular determinants of diltiazem block in domains IIIS6 and IVS6 of L-type Ca(2+) channels. Mol Pharmacol. 2000;58(6):1264-70.
23. Kanaya S et al, Diltiazem and verapamil preferentially block inactivated cardiac calcium channels. J Mol Cell Cardiol. 1983;15(2):145-8.
24. Hermann P et al, Pharmacokinetics of diltiazem after intravenous and oral administration. Eur J Clin Pharmacol. 1983;24(3):349-52.
25. Joyal M et al, Pharmacodynamic aspects of intravenous diltiazem administration. Am Heart J. 1986;111(1):54-61.
26. Rovei V et al, Pharmacokinetics and metabolism of diltiazem in man. Acta Cardiol. 1980;35(1):35-45.
27. Holbrook RH Jr, Gibson RN, Voss EM, Tocolytic and cardiovascular effects of the calcium antagonist diltiazem in the near-term pregnant rabbit. Am J Obstet Gynecol. 1988;159(3):591-5.
28. Elsayed EM et al, The effect of thiola, piroxicam and diltiazem on the uterine contractility of gamma-irradiated rats. Pharmacol Res. 1996;34(5-6):231-6.
29. Janero DR, Burghardt B, Lopez R, Protection of cardiac membrane phospholipid against oxidative injury by calcium antagonists. Biochem Pharmacol. 1988;37(21):4197-203.
30. Shridi F, Robak J, The influence of calcium channel blockers on superoxide anions. Pharmacol Res Commun. 1988;20(1):13-21.
31. Watts JA et al, Effects of diltiazem on lactate, ATP, and cytosolic free calcium levels in ischemic hearts. J Cardiovasc Pharmacol. 1990;15(1):44-9.
32. Khandelwal M et al, Role of diltiazem in pregnant women with chronic renal disease. J Matern Fetal Neonatal Med. 2002;12(6):408-12.
33. Stowers KH, Hartman AD, Gustin J, Diltiazem for the management of malignancy-associated perineal pain and tenesmus. J Palliat Med. 2014;17(9):1075-7
34. Dubé LM, Mousseau N, McGilveray IJ, High-performance liquid chromatographic determination of diltiazem and four of its metabolites in plasma: evaluation of their stability. J Chromatogr. 1988;430(1):103-11.