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Diltiazem

PubChem CID
39186
Structure
Diltiazem_small.png
Diltiazem_3D_Structure.png
Diltiazem__Crystal_Structure.png
Molecular Formula
Synonyms
  • diltiazem
  • 42399-41-7
  • d-cis-Diltiazem
  • Cardizem
  • Dilcontin
Molecular Weight
414.5 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-06-24
  • Modify:
    2025-01-18
Description
Diltiazem is a 5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate in which both stereocentres have S configuration. A calcium-channel blocker and vasodilator, it is used as the hydrochloride in the management of angina pectoris and hypertension. It has a role as a calcium channel blocker, a vasodilator agent and an antihypertensive agent. It is a conjugate base of a diltiazem(1+). It is an enantiomer of an ent-diltiazem.
Diltiazem is a benzothiazepine derivative with antihypertensive and vasodilating properties. Approved in 1982 by the FDA, it is a member of the non-dihydropyridine calcium channel blockers drug class. It works through various mechanisms of action, but it primarily works by inhibiting the calcium influx into cardiac and vascular smooth muscle during depolarization. Compared to dihydropyridine drugs, such as [nifedipine], that preferentially act on vascular smooth muscle and [verapamil] that directly acts on the heart muscle, diltiazem displays an intermediate specificity to target both the cardiac and vascular smooth muscle. Being a potent vasodilator, diltiazem is used clinically as an antihypertensive, anti-arrhythmic, and as an anti-anginal agent for the management of cardiovascular conditions such as hypertension, chronic stable angina, atrial fibrillation, atrial flutter. Apart from its main FDA-approved indications, diltiazem has also been used for numerous off-label indications, such as anal fissures (in topical formulations), migraine prophylaxis, pulmonary hypertension, and rest-related cramps in the lower extremities. Typically available in extended-release oral and intravenous formulations, diltiazem is marketed under various brand names with Cardizem and Tiazac being the most common ones.
Diltiazem is a Calcium Channel Blocker. The mechanism of action of diltiazem is as a Calcium Channel Antagonist, and Cytochrome P450 3A4 Inhibitor.
See also: Diltiazem Hydrochloride (has salt form); Diltiazem Malate (has salt form); Diltiazem maleate (is active moiety of).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Diltiazem.png

1.2 3D Conformer

1.3 Crystal Structures

COD Number
Associated Article
Stepanovs, D.; Jure, M.; Gosteva, M.; Popelis, J.; Kiselovs, G.; Mishnev, A.. Crystal structures and physicochemical properties of diltiazem base and its acetylsalicylate, nicotinate andl-malate salts. CrystEngComm 2016;18(7):1235-. DOI: 10.1039/C5CE01204J
Crystal Structure Depiction
Crystal Structure Depiction
Hermann-Mauguin space group symbol
P 21 21 21
Hall space group symbol
P 2ac 2ab
Space group number
19
a
9.3387 Å
b
13.9027 Å
c
16.5550 Å
α
90.00 °
β
90.00 °
γ
90.00 °
Z
4
Z'
1
Residual factor
0.1146

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

[(2S,3S)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

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
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

HSUGRBWQSSZJOP-RTWAWAEBSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CC(=O)O[C@@H]1[C@@H](SC2=CC=CC=C2N(C1=O)CCN(C)C)C3=CC=C(C=C3)OC
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C22H26N2O4S
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

42399-41-7

2.3.2 European Community (EC) Number

2.3.3 UNII

2.3.4 ChEBI ID

2.3.5 ChEMBL ID

2.3.6 DrugBank ID

2.3.7 DSSTox Substance ID

2.3.8 HMDB ID

2.3.9 KEGG ID

2.3.10 Metabolomics Workbench ID

2.3.11 NCI Thesaurus Code

2.3.12 Nikkaji Number

2.3.13 PharmGKB ID

2.3.14 Pharos Ligand ID

2.3.15 RXCUI

2.3.16 Wikidata

2.3.17 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Aldizem
  • Cardil
  • Cardizem
  • CRD 401
  • CRD-401
  • CRD401
  • Dilacor
  • Dilacor XR
  • Dilren
  • Diltiazem
  • Diltiazem Hydrochloride
  • Diltiazem Malate
  • Dilzem
  • Tiazac

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
414.5 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
3.1
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
0
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
6
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
7
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
414.16132849 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
414.16132849 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
84.4 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
29
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
565
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
2
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Color / Form

White crystalline powder
Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present., p. VA4 (1985) 252

3.2.3 Boiling Point

Decomposes
Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present., p. VA2 (1985) 212

3.2.4 Melting Point

187-188
Kugita, H., Inoue, H., Ikezaki, M. and Takeo, S.; U.S. Patent 3,562,257; assigned to Tanabe Seiyaku Co.,Ltd., Japan.
212 °C (decomposes)
Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present., p. VA2 (1985) 449
231 °C

3.2.5 Solubility

465 mg/L
MCFARLAND,JW ET AL. (2001)
Soluble in methanol or chloroform
Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present., p. VA4 (1985) 252
In water, 465 mg/l @ 25 °C
McFarland JW et al; J Chem Inf Comput Sci 41: 1355-9 (2001)
1.68e-02 g/L

3.2.6 LogP

2.8
Human Metabolome Database (HMDB)
log Kow = 2.70
Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 177
2.8

3.2.7 Stability / Shelf Life

Intact vials should be stored under refrigeration and protected from freezing. Diltiazem HCl may be stored for up to one month at room temp but should then be destroyed. /Diltiazem HCl/
Trissel, L.A. Handbook on Injectable Drugs. 9th ed. Bethesda, MD. American Society of Health-System Pharmacists' Product Development. 1996., p. 346
The photostability of diltiazem was studied in aq solns at different pH values. Firstly, the hydrolysis of the drug to desacetyldiltiazem in alkaline medium was evaluated and then the drug photodegradation under exposure to UVA-UVB radiation (solar simulator) was monitored by HPLC methods. The main photoproduct was isolated and characterized as diltiazem-S-oxide on the basis of the NMR and mass spectra. The HPLC method was also applied to the selective analysis of diltiazem in commercial formulations. Tests on mutagenicity and photomutagenicity of the drug were also carried out using Salmonella typhimurium TA 102 strain. In this testing the drug neither was mutagenic nor toxic.
Andrisano V, et al; J Pharm Biomed Anal 25(3-4): 589-597 (2001)

3.2.8 Optical Rotation

Mol wt 450.99. Fine needles from ethanol-isopropanol, mp 207.5-212 °C. Odorless, with a bitter taste. Specific optical rotation at 24 °C for D (sodium) line = +98.3 plus or minus 1.4 deg (c = 1.002 in methanol). Freely soluble in water, methanol, chloroform, formic acid. Slightly soluble in absolute ethanol. Practically insoluble in benzene. Insoluble in ether /Hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 563

3.2.9 Caco2 Permeability

-4.38
ADME Research, USCD

3.2.10 Dissociation Constants

Basic pKa
8.02
Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharm Res. 2014; 31(4):1082-95. DOI:10.1007/s11095-013-1232-z. PMID:24249037
Basic pKa
8.06
Comparison of the accuracy of experimental and predicted pKa values of basic and acidic compounds. Pharm Res. 2014; 31(4):1082-95. DOI:10.1007/s11095-013-1232-z. PMID:24249037
pKa = 8.06
Gerhartz, W. (exec ed.). Ullmann's Encyclopedia of Industrial Chemistry. 5th ed.Vol A1: Deerfield Beach, FL: VCH Publishers, 1985 to Present., p. VA4 (1985) 212

3.2.11 Collision Cross Section

197.3 Ų [M+H]+ [CCS Type: DT; Method: single field calibrated]
197.8 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

193.96 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

180.56 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

194.75 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

193.4 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111

3.3 Chemical Classes

Pharmaceutical

3.3.1 Drugs

Pharmaceuticals -> unsed in Switzerland 2014-2016
S113 | SWISSPHARMA24 | 2024 Swiss Pharmaceutical List with Metabolites | DOI:10.5281/zenodo.10501043
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceutical
S120 | DUSTCT2024 | Substances from Second NORMAN Collaborative Dust Trial | DOI:10.5281/zenodo.13835254
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Calcium Channel Blockers; Antiarrhythmics; Vasodilator Agents
Human drug -> Discontinued
Human drug -> Prescription; Discontinued
Human drug -> Prescription
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

4 Spectral Information

4.1 Mass Spectrometry

4.1.1 GC-MS

1 of 2
Source of Spectrum
Mass Spectrometry Committee of the Toxicology Section of the American Academy of Forensic Sciences
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. Portions provided by AAFS, Toxicology Section. All Rights Reserved.
Thumbnail
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2 of 2
Source of Spectrum
Mass Spectrometry Committee of the Toxicology Section of the American Academy of Forensic Sciences
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. Portions provided by AAFS, Toxicology Section. All Rights Reserved.
Thumbnail
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4.1.2 MS-MS

1 of 4
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

178.02664 100

150.03224 56.70

72.07798 9.60

109.00677 9

137.05514 6.50

Thumbnail
Thumbnail
2 of 4
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

415.15645 100

178.02567 25.60

370.09726 9.90

312.09394 1.90

310.07944 1.30

Thumbnail
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4.1.3 LC-MS

1 of 3
View All
MoNA ID
MS Category
Experimental
MS Type
LC-MS
MS Level
MS1
Instrument
ZQ, Waters
Instrument Type
LC-ESI-Q
Ionization
ESI
Ionization Mode
positive
Retention Time
13.340 min
Top 5 Peaks

178 100

415 20.82

179 7.11

370 6.31

312 5.11

Thumbnail
Thumbnail
License
CC BY-NC
2 of 3
View All
MoNA ID
MS Category
Experimental
MS Type
LC-MS
MS Level
MS1
Instrument
ZQ, Waters
Instrument Type
LC-ESI-Q
Ionization
ESI
Ionization Mode
positive
Retention Time
13.340 min
Top 5 Peaks

178 100

150 8.21

179 5.91

137 5.11

180 4.30

Thumbnail
Thumbnail
License
CC BY-NC

4.2 IR Spectra

4.2.1 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Film (MeCl2) (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Biomol International, L.P.
Catalog Number
Free base of CA-205
Lot Number
Free base of P4678a
Copyright
Copyright © 2009-2024 John Wiley & Sons, Inc. All Rights Reserved.
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6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

**Oral** Indicated for the management of hypertension, to lower blood pressure, alone or in combination with other antihypertensive agents. Indicated for use to improve exercise tolerance in patients with chronic stable angina. Indicated for the management of variant angina (Prinzmetal's angina). **Intravenous** Indicated for the short-term management of atrial fibrillation or atrial flutter for temporary control of rapid ventricular rate. Indicated for the rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm. This includes AV nodal reentrant tachycardias and reciprocating tachycardias associated with an extranodal accessory pathway such as the WPW syndrome or short PR syndrome. **Off-label** Indicated for off-label uses in anal fissures (as topical formulation), migraine prophylaxis, cramps in lower leg related to rest, pulmonary hypertension, idiopathic dilated cardiomyopathy, and proteinuria associated with diabetic nephropathy.

7.2 LiverTox Summary

Diltiazem hydrochloride is a first generation calcium channel blocker that is widely used in the therapy of hypertension and angina pectoris. Diltiazem therapy is associated with serum enzyme elevations and has been linked to rare instances of clinically apparent liver injury.

7.3 Drug Classes

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Calcium Channel Blockers; Antiarrhythmics; Vasodilator Agents

7.4 Drug Labels

Drug and label

7.5 Clinical Trials

7.5.1 ClinicalTrials.gov

7.5.2 EU Clinical Trials Register

7.5.3 NIPH Clinical Trials Search of Japan

7.6 Therapeutic Uses

Diltiazem ... may reduce the incidence of reinfarction in patients with a first non-Q-wave infarction who are not candidates for a beta-adrenergic receptor antagonist.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 860
... Diltiazem ... /has/ been shown to provide symptomatic relief in Raynaud's disease.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 860
Diltiazem ... /is/ indicated, alone or in combination with other agents, for treatment of hypertension. /Included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional 21 st ed. Volume 1. MICROMEDEX Thomson Health Care, Englewood, CO. 2001. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 730
... Parenteral diltiazem /is/ indicated in the treatment of supraventricular tachyarrhythmias. Diltiazem ... produces rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardia (including those associated with accessory bypass tracts, such as Wolff-Parkinson-White [W-P-W] or Lown-Ganong-Levine [L-G-L] syndrome) in patients who do not respond to vagal maneuvers {161} when the atrioventricular (AV) node is required for reentry to sustain tachycardia {125}. Parenteral diltiazem ... also produces temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation. ... /Included in US product labeling/
MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional 21 st ed. Volume 1. MICROMEDEX Thomson Health Care, Englewood, CO. 2001. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 730
For more Therapeutic Uses (Complete) data for DILTIAZEM (16 total), please visit the HSDB record page.

7.7 Drug Warnings

The toxic effects of sustained-release calcium channel blockers may be delayed more than 12 hr after ingestion. All patients with sustained-release calcium channel blocker overdose should be admitted to the hospital for observation, even if they are asymptomatic. /Calcium channel blockers/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 533
Withdrawal of calcium channel blocking drugs from severely hypertensive patients, even in the absence of previous angina or myocardial infarction, may precipitate myocardial infarction. Worsening angina & myocardial infarction have been described after the withdrawal of calcium channel blocking agents in patients with normal coronary angiography who are being treated for ischemic chest pain. /Calcium channel blockers/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 533
Patients with ventricular dysfunction, SA or AV nodal conduction disturbances, and systolic blood pressures below 90 mm Hg should not be treated with ... diltiazem, particularly iv.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 859
The most common adverse cardiovascular effect noted with IV diltiazem is symptomatic or asymptomatic hypotension, which occurred in 3.2 or 4.3%, respectively, of patients receiving the drug in clinical trials. Hypotension or postural hypotension also was noted in approximately 1% or less of patients receiving oral diltiazem. If symptomatic hypotension occurs, appropriate therapy (e.g., placement of the patients in the Trendelenburg's position, plasma volume expansion) should be initiated. Hypotension occurred secondary to the vasodilating action of diltiazem on vascular smooth muscle. Vasodilation or flushing occurred in 1.7% of patients receiving IV diltiazem and in approximately 1% or less of patients receiving oral diltiazem in clinical trials.
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2002. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2002 (Plus Supplements)., p. 1610
For more Drug Warnings (Complete) data for DILTIAZEM (18 total), please visit the HSDB record page.

7.8 Reported Fatal Dose

At /blood/ levels /of diltiazem/ above 6,100 ug/L, most patients die.
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 537

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Diltiazem is an antihypertensive and vasodilating agent that works by relaxing the vascular muscle and reducing blood pressure. This is related to the long-term therapeutic effects, as lowering the blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. Diltiazem inhibits the influx of extracellular calcium ions across the myocardial and vascular smooth muscle cell membranes during depolarization. Diltiazem is classified as a negative inotrope (decreased force) and negative chronotrope (decreased rate). It is also considered a rate-control drug as it reduces heart rate. Diltiazem is exerts hemodynamic actions by reducing blood pressure, systemic vascular resistance, the rate-pressure product, and coronary vascular resistance while increasing coronary blood flow. Diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In supraventricular tachycardia, diltiazem prolongs AV nodal refractories. As the magnitude of blood pressure reduction is related to the degree of hypertension, the antihypertensive effect of diltiazem is most pronounced in individuals with hypertension. In a randomized, double-blind, parallel-group, dose-response study involving patients with essential hypertension, there was a reduction in the diastolic blood pressure by 1.9, 5.4, 6.1, and 8.6 mmHg in the patients receiving diltiazem at doses of 120, 240, 360, and 540 mg, respectively. In patients receiving placebo, there was a reduction in the diastolic blood pressure by 2.6 mmHg.In a randomized, double-blind study involving patients with chronic stable angina, variable doses of diltiazem administered at night all caused an increased exercise tolerance in the after 21 hours, compared to placebo. In the NORDIL study of patients with hypertension, the therapeutic effectiveness of diltiazem in reducing cardiovascular morbidity and mortality was assessed. When using the combined primary endpoint as fatal and non-fatal stroke, myocardial infarction, and other cardiovascular death, fatal and non-fatal stroke was shown to be reduced by 25% in the diltiazem group. Although the clinical significance to this effect remains unclear, it is suggested that diltiazem may exert a protective role against cerebral stroke in hypertensive patients.

8.2 MeSH Pharmacological Classification

Antihypertensive Agents
Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS. (See all compounds classified as Antihypertensive Agents.)
Vasodilator Agents
Drugs used to cause dilation of the blood vessels. (See all compounds classified as Vasodilator Agents.)
Calcium Channel Blockers
A class of drugs that act by selective inhibition of calcium influx through cellular membranes. (See all compounds classified as Calcium Channel Blockers.)
Cardiovascular Agents
Agents that affect the rate or intensity of cardiac contraction, blood vessel diameter, or blood volume. (See all compounds classified as Cardiovascular Agents.)

8.3 FDA Pharmacological Classification

FDA UNII
EE92BBP03H
Active Moiety
DILTIAZEM
Pharmacological Classes
Mechanisms of Action [MoA] - Calcium Channel Antagonists
Pharmacological Classes
Established Pharmacologic Class [EPC] - Calcium Channel Blocker
Pharmacological Classes
Mechanisms of Action [MoA] - Cytochrome P450 3A4 Inhibitors
FDA Pharmacology Summary
Diltiazem is a Calcium Channel Blocker. The mechanism of action of diltiazem is as a Calcium Channel Antagonist, and Cytochrome P450 3A4 Inhibitor.

8.4 ATC Code

C - Cardiovascular system

C05 - Vasoprotectives

C05A - Agents for treatment of hemorrhoids and anal fissures for topical use

C05AE - Muscle relaxants

C05AE03 - Diltiazem

C - Cardiovascular system

C08 - Calcium channel blockers

C08D - Selective calcium channel blockers with direct cardiac effects

C08DB - Benzothiazepine derivatives

C08DB01 - Diltiazem

8.5 Absorption, Distribution and Excretion

Absorption
Diltiazem is readily absorbed from the gastrointestinal tract. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50 to 200 ng/mL. Following oral administration of extended formulations of 360 mg diltiazem, the drug in plasma was detectable within 3 to 4 hours and the peak plasma concentrations were reached between 11 and 18 hours post-dose. Diltiazem peak and systemic exposures were not affected by concurrent food intake. Due to hepatic first-pass metabolism, the absolute bioavailability following oral administration is about 40%, with the value ranging from 24 to 74% due to high interindividual variation in the first pass effect. The bioavailability may increase in patients with hepatic impairment.
Route of Elimination
Due to its extensive metabolism, only 2% to 4% of the unchanged drug can be detected in the urine. The major urinary metabolite in healthy volunnteers was N-monodesmethyl diltiazem, followed by deacetyl N,O-didesmethyl diltiazem, deacetyl N-monodesmethyl diltiazem, and deacetyl diltiazem; however, there seems to be large inter-individual variability in the urinary excretion of DTZ and its metabolites.
Volume of Distribution
The apparent volume of distribution of diltiazem was approximately 305 L following a single intravenous injection in healthy male volunteers.
Clearance
Following a single intravenous injection in healthy male volunteers, the systemic clearance of diltiazem was approximately 65 L/h. After constant rate intravenous infusion, the systemic clearance decreased to 48 L/h.
The protein binding of diltiazem is 80-90%, & the volume of distribution is approx 5.3 L/kg. Clearance of diltiazem after oral ingestion follows first-order kinetics, with a half-life of 5-10 hr, independent of the amount ingested. In sustained release preparations, however, the peak absorption time is delayed & the half-life may be very prolonged because of continued GI absorption.
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 533
Although the absorption of ... agents /like diltiazem/ is nearly complete after oral admin, their bioavailability is reduced, in some cases markedly, because of first-pass hepatic metab. The effects of these drugs are evident within 30-60 min of an oral dose ... . During repeated oral admin, bioavailability and half-life may incr because of saturation of hepatic metabolism. A major metabolite of diltiazem is desacetyldiltiazem, which has about 1/2 of diltiazem's potency as a vasodilator.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 858
Diltiazem is excreted into human milk.
Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams & Wilkins 1994., p. 288
The pharmacokinetic changes of diltiazem ... and its main metabolite, deacetyldiltiazem (DAD) were studied after oral admin of diltiazem to normal rabbits and mild and medium folate-induced renal failure rabbits. Diltiazem 10 mg/kg was given to the rabbits ... orally (n=6). Plasma concns of diltiazem and DAD were determined by a high performance liquid chromatography assay. The area under the plasma concn-time curves (AUC) and max plasma concn (Cmax) of diltiazem were significantly increased in mild and medium folate-induced renal failure rabbits. The metabolite ratio of the diltiazem to DAD were significantly decreased in mild and medium folate-induced renal failure rabbits. The volume of distribution (Vd) and total body clearance (CLt) of diltiazem were significantly decreased in mild and medium folate-induced renal failure rabbits. The elimination rate constant (beta) of diltiazem was significantly decreased in folate-induced renal failure rabbits, but that of DAD was significantly increased. These findings suggest that the hepatic metab of diltiazem was inhibited ... .
Choi JS, et al; Arch Pharm Res 24(4): 333-337 (2001)
The pharmacokinetics of diltiazem in rabbits after subconjunctival and topical admin was studied. Diltiazem successfully penetrated the aq humor of rabbit eyes. The peak aq concns were 3.8 +/- 0.4 ug/ml after topical application and 15.3 +/- 1.1 ug/ml after subconjunctival injection. The peak aq concn was achieved 1/2 hrs after admin in both cases.
Oruc S, et al; Eur J Ophthalmol 10(1): 46-50 (2000)

8.6 Metabolism / Metabolites

Diltiazem is subject to extensive first-pass metabolism, which explains its relatively low absolute oral bioavailability. It undergoes N-demethylation primarily mediated by CYP3A4. CYP2D6 is responsible for O-demethylation and esterases mediate deacetylation. There was large inter-individual variability in the circulating plasma levels of metabolites in healthy volunteers. In healthy volunteers, the major circulating metabolites in the plasma are N-monodesmethyl diltilazem, deacetyl diltiazem, and deacetyl N-monodesmethyl diltiazem, which are all pharmacologically active. Deacetyl diltiazem retains about 25-50% of the pharmacological activity to that of the parent compound. Deacetyl diltiazem can be further transformed into deacetyl diltiazem N-oxide or deacetyl O-desmethyl diltiazem. N-monodesmethyl diltilazem can be further metabolized to N,O-didesmethyl diltiazem. Deacetyl N-monodesmethyl diltiazem can be further metabolized to deacetyl N,O-didesmethyl diltiazem, which can be glucuronidated or sulphated. Diltiazem can be O-demethylated by CYP2D6 to form O-desmethyl diltiazem.
A major metabolite of diltiazem is desacetyldiltiazem, which has about 1/2 of diltiazem's potency as a vasodilator.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 858
Diltiazem undergoes extensive metabolism in hepatic and extrahepatic tissues. Deacetyldiltiazem (M1) and N-demethyldiltiazem (MA) are 2 of the main basic metabolites of diltiazem that retain pharmacological activity. This drug impairs its own metab after chronic admin in the adult patient.
Fraile LJ, et al; Xenobiotica 31(4): 177-185 (2001)
Diltiazem has known human metabolites that include N-Demethyldiltiazem and O-Demethyldiltiazem.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560
Diltiazem is metabolized by and acts as an inhibitor of the CYP3A4 enzyme. Half Life: 3.0 - 4.5 hours

8.7 Biological Half-Life

The plasma elimination half-life is approximately 3.0 to 4.5 hours following single and multiple oral doses. The half-life may slightly increase with dose and the extent of hepatic impairment. The apparent elimination half-life for diltiazem as extended-release tablets after single or multiple dosing is 6 to 9 hours. The plasma elimination half-life is approximately 3.4 hours following administration of a single intravenous injection. The elimination half-lives of pharmacologically active metabolites are longer than that of diltiazem.
Clearance of diltiazem after oral ingestion follows first-order kinetics, with a half-life of 5-10 hr ... .
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 533

8.8 Mechanism of Action

Excitation of cardiac muscle involves the activation of a slow calcium inward current that is induced by L-type slow calcium channels, which are voltage-sensitive, ion-selective channels associated with a high activation threshold and slow inactivation profile. L-type calcium channels are the main current responsible for the late phase of the pacemaker potential. Acting as the main Ca2+ source for contraction in smooth and cardiac muscle, activation of L-type calcium channels allows the influx of calcium ions into the muscles upon depolarization and excitation of the channel. It is proposed that this cation influx may also trigger the release of additional calcium ions from intracellular storage sites. Diltiazem is a slow calcium channel blocker that binds to the extracellular site of the alpha-1C subunit of the channel, which is thought to be the S5-6 linker region of the transmembrane domain IV and/or S6 segment of domain III. Diltiazem can get access to this binding site from either the intracellular or extracellular side, but it requires a voltage-induced conformational changes in the membrane. Diltiazem inhibits the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. In isolated human atrial and ventricular myocardium, diltiazem suppressed tension over the range of membrane potentials associated with calcium channel activity but had little effect on the tension-voltage relations at more positive potentials. This effect is thought to be mediated by the voltage-dependent block of the L-type calcium channels and inhibition of calcium ion release from the ER stores, without altering the sodium-calcium coupled transport or calcium sensitivity of myofilaments. Through inhibition of inward calcium current, diltiazem exerts a direct ionotropic and energy sparing effect on the myocardium. Diltiazem fslows atrioventricular nodal conduction, which is due to its ability to impede slow channel function. Reduced intracellular calcium concentrations equate to increased smooth muscle relaxation resulting in arterial vasodilation and therefore, decreased blood pressure. The decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, causing dilation of the coronary and systemic arteries, increased oxygen delivery to the myocardial tissue, decreased total peripheral resistance, decreased systemic blood pressure, and decreased afterload. Through its actions on reducing calcium levels in cardiac and vascular smooth muscles, diltiazem causes a reduction in the contractile processes of the myocardial smooth muscle cells and vasodilation of the coronary and systemic arteries, including epicardial and subendocardial. This subsequently leads to increased oxygen delivery to the myocardial tissue, improved cardiac output due to increased stroke volume, decreased total peripheral resistance, decreased systemic blood pressure and heart rate, and decreased afterload. Diltiazem lowers myocardial oxygen demand through a reduction in heart rate, blood pressure, and cardiac contractility; this leads to a therapeutic effect in improving exercise tolerance in chronic stable angina.
The effects of D-cis- and L-cis-diltiazem on the hydrogen peroxide (H2O2)-induced derangements of mechanical function and energy metab, and accumulation of intracellular Na+ were studied in isolated rat hearts. The intracellular concn of Na+ ([Na+]i) in the myocardium was measured using a nuclear magnetic resonance technique. H2O2 (600 uM) increased the left ventricular end-diastolic pressure, decreased the tissue level of ATP, and increased the release of lactate dehydrogenase from the myocardium. These alterations induced by H2O2 were significantly attenuated by D-cis-diltiazem (15 uM) or L-cis-diltiazem (15 uM). H2O2 (1 mM) produced a marked incr in the myocardial [Na+]i, which was effectively inhibited by ... D-cis-diltiazem (15 uM) or L-cis-diltiazem (15 uM). ... The protective action of D-cis- and L-cis-diltiazem may be due to their ability to inhibit the H2O2-induced incr in [Na+]i, at least in part.
Xiao CY, et al; Eur J Pharmacol 374(3): 387-398 (1999)

8.9 Human Metabolite Information

8.9.1 Cellular Locations

Membrane

8.9.2 Metabolite Pathways

8.10 Transformations

9 Use and Manufacturing

9.1 Uses

Medication
Medication (Vet)

Use (kg; approx.) in Germany (2009): >5000

Use (kg) in USA (2002): 97800

Consumption (g per capita; approx.) in Germany (2009): 0.0611

Consumption (g per capita) in the USA (2002): 0.347

Excretion rate: 0.1

Calculated removal (%): 11.8

For the treatment of hypertension.

9.1.1 Use Classification

Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

9.2 Methods of Manufacturing

p-Anisaldehyde + methyl chloroacetate + 2-aminothiophenol + acetic anhydride + 2-dimethylaminoethyl chloride hydrochloride (Darzens reaction/epoxidation/saponification/racemate separation/condensation/amine formation)
Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994., p. 318
Prepn (unspec stereochem): H. Kugita et al., DE 1805714; eidem, US 3562257 (1969, 1971 both to Tanabe Seiyaku); eidem, Chem. Pharm. Bull. 19, 595 (1971). ...Stereospecific synthesis: K. Igarashi, T. Honma, DE 3415035; eidem, US 4552695 (1984, 1985 both to Shionogi)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, Whitehouse Station, NJ: Merck and Co., Inc., 2001., p. 563

9.3 Formulations / Preparations

Available commercially as the (+)-cis-isomer hydrochloride salt.
Ashford, R.D. Ashford's Dictionary of Industrial Chemicals. London, England: Wavelength Publications Ltd., 1994., p. 318
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2001. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2001 (Plus Supplements)., p. 1557
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2001. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2001 (Plus Supplements)., p. 1557
Tiazac
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 949
For more Formulations/Preparations (Complete) data for DILTIAZEM (6 total), please visit the HSDB record page.

10 Identification

10.1 Analytic Laboratory Methods

Analyte: diltiazem hydrochloride; matrix: pharmaceutical preparation (tablet); procedure: liquid chromatography with detection at 240 nm and comparison to standards (assay purity) /diltiazem hydrochloride/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p628 (2003)
Analyte: diltiazem hydrochloride; matrix: pharmaceutical preparation (tablet); procedure: retention time of liquid chromatogram with comparison to standards (chemical identification) /diltiazem hydrochloride/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p628 (2003)
Analyte: diltiazem hydrochloride; matrix: pharmaceutical preparation (tablet); procedure: colorimetric reaction with ammonium thiocyanate and cobalt chloride (chemical identification) /diltiazem hydrochloride/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p628 (2003)
Analyte: diltiazem hydrochloride; matrix: pharmaceutical preparation (extended-release capsule); procedure: liquid chromatography with detection at 240 nm and comparison to standards (assay purity) /diltiazem hydrochloride/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 26/The National Formulary, NF 21; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p625 (2003)
For more Analytic Laboratory Methods (Complete) data for DILTIAZEM (10 total), please visit the HSDB record page.

11 Safety and Hazards

11.1 Accidental Release Measures

11.1.1 Disposal Methods

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

11.2 Handling and Storage

11.2.1 Storage Conditions

Diltiazem hydrochloride tablets should be stored in tight, light-resistant, and extended-release capsules in tight containers at 15-30 °C, unless otherwise specified by the manufacturer. /Diltiazem hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2001. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2001 (Plus Supplements)., p. 1557
Extended-release tablets containing diltiazem malate alone or in fixed combination with enalapril maleate should be stored in well-closed containers at 15-30 °C. /Diltiazem malate/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2001. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2001 (Plus Supplements)., p. 1557
Diltiazem hydrochloride injection in vials should be refrigerated at 2-8 °C; freezing of the injection should be avoided. Diltiazem hydrochloride injection may be stored at room temp for up to 1 month; after that time, the injection should be discarded. Diltiazem hydrochloride powder for injection in single-use vials ... or in single-use syringes ... should be stored at a room temp of 15-30 °C; freezing of the powder for injection should be avoided. Following reconstitution of diltiazem hydrochloride powder for injection from single-dose vials and transferred to polyvinyl chloride (PVC) bags ... or after actuation of the single-use syringe, the reconstituted solns of diltiazem hydrochloride are stable for 24 hr at controlled room temp; unused portions of reconstituted soln in the PVC bags or single-use syringes should be discarded after this period. /Diltiazem hydrochloride/
McEvoy, G.K. (ed.). American Hospital Formulary Service- Drug Information 2001. Bethesda, MD: American Society of Health-System Pharmacists, Inc. 2001 (Plus Supplements)., p. 1557

11.3 Regulatory Information

New Zealand EPA Inventory of Chemical Status
Diltiazem: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

11.3.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl diltiazem hydrochloride and diltiazem maleate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Diltiazem hydrochloride, diltiazem maleate/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of December 3, 2002: https://www.fda.gov/cder/ob/

11.4 Other Safety Information

Chemical Assessment

IMAP assessments - 1,5-Benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, (2S-cis)-: Environment tier I assessment

IMAP assessments - 1,5-Benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, (2S-cis)-: Human health tier I assessment

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, diltiazem, like verapamil, inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue.

12.1.2 USGS Health-Based Screening Levels for Evaluating Water-Quality

Chemical
Diltiazem
Chemical Classes
Pharmaceutical
Reference
Smith, C.D. and Nowell, L.H., 2024. Health-Based Screening Levels for evaluating water-quality data (3rd ed.). DOI:10.5066/F71C1TWP

12.1.3 Hepatotoxicity

Diltiazem therapy is associated with a low rate of mild and transient elevations in serum aminotransferase levels which are usually asymptomatic and often resolve even with continuation of therapy. Clinically apparent, acute liver injury with jaundice due to diltiazem is rare and only isolated case reports have been published. In large case series of drug induced liver injury, calcium channel blockers are rarely mentioned. Most cases attributed to diltiazem have been marked by a short latency period (3 to 14 days) and features of hypersensitivity with fever, rash and eosinophilia. The pattern of liver injury was ranged from cholestatic to hepatocellular. Jaundice is often absent and usually mild. Autoantibody formation has not been described. Thus, liver injury from diltiazem is likely to be idiosyncratic in nature and is typically mild and self-limited with resolution within 4 to 8 weeks of stopping. Acute hepatic injury is listened as a possible adverse event in the diltiazem product label.

Likelihood score: C (probable but rare cause of clinically apparent liver injury).

12.1.4 Drug Induced Liver Injury

Compound
diltiazem
DILI Annotation
Most-DILI-Concern
Severity Grade
4
Label Section
Warnings and precautions
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

12.1.5 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

12.1.6 Health Effects

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. 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. (Wikipedia)

12.1.7 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Based on limited data, amounts of diltiazem ingested by the infant are small and would not be expected to cause any adverse effects in breastfed infants.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Relevant published information was not found as of the revision date.

12.1.8 Exposure Routes

Intravenous, Oral. Diltiazem is well absorbed from the gastrointestinal tract but undergoes substantial hepatic first-pass effect.

12.1.9 Symptoms

LD<sub>50</sub>=740mg/kg (orally in mice)

12.1.10 Acute Effects

12.1.11 Toxicity Data

LD<sub>50</sub>=740mg/kg (orally in mice)

12.1.12 Treatment

In the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastrointestinal decontamination. If bradycardia and/or high-degree AV block occurs, administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockage, administer isoproterenol cautiously. Fixed high-degree AV block should be treated with cardiac pacing. In cases of cardiac failure, administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics. If hypotension occurs, use vasopressors (e.g. dopamine or levarterenol bitartrate). (L1712)
L1712: RxList: The Internet Drug Index (2009). http://www.rxlist.com/

12.1.13 Interactions

Diltiazem interacts with Propranolol reducing oral clearance with increased concns of propanolol by inhibition of first-pass metab. Propanolol dose may need to be reduced. /from table/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 534
Diltiazem interacts with cyclosporine increasing cyclosporine concns. Reduce cyclosporine dose after starting... diltiazem; monitor cyclosporine concns. /from table/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 534
Diltiazem interacts with disopyramide, flecainide /causing/ cardiac failure by additive depression of myocardial contractility. Avoid use if possible, particularly in patients with impaired myocardial function. /from table/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 534
Diltiazem interacts with Amiodarone, flecainide /causing/ sinus arrest, heart block by additive depression of sinus node function & AV nodal conduction. Use combination with extreme caution. /from table/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 534
For more Interactions (Complete) data for DILTIAZEM (15 total), please visit the HSDB record page.

12.1.14 Antidote and Emergency Treatment

An adult dose of 10 ... calcium gluconate over 5 min may be used to reverse hypotension with careful monitoring of rhythm. A repeat bolus (after 10-15 min) or iv drip (of the 10% calcium gluconate soln) may be needed. Calcium levels must be monitored. The optimal calcium dosage required for the treatment of calcium channel blocker toxicity has not been determined. Hypercalcemia may be significant if more than 45 mEq of calcium is admin acutely. /Calcium channel blockers/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 538
Glucagon exhibits chronotropic & inotropic effects in calcium channel blocker overdose. The binding of glucagon to its specific catecholamine-independent receptors activates adenyl cyclase & converts intracellular ATP to cyclic AMP. The intracellular cyclic AMP stimulates the uptake of calcium by the sarcoplasmic reticulum & plasma membrane-enriched fraction. Calcium is important for the coupling of the action potential of the contraction press. Increased intracellular calcium leads to increased myocardial contractility. This effect on myocardial cells appears to be influenced by the amount of circulating ionized calcium, the presence of phosphodiesterase inhibitors, & the degree of heart failure. Normal serum ionized calcium may be a prerequisite for full responsivity of myocardial cells to glucose. Iv glucagon ... is often followed by a rise in blood pressure. If an initial bolus ... is unsuccessful at increasing blood pressure, it appears reasonable to double that dose. If the hemodynamic status improves, a glucagon infusion can be started ... . Glucagon can be admin safely for as long as 48 hr with few ill effects. The most common adverse drug reactions associated with its use are nausea, emesis, & hyperglycemia. Careful monitoring of total serum calcium & preferably of total serum ionized calcium, as well as supplemental infusions of calcium chloride, appear to constitute an optimal management program. If these modalities do not restore the hemodynamic status, a bolus infusion of amrinone may be useful. Some recent literature reports anecdotal success with glucagon, although other reports describe the use of up to 10 mg of glucagon iv without clinical improvement. /Calcium channel blockers/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 538
Various catecholamines & sympathomimetic agents, including isoproterenol, dopamine, dobutamine, epinephrine, & norepinephrine, have been used to counter the hypotensive effects of calcium channel blocker overdose, all with mixed results. It remains unclear which catecholamine or combination of catecholamines is better for the treatment of calcium channel blocker toxicity based on current data in the literature. On the basis of their pharmacologic profiles, beta-adrenergic receptor agonists such as dobutamine & isoproterenol would be logical choices when primarily cardiac chronotropy & inotropy are affected. Direct alpha-adrenergic receptor agonists may be a better choice if the toxicity is related primarily to decreased systemic vascular resistances. Combining alpha- & beta-adrenergic receptor agonists (such as dobutamine & norepinephrine) or using agents with both alpha- & beta-adrenergic effects (such as epinephrine) may ameliorate both cardiac dysfunction & decreased systemic vascular resistance. /Calcium channel blockers/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 539
Cardiac pacing is indicated for significant bradycardia & high-grade conduction blocks. The incr in heart rate alone induced by cardiac pacing can improve cardiac output. Cardiac pacing (both external & internal) does not always capture or improve the hemodynamics in calcium channel blocker toxic patients. Intraaortic balloon counterpulsation directly augments cardiac output in the failing heart. By temporarily providing adequate cardiac output, it provides a window of opportunity for the metab & elimination of the offending calcium channel blocker. Cardiac pacing may be used in concert with intraaortic balloon counterpulsation for significant bradycardia & high-grade blocks. /Calcium channel blockers/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 540
...A patient who developed tetany with sudden respiratory arrest after the infusion of iv diltiazem /is described/. The admin of calcium chloride rapidly resolved the patient's tetany with prompt recovery of respiratory function, averting the need for more aggressive airway management & ventilatory support. The emergency physician should be aware that life-threatening tetany may accompany the admin of iv diltiazem & that calcium chloride may be a rapid & effective remedy.
Vinson DR, et al; Ann Emerg Med 34(5): 676-678 (1999)

12.1.15 Medical Surveillance

Patients with hemodynamic compromise from calcium channel blocker overdose that does not respond to initial therapy should receive invasive hemodynamic monitoring. Specific cardiac output & systemic vascular resistance measurement may determine the optimal pharmacologic therapy & fluid supplement. /Calcium channel blocker/
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 539

12.1.16 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ An 18 yr old man ingested 720 mg of diltiazem & developed sinus tachycardia; one 300 mg ingestion of diltiazem by a 50 yr old was nontoxic. Similarly, a 120 mg diltiazem ingestion by an 18 month old was nontoxic. A 50 yr old ingested 5880 mg of diltiazem with beer, became hypotensive & had a short period of ventricular asystole; he survived.
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 532
/HUMAN EXPOSURE STUDIES/ A patient received diltiazem throughout pregnancy with twins. The infants were delivered at 37 wk gestation. There were no apparent maternal or fetal adverse effects throughout pregnancy, through the neonatal period, & up to 6 months later.
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 533
/HUMAN EXPOSURE STUDIES/ Diltiazem has both central & peripheral circulatory effects, although the central effects appear to predominate, placing it closer to the verapamil end of the spectrum. Diltiazem ... /has/ negative inotropic effects.
Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 533
/HUMAN EXPOSURE STUDIES/ Oral admin of diltiazem results in a sustained fall in both heart rate and mean arterial blood pressure. Despite the fact that diltiazem and verapamil produce similar effects on the /sinoatrial/ and /atrioventricular/ nodes, the negative inotropic effect of diltiazem is more modest.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 10th ed. New York, NY: McGraw-Hill, 2001., p. 857
For more Human Toxicity Excerpts (Complete) data for DILTIAZEM (9 total), please visit the HSDB record page.

12.1.17 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A 24-month study in rats at oral dosage of up to 100 mg/kg/day showed no evidence of carcinogenicity.[
Medical Economics Co; Physicians Desk Reference 56th ed p 1018 (2002)]
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No evidence of impaired fertility was observed in a study performed in male and female rats at oral dosages of up to 100 mg/kg/day.[
Medical Economics Co; Physicians Desk Reference 56th ed p. 1018 (2002)]
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In some animal species given high doses, diltiazem produced embryo and fetal toxicity, inducing teratogenic effects involving the skeletal system. In fetal sheep, diltiazem, like ritodrine and magnesium sulfate, inhibited bladder contractions, resulting in residual urine.
Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams & Wilkins 1994., p. 287
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Diltiazem undergoes extensive metabolism in hepatic and extrahepatic tissues. Deacetyldiltiazem (M1) and N-demethyldiltiazem (MA) are 2 of the main basic metabolites of diltiazem that retain pharmacological activity. This drug impairs its own metab after chronic admin in the adult patient. The study examines the possibility that intra-uterine exposure following chronic maternal therapy with dilitiazem from mid-gestation to term also impairs diltiazem metab of its offspring. Diltiazem was incubated in homogenates from liver, lung, brain and gut and in the whole blood of animals whose mothers were exposed to chronic treatment with diltiazem or unexposed (placebo) ... Diltiazem deacetylase activity observed in liver, lung and brain homogenates from 1-, 8-, & 16-day-old rabbits was significantly lower in exposed animals. In gut homogenates, this age-dependent effect was not so clear. This inhibition could not be detected in any organ of 30-day-old rabbits. On the other hand, the activity observed in whole blood was not altered by intra-uterine chronic exposure to diltiazem. Diltiazem demethylase activity showed no differences in tissue homogenates and in whole blood from exposed compared with the unexposed rabbit. ... The findings suggest that intra-uterine chronic exposure to diltiazem has a large and prolonged effect on newborn metab deacetylase activity compared with the unexposed rabbit.
Fraile LJ, et al; Xenobiotica 31(4): 177-185 (2001)
/GENOTOXICITY/ There was no mutagenic response in vitro or in vivo in mammalian cell assays or in vitro in bacteria.[
Medical Economics Co; Physicians Desk Reference 56th ed p. 1018 (2002)]

12.1.18 Ongoing Test Status

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. /Diltiazem hydrochloride/ [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=33286-22-5]

12.1.19 Protein Binding

Diltiazem is about 70-80% bound to plasma proteins, according to _in vitro_ binding studies. About 40% of the drug is thought to bind to alpha-1-glycoprotein at clinically significant concentrations while about 30% of the drug is bound to albumin.

12.2 Ecological Information

12.2.1 Environmental Water Concentrations

SURFACE WATER: In a survey conducted by the United States Geological Survey, diltiazem was detected at a max concn of 0.049 ug/l (0.021 ug/l median concn, 0.012 ug/l reporting level) at a 13.1% frequency in 84 submitted water samples from a network of 139 US stream sampling sites across 30 states during 1999-2000(1).
(1) Kolpin DW et al; Environ Sci Technol 36: 1202-11 (2002)

12.2.2 Milk Concentrations

Diltiazem is excreted into human milk.
Briggs, G.G, R.K. Freeman, S.J. Yaffe. A Reference Guide to Fetal and Neonatal Risk. Drugs in Pregnancy and Lactation. 4th ed. Baltimore, MD: Williams & Wilkins 1994., p. 288

12.2.3 Body Burden

A 15-yr-old woman was admitted to the ICU after ... auto-intoxication with 10 tablets of 200 mg diltiazem sustained release. ... Max plasma lactate concn was 10 mmol/l and the highest measured plasma diltiazem level was 500 micrograms/l.

13 Associated Disorders and Diseases

Disease
Colorectal cancer
References

PubMed: 7482520, 22148915, 19006102, 23940645, 24424155, 20156336, 19678709, 25105552, 21773981, 25037050, 27015276, 27107423, 27275383, 28587349

Silke Matysik, Caroline Ivanne Le Roy, Gerhard Liebisch, Sandrine Paule Claus. Metabolomics of fecal samples: A practical consideration. Trends in Food Science & Technology. Vol. 57, Part B, Nov. 2016, p.244-255: http://www.sciencedirect.com/science/article/pii/S0924224416301984

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Wiley References

14.6 Nature Journal References

14.7 Chemical Co-Occurrences in Literature

14.8 Chemical-Gene Co-Occurrences in Literature

14.9 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Protein Bound 3D Structures

16.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

16.2 Chemical-Target Interactions

16.3 Drug-Drug Interactions

16.4 Drug-Food Interactions

Avoid natural licorice. The risk of cardiovascular adverse effects may be increased.

16.5 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Classification

18.1 MeSH Tree

18.2 NCI Thesaurus Tree

18.3 ChEBI Ontology

18.4 KEGG: ATC

18.5 KEGG: Target-based Classification of Drugs

18.6 KEGG: Drug Groups

18.7 WHO ATC Classification System

18.8 FDA Pharm Classes

18.9 ChemIDplus

18.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

18.11 ChEMBL Target Tree

18.12 NORMAN Suspect List Exchange Classification

18.13 CCSBase Classification

18.14 EPA DSSTox Classification

18.15 MolGenie Organic Chemistry Ontology

19 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
    1,5-Benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, (2S-cis)-
    https://services.industrialchemicals.gov.au/search-assessments/
  2. CAS Common Chemistry
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    https://creativecommons.org/licenses/by-nc/4.0/
  3. ChemIDplus
    cis-3-Acetoxy-5-(2-(dimethylamino)ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one
    https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0056209451
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  4. DrugBank
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    https://www.drugbank.ca/legal/terms_of_use
  5. EPA DSSTox
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    https://comptox.epa.gov/dashboard/chemical-lists/
  6. European Chemicals Agency (ECHA)
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  7. FDA Global Substance Registration System (GSRS)
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  8. Hazardous Substances Data Bank (HSDB)
  9. Human Metabolome Database (HMDB)
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  11. CCSbase
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  12. ChEBI
  13. FDA Pharm Classes
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    http://www.ebi.ac.uk/Information/termsofuse.html
  19. ClinicalTrials.gov
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  20. Crystallography Open Database (COD)
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  23. IUPHAR/BPS Guide to PHARMACOLOGY
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    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  24. Therapeutic Target Database (TTD)
  25. Drug Induced Liver Injury Rank (DILIrank) Dataset
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  26. NORMAN Suspect List Exchange
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    https://creativecommons.org/licenses/by/4.0/
    DILTIAZEM
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  27. Drugs and Lactation Database (LactMed)
  28. Drugs@FDA
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  29. EU Clinical Trials Register
  30. NIST Mass Spectrometry Data Center
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    https://www.nist.gov/srd/public-law
  31. Japan Chemical Substance Dictionary (Nikkaji)
  32. KEGG
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    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
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    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
  33. MassBank of North America (MoNA)
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    https://mona.fiehnlab.ucdavis.edu/documentation/license
  34. Metabolomics Workbench
  35. Nature Chemical Biology
  36. NIPH Clinical Trials Search of Japan
  37. NLM RxNorm Terminology
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  39. Pharos
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    https://pharos.nih.gov/about
  40. Protein Data Bank in Europe (PDBe)
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  42. SpectraBase
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  44. Thieme Chemistry
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  45. USGS Health-Based Screening Levels for Evaluating Water-Quality Data
  46. WHO Anatomical Therapeutic Chemical (ATC) Classification
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    https://www.nlm.nih.gov/copyright.html
  51. PubChem
  52. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  53. PATENTSCOPE (WIPO)
  54. NCBI
CONTENTS