Contents

Diltiazem

Diltiazem

Clinical data
Pronunciation	/dɪlˈtaɪəzɛm/
Trade names	Cardizem, Dilacor XR, Cartia XT, others
AHFS/Drugs.com	Monograph
MedlinePlus	a684027
License data	US DailyMed: Diltiazem
Pregnancy category	AU:C[1]
Routes of administration	By mouth, intravenous
Drug class	Nondihydropyridine calcium channel blocker
ATC code	C05AE03 (WHO) C08DB01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only)[2][3] US: ℞-only[4][5][6] EU: Rx-only[7] In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	40%
Metabolism	Liver
Elimination half-life	3–4.5 hours
Excretion	Kidney Bile duct
Identifiers
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
CAS Number	42399-41-7 Y
PubChem CID	39186
IUPHAR/BPS	2298
DrugBank	DB00343 Y
ChemSpider	35850 Y
UNII	EE92BBP03H
KEGG	D07845 Y
ChEBI	CHEBI:101278 Y
ChEMBL	ChEMBL23 Y
PDB ligand	D6C (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID9022940
ECHA InfoCard	100.050.707
Chemical and physical data
Formula	C22H26N2O4S
Molar mass	414.52 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C2N(c3c(S[C@@H](c1ccc(OC)cc1)[C@H]2OC(=O)C)cccc3)CCN(C)C
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 Y Key:HSUGRBWQSSZJOP-RTWAWAEBSA-N Y
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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.^[8] It may also be used in hyperthyroidismifbeta blockers cannot be used.^[8] It is taken by mouthorinjection into a vein.^[8] When given by injection, effects typically begin within a few minutes and last a few hours.^[8]

Common side effects include swelling, dizziness, headaches, and low blood pressure.^[8] Other severe side effects include an overly slow heart beat, heart failure, liver problems, and allergic reactions.^[8] Use is not recommended during pregnancy.^[8] 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.^[8] Additionally, it acts on the heart to prolong the period until it can beat again.^[9] It does this by blocking the entry of calcium into the cells of the heart and blood vessels.^[10] It is a class IV antiarrhythmic.^[11]

Diltiazem was approved for medical use in the United States in 1982.^[8] It is available as a generic medication.^[8] In 2021, it was the 84th most commonly prescribed medication in the United States, with more than 8 million prescriptions.^[12][13] An extended release formulation is also available.^[8][14]

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.^[15][16]
• 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.^[17]

Atrial fibrillation^[18]oratrial 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]

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

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.

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 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]

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]

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.

Diltiazem is prescribed off-label by doctors in the US for prophylaxisofcluster 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 petroletum or Phlojel. Phlojel absorbs the diltiazem into the problem area better than the petroletum base. It has good short-term success rates.^[41][42]