Diltiazem

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Diltiazem
Diltiazem structure.svg
Diltiazem ball-and-stick.png
Systematic (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
Clinical data
Trade names Cardizem, Dilacorxr
AHFS/Drugs.com monograph
MedlinePlus a684027
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability 40%
Metabolism Hepatic
Biological half-life 3–4.5 hours
Excretion Renal
Biliary
Lactic (in lactating females)
Identifiers
CAS Number 42399-41-7 YesY
ATC code C05AE03 (WHO) C08DB01
PubChem CID: 39186
IUPHAR/BPS 2298
DrugBank DB00343 YesY
ChemSpider 35850 YesY
UNII EE92BBP03H YesY
KEGG D07845 YesY
ChEBI CHEBI:101278 YesY
ChEMBL CHEMBL23 YesY
Chemical data
Formula C22H26N2O4S
Molecular mass 414.519 g/mol
  • O=C2N(c3c(S[C@@H](c1ccc(OC)cc1)[C@H]2OC(=O)C)cccc3)CCN(C)C
  • InChI=1S/C22H26N2O4S/c1-15(25)28-20-21(16-9-11-17(27-4)12-10-16)29-19-8-6-5-7-18(19)24(22(20)26)14-13-23(2)3/h5-12,20-21H,13-14H2,1-4H3/t20-,21+/m1/s1 YesY
  • Key:HSUGRBWQSSZJOP-RTWAWAEBSA-N YesY
  (verify)

Diltiazem (INN) (/dɪlˈtaɪəzɛm/) is a nondihydropyridines (non-DHP) calcium channel blocker used in the treatment of hypertension, angina pectoris, and some types of arrhythmia. It relaxes the smooth muscles in the walls of arteries, which opens (dilates) the arteries, allows blood to flow more easily, and lowers blood pressure. Additionally, it lowers blood pressure by acting on the heart itself to reduce the rate, strength, and conduction speed of each beat.

It is also used off-label as an effective preventive medication for migraine. It is a class 3 antianginal drug, and a class IV antiarrhythmic. It is a common adulterant of cocaine seized in the UK,[1] and has been found to reduce cocaine cravings in rats, indicating it may prolong the "high" (see below).

Diltiazem is metabolized by and acts as an inhibitor of the CYP3A4 enzyme which can cause it to interact with a variety of other medications.

Mechanism

180mg Cardizem capsule

Diltiazem is a potent vasodilator, increasing blood flow and variably decreasing the heart rate via strong depression of A-V node conduction. Its pharmacological activity is somewhat similar to verapamil, another nondihydropyridine (non-DHP) calcium channel blocker. [2] Chemically, it is based upon a 1,4-thiazepine ring making it a benzothiazepine-type calcium channel blocker.

It is a vasodilator of coronary and peripheral vessels, which reduces peripheral resistance and afterload, though not as potent as the dihydropyridine (DHP) calcium channel blockers. This results in minimal reflex sympathetic changes.

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 symptoms. These effects also reduce blood pressure by causing less blood to be pumped out.

Nontherapeutic effects and toxicities

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.[3]

Indications

The drug is indicated for angina:

  • Stable angina (exercise-induced) – diltiazem increases coronary blood flow and decreases myocardial oxygen consumption, secondary to decreased peripheral resistance, heart rate, and contractility.[4][5]
  • 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.

For supraventricular tachycardias (PSVT), diltiazem appears to be as effective as verapamil in treating re-entrant supraventricular tachycardia.[6]

Atrial fibrillation[7] 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.[8]

Contraindications and precautions

  • In congestive heart failure, patients with reduced ventricular function may not be able to counteract the 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.

Drug interactions

Because of its inhibition of hepatic cytochromes CYP3A4, CYP2C9 and CYP2D6, there are a significant number of drug interactions, more than can be listed here.[9] Some of the more important interactions are listed below.

Beta-blockers

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.[10]

Quinidine

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.[11]

Potential future indications

Diltiazem is prescribed off-label by doctors in the US for prophylaxis of cluster migraine. Some research on diltiazem and other calcium channel antagonists in the treatment and prophylaxis of migraine is ongoing.[4][12][13][14][15][16][17]

Recent research has shown diltiazem is able to reduce cocaine cravings in drug-addicted rats.[18] This is believed to be due to the effects of calcium blockers on dopaminergic and glutamatergic signaling in the brain.[19] Diltiazem also enhances the analgesic effect of morphine in animal tests, without increasing respiratory depression,[20] and reduces the development of tolerance.[21]

Diltiazem is also being used in the treatment of anal fissures. It can be taken orally or applied topically with increased effectiveness.[22] When applied topically, it is made into a cream form using either vaseline or Phlojel. Phlojel absorbs the diltiazem into the problem area better than the vaseline base. It has good short term success rates.[23][24] Like all nonsurgical treatments of anal fissure, it does not address the long term problem of increased basal anal tone and does not decrease the subsequent recurrence rate that can vary between 40 and 60%.

References

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  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  18. ↑ Common Heart Drug May Reduce Cocaine Cravings. Sciencedaily.com (2008-02-28). Retrieved on 2012-10-21.
  19. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  24. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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