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Diltiazem
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
Identifiers
CAS number 42399-41-7
ATC code C08DB01
PubChem 39186
DrugBank APRD00473
ChemSpider 35850
Chemical data
Formula C22H26N2O4S 
Mol. mass 414.519 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 40%
Metabolism Hepatic
Half life 3-4.5 hours
Excretion Renal
Biliary
Lactic (in lactiferous females)
Therapeutic considerations
Pregnancy cat. D: (USA)
Legal status
Routes Oral
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Diltiazem is a non-DHP member of the group of drugs known as benzothiazepines, which are a class of calcium channel blockers, used in the treatment of hypertension, angina pectoris, and some types of arrhythmia. It is also an effective preventive medication for migraine. It is a class 3 anti-anginal drug, and a class IV antiarrhythmic. It incites very minimal reflex sympathetic changes. It is based upon a 1,4-thiazepine ring.

Diltiazem is metabolized by and acts as an inhibitor of the CYP3A4 enzyme.

Contents

Brand names

  • Progor
  • Herben
  • Altiazem
  • Cardizem
  • Cartia XT
  • Tiazac
  • Tiazac XC
  • Tiamate
  • Tildiem in particular in Europe
  • Adizem
  • Viazem
  • Dilatam
  • Dilzem
  • Angiozem
  • Dilatem
  • Dilcardia
  • Diltelan
  • Diltime
  • Dyalec
  • Filazem
  • Tildiem
  • Vasmulax
  • Zandil
  • Zemtrial
  • Angizem CD
  • Angizem
  • Dilcontin SR in India (Sustained Release)
  • Dilt-CD
  • Dilt-XR

Mechanism

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.[1]

Potent vasodilator of coronary vessels.

Vasodilator of peripheral vessels. This reduces peripheral resistance and afterload.

Negative inotropic effect. Diltiazem causes a modest decrease in heart muscle contractility and reduces myocardium oxygen consumption.

Negative chronotropic effect. Diltiazem causes a modest lowering of heart rate. This effect is due to slowing of the SA (sinoatrial) node. It results in reduced myocardium oxygen consumption.

Negative dromotropic effect. By slowing conduction through the AV (atrioventricular) node, diltiazem increases the time needed for each beat. This results in reduced myocardium oxygen consumption by the body.

Nontherapeutic effects and toxicities

Reflex sympathetic response. Caused by the peripheral dilation of vessels and the resulting drop in BP; the response works to counteract the negative inotropic, chronotropic and dromotropic effects of diltiazem. Symptoms include hypotension, bradycardia, dizziness, flushing.[2]

Indications

Angina:

  • Stable angina (exercise-induced) . Diltiazem increases coronary blood flow and decreases myocardial oxygen consumption, secondary to decreased peripheral resistance, heart rate, and contractility.[3][4]
  • Variant angina. Diltiazem is effective due to its direct effects on coronary dilation.
  • Unstable angina (preinfarction, crescendo). Diltiazem may be particularly effective if the underlying mechanism is vasospasm.

Supraventricular tachycardias. Diltiazem appears to be as effective as verapamil in treating reentrant supraventricular tachycardia.[5]

Atrial fibrillation[6] or atrial flutter.

Hypertension. 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.[7]

Contraindications and precautions

CHF. 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.

SA node or AV conduction disturbances. 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.

Wolff-Parkinson-White syndrome. Diltiazem may paradoxically increase ventricular rate in patients with WPW 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, chronic obstructive pulmonary disease, and Prinzmetal's angina.

Drug interactions

Beta-blockers

Intravenous diltiazem should be used with caution with beta-blockers, because while the combination is most therauputically beneficial, there are rare instances of dysrhythmia and AV node block [8].

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.

Miscellaneous

Inhibition of hepatic enzymes. Diltiazem and verapamil inhibit hepatic cytochromes CYP3A4, CYP2C9 and CYP2D6, possibly resulting in drug interactions.

Potential future indications

Recent research has shown that diltiazem is able to reduce cocaine cravings in drug-addicted rats.[9] This is believed to be due to the effects of calcium blockers on dopaminergic and glutamatergic signalling in the brain.[10] Diltiazem also enhances the analgesic effect of morphine in animal tests, without increasing respiratory depression,[11] and reduces the development of tolerance.[12]

Diltiazem is also being used in the treatment of anal fissures. It can be taken orally or applied topically with equal effectiveness. When applied topically, it is made into a cream form using either vaseline or Phlogel. Phlogel absorbs the diltiazem into the problem area better than the vaseline base. It has good short term success rates. [13][14] Like all non-surgical 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 to 60%.

References

  1. ^ O'Connor SE, Grosset A, Janiak P. The pharmacological basis and pathophysiological significance of the heart rate-lowering property of diltiazem. Fundamental and Clinical Pharmacology. 1999;13(2):145-53. PMID 10226758
  2. ^ Ramoska EA, Spiller HA, Winter M, Borys D. A one-year evaluation of calcium channel blocker overdoses: toxicity and treatment. Annals of Emergency Medicine. 1993 Feb;22(2):196-200. PMID 8427431
  3. ^ Grossman E, Messerli FH. Calcium antagonists. Progress in Cardiovascular Disease. 2004 Jul-Aug;47(1):34-57. PMID 15517514
  4. ^ Claas SA, Glasser SP. Long-acting diltiazem HCl for the chronotherapeutic treatment of hypertension and chronic stable angina pectoris. Expert Opinion on Pharmacotherapy. 2005 May;6(5):765-76. PMID 15934903
  5. ^ Gabrielli A, Gallagher TJ, Caruso LJ, Bennett NT, Layon AJ. Diltiazem to treat sinus tachycardia in critically ill patients: a four-year experience. Critical Care Medicine. 2001 Oct;29(10):1874-9. PMID 11588443
  6. ^ Wattanasuwan N, Khan IA, Mehta NJ, et al. (February 2001). "Acute ventricular rate control in atrial fibrillation: IV combination of diltiazem and digoxin vs. IV diltiazem alone". Chest 119 (2): 502–6. PMID 11171729. http://www.chestjournal.org/cgi/pmidlookup?view=long&pmid=11171729. 
  7. ^ Basile J. The role of existing and newer calcium channel blockers in the treatment of hypertension. Journal of Clinical Hypertension. 2004 Nov;6(11):621-29. PMID 15538095
  8. ^ http://www.ncbi.nlm.nih.gov/pubmed/10774785
  9. ^ http://www.sciencedaily.com/releases/2008/02/080227155016.htm>
  10. ^ Mills K, Ansah TA, Ali SF, Mukherjee S, Shockley DC. Augmented behavioral response and enhanced synaptosomal calcium transport induced by repeated cocaine administration are decreased by calcium channel blockers. Life Sciences. 2007 Jul 26;81(7):600-8. PMID 17689567
  11. ^ Kishioka S, Ko MC, Woods JH. Diltiazem enhances the analgesic but not the respiratory depressant effects of morphine in rhesus monkeys. European Journal of Pharmacology. 2000 May 26;397(1):85-92. PMID 10844102
  12. ^ Verma V, Mediratta PK, Sharma KK. Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers. Indian Journal of Experimental Biology. 2001 Jul;39(7):636-42. PMID 12019755
  13. ^ Nash GF, Kapoor K, Saeb-Parsy K, Kunanadam T, Dawson PM. The long-term results of diltiazem treatment for anal fissure. International Journal of Clinical Practice. 2006 Nov;60(11):1411-3. PMID 16911570
  14. ^ Sajid MS, Rimple J, Cheek E, Baig MK. The efficacy of diltiazem and glyceryltrinitrate for the medical management of chronic anal fissure: a meta-analysis. International Journal of Colorectal Disease. 2008 Jan;23(1):1-6. PMID 17846781

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