Diltiazem, sold under the trade name Cardizem among others, is a calcium channel blocker used to treat high blood pressure, angina, and certain heart arrhythmias.[1] It may also be used in hyperthyroidism if beta blockers cannot be used.[1] It is taken by mouth or injection into a vein.[1] When given by injections effects typically begin within a few minutes and last a few hours.[1] Common side effects include swelling, dizziness, headaches, and low blood pressure.[1] Other severe side effects include an overly slow heart beat, heart failure, liver problems, and allergic reactions.[1] Use is not recommended during pregnancy.[1] It is unclear if use when breastfeeding is safe.[2] Diltiazem works by relaxing the smooth muscle in the walls of arteries, resulting in them opening and allowing blood to flow more easily.[1] Additionally, it acts on the heart to prolong the period until it can beat again.[3] It does this by blocking the entry of calcium into the cells of the heart and blood vessels.[4] It is a class IV antiarrhythmic.[5] Diltiazem was approved for medical use in the United States in 1982.[1] It is available as a generic medication.[1] In the United States the wholesale cost per day of the by mouth formulation is less than 0.70 USD as of 2018.[6] In 2016 it was the 63rd most prescribed medication in the United States with more than 12 million prescriptions.[7] An extended release formulation is also available.[1] Diltiazem is indicated for: For supraventricular tachycardias (PSVT), diltiazem appears to be as effective as verapamil in treating re-entrant supraventricular tachycardia.[10] Atrial fibrillation[11] 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.[12] 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, and flushing.[13] Because of its inhibition of hepatic cytochromes CYP3A4, CYP2C9 and CYP2D6, there are a number of drug interactions.[14] 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.[15] 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.[16] Concurrent use of fentanyl with diltiazem, or any other CYP3A4 inhibitors, as these medications decrease the breakdown of fentanyl and thus increases its effects.[17] 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.[18] 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,[19] which reduces peripheral resistance and afterload, though not as potent as the dihydropyridine (DHP) calcium channel blockers. This results in minimal reflexive 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, 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 prophylaxis of cluster headaches. Some research on diltiazem and other calcium channel antagonists in the treatment and prophylaxis of migraine is ongoing.[8][20][21][22][23][24][25][needs update] Recent research[when?] has shown diltiazem may reduce cocaine cravings in drug-addicted rats.[26] This is believed to be due to the effects of calcium blockers on dopaminergic and glutamatergic signaling in the brain.[27] Diltiazem also enhances the analgesic effect of morphine in animal tests, without increasing respiratory depression,[28] and reduces the development of tolerance.[29] Diltiazem is also being used in the treatment of anal fissures. It can be taken orally or applied topically with increased effectiveness.[30] 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.[31][32] 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%.[citation needed]