Diltiazem
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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 Hypertension, also known as high blood pressure, is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms itself. It is, however, a major ri ...
, angina, and certain
heart arrhythmia Arrhythmias, also known as cardiac arrhythmias, are irregularities in the cardiac cycle, heartbeat, including when it is too fast or too slow. Essentially, this is anything but normal sinus rhythm. A resting heart rate that is too fast – ab ...
s. It may also be used in
hyperthyroidism Hyperthyroidism is a endocrine disease in which the thyroid gland produces excessive amounts of thyroid hormones. Thyrotoxicosis is a condition that occurs due to elevated levels of thyroid hormones of any cause and therefore includes hyperth ...
if
beta blocker Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms ( arrhythmia), and to protect the heart from a second heart attack after a first heart attack ( secondary prevention ...
s cannot be used. It is taken
by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...
or given by injection into a vein. When given by injection, effects typically begin within a few minutes and last a few hours. Common side effects include swelling, dizziness, headaches, and low blood pressure. Other severe side effects include an overly slow heart beat,
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...
, liver problems, and allergic reactions. Use is not recommended during
pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
. It is unclear if use when
breastfeeding Breastfeeding, also known as nursing, is the process where breast milk is fed to a child. Infants may suck the milk directly from the breast, or milk may be extracted with a Breast pump, pump and then fed to the infant. The World Health Orga ...
is safe. Diltiazem works by relaxing the
smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...
in the walls of arteries, resulting in them opening and allowing blood to flow more easily. Additionally, it acts on the
heart The heart is a muscular Organ (biology), organ found in humans and other animals. This organ pumps blood through the blood vessels. The heart and blood vessels together make the circulatory system. The pumped blood carries oxygen and nutrie ...
to prolong the period until it can beat again. It does this by blocking the entry of calcium into the cells of the heart and blood vessels. It is a class IV antiarrhythmic. Diltiazem was approved for medical use in the United States in 1982. It is available as a
generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
. In 2022, it was the 100th most commonly prescribed medication in the United States, with more than 6million prescriptions. An extended release formulation is also available.


Medical uses

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. * Variant angina – it is effective owing to its direct effects on coronary dilation. *
Unstable angina In dynamical systems instability means that some of the outputs or internal states increase with time, without bounds. Not all systems that are not stable are unstable; systems can also be marginally stable or exhibit limit cycle behavior ...
( 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.
Atrial fibrillation Atrial fibrillation (AF, AFib or A-fib) is an Heart arrhythmia, abnormal heart rhythm (arrhythmia) characterized by fibrillation, rapid and irregular beating of the Atrium (heart), atrial chambers of the heart. It often begins as short periods ...
or atrial flutter is another indication. The initial bolus should be 0.25 mg/kg,
intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
(IV). Because of its vasodilatory effects, diltiazem is useful for treating
hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
. Calcium channel blockers are well tolerated, and especially effective in treating low- renin hypertension. It is also used as topical application for anal fissures because it promotes healing due to its vasodilatory property.


Contraindications and precautions

* In
congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF typically pr ...
, 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 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 The atrioventricular node (AV node, or Aschoff-Tawara node) electrically connects the heart's atria and ventricles to coordinate beating in the top of the heart; it is part of the electrical conduction system of the heart. The AV node lies at the ...
conduction disturbances,
bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...
, impaired left ventricle function, peripheral artery occlusive disease, and
chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a type of progressive lung disease characterized by chronic respiratory symptoms and airflow limitation. GOLD defines COPD as a heterogeneous lung condition characterized by chronic respiratory s ...
.


Side effects

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 Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...
,
bradycardia Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...
,
dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...
, flushing, fatigue, headaches and edema. Rare side effects are congestive heart failure, myocardial infarction, and hepatotoxicity.


Drug interactions

Because of its inhibition of hepatic cytochromes
CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
, CYP2C9 and CYP2D6, there are a number of drug interactions. 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.


Quinidine

Quinidine Quinidine is a class I antiarrhythmic agent, class IA antiarrhythmic agent used to treat heart rhythm disturbances. It is a diastereomer of Antimalarial medication, antimalarial agent quinine, originally derived from the bark of the cinchona tre ...
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.


Fentanyl

Concurrent use of fentanyl with diltiazem, or any other CYP3A4 inhibitors, as these medications decrease the breakdown of fentanyl and thus increase its effects.


Mechanism of action

Diltiazem, also known as (2S,3S)-3-acetoxy-5- -(dimethylamino)ethyl2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochlorid has a vasodilating activity attributed to the (2S,3S)-isomer. Diltiazem is a potent vasodilator, increasing blood flow and variably decreasing the
heart rate Heart rate is the frequency of the cardiac cycle, heartbeat measured by the number of contractions of the heart per minute (''beats per minute'', or bpm). The heart rate varies according to the body's Human body, physical needs, including the nee ...
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. 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, 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 Chronotropic effects (from ''chrono-'', meaning time, and ''tropos'', "a turn") are those that change the heart rate. Chronotropic drugs may change the heart rate and cardiac cycle, rhythm by affecting the electrical conduction system of the hea ...
, 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 The sinoatrial node (also known as the sinuatrial node, SA node, sinus node or Keith–Flack node) is an ellipse, oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of Cell (biology), cells known as pa ...
, and a slowing of conduction through the
atrioventricular node The atrioventricular node (AV node, or Aschoff-Tawara node) electrically connects the heart's atria and ventricles to coordinate beating in the top of the heart; it is part of the electrical conduction system of the heart. The AV node lies at the ...
– increasing the time needed for each beat. Each of these effects results in reduced oxygen consumption by the heart, reducing angina, typically
unstable angina In dynamical systems instability means that some of the outputs or internal states increase with time, without bounds. Not all systems that are not stable are unstable; systems can also be marginally stable or exhibit limit cycle behavior ...
, symptoms. These effects also reduce blood pressure by causing less blood to be pumped out.


Research

Diltiazem is prescribed off-label by doctors in the US for
prophylaxis Preventive healthcare, or prophylaxis, is the application of healthcare measures to prevent diseases.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental health a ...
of cluster headaches. Some research on diltiazem and other calcium channel antagonists in the treatment and prophylaxis of migraine is ongoing. Recent research has shown diltiazem may reduce cocaine cravings in drug-addicted rats. This is believed to be due to the effects of calcium blockers on
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
rgic and
glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...
rgic signaling in the brain. Diltiazem also enhances the
analgesic An analgesic drug, also called simply an analgesic, antalgic, pain reliever, or painkiller, is any member of the group of drugs used for pain management. Analgesics are conceptually distinct from anesthetics, which temporarily reduce, and in s ...
effect of
morphine Morphine, formerly also called morphia, is an opiate that is found naturally in opium, a dark brown resin produced by drying the latex of opium poppies (''Papaver somniferum''). It is mainly used as an analgesic (pain medication). There are ...
in animal tests, without increasing respiratory depression, and reduces the development of tolerance. Diltiazem is also being used in the treatment of anal fissures. It can be taken orally or applied topically with increased effectiveness. When applied topically, it is made into a cream form using either petrolatum or Phlojel. Phlojel absorbs the diltiazem into the problem area better than the petrolatum base. It has good short-term success rates.


References

{{Authority control Calcium channel blockers CYP2D6 inhibitors CYP3A4 inhibitors Benzothiazepines 4-Methoxyphenyl compounds Drugs developed by AbbVie Drugs developed by Merck Lactams Acetate esters Chemical substances for emergency medicine Wikipedia medicine articles ready to translate Dimethylamino compounds