Diltiazem (DB00343): A Comprehensive Pharmacological and Clinical Monograph

Section I: Executive Summary

Diltiazem is a non-dihydropyridine calcium channel blocker of the benzothiazepine class, distinguished by its balanced effects on both cardiac tissue and vascular smooth muscle. Its primary mechanism of action involves the inhibition of L-type calcium channels, which results in a constellation of therapeutic effects, including negative chronotropy (reduced heart rate), dromotropy (slowed atrioventricular conduction), and mild negative inotropy (reduced cardiac contractility), coupled with potent coronary and peripheral vasodilation.

Clinically, diltiazem is well-established for the management of hypertension, chronic stable angina, and variant (Prinzmetal's) angina. In its intravenous formulation, it is a cornerstone for the acute management of supraventricular arrhythmias, particularly for rate control in atrial fibrillation or flutter and for the conversion of paroxysmal supraventricular tachycardia. Its therapeutic scope has expanded to include numerous off-label applications, such as the topical treatment of anal fissures, and it is the subject of significant investigational research for disease modification in preclinical hypertrophic cardiomyopathy, treatment of coronary microvascular dysfunction, and even as a potential anticancer agent through a newly discovered mechanism involving urokinase receptor (uPAR) inhibition.

The safety profile of diltiazem is generally favorable; however, its clinical use is complicated by a significant potential for drug-drug interactions. As a substrate and moderate inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme system and an inhibitor of the P-glycoprotein (P-gp) efflux transporter, diltiazem can profoundly alter the pharmacokinetics of numerous co-administered medications. Of particular concern is its interaction with certain statins, immunosuppressants, and direct oral anticoagulants (DOACs), where the risk of toxicity is markedly increased. Additive pharmacodynamic effects with other cardioactive agents, such as beta-blockers and digoxin, necessitate cautious use and careful titration. Key contraindications include sick sinus syndrome or high-grade AV block (without a pacemaker), severe hypotension, and acute myocardial infarction with pulmonary congestion.

This monograph concludes that while diltiazem remains a valuable therapeutic agent with a unique pharmacological niche, its safe and effective use hinges on a deep understanding of its complex interaction profile. Clinicians must prioritize thorough medication screening, consider alternatives in high-risk scenarios (e.g., patients on specific DOACs), and educate patients on critical food and supplement interactions. The future of diltiazem is evolving from its traditional cardiovascular roles toward precision-based applications and novel therapeutic repurposing, underscoring its continued relevance in clinical medicine and research.

Section II: Drug Identification and Physicochemical Characteristics

2.1. Nomenclature, Classification, and Identifiers

Diltiazem is a small molecule drug classified as a non-dihydropyridine (non-DHP) calcium channel blocker (CCB).[1] Chemically, it is a derivative of the benzothiazepine class, a structural feature that distinguishes it from other CCBs like the phenylalkylamines (e.g., verapamil) and the dihydropyridines (e.g., nifedipine).[1] Its formal chemical name is (2S,3S)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one, which precisely describes its stereochemistry and functional groups.[1] An alternative nomenclature is 5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl acetate.[5]

For regulatory and research purposes, diltiazem is assigned the Anatomical Therapeutic Chemical (ATC) classification code C08DB01.[6] It is uniquely identified across various databases by a set of standard codes:

• DrugBank ID: DB00343 [1]
• CAS Number: 42399-41-7 (for the diltiazem base).[1] The commonly used hydrochloride salt is identified by CAS RN 33286-22-5.[6]
• Other Key Identifiers: PubChem CID: 39186; UNII: EE92BBP03H; ChEBI: 101278; and ChEMBL: ChEMBL23.[1]

2.2. Chemical Structure and Stereochemistry

Diltiazem's molecular formula is C22​H26​N2​O4​S, with a molecular weight of approximately 414.52 g/mol for the base and 450.98 g/mol for the hydrochloride salt.[7] The core of the molecule is a 1,5-benzothiazepine structure, which consists of a seven-membered thiazepine ring fused to a benzene ring.[1]

The stereochemistry of diltiazem is fundamental to its biological activity. The therapeutic agent is specifically the cis-(+)-isomer, corresponding to the (2S,3S) absolute configuration at the two chiral centers on the thiazepine ring.[1] This precise three-dimensional arrangement is critical for the drug's ability to bind with high affinity and specificity to its target, the L-type calcium channel. The specific spatial orientation of the methoxyphenyl and acetoxy groups relative to the benzothiazepine core allows for an optimal fit within the binding pocket on the channel's alpha-1 subunit.[1] Any deviation from this stereoisomeric form would likely result in a dramatic loss of pharmacological activity or a different biological profile, highlighting that the drug's unique balance of cardiac and vascular effects is a direct consequence of its specific molecular geometry. The definitive stereochemical identity is captured by its InChI and InChIKey identifiers.[1]

2.3. Physical and Chemical Properties

Diltiazem hydrochloride, the form used in most pharmaceutical preparations, is a white to off-white crystalline powder that possesses a bitter taste.[6] It is soluble in water, methanol, and chloroform, which facilitates its formulation into both oral and intravenous dosage forms.[5] The reported water solubility is 465 mg/L at 25°C.[5] Its partition coefficient (logP) is reported to be between 2.7 and 2.8, indicating moderate lipophilicity, which allows it to readily cross cell membranes to reach its site of action.[5] The pKa is approximately 7.7, meaning it is partially ionized at physiological pH.[7] Reports on the melting point vary, with values ranging from 104°C for the base to over 210°C (with decomposition) for the salt, a difference attributable to the specific chemical form and experimental conditions.[5]

Table 2.1: Summary of Physicochemical Properties of Diltiazem

Property	Value	Source(s)
Chemical Name	(2S,3S)-3-acetoxy-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one	1
CAS Number (Base)	42399-41-7	1
CAS Number (HCl Salt)	33286-22-5	6
Molecular Formula	C22​H26​N2​O4​S	1
Molecular Weight (Base)	414.52 g/mol	7
Molecular Weight (HCl Salt)	450.98 g/mol	6
Appearance	White to off-white crystalline powder, bitter taste	6
Solubility	Soluble in water, methanol, chloroform	5
Melting Point	104-106°C (base); up to 212°C with decomposition (salt)	5
LogP	2.7 - 2.8	5
pKa	7.70 (Uncertain)	7

Section III: Clinical Pharmacology

3.1. Mechanism of Action (MOA)

Diltiazem exerts its therapeutic effects by acting as a potent, voltage-dependent inhibitor of L-type (slow) calcium channels, which are critical for the contractile processes in cardiac and vascular smooth muscle.[1] These channels, upon membrane depolarization, allow the influx of extracellular calcium ions, which serves as the primary trigger for muscle contraction.[12]

The molecular target of diltiazem is the alpha-1C subunit of the L-type calcium channel.[1] It binds to a specific site on the extracellular side of the channel, believed to involve the S5-S6 linker region of transmembrane domain IV and/or the S6 segment of domain III.[12] This binding site is distinct from those of dihydropyridine and phenylalkylamine CCBs, which accounts for diltiazem's unique pharmacological profile. By binding to this site, diltiazem stabilizes the channel in a state that is less permeable to calcium, thereby inhibiting the influx of calcium ions into the cell during depolarization.[5]

The functional consequences of this calcium influx inhibition differ based on the tissue type:

• In Vascular Smooth Muscle: The reduction of intracellular calcium concentration leads to smooth muscle relaxation, resulting in vasodilation. This effect is more pronounced in arterial vessels than in venous vessels. The resulting decrease in total peripheral resistance (afterload) is the primary mechanism behind diltiazem's antihypertensive effect.[1]
• In Cardiac Muscle: Diltiazem has three principal effects on the heart, classifying it as having negative inotropic, chronotropic, and dromotropic properties.[1]
• Negative Inotropy: By limiting calcium entry into myocardial cells, it reduces the force of cardiac contraction. This effect is generally mild in clinical settings but can become significant in patients with pre-existing heart failure.[4]
• Negative Chronotropy: It directly slows the rate of spontaneous depolarization in the sinoatrial (SA) node, the heart's natural pacemaker, leading to a decrease in heart rate.[1]
• Negative Dromotropy: It markedly slows electrical conduction through the atrioventricular (AV) node. This increases the AV nodal refractory period and prolongs the PR interval on an electrocardiogram (ECG), an effect that is central to its use in controlling ventricular rate in supraventricular tachyarrhythmias.[1]

3.2. Pharmacodynamics (PD)

The pharmacodynamic effects of diltiazem are a direct result of its mechanism of action on cardiovascular tissues.

• Hemodynamic Effects: Diltiazem produces a dose-dependent decrease in systemic blood pressure and a reduction in peripheral resistance.[10] This antihypertensive effect is more pronounced in individuals with pre-existing hypertension compared to those with normal blood pressure.[4] A key clinical advantage is that this blood pressure reduction is not typically accompanied by reflex tachycardia or significant postural hypotension.[1] In addition to its effects on peripheral vasculature, diltiazem is a potent dilator of coronary arteries, including both large epicardial vessels and smaller subendocardial vessels. This action increases coronary blood flow and enhances myocardial oxygen supply, which is a crucial component of its antianginal efficacy.[1] While diltiazem demonstrates a negative inotropic effect in isolated tissue preparations, its clinical effect on cardiac output in patients with normal ventricular function is often neutral or even slightly positive, as the reduction in afterload can offset the mild decrease in contractility.[4]
• Electrophysiological Effects: Diltiazem's most significant electrophysiological action is the prolongation of the AV nodal conduction time (AH interval) and refractory period.[4] This effect forms the basis for its use in controlling rapid ventricular rates in atrial fibrillation and atrial flutter. In patients with sick sinus syndrome, diltiazem can significantly prolong the sinus cycle length, potentially leading to severe bradycardia or sinus arrest.[4]
• Concentration-Effect Relationship: There is a well-defined and predictable relationship between the plasma concentration of diltiazem and its effect on heart rate. Studies in patients with atrial fibrillation have demonstrated a strong sigmoidal Emax relationship, where increasing plasma concentrations lead to a progressively greater reduction in heart rate.[16] For example, mean plasma concentrations of 79 ng/mL, 172 ng/mL, and 294 ng/mL are predicted to produce 20%, 30%, and 40% reductions in heart rate, respectively.[16] However, the relationship between plasma concentration and blood pressure reduction is not as direct or predictable.[16] This apparent disconnect arises because blood pressure is a complex physiological parameter influenced not only by direct vasodilation but also by the body's powerful counter-regulatory mechanisms, such as the renin-angiotensin system and sympathetic nervous system activity. The final blood pressure is a net result of diltiazem's action and the individual patient's compensatory response. This means that for hypertension, clinical efficacy must be guided by blood pressure monitoring rather than by targeting specific plasma levels.

3.3. Pharmacokinetics (PK) / ADME

The absorption, distribution, metabolism, and excretion (ADME) profile of diltiazem is complex and has significant clinical implications.

• Absorption: Following oral administration, diltiazem is well absorbed from the gastrointestinal tract. However, it undergoes extensive first-pass metabolism in the liver, which significantly reduces its systemic availability. The absolute bioavailability is only about 40% compared to intravenous administration.[10] While food intake does not significantly impact the absorption of extended-release formulations, co-ingestion with alcohol can be hazardous. Alcohol has been shown to accelerate the release rate of diltiazem from some ER capsules, a phenomenon known as "dose-dumping," which can lead to a rapid and potentially toxic spike in plasma concentrations.[18]
• Distribution: Diltiazem is approximately 70-80% bound to plasma proteins, primarily albumin. This binding is not significantly affected by therapeutic concentrations of other common drugs like warfarin or digoxin.[10] It has a large volume of distribution, on the order of 300-400 liters, indicating extensive distribution into tissues.[16]
• Metabolism: Diltiazem is extensively metabolized by the liver, with only 2-4% of the parent drug being excreted unchanged in the urine.[10] The metabolism is primarily mediated by the cytochrome P450 enzyme system.
• CYP3A4: Diltiazem is both a substrate and a moderate inhibitor of CYP3A4.[5] This is the most critical aspect of its pharmacokinetic profile, as it is the root cause of numerous clinically significant drug-drug interactions.
• CYP2D6: Diltiazem also undergoes O-demethylation via the CYP2D6 enzyme.[22]
• Active Metabolites: Metabolism of diltiazem produces several metabolites, some of which are pharmacologically active. The main active metabolite, desacetyl diltiazem, circulates at plasma levels of 10-20% of the parent drug and retains 25-50% of its coronary vasodilator potency.[10]
• Excretion: The metabolites of diltiazem are eliminated from the body through both renal and biliary pathways.[4] The elimination half-life of the parent drug varies considerably depending on the formulation, ranging from approximately 3.0-4.5 hours for immediate-release and intravenous forms to 6-9 hours for once-daily extended-release products.[10]

A crucial and often underappreciated aspect of diltiazem's pharmacokinetics is the contribution of its long-acting metabolites. While the parent drug has a relatively short half-life, studies using radiolabeled diltiazem show that the half-life of total radioactivity is about 20 hours.[10] This indicates that metabolites are eliminated much more slowly than the parent compound. This finding, combined with pharmacogenomic data, reveals a source of significant inter-patient variability. For instance, individuals who are genetically "poor metabolizers" for the CYP2D6 enzyme pathway exhibit markedly higher (five-fold or more) systemic exposure to the active metabolites desacetyl diltiazem and N-demethyldesacetyl diltiazem.[22] Consequently, in these patients, the overall and prolonged clinical effect may be driven more by the accumulation of these long-acting active metabolites than by the parent drug itself. This can explain why some patients experience disproportionately strong effects or delayed toxicity, such as profound bradycardia, that may not correlate simply with the prescribed dose of the parent drug.

Section IV: Formulations, Dosing, and Administration

4.1. Overview of Available Formulations

Diltiazem is marketed in a variety of formulations to accommodate different clinical needs, from acute in-hospital management to chronic outpatient therapy.[1]

• Oral Immediate-Release (IR) Tablets: This formulation has a rapid onset but short duration of action, necessitating frequent dosing, typically three to four times per day, to maintain therapeutic concentrations.[23]
• Oral Extended-Release (ER) Capsules and Tablets: To improve patient convenience and adherence, several ER formulations have been developed for once-daily or twice-daily administration. These products utilize various technologies, such as coated beads or matrix systems, to control the rate of drug release over an extended period.[3] Advanced formulations, such as delay-onset sustained-release pellets, have also been designed to align with chronopharmacological principles, targeting circadian variations in conditions like hypertension.[3]
• Intravenous (IV) Injection: For rapid control of arrhythmias in an acute care setting, diltiazem is available as an injectable solution or as a lyophilized powder for reconstitution.[1]

4.2. Brand Names and Generic Availability

Diltiazem is sold under numerous brand names worldwide and is also widely available in less expensive generic versions for all formulations.[23] In the United States, common brand names include Cardizem® (for IR tablets and IV), Cardizem CD®, Cardizem LA®, Tiazac®, Cartia XT®, and Taztia XT® (for various ER formulations).[1] International brand names include Adizem®, Herbesser®, and Tildiem®.[7]

4.3. Recommended Dosing Regimens

Dosing of diltiazem must be individualized and titrated according to the patient's clinical response and the specific indication and formulation being used.

• Hypertension: For extended-release products, the typical starting dose is 180 to 240 mg once daily. The dose can be adjusted after approximately 14 days, as this is when the maximum antihypertensive effect is usually observed. The usual maintenance dosage range is 240 to 360 mg daily, with a maximum dose of up to 540 mg per day for some products.[4]
• Angina Pectoris: For immediate-release tablets, therapy is often initiated at 30 mg four times daily and gradually titrated to a maintenance dose of 180 to 360 mg per day in divided doses.[23] For extended-release formulations, a common starting dose is 120 to 180 mg once daily, which can be titrated up to a maximum of 360 to 540 mg daily depending on patient response and the specific product.[6]
• Supraventricular Arrhythmias (IV): For acute rate control or conversion of PSVT, treatment begins with an initial bolus dose of 0.25 mg/kg of actual body weight, administered intravenously over two minutes. If the initial response is insufficient, a second bolus of 0.35 mg/kg may be administered after 15 minutes. For sustained rate control in atrial fibrillation or flutter, a continuous intravenous infusion may be initiated at a rate of 5 to 10 mg/hour, and titrated up to 15 mg/hour as needed for heart rate control.[2]

Table 4.1: Diltiazem Dosing and Administration by Indication and Formulation

Indication	Formulation	Brand Name Examples	Starting Dose	Maintenance/Titration Range	Maximum Dose
Hypertension	ER Tablets/Capsules (Once-Daily)	Cardizem CD, Cardizem LA, Tiazac, Cartia XT	180-240 mg once daily	120-540 mg once daily	540 mg/day
Chronic Stable Angina	IR Tablets	Cardizem	30 mg four times daily	180-360 mg/day in 3-4 divided doses	360 mg/day
	ER Tablets/Capsules (Once-Daily)	Cardizem CD, Cardizem LA, Tiazac	120-180 mg once daily	Up to 540 mg once daily	540 mg/day
Variant Angina	IR/ER Formulations	(As for Chronic Stable Angina)	(As for Chronic Stable Angina)	(As for Chronic Stable Angina)	(As for Chronic Stable Angina)
Atrial Fibrillation/Flutter & PSVT (Acute)	IV Injection	Cardizem	Bolus: 0.25 mg/kg over 2 min; may repeat with 0.35 mg/kg after 15 min	Infusion: Start 5-10 mg/hr, titrate as needed	15 mg/hr

Section V: Therapeutic Applications

5.1. Approved Indications

Diltiazem has several well-established, FDA-approved indications for the treatment of cardiovascular diseases.

• Hypertension: Diltiazem is indicated for the management of high blood pressure, either as monotherapy or in combination with other antihypertensive agents.[2] It is particularly effective in patient populations with low-renin hypertension.[1] The long-term benefit of using diltiazem for this indication is a reduction in the risk of major cardiovascular events, including stroke and myocardial infarction, which are known consequences of untreated hypertension.[12]
• Chronic Stable Angina: Diltiazem is used to manage chronic stable angina (exercise-induced angina). It improves exercise tolerance and reduces the frequency of anginal attacks by balancing myocardial oxygen supply and demand. It decreases oxygen demand by lowering heart rate and blood pressure, and it increases oxygen supply through potent coronary artery vasodilation.[1]
• Variant (Prinzmetal's) Angina: Diltiazem is highly effective for managing variant angina, a condition caused by coronary artery spasm. Its efficacy stems from its direct ability to relax coronary smooth muscle, thereby preventing and relieving vasospasm.[1]
• Supraventricular Arrhythmias: The intravenous form of diltiazem is approved for two key arrhythmogenic indications:

1. Atrial Fibrillation or Atrial Flutter: It is used for the temporary control of a rapid ventricular response (RVR) in these common arrhythmias.[1] A 2023 meta-analysis confirmed that IV diltiazem is more effective than IV metoprolol for achieving target rate control in this setting.[27]
2. Paroxysmal Supraventricular Tachycardia (PSVT): It is indicated for the rapid conversion of PSVT to normal sinus rhythm. This includes re-entrant tachycardias involving the AV node or those associated with accessory pathways, such as in Wolff-Parkinson-White (WPW) syndrome.[2]

5.2. Off-Label and Investigational Uses

Beyond its approved indications, diltiazem is used off-label for a variety of conditions, leveraging its known pharmacological properties.

• Anal Fissures: A 2% topical diltiazem cream or ointment is commonly used to treat chronic anal fissures. By causing local vasodilation, it relaxes the internal anal sphincter, which reduces pain and improves blood flow to the area, thereby promoting healing.[1] This use is supported by several clinical trials.[29]
• Migraine and Cluster Headache Prophylaxis: Diltiazem is prescribed off-label for the prevention of migraine and cluster headaches, with ongoing research exploring its efficacy.[1] The mechanism is thought to involve the stabilization of cerebrovascular tone.
• Pulmonary Hypertension: It is used off-label in the management of pulmonary hypertension, where its vasodilatory effects on the pulmonary vasculature may be beneficial.[5]
• Other Documented Uses: Additional off-label applications include the treatment of rest-related leg cramps, management of idiopathic dilated cardiomyopathy, and reduction of proteinuria in patients with diabetic nephropathy.[12]

5.3. Emerging Research and Drug Repurposing

The therapeutic journey of diltiazem is evolving, moving from treating established diseases to intervening in earlier pathophysiological stages and exploring entirely new mechanisms of action.

• Preclinical Hypertrophic Cardiomyopathy (HCM): The VANISH trial (NCT00319982) represented a paradigm shift in thinking. This study investigated whether diltiazem could serve as a preemptive, disease-modifying therapy in individuals with a genetic mutation for HCM but who had not yet developed the clinical phenotype of left ventricular hypertrophy (G+/LVH-).[31] The scientific premise was to target the early pathogenic step of abnormal cellular calcium handling, a known consequence of sarcomere mutations, with the goal of preventing or attenuating the development of the disease itself, rather than merely treating its symptoms later in life.[31]
• Coronary Microvascular Dysfunction (CMD): The ongoing EDIT-CMD trial (NCT04777045) is a randomized, placebo-controlled study designed to determine if diltiazem can improve coronary microvascular function in symptomatic patients who have angina but no obstructive coronary artery disease.[27] This targets a more nuanced level of cardiovascular pathology than traditional angina management.
• COVID-19: In a novel application, the DICOV trial (NCT05563168) is exploring diltiazem as an adjunctive therapy for hospitalized patients with COVID-19 pneumonia. The hypothesis is that diltiazem may stimulate the innate immune response in respiratory epithelial cells, thereby facilitating faster viral eradication.[33]
• Anticancer and Antimetastatic Effects: Perhaps the most striking area of new research is in oncology. Preclinical studies have uncovered a completely novel mechanism for diltiazem, independent of its calcium channel blocking activity. It has been identified as an inhibitor of the urokinase receptor (uPAR), a protein that is overexpressed in many cancers and plays a pivotal role in tumor invasion, angiogenesis, and metastasis.[34] In vitro and in vivo models have shown that diltiazem can suppress tumor growth and metastasis in a uPAR-dependent manner.[34] This discovery positions diltiazem as a candidate for drug repurposing in cancer therapy, representing a significant expansion of its known biological activity.[35]

This evolution of diltiazem's use—from treating macro-level symptoms like hypertension, to targeting specific muscle function in anal fissures, to intervening in preclinical disease states like HCM, and finally to the discovery of a new molecular target in cancer—demonstrates a sophisticated progression from symptomatic treatment to mechanism-based, and potentially disease-modifying, therapy.

Section VI: Safety and Tolerability

6.1. Adverse Drug Reactions (ADRs)

Diltiazem is generally well-tolerated, with most adverse effects being predictable extensions of its pharmacological actions.

• Common ADRs: The most frequently reported side effects are related to its vasodilatory properties and include peripheral edema (particularly of the ankles), headache, dizziness, and flushing.[1]
• Cardiovascular ADRs: Due to its effects on cardiac conduction and contractility, diltiazem can cause bradycardia (slow heart rate), atrioventricular (AV) block of varying degrees (first, second, or third), and symptomatic hypotension. In patients with pre-existing impaired left ventricular function, it may precipitate or worsen congestive heart failure.[1] Palpitations may also occur.[38]
• Hepatic ADRs: Mild, transient elevations in liver enzymes (e.g., AST, ALT) can be observed. While rare, cases of significant acute hepatic injury have been reported. These reactions tend to occur within the first one to eight weeks of therapy and are typically reversible upon discontinuation of the drug.[1]
• Dermatologic ADRs: Skin rashes can occur. Although infrequent, serious and potentially life-threatening dermatologic reactions have been reported, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme. The persistence of any significant rash warrants immediate discontinuation of diltiazem.[14]
• Other ADRs: Other reported side effects include constipation, nausea, fatigue, weakness, and nasal congestion.[37]

6.2. Contraindications

The use of diltiazem is absolutely contraindicated in several clinical situations due to the high risk of serious adverse events.

• Cardiac Conduction Abnormalities: Diltiazem should not be used in patients with sick sinus syndrome or in those with second- or third-degree AV block, unless a functioning ventricular pacemaker is in place to prevent severe bradycardia or asystole.[1]
• Severe Hypotension: It is contraindicated in patients with severe hypotension, defined as a systolic blood pressure less than 90 mmHg.[14]
• Acute Myocardial Infarction with Pulmonary Congestion: Diltiazem should not be used in patients who have had an acute MI and also have evidence of pulmonary congestion on a chest X-ray, due to the risk of worsening heart failure from its negative inotropic effects.[21]
• Hypersensitivity: A known hypersensitivity or allergic reaction to diltiazem is a contraindication.[21]
• Concomitant IV Beta-Blockers: The concurrent administration of intravenous diltiazem and intravenous beta-blockers is contraindicated due to the profound additive effects on cardiac conduction and contractility.[21]

6.3. Warnings and Precautions

• Impaired Ventricular Function: Caution should be exercised when using diltiazem in patients with congestive heart failure or impaired left ventricular function, as its negative inotropic effects can exacerbate the condition.[1]
• Renal and Hepatic Impairment: As diltiazem is extensively metabolized by the liver and its metabolites are excreted by the kidneys, patients with hepatic or renal impairment may have increased exposure to the drug. It should be used with caution in these populations, and periodic monitoring of liver and kidney function is recommended.[4]
• Wolff-Parkinson-White (WPW) Syndrome: In patients with WPW syndrome who also have atrial fibrillation or flutter, diltiazem can paradoxically accelerate the ventricular rate. This occurs because it may enhance conduction over the accessory pathway while blocking the AV node, leading to a potentially life-threatening tachycardia.[1]
• Diabetes Mellitus: Diltiazem has been reported to influence insulin secretion and may lead to an increase in blood glucose levels. Therefore, careful monitoring is advised when it is used in patients with diabetes.[4]
• Pregnancy and Lactation: The use of diltiazem during pregnancy is generally not recommended due to a lack of sufficient safety data.[1] While studies suggest minimal risk to an infant during breastfeeding, its safety is not definitively established, and it should be used with caution.[1]

Section VII: Clinically Significant Interactions

Diltiazem's interaction profile is extensive and clinically significant, primarily driven by its effects on drug-metabolizing enzymes and transporters. A thorough understanding of these interactions is essential for its safe use.

7.1. Pharmacokinetic Interactions (CYP450 and P-glycoprotein)

• Diltiazem as a Moderate CYP3A4 Inhibitor: This is the most important mechanism underlying diltiazem's drug interactions. By inhibiting CYP3A4, diltiazem can significantly increase the plasma concentrations and potential toxicity of numerous co-administered drugs that are metabolized by this enzyme.
• Statins: Diltiazem markedly increases the levels of CYP3A4-metabolized statins like lovastatin and simvastatin, elevating the risk of myopathy and rhabdomyolysis. Dose limitations for these statins are recommended when used concurrently.[20]
• Benzodiazepines: It increases the exposure of orally administered midazolam and triazolam, leading to prolonged sedation and respiratory depression.[10]
• Immunosuppressants: Diltiazem can raise the concentrations of cyclosporine and tacrolimus to toxic levels. Close monitoring of drug levels and dose adjustments are mandatory.[37]
• Diltiazem as a CYP3A4 Substrate: Diltiazem's own metabolism can be affected by other drugs.
• CYP3A4 Inducers: Potent inducers like rifampin, St. John's Wort, carbamazepine, and phenytoin can accelerate the metabolism of diltiazem, leading to lower plasma levels and a potential loss of therapeutic efficacy.[20]
• CYP3A4 Inhibitors: Strong inhibitors such as ketoconazole or ritonavir can decrease diltiazem's metabolism, increasing its plasma concentrations and the risk of adverse effects like bradycardia and hypotension.[41]
• Diltiazem as a P-glycoprotein (P-gp) Inhibitor: Diltiazem also inhibits the P-gp efflux transporter, which is involved in the absorption and clearance of many drugs.
• Digoxin: Diltiazem can increase serum digoxin concentrations by approximately 20%, increasing the risk of digoxin toxicity. Monitoring of digoxin levels is recommended.[4]
• Direct Oral Anticoagulants (DOACs): This interaction represents a major safety concern. DOACs such as rivaroxaban and apixaban are substrates for both CYP3A4 and P-gp. Diltiazem inhibits both of these clearance pathways, creating a "perfect storm" that can significantly increase DOAC exposure and bleeding risk. A real-world study found that concomitant use was associated with a 56% higher risk of bleeding-related hospitalization.[42] The risk is particularly pronounced in patients with renal impairment, as they are more reliant on these hepatic and intestinal clearance pathways. The FDA label for rivaroxaban recommends avoiding this combination.[42]

7.2. Pharmacodynamic Interactions

These interactions occur when diltiazem's physiological effects are added to or potentiated by other drugs.

• Additive Negative Chronotropic/Dromotropic Effects: The risk of severe bradycardia, AV block, and even asystole is increased when diltiazem is combined with other agents that slow heart rate or AV nodal conduction.
• Beta-Blockers: This is a classic and potentially dangerous combination. While sometimes used together under expert supervision, it requires extreme caution and careful titration due to the high risk of additive cardiodepressant effects.[4]
• Digoxin: Additive effects on slowing AV conduction can lead to advanced heart block.[4]
• Amiodarone: Co-administration should be done with caution, especially in patients with underlying sinus node or AV node dysfunction.[4]
• Additive Hypotensive Effects: The concurrent use of diltiazem with other antihypertensive drugs, general anesthetics, or alcohol can lead to excessive and symptomatic hypotension.[14]

7.3. Food and Herbal Supplement Interactions

• Grapefruit Juice: As a known inhibitor of intestinal CYP3A4, grapefruit juice can increase the bioavailability and plasma concentrations of diltiazem, potentiating its effects and side effects. Patients should be advised to avoid or significantly limit their intake of grapefruit and grapefruit juice.[20]
• Alcohol: Alcohol can have an additive blood pressure-lowering effect with diltiazem. More critically, for certain extended-release formulations (e.g., Cardizem CD), alcohol can disrupt the release mechanism, causing "dose-dumping." This leads to a rapid, unintended release of the drug, which can cause a sharp increase in plasma levels and a heightened risk of toxicity.[19]
• St. John's Wort: This herbal supplement is a potent inducer of CYP3A4 and can significantly decrease diltiazem plasma concentrations, potentially rendering the therapy ineffective. Its use should be avoided.[20]
• Red Yeast Rice: Some red yeast rice products contain monacolin K, which is chemically identical to lovastatin. Co-administration is effectively the same as combining diltiazem with a statin and carries the same risk of myopathy; therefore, it should be avoided.[20]

Table 7.1: Clinically Significant Diltiazem Drug Interactions

Interacting Drug/Class	Mechanism of Interaction (PK/PD)	Clinical Consequence	Management Recommendation & Severity
Beta-Blockers (e.g., Metoprolol, Atenolol)	PD: Additive negative chronotropic, dromotropic, and inotropic effects.	Severe bradycardia, AV block, heart failure.	Major: Use with extreme caution and close monitoring. Avoid concurrent IV use.
Digoxin	PK: P-gp inhibition increases digoxin levels. PD: Additive AV nodal slowing.	Digoxin toxicity, advanced heart block.	Moderate: Monitor digoxin levels and for signs of toxicity.
DOACs (Rivaroxaban, Apixaban)	PK: Inhibition of both CYP3A4 and P-gp.	Markedly increased DOAC levels, significantly increased risk of major bleeding.	Major: Avoid combination if possible, especially with renal impairment. If unavoidable, monitor closely for bleeding.
Statins (Simvastatin, Lovastatin)	PK: CYP3A4 inhibition increases statin levels.	Increased risk of myopathy and rhabdomyolysis.	Major: Limit simvastatin dose to 10 mg/day, lovastatin to 20 mg/day, or use a non-CYP3A4 metabolized statin (e.g., pravastatin, rosuvastatin).
Immunosuppressants (Cyclosporine, Tacrolimus)	PK: CYP3A4 inhibition increases immunosuppressant levels.	Increased risk of nephrotoxicity and other dose-related toxicities.	Major: Requires therapeutic drug monitoring and significant dose reduction of the immunosuppressant.
CYP3A4 Inducers (Rifampin, St. John's Wort, Phenytoin)	PK: Induction of diltiazem's metabolism.	Decreased diltiazem levels, loss of therapeutic effect (e.g., uncontrolled hypertension/angina).	Major: Avoid combination. If unavoidable, may need to increase diltiazem dose with monitoring.
Alcohol	PD: Additive hypotension. PK: Dose-dumping from some ER formulations.	Dizziness, syncope. Sudden increase in diltiazem levels, risk of toxicity.	Moderate: Counsel patients to limit alcohol. Advise to avoid simultaneous consumption with ER capsules.
Grapefruit Juice	PK: Inhibition of intestinal CYP3A4.	Increased diltiazem bioavailability and plasma levels, increased risk of side effects.	Moderate: Advise patients to avoid or limit consumption.

Section VIII: Clinical Evidence and Future Perspectives

8.1. Synthesis of Meta-Analyses and Systematic Reviews

The extensive clinical use of diltiazem is supported by a large body of evidence, though recent systematic reviews have also highlighted important gaps in knowledge.

• Diltiazem versus Metoprolol for Atrial Fibrillation with RVR: A comprehensive meta-analysis published in 2023, which included 19 studies and over 1,700 patients, provided key comparative efficacy and safety data. The analysis found that intravenous diltiazem was significantly more effective than intravenous metoprolol in achieving the target heart rate for patients with atrial fibrillation and a rapid ventricular response (Odds Ratio: 1.65).[27] While the risk of hypotension was similar between the two drugs, diltiazem was associated with a higher incidence of bradycardia. The authors concluded that diltiazem may be a superior choice for initial rate control, but they also emphasized the need for higher-quality, long-term studies to confirm these findings and better delineate long-term safety profiles.[27]
• Dual Calcium Channel Blocker Therapy: The concept of combining a dihydropyridine (DHP) with a non-dihydropyridine (NDHP) CCB like diltiazem for hypertension has been explored. A 2012 meta-analysis of six small trials (totaling only 153 patients) suggested that this dual therapy provided a greater reduction in blood pressure compared to monotherapy with either agent alone.[46] However, the evidence base is very limited, and this approach is not standard clinical practice.
• Gaps in Long-Term Safety Data: Several systematic reviews, including those conducted for national guideline development, have consistently pointed out a lack of robust, long-term safety and efficacy data for diltiazem, especially in specific, high-risk patient populations. For example, evidence regarding its use in patients with heart failure is limited and of very low quality according to GRADE criteria.[47] Similarly, there is a paucity of well-designed trials in pediatric populations, making drug selection for hypertension in children challenging.[49] For critical outcomes such as all-cause mortality and stroke, the available evidence is often imprecise and subject to a high risk of bias.[48]

8.2. Ongoing Clinical Trials and Future Directions

The research landscape for diltiazem continues to evolve, with ongoing trials exploring its use in novel and refined indications.

• The EDIT-CMD trial (NCT04777045) is a randomized, placebo-controlled study investigating whether diltiazem can improve outcomes in patients with coronary microvascular dysfunction, a condition characterized by angina in the absence of obstructive coronary artery disease.[32]
• The DICOV trial (NCT05563168) is assessing diltiazem as a potential adjunctive therapy in hospitalized COVID-19 patients, based on a novel hypothesis related to modulating the innate immune response.[33]

The future trajectory of diltiazem appears to be twofold:

1. Precision Medicine in Cardiovascular Disease: Moving beyond broad indications, future use will likely focus on more targeted applications. This includes leveraging pharmacogenomic data (e.g., CYP2D6 status) to predict patient response and risk of toxicity from metabolites, and applying diltiazem to specific pathophysiological states like preclinical hypertrophic cardiomyopathy or coronary microvascular dysfunction, where its unique mechanisms may offer distinct advantages.
2. Drug Repurposing for Non-Cardiovascular Indications: The preclinical discovery of diltiazem's activity as a urokinase receptor (uPAR) inhibitor opens up an entirely new field of investigation in oncology.[34] If these findings translate to clinical efficacy, diltiazem could be repurposed as an antimetastatic agent, representing a major expansion of its therapeutic utility based on a mechanism completely unrelated to calcium channel blockade.

Section IX: Concluding Analysis and Recommendations

Diltiazem is a mature and effective cardiovascular agent that occupies a distinct therapeutic space due to its unique, balanced pharmacological profile affecting both the heart and vasculature. Its long history of use has established its efficacy in hypertension, angina, and arrhythmia management. However, this monograph reveals that a simple understanding of its primary mechanism is insufficient for its safe and optimal use. The complexity of its hepatic metabolism and its potent inhibitory effects on both CYP3A4 and P-glycoprotein create a clinically significant and intricate interaction profile that demands a high level of clinician vigilance.

Based on the comprehensive analysis of the available evidence, the following recommendations are provided for clinicians:

1. Prioritize Comprehensive Interaction Screening: Before initiating diltiazem, a meticulous review of the patient's complete medication list, including over-the-counter drugs and herbal supplements, is mandatory. Special attention must be paid to substrates of CYP3A4 (e.g., simvastatin, lovastatin, certain benzodiazepines), substrates of P-gp (e.g., digoxin), and particularly drugs that are substrates of both pathways, such as the direct oral anticoagulants rivaroxaban and apixaban.
2. Use Alternative Agents in High-Risk Scenarios: Given the documented 56% increased risk of bleeding-related hospitalization, the combination of diltiazem with rivaroxaban or apixaban should be avoided whenever possible, especially in patients with any degree of renal impairment. In such cases, alternative agents for rate control that do not share these interaction pathways (e.g., beta-blockers, digoxin, used cautiously) should be strongly considered.
3. Titrate to Clinical Effect, Not Standard Dose: Due to non-linear pharmacokinetics at higher doses and significant inter-patient variability driven by pharmacogenomics (e.g., CYP2D6 status affecting metabolite accumulation), dosing should be carefully titrated based on the individual patient's clinical response—specifically, their measured blood pressure and heart rate—rather than relying solely on standard dosing algorithms.
4. Emphasize Patient Education: Patient counseling is critical for safety. Patients must be explicitly warned about the significant interactions with alcohol, which can cause dose-dumping from extended-release capsules, and grapefruit juice, which increases drug levels. They must also be instructed not to start any new medications or herbal supplements, particularly St. John's Wort, without consulting their healthcare provider.
5. Monitor for Subtle and Delayed Toxicity: Clinicians should be aware that adverse effects, such as profound bradycardia or hepatotoxicity, may not appear immediately and can be driven by the slow accumulation of long-acting active metabolites. Periodic monitoring of hepatic function is prudent. Unexpected or disproportionately severe side effects should prompt consideration of underlying pharmacokinetic variability and may require dose reduction or discontinuation.

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