Mechanism of Action of Diltiazem

Mechanism of Action of Diltiazem

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Introduction

Diltiazem is a non-dihydropyridine calcium channel blocker (CCB) belonging to the benzothiazepine class. It is widely used in the management of hypertension, angina pectoris, and supraventricular arrhythmias. Diltiazem occupies an intermediate position between verapamil and dihydropyridines, exerting significant effects on both the heart and vascular smooth muscle. Because of its dual cardiac and vascular actions, diltiazem is a high-yield drug in pharmacology, cardiology, and clinical entrance examinations.

MOA of diltiazem
Mechanism of action of diltiazem
Diltiazem Mechanism of Action Flowchart
Stepwise mechanism of action of diltiazem flowchart

Mechanism of Action (Step-wise)

Diltiazem exerts its pharmacological effects by inhibiting L-type calcium channels in cardiac and smooth muscle cells.

Step-wise mechanism:

  1. L-Type Calcium Channels
    L-type calcium channels are responsible for calcium influx during depolarization in cardiac myocytes, nodal tissue, and vascular smooth muscle.
  2. Blockade of L-Type Calcium Channels
    Diltiazem selectively inhibits L-type calcium channels on:
    • Cardiac myocytes
    • Sinoatrial (SA) node
    • Atrioventricular (AV) node
    • Vascular smooth muscle cells
  3. Reduced Calcium Influx
    Inhibition of calcium entry decreases intracellular calcium concentration.
  4. Cardiac Effects – Negative Chronotropy
    Reduced calcium influx in the SA node slows spontaneous depolarization, decreasing heart rate.
  5. Cardiac Effects – Negative Dromotropy
    In the AV node, decreased calcium conduction slows AV nodal conduction and increases refractory period.
  6. Cardiac Effects – Negative Inotropy
    Reduced calcium availability in myocardial cells decreases contractile force.
  7. Vascular Effects – Vasodilation
    In vascular smooth muscle, reduced intracellular calcium causes relaxation, leading to arterial vasodilation.
  8. Overall Hemodynamic Outcome
    • Decreased heart rate
    • Reduced myocardial oxygen demand
    • Lower blood pressure
    • Improved coronary blood flow

Pharmacokinetics

  • Absorption: Well absorbed orally
  • Bioavailability: ~40% due to first-pass metabolism
  • Distribution: Widely distributed; high protein binding
  • Metabolism: Hepatic metabolism via CYP3A4
  • Elimination: Biliary and renal excretion of metabolites
  • Half-life: Approximately 3–5 hours (extended with sustained-release forms)

Dose adjustment may be required in hepatic impairment.

Clinical Uses

Diltiazem is commonly used in cardiovascular disorders:

  • Hypertension
  • Chronic stable angina
  • Variant (Prinzmetal) angina
  • Supraventricular tachyarrhythmias (e.g., atrial fibrillation, atrial flutter – rate control)
  • Hypertrophic cardiomyopathy (selected cases)

It is particularly useful when both rate control and blood pressure reduction are desired.

Adverse Effects

Adverse effects are related to excessive calcium channel blockade:

  • Cardiac:
    • Bradycardia
    • Atrioventricular block
    • Worsening heart failure (rare)
  • Vascular:
    • Hypotension
    • Peripheral edema (less than dihydropyridines)
  • Gastrointestinal:
    • Constipation
    • Nausea

Diltiazem should be used cautiously with beta blockers due to additive cardiac depression.

Comparative Analysis (must include a table + explanation)

Comparison of Calcium Channel Blockers

FeatureDiltiazemVerapamilAmlodipine
Drug classNon-dihydropyridineNon-dihydropyridineDihydropyridine
Primary cardiac effectModerateStrongMinimal
Heart rate reductionYesStrongNo
VasodilationModerateMildStrong
Use in arrhythmiasYesYesNo

Explanation:
Diltiazem provides balanced cardiac and vascular effects, unlike verapamil (predominantly cardiac) and amlodipine (predominantly vascular). This makes diltiazem suitable for patients requiring both heart rate control and antihypertensive therapy.

MCQs (10–15)

  1. Diltiazem primarily blocks which channel?
    a) Sodium channel
    b) Potassium channel
    c) L-type calcium channel
    d) T-type calcium channel

Answer: c) L-type calcium channel

  1. Diltiazem belongs to which class of calcium channel blockers?
    a) Dihydropyridine
    b) Phenylalkylamine
    c) Benzothiazepine
    d) Piperazine

Answer: c) Benzothiazepine

  1. Diltiazem decreases heart rate by acting on the:
    a) Ventricular myocardium
    b) Purkinje fibers
    c) SA node
    d) Bundle branches

Answer: c) SA node

  1. Diltiazem slows AV conduction primarily by:
    a) Sodium channel blockade
    b) Potassium channel blockade
    c) Calcium channel blockade
    d) Beta-receptor blockade

Answer: c) Calcium channel blockade

  1. Diltiazem is useful in which arrhythmia?
    a) Ventricular tachycardia
    b) Atrial fibrillation
    c) Ventricular fibrillation
    d) Torsades de pointes

Answer: b) Atrial fibrillation

  1. Which effect is shared by diltiazem and verapamil?
    a) Reflex tachycardia
    b) AV nodal suppression
    c) Strong peripheral edema
    d) Renin activation

Answer: b) AV nodal suppression

  1. Diltiazem reduces myocardial oxygen demand by:
    a) Increasing preload
    b) Increasing contractility
    c) Decreasing heart rate and contractility
    d) Increasing afterload

Answer: c) Decreasing heart rate and contractility

  1. A contraindication to diltiazem is:
    a) Stable angina
    b) Hypertension
    c) Second-degree AV block
    d) Variant angina

Answer: c) Second-degree AV block

  1. Compared to amlodipine, diltiazem causes:
    a) More reflex tachycardia
    b) Greater heart rate reduction
    c) No effect on AV node
    d) Stronger vasodilation

Answer: b) Greater heart rate reduction

  1. Diltiazem is metabolized mainly by:
    a) CYP2D6
    b) CYP1A2
    c) CYP3A4
    d) CYP2C9

Answer: c) CYP3A4

FAQs (minimum 5)

  1. What is the primary mechanism of diltiazem?
    Blockade of L-type calcium channels in cardiac and vascular smooth muscle.
  2. Why does diltiazem slow heart rate?
    Because calcium channels mediate depolarization in the SA and AV nodes.
  3. Is diltiazem a dihydropyridine?
    No, it is a non-dihydropyridine calcium channel blocker.
  4. Can diltiazem be used for arrhythmias?
    Yes, especially for rate control in supraventricular tachyarrhythmias.
  5. Does diltiazem cause reflex tachycardia?
    No, it typically reduces heart rate.
  6. Why should diltiazem be used cautiously with beta blockers?
    Because combined use can cause excessive bradycardia or AV block.

References

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