Diltiazem
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diltiazem
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Diltiazem
Class & Chemistry
Diltiazem is a benzothiazepine - the only benzothiazepine calcium channel blocker in clinical use. It is classified as a non-dihydropyridine (non-DHP) calcium channel blocker, sharing this class with verapamil (a phenylalkylamine), but with a distinct pharmacological profile intermediate between verapamil and the dihydropyridines (e.g., nifedipine, amlodipine).
Mechanism of Action
Diltiazem blocks voltage-gated L-type calcium channels in:
- Vascular smooth muscle - arterial vasodilation
- Myocardium - negative inotropy
- SA node - negative chronotropy (slows automaticity)
- AV node - negative dromotropy (slows conduction, prolongs refractory period, prolongs PR interval)
It is classified as Vaughan-Williams Class IV (Ca²+ channel blocker) for antiarrhythmic purposes.
The relative selectivity of diltiazem is intermediate: more cardiac-selective than dihydropyridines, but with less SA/AV nodal depression than verapamil and more vasodilation than verapamil.
Pharmacodynamics
| Effect | Diltiazem | Verapamil | Dihydropyridines |
|---|---|---|---|
| Vasodilation | Moderate | Less | Greatest |
| Negative inotropy | Moderate | Greatest | Minimal |
| SA/AV node depression | Moderate | Greatest | Minimal |
| Reflex tachycardia | Minimal | None | Prominent |
IV administration: produces arterial vasodilation and lowers arterial pressure. This initially stimulates baroreceptor-mediated tachycardia and increases cardiac output - but heart rate subsequently falls because diltiazem exerts potent negative chronotropic and dromotropic effects. Net result: heart rate decreases.
Oral administration: reduces heart rate, arterial pressure, and myocardial oxygen demand. Both routes cause coronary vasodilation.
(Barash Clinical Anesthesia, 9e)
Pharmacokinetics
| Parameter | Immediate-Release (IR) | Extended-Release (ER) |
|---|---|---|
| Oral bioavailability | ~40% (extensive first-pass) | ~93-98% absorption |
| Protein binding | ~70-80% | same |
| Metabolism | Hepatic - CYP3A4 (primary), CYP2D6; extensive first-pass | same |
| Active metabolites | Yes (desacetyldiltiazem) | same |
| Half-life | ~3-4.5 hours (IR); longer with ER | ~6-9 hours |
| Excretion | Primarily feces/bile; some urine | same |
- Undergoes extensive first-pass hepatic metabolism (similar to verapamil)
- Elimination is slower in elderly and those with hepatic impairment
- CYP3A4 substrate AND inhibitor - relevant for drug interactions
- IV form has a short duration of action, necessitating a continuous infusion or repeat boluses
(Tintinalli's Emergency Medicine; Goodman & Gilman's)
Clinical Indications
1. Supraventricular Tachyarrhythmias
- Atrial fibrillation / Atrial flutter - ventricular rate control (primary use of IV diltiazem in the ED)
- Paroxysmal SVT (PSVT) - verapamil is more commonly used for conversion, but diltiazem is effective; adenosine remains first-line per ACLS guidelines for symptomatic SVT
2. Hypertension
- Oral diltiazem is used for chronic hypertension management
- Particularly useful when beta-blockers are contraindicated (e.g., reactive airway disease/asthma)
3. Angina
- Stable angina (chronic) - reduces myocardial O₂ demand via HR reduction and vasodilation
- Vasospastic (Prinzmetal's) angina - coronary vasodilation
- Useful alternative to beta-blockers in patients with symptomatic CAD + contraindication to beta-blockade
- May prevent subsequent myocardial injury in post-MI patients who cannot receive a beta-blocker
(Barash Clinical Anesthesia, 9e; Tintinalli's; Washington Manual)
Dosing
Adult Doses
IV (for rate control in AF/atrial flutter):
- Initial bolus: 0.25 mg/kg IV over 2 minutes
- If inadequate response: repeat bolus 0.35 mg/kg over 2 minutes
- Continuous infusion: 5-10 mg/h, can titrate up in 5 mg/h increments to max 15 mg/h
- Transition to oral once rate is controlled
Oral - Hypertension/Angina:
- Immediate release: 30-120 mg PO TID-QID; usual range 180-360 mg/day
- Extended release (once daily): 120-360 mg PO once daily; max 540 mg/day
- Extended release (BID): various formulations dosed Q12h
Pediatric (Hypertension):
- Child: 1.5-2 mg/kg/24h PO divided TID-QID; max 3.5 mg/kg/24h (alternative max 6 mg/kg/24h up to 360 mg/24h)
- Adolescent: same as adult
(Tintinalli's Emergency Medicine; Harriet Lane Handbook, 23e)
Contraindications
- Sick sinus syndrome (without pacemaker)
- Second- or third-degree AV block (without pacemaker)
- Severe hypotension or cardiogenic shock
- Acute MI with pulmonary congestion
- WPW syndrome / pre-excitation with AF or atrial flutter - risk of life-threatening VF by accelerating accessory pathway conduction
- Wide-complex tachyarrhythmias of unknown or ventricular origin
- Concurrent IV beta-blocker administration (or within a few hours)
- Ventricular tachycardia
Adverse Effects
- Bradycardia / AV block - most clinically important with IV use; especially in patients also on beta-blockers or digoxin
- Hypotension - particularly with IV bolus; more common in patients with underlying LV dysfunction
- Negative inotropy - can worsen heart failure (use with caution in HFrEF)
- Dizziness, headache, peripheral edema (less than dihydropyridines)
- Nausea, vomiting
- Rare: acute hepatic injury, severe skin reactions (SJS/TEN)
Drug Interactions (Major)
Diltiazem is a CYP3A4 substrate AND inhibitor (also inhibits CYP2D6):
| Drug | Effect |
|---|---|
| Beta-blockers (IV) | Additive AV block, severe bradycardia - avoid concurrent IV |
| Digoxin | Diltiazem increases digoxin levels (decreased elimination) |
| Cyclosporine / tacrolimus / sirolimus | Decreased elimination - toxicity risk |
| Statins (atorvastatin, lovastatin, simvastatin) | Increased statin levels - myopathy risk |
| Carbamazepine | Increased carbamazepine levels |
| Fentanyl / benzodiazepines | Enhanced sedation/toxicity |
| Ivabradine | Increased bradycardia risk |
| Quinidine | Increased quinidine levels |
| Colchicine | Decreased colchicine elimination |
(Katzung's Pharmacology, 16e; Harriet Lane Handbook, 23e; Brenner & Rector's Kidney)
Key Comparisons
- vs. Verapamil: Verapamil has greater AV nodal depression and negative inotropy; diltiazem has more vasodilation. For SVT conversion, verapamil achieves ~90% conversion (similar to adenosine); for AF rate control, diltiazem is preferred.
- vs. Dihydropyridines: Diltiazem has significant cardiac effects (chronotropy, dromotropy); dihydropyridines are predominantly vasodilators with reflex tachycardia. Diltiazem does NOT cause significant reflex tachycardia.
- Amlodipine is a peripheral vasodilator; diltiazem is intermediate (both myocardial + peripheral); verapamil has the most negative inotropic effect. (Lippincott Illustrated Reviews Pharmacology)
Special Populations
- Hepatic impairment: Use with caution - decreased first-pass and slower clearance; increased drug levels
- Renal impairment: Use with caution; dose adjustment considerations apply
- Elderly: Slower elimination - start low and titrate
- Pregnancy: Use with caution (potential teratogenicity)
- Breastfeeding: Use with caution - diltiazem is excreted in breast milk
Formulations (Brand Names)
Cardizem, Cardizem CD, Cardizem LA, Cartia XT, Matzim LA, Taztia XT, Tiazac (and many generics).
Available as: IR tablets (30, 60, 90, 120 mg), ER tablets/capsules (120-420 mg), oral liquid (12 mg/mL), injection (5 mg/mL).
Sources: Barash Clinical Anesthesia 9e; Katzung Basic & Clinical Pharmacology 16e; Tintinalli's Emergency Medicine; Goodman & Gilman's Pharmacological Basis of Therapeutics; Harriet Lane Handbook 23e; Lippincott Illustrated Reviews Pharmacology; Washington Manual of Medical Therapeutics
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