Can diltiazem be given to patients with Chronic Kidney Disease (CKD)?

Can Diltiazem Be Given in CKD Patients?

Yes, diltiazem can be safely administered to patients with chronic kidney disease without dose adjustment, as it undergoes extensive hepatic metabolism rather than renal excretion. 1, 2

Pharmacokinetic Rationale

Diltiazem is extensively metabolized by the liver with only 2-4% of unchanged drug appearing in the urine, making it fundamentally different from renally-cleared medications. 1 A pharmacokinetic study in 9 patients with severely impaired renal function (GFR 0.03-0.87 mL/s/1.73 m²) demonstrated that diltiazem and its main metabolite desacetyldiltiazem had identical pharmacokinetic profiles (peak plasma concentration, half-life, and urinary excretion) compared to patients with normal renal function. 2

The FDA label explicitly states that a single study in nine patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal function. 1

Dosing Recommendations

• Standard dosing applies: Start with 30 mg four times daily before meals and at bedtime, titrating gradually at 1-2 day intervals to an optimum range of 180-360 mg/day. 1
• No routine dose adjustment required for renal impairment based on pharmacokinetic data. 1, 2
• The FDA label notes there are no available data concerning specific dosage requirements in patients with impaired renal function, but if the drug must be used in such patients, titration should be carried out with particular caution. 1

Renal Effects and Safety Profile

Diltiazem does not adversely affect kidney function and may actually improve renal hemodynamics in certain CKD patients. 3, 4

• In a 6-week study of hypertensive patients with creatinine clearances of 64-153 mL/min, diltiazem effectively reduced blood pressure while plasma urea, creatinine, uric acid, GFR, and ERPF remained stable throughout treatment. 3
• In patients with baseline GFR ≤80 mL/min/1.73 m², diltiazem therapy was associated with marked improvement in GFR (48% increase) and effective renal plasma flow (36% increase). 4
• Diltiazem decreased renal vascular resistance without overall negative effects on glomerular filtration rate or renal plasma blood flow. 4

Important Monitoring Parameters

Despite the lack of need for dose adjustment, regular monitoring is essential:

• Hepatic function: Since diltiazem is extensively metabolized by the liver, laboratory parameters of hepatic function should be monitored at regular intervals during prolonged use. 1
• Electrolytes: Plasma potassium may decrease (from 4.0 to 3.7 mEq/L in one study), requiring periodic monitoring. 3
• Plasma glucose: May increase modestly and requires periodic check-ups. 3

Critical Drug Interactions in CKD

Avoid routine combination with beta-blockers due to increased risk of bradycardia and heart block. 5 This is particularly important as both drug classes affect cardiac conduction, and the additive effects can be problematic. 1

Do not use in patients with heart failure with reduced ejection fraction (HFrEF). 5 The 2017 ACC/AHA guidelines explicitly state this contraindication for non-dihydropyridine calcium channel blockers including diltiazem. 5

Diltiazem is both a substrate and inhibitor of CYP3A4, requiring careful attention to drug interactions, especially in patients with renal and/or hepatic impairment who may require dosage adjustments of concomitant medications. 1

Comparison with Other Antihypertensives in CKD

Non-dihydropyridine calcium channel blockers like diltiazem differ mechanistically from dihydropyridine CCBs (amlodipine, nifedipine). 6 While dihydropyridines effectively reduce systemic hypertension but lack activity in reducing proteinuria, non-dihydropyridine CCBs including diltiazem could potentially attenuate sympathetic activity and reduce protein excretion in CKD patients. 6

However, ACE inhibitors remain superior to diltiazem for CKD progression. 7 A comparative study showed that enalapril treatment reduced plasma creatinine and albuminuria to sham levels, while diltiazem actually enhanced these parameters despite similar blood pressure control. 7

Common Pitfalls to Avoid

• Do not withhold diltiazem solely based on CKD diagnosis, as renal impairment does not alter its pharmacokinetics. 2
• Do not combine with beta-blockers without careful consideration, particularly in patients with left ventricular dysfunction or cardiac conduction abnormalities. 1
• Do not use as first-line therapy for CKD-related hypertension when proteinuria is present; ACE inhibitors or ARBs are preferred. 7
• Do not neglect hepatic function monitoring during prolonged therapy, as this is the primary route of elimination. 1