TRANDOLAPRIL AND VERAPAMIL HYDROCHLORIDE
Clinical safety rating: safe
CYP3A4 inhibitors can increase levels and inducers can decrease levels Can cause bradycardia and heart failure.
Trandolapril is an angiotensin-converting enzyme (ACE) inhibitor that prevents conversion of angiotensin I to angiotensin II, reducing vasoconstriction and aldosterone secretion. Verapamil is a calcium channel blocker (phenylalkylamine class) that inhibits calcium ion influx across cardiac and smooth muscle cells, decreasing myocardial contractility, heart rate, and vascular resistance.
| Metabolism | Trandolapril is hydrolyzed in the liver to its active metabolite trandolaprilat, which is further metabolized minimally. Verapamil is extensively metabolized in the liver via CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. |
| Excretion | Trandolapril: Renal 33% (as trandolaprilat), fecal 66% (as parent and metabolites). Verapamil: Renal 70% (as metabolites, <5% unchanged), fecal 16%. |
| Half-life | Trandolaprilat (active metabolite): 24-30 hours (terminal) in healthy adults; prolonged in renal impairment (creatinine clearance <30 mL/min: 2-3 fold). Verapamil: 6-12 hours (terminal) after multiple doses; prolonged in hepatic cirrhosis (up to 14-16 hours). |
| Protein binding | Trandolaprilat: 80% (primarily albumin). Verapamil: 90% (albumin, alpha-1-acid glycoprotein). |
| Volume of Distribution | Trandolaprilat: 8-12 L/kg (extensive tissue distribution, saturable ACE binding). Verapamil: 4-6 L/kg (highly distributed, indicates lipid solubility). |
| Bioavailability | Trandolapril: Approx 10% (oral) as active trandolaprilat (prodrug conversion and first-pass). Verapamil: 20-35% (oral, immediate-release) due to extensive first-pass metabolism; sustained-release formulations exhibit reduced bioavailability (approx 10-20%). |
| Onset of Action | Oral: Trandolapril: Antihypertensive effect within 1-2 hours; peak at 4-8 hours. Verapamil: 1-2 hours. |
| Duration of Action | Trandolapril: 24 hours (once-daily dosing). Verapamil: Extended-release formulation (ER) provides 24-hour coverage; immediate-release (IR) duration is 8-12 hours. |
Oral: 1 tablet (trandolapril 2 mg/verapamil HCl 180 mg) once daily; may increase to 2 tablets once daily. Maximum: trandolapril 8 mg/verapamil 480 mg per day.
| Dosage form | TABLET, EXTENDED RELEASE |
| Renal impairment | CrCl 30-60 mL/min: No adjustment. CrCl <30 mL/min: Use with caution; contraindicated if CrCl <10 mL/min. Trandolapril dose adjustment may be needed per trandolapril guidelines. |
| Liver impairment | Child-Pugh A or B: Reduce dose or extend interval; verapamil elimination half-life prolonged. Child-Pugh C: Contraindicated. |
| Pediatric use | Safety and efficacy not established in pediatric patients. |
| Geriatric use | Start at lower end of dosing range; consider reduced renal function and increased sensitivity to antihypertensive effects. Monitor electrolytes and renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
CYP3A4 inhibitors can increase levels and inducers can decrease levels Can cause bradycardia and heart failure.
| FDA category | Animal |
| Breastfeeding | Verapamil is excreted into breast milk in low amounts (M/P ratio ~0.6); trandolaprilat (active metabolite) concentrations are very low. No adverse effects reported in breastfed infants. Monitor infant for hypotension, bradycardia, and renal effects if used. |
| Teratogenic Risk | First trimester: Limited human data; animal studies show fetotoxicity (reduced fetal weight, ossification delays) at high doses. Second and third trimesters: ACE inhibitor component (trandolapril) is associated with oligohydramnios, fetal renal dysfunction, skull ossification defects, and neonatal renal failure; verapamil may cause fetal bradycardia and hypotension. Avoid in second and third trimesters. |
■ FDA Black Box Warning
Fetal toxicity: Drugs acting directly on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as pregnancy is detected.
| Common Effects | angina |
| Serious Effects |
History of angioedema related to ACE inhibitors; hereditary/idiopathic angioedema; concomitant use with aliskiren in patients with diabetes or renal impairment (GFR <60 mL/min); sick sinus syndrome or AV block (except in patients with pacemaker); severe hypotension; cardiogenic shock; second- or third-degree AV block; concomitant use with ivabradine; hypersensitivity to trandolapril, verapamil, or any component.
| Precautions | Angioedema (head/neck, intestinal); anaphylactoid reactions; hypotension (especially volume-depleted, CHF, or high-dose diuretic); hyperkalemia; impaired renal function; cough; liver impairment; cholestatic jaundice; avoid grapefruit juice (CYP3A4 inhibition); monitor digoxin levels; AV block/bradycardia; heart failure exacerbation in patients with severe left ventricular dysfunction. |
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| Fetal Monitoring | Monitor maternal blood pressure, serum potassium, and renal function. Fetal monitoring includes ultrasound for oligohydramnios and fetal growth; fetal heart rate monitoring for bradycardia if verapamil used in late pregnancy. |
| Fertility Effects | Animal studies with trandolapril show no impairment of fertility; verapamil has been associated with reversible decreases in sperm motility in vitro. Clinical data on human fertility are lacking. |