Trandolapril: Description, Pharmacodynamic and pharmacokinetic properties

Description

Trandolapril is a non-sulfhydryl ACE inhibitor. It is a prodrug rapidly hydrolyzed mainly in the liver to its biologically active metabolite, trandolaprilat. The time to reach peak plasma concentrations of trandolaprilat is about 6 hours; the effective plasma half-life of accumulation at steady state is 24 hours. Trandolapril is used for the treatment of hypertension, heart failure, and left-ventricular dysfunction Physician's Desk Reference (2004). For antihypertensive therapy, it is used alone or in combination with hydrochlorothiazide or verapamil.

Pharmacodynamic and pharmacokinetic properties

Trandolapril is a non-sulfhydryl prodrug rapidly hydrolyzed in the liver to the active diacid compound, trandolaprilat. Trandolaprilat has a high binding affinity for ACE, and the drug concentration required to inhibit ACE activity by 50% (IC50) is less than that of enalaprilat, captopril and quinaprilat and similar to that of ramiprilat. Maximal ACE inhibition after repeated doses occurs at 3 hours in younger patients and at 1.5 hours in older patients. Trandolapril is a highly lipophilic drug, which may facilitate tissue ACE inhibition with potential effects in cardiovascular remodelling. The main pharmacodynamic effects of trandolapril are achieved by a reduction in plasma angiotensin-II levels. This reduces peripheral vasoconstriction, blood pressure, and total peripheral resistance and decreases sodium and water retention by the kidney. ACE inhibitors increase bradykinins production, which explains their main side effect of dry cough.

Advantages of trandolapril over other ACE inhibitors

Appropriate, recommended and optimal dosage with ACE inhibitors is becoming more prominent in cardiovascular literature. There is solid evidence from pharmacokinetic and hard endpoint clinical trials for the optimal use of trandolapril dosage. Despite the fact that most ACE inhibitors are recommended for once-daily administration, only fosinopril, ramipril, and trandolapril have trough-to-peak effect ratios of over 50%. Other ACE inhibitors, such as perindopril, have obtained indications for heart failure with a dosage of 4 mg daily, but should it be 8 mg or even 16 mg per day? Current US guidelines for the management of chronic heart failure acknowledge this problem, and they do not establish a precise recommended dosage for enalapril, lisinopril or perindopril. The task force for the diagnosis and treatment of chronic heart failure, the European Society of Cardiology, also leave the clinician with this dilemma. Therefore, in Europe, only enalapril and trandolapril (4 mg daily) have precise recommended evidence-based dosages.

Adverse Effects

Adverse effects associated with the use of trandolapril include persistent non-productive cough, angioedema, hyperkalemia, bradycardia, hypotension, myalgia, and gastritis Physician's Desk Reference (2004).

[1] Trandolapril - an overview | ScienceDirect Topics https://www.sciencedirect.com/topics/medicine-and-dentistry/trandolapril

[2] Ariel Diaz, Anique Ducharme. “Update on the use of trandolapril in the management of cardiovascular disorders.” Vascular Health and Risk Management 4 6 (2008): 1147–58.

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