Spirapril

Summary

Spirapril is an orally administered, pro‑drug angiotensin‑converting enzyme (ACE) inhibitor approved for the treatment of mild‑to‑moderate essential hypertension. After ingestion it is converted to the active metabolite spiraprilat, which lowers blood pressure by reducing angiotensin II formation. Clinical studies have shown it provides roughly 10 mmHg reductions in diastolic pressure and is comparable to other ACE inhibitors such as enalapril.

Mechanism of Action

Spirapril is a non‑sulfhydryl ACE‑inhibitor pro‑drug that, after oral absorption, is hydrolysed to spiraprilat. Spiraprilat binds to the active site of angiotensin‑converting enzyme, preventing conversion of angiotensin I to the vasoconstrictor angiotensin II and reducing breakdown of bradykinin. The resulting vasodilation and decreased aldosterone release lower systemic vascular resistance and blood volume, producing antihypertensive effects. Dual renal and hepatic clearance of spiraprilat distinguishes its elimination pathway from many ACE inhibitors.

What the Research Shows

A multicentre, double‑blind trial in 283 patients with diastolic BP 100–115 mmHg showed that spirapril (3–24 mg once daily) lowered DBP by about 10 mmHg versus 5 mmHg with placebo, with all doses showing similar efficacy. A head‑to‑head study (n=251) found spirapril 6 mg reduced DBP more than enalapril (‑17.4 vs ‑14.8 mmHg at peak) while SBP reductions were comparable. Pharmacokinetic work demonstrated bioequivalence when combined with hydrochlorothiazide, indicating no interaction. A systematic review of ACE‑inhibitor cough risk ranked spirapril lowest among eleven agents, suggesting a relatively low cough incidence. Overall, spirapril appears effective, well tolerated, and at least as potent as other ACE inhibitors in short‑term hypertension trials.

Reported Benefits

Clinical data indicate spirapril provides consistent diastolic blood‑pressure reductions of roughly 10 mmHg, comparable or superior to enalapril in some measures. Once‑daily dosing is feasible due to a long half‑life (~40 h). The drug shows a low propensity for dry cough relative to other ACE inhibitors. Fixed‑dose combination with hydrochlorothiazide is bioequivalent, offering convenient combination therapy. Dual renal and hepatic elimination may reduce accumulation risk in patients with moderate renal impairment, although data are limited.

Limitations of the Evidence

Evidence is limited to short‑term hypertension studies; long‑term cardiovascular outcomes have not been established. Comparative trials with other ACE inhibitors are few, and data on effects in severe renal or hepatic failure are conflicting or absent. The dose‑response appears flat between 6 and 24 mg, leaving uncertainty about optimal dosing in diverse populations. Information on use in heart failure, post‑myocardial infarction, or pregnancy is not provided in the cited literature.

Safety Considerations

Spirapril was generally well tolerated; adverse events were similar to placebo, with headache reported slightly more often (5.8 % vs 1.7 %). Laboratory parameters showed no clinically relevant changes, and no dose‑related safety signals emerged. The incidence of ACE‑inhibitor cough appears low. No major drug‑drug interactions were identified, including with hydrochlorothiazide. Caution may be warranted in patients with severe hepatic impairment, as hepatic clearance contributes to elimination, though specific data are lacking.

How It Is Administered

Spirapril is supplied as oral tablets, typically administered once daily. The usual dose in clinical studies was 6 mg, with higher doses (up to 24 mg) showing no additional benefit. It is available as monotherapy and as a fixed‑dose bi‑layer tablet combined with hydrochlorothiazide, with bioequivalence demonstrated between the two formulations.

Routes of Administration

Goals & Uses

• Heart failureCardiovascularModerate
• Hypertension managementCardiovascularHigh
• Renoprotection in chronic kidney diseaseNephrologyLow
• HypertensionCardiovascularHigh

Contraindications

• PregnancyPopulationHighPotential fetal risk or insufficient safety data
• History of ACE inhibitor-induced angioedemaImmunologic/AllergicHigh
• Severe hypersensitivity to spirapril or excipientsAllergyHigh
• Concurrent use of aliskiren in diabetic patientsDrug InteractionHigh
• Bilateral renal artery stenosisVascular/RenalHigh

Adverse Effects

• CoughRespiratoryCommonPersistent or episodic cough
• HypotensionCardiovascularUncommonLow blood pressure
• Hypotension (first-dose effect)CardiovascularCommon
• Renal impairmentRenalUncommon
• HyperkalemiaElectrolyte ImbalanceUncommon
• Dry coughRespiratoryCommon
• AngioedemaImmunologicRare
• Dizziness/headacheNeurologicalCommon

Drug Interactions

• Potassium‑sparing diuretics (e.g., spironolactone)Moderate
• Potassium-sparing diuretics (e.g., spironolactone, amiloride)High
• AliskirenHigh
• NSAIDsLowMay increase renal risk in susceptible patients
• Antidiabetic agents (insulin, sulfonylureas)Moderate
• LithiumHigh

Population Constraints

• Renal impairmentOrgan ImpairmentRelative
• Pediatric patientsAgeRelative
• ElderlyAgeRelative
• Patients with severe renal artery stenosisRenalAbsolute
• Patients with severe hepatic impairmentHepaticRelative
• Elderly patientsAgeRelative
• Pregnant womenReproductiveAbsolute

Regulatory Status

• European UnionApprovedApproved: HypertensionApproved in several EU member states.
• JPApprovedApproved: Hypertension, Heart failureMarketed as Renormax.
• United StatesUnapprovedNot submitted for FDA approval.
• United KingdomUnknownLimited availability data post-Brexit; not a commonly listed product in MHRA databases.

Approved in Japan and several EU member states; not approved in the United States.

Evidence & Sources

• A multicentre multidose study of the efficacy and safety of spirapril in mild-to-moderate essential hypertension. UK Study Group of Spirapril in Hypertension
  Journal ArticleModerateFairhurst GJ1994-01-01T00:00:00.000000Z
• Angiotensin-converting enzyme inhibitor induced cough compared with placebo, and other antihypertensives: A systematic review, and network meta-analysis
  Journal ArticleHighHu Y, et al.2023-01-01T00:00:00.000000Z
• Drug interaction of spirapril hydrochloride monohydrate and hydrochlorothiazide. A clinical study to compare the pharmacokinetics after administration of spirapril hydrochloride monohydrate tablets, hydrochlorothiazide tablets and fixed combination bi-layer tablets
  Journal ArticleModerateSchürer M, et al.2003-01-01T00:00:00.000000Z
• Spirapril. A preliminary review of its pharmacology and therapeutic efficacy in the treatment of hypertension
  Journal ArticleModerateNoble S, Sorkin EM1995-01-01T00:00:00.000000Z
• Comparison of efficacy of spirapril and enalapril in control of mild-to-moderate hypertension
  Journal ArticleModerateGuitard C, et al.1997-01-01T00:00:00.000000Z
• Efficacy and safety of spirapril in mild-to-moderate hypertension
  Journal ArticleModerateHayduk K, Kraul H1999-01-01T00:00:00.000000Z

Frequently Asked Questions