Makupril

Uses

Makupril is an ACE inhibitor prodrug used to treat hypertension, congestive heart failure, and slow rate of progression of renal disease.

Makupril is indicated for the treatment of hypertension and as an adjunct therapy in the treatment of heart failure. Makupril in combination with hydrochlorothiazide is indicated for the treatment of hypertension.

Makupril is also used to associated treatment for these conditions: Congestive Heart Failure (CHF), Diabetic Nephropathy, High Blood Pressure (Hypertension), Left Ventricular Dysfunction

How Makupril works

Angiotensin II constricts coronary blood vessels and is positively inotropic, which under normal circumstances, would increase vascular resistance and oxygen consumption. This action can eventually lead to myocyte hypertrophy and vascular smooth muscle cell proliferation. Angiotensin II also stimulates production of plasminogen activator inhibitor-1 (PAI-1), increasing the risk of thrombosis.

Makuprilat prevents the conversion of angiotensin I to angiotensin II by inhibition of angiotensin converting enzyme, and also reduces the breakdown of bradykinin. Reduced levels of angiotensin II lead to lower levels of PAI-1, reducing the risk of thrombosis, especially after a myocardial infarction.

Toxicity

The oral LD₅₀ in rats is 3541mg/kg and in mice is 1739mg/kg.

Patients experiencing an overdose may present with symptoms of severe hypotension. Due to the extensive protein binding of quinapril and the active metabolite quinaprilat, hemodialysis is not expected to remove the drug from circulation. Treat patients with symptomatic and supportive measures, including normal saline infusions to restore normal blood pressure.

Food Interaction

• Avoid fatty foods.
• Avoid hypertensive herbs (e.g. bayberry, blue cohosh, cayenne, ephedra, and licorice).
• Avoid potassium-containing products. Potassium products increase the risk of hyperkalemia.
• Limit salt intake. Salt may attenuate the antihypertensive effect.

[Moderate] GENERALLY AVOID: Moderate-to-high dietary intake of potassium can cause hyperkalemia in some patients who are using angiotensin converting enzyme (ACE) inhibitors.

In some cases, affected patients were using a potassium-rich salt substitute.

ACE inhibitors can promote hyperkalemia through inhibition of the renin-aldosterone-angiotensin (RAA) system.

MANAGEMENT: It is recommended that patients who are taking ACE inhibitors be advised to avoid moderately high or high potassium dietary intake.

Particular attention should be paid to the potassium content of salt substitutes.

Makupril Drug Interaction

Moderate: aspirin, rosuvastatin, insulin glargine, furosemide, levothyroxine, alprazolamMinor: amlodipineUnknown: duloxetine, apixaban, omega-3 polyunsaturated fatty acids, sitagliptin, atorvastatin, metoprolol, metoprolol, esomeprazole, clopidogrel, acetaminophen, cyanocobalamin, ascorbic acid, cholecalciferol

Makupril Disease Interaction

Major: angioedema, bone marrow suppression, CHF, hemodialysis, hyperkalemia, hypotensionModerate: liver disease, renal dysfunction

Volume of Distribution

The mean volume of distribution of quinaprilat is 13.9L.

Elimination Route

Makupril if 50-80% bioavailable. Makupril has a T_max of 6 while quinaprilat has a T_max of 2.5h. The C_max of quinaprilat is highly variable but reaches 1526ng/mL with an AUC of 2443ng*h/mL in healthy males given a 10mg dose. A high fat meal reduces the absorption of quinapril by 25-30%.

Half Life

The active metabolite quinaprilat has an elimination half life of 2.3 hours.

Clearance

The clearance of quinaprilat is 68mL/min.

Elimination Route

Makuprilat is up to 96% eliminated in the urine. The eliminated metabolites PD109488 and PD113413 account for approximately 6% of a dose of quinapril each. A small fraction of the dose recovered in the urine is accounted for by unmetabolized quinapril.

Innovators Monograph

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