Continuing Education Activity

Fosinopril is classified as an angiotensin-converting enzyme inhibitor and has been available for nearly three decades. Fosinopril has some key features that make it different from enalapril and captopril; 1) it has a long half-life, 2) it is hydrophilic, and 3) it is not broken down by the liver. Fosinopril is a competitive inhibitor of angiotensin-converting enzyme (ACE) and prevents the conversion of angiotensin I to angiotensin II, which is a potent vasoconstrictor. This activity covers fosinopril, including mechanism of action, pharmacology, adverse event profiles, eligible patient populations, monitoring, and highlights the role of the interprofessional team in the management of hypertension with fosinopril.

Objectives:

• Summarize the mechanism of action of fosinopril.
• Identify the various indications for initiating fosinopril therapy.
• Review the adverse event profile of fosinopril.
• Explain the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients receiving treatment with fosinopril.

Indications

Fosinopril is an angiotensin-converting enzyme (ACE) inhibitor that aims to decrease systemic blood pressure in hypertensive patients. Fosinopril is most often prescribed for patients suffering from hypertension (<140/90 mmHg for non-complicated patients and <130/80 mmHg for patients with either diabetes or chronic kidney disease).[1] Other ACE inhibitors approved in the US are captopril, enalapril, lisinopril, benazepril, quinapril, ramipril, moexipril, and trandolapril.[2]

Fosinopril is also prescribed as an adjunctive treatment of heart failure (HF) along with conventional therapy that includes diuretics with or without digitalis. Once-daily fosinopril treatment has been shown to improve HF signs and symptoms and reduce hospitalizations for worsening HF.[3] In a fosinopril Efficacy/Safety Trial (FEST) Study Group, fosinopril improves exercise tolerance and attenuates clinical deterioration in patients with heart failure.[4] 

Also, in the Fosinopril Acute Myocardial Infarction Study (FAMIS), early treatment with fosinopril has shown to benefit patients with acute myocardial infarction in addition to a prevention of left ventricular (LV) remodeling.[5]

Fosinopril also works as a preventative therapy for patients with diabetic nephropathy. In a randomized clinical trial of patients with diabetic nephropathy, fosinopril combined treatment with losartan resulted in reduced 24-hour total urine protein excretion, serum creatinine, and BUN.[6]

Off-label use of fosinopril also includes the treatment of HIV-associated nephropathy (HIVAN).[7]

Mechanism of Action

Fosinopril is an ester prodrug that hydrolyzes in the liver to fosinoprilat, the active metabolite form. Fosinoprilat then uses competitive inhibition to bind to ACE resulting in decreased formation of angiotensin II, reduced aldosterone concentrations, and diminished systemic vasoconstriction. By interacting with the renin-angiotensin-aldosterone system (RAAS) components, fosinopril can reduce the tendency of vasoconstriction and promote sodium excretion. It helps in heart failure by protecting the myocardium from the angiotensin II remodeling effects.

Administration

Fosinopril received official approval for use in 1991 and is available for administration in 10, 20, or 40 mg oral tablets. It is traditional to prescribe the drug at a low dose and increase the dosage as needed while evaluating the patient’s response and tolerance. The maximum dose is typically 80 mg for the average patient with hypertension. In patients with sodium or water depletion or renal failure, the initial dosing is reduced to 5 mg. It’s not uncommon to co-administer hydrochlorothiazide with fosinopril to regulate fluid volume and counteract high blood pressure.[8]

Hypertension

• Monotherapy: The recommended initial adult dose of fosinopril is 10 mg once daily, both as monotherapy and when the drug is added to diuretic treatment. The dose can then be adjusted according to the patient’s blood pressure at peak (in 2 to 6 hours) and trough ( at 24 hours) blood levels. Most patients gain optimum blood pressure control with 20 to 40 mg daily, and only some need 80 mg. However, if blood pressure control response is not adequate around the end of the dosing interval, dividing the daily dose may give better control.
• Co-administration with Diuretics: A diuretic can be added if blood pressure is inadequately controlled with fosinopril alone. Co-administration of fosinopril with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can increase serum potassium.
• In patients currently treated with a diuretic, symptomatic hypotension can result following the initial dose of fosinopril. To reduce the chances of hypotension, the diuretic should, if possible, be discontinued two to three days before beginning therapy with fosinopril. Then, if blood pressure is not adequately controlled, the diuretic should be resumed. If diuretic treatment cannot be stopped, start fosinopril at 10 mg with close medical supervision for several hours and until the patient’s blood pressure is stabilized.
• Pediatrics: Monotherapy- In children weighing more than 50 kg, the recommended dose of fosinopril is 5-10 mg once daily.

Heart Failure

• Fosinopril should be started at 10 mg once daily and observe patients under medical supervision for at least 2 hours for any hypotension and/or orthostasis, and if any present, until blood pressure stabilizes.
• A starting dose of 5 mg is recommended in patients with heart failure and moderate to severe renal failure. Then, the dose should be increased over several weeks to be tolerated but not more than 40 mg daily. The usual effective dose range is 20-40 mg per day.

Hypertension/Heart Failure with Renal Impairment

In patients with renal impairment, the total clearance of fosinoprilat slows by 50 %. However, hepatobiliary elimination partially compensates for diminished renal elimination. Hence, the total body clearance of fosinoprilat stays normal with all degrees of renal impairments (CrCl < 80 mL/min/1.73 m2), including end-stage renal diseases.

Pregnant Women

Fosinopril is contraindicated during pregnancy due to its ability to cross the placenta. As a result, it may increase the risk of fetal malformations and cause congenital disabilities or death to the developing fetus. Therefore, if the patient reports pregnancy at any time during treatment, fosinopril therapy should stop immediately. In general, all ACE inhibitors should be avoided when treating hypertension in pregnancy.

Breastfeeding Patients

The manufacturer recommends against breastfeeding while using fosinopril as it is secreted in breast milk.[9]

Adverse Effects

A few common symptoms reported with fosinopril include fatigue, dizziness, gastrointestinal disturbances, dry cough, and a skin rash.[8] 

Long-term usage of fosinopril can produce a dry cough due to ACE inhibition and the resulting accumulation of bradykinin. A less common side effect of which to be aware is angioedema.

Other rarely reported adverse reactions are elevated serum aminotransferase concentrations and acute liver damage. Less than two percent of patients using fosinopril have reported increased serum aminotransferase levels without explanation. Since acute liver damage is an extremely rare reaction, only a handful of clinical reports have been documented and analyzed. Unfortunately, the few reports are insufficient to determine a consistent mechanism of injury, so the path of liver damage remains unknown in these patients. The metabolite reaction in the liver is proposed to cause the idiosyncratic adverse effect and remains under investigation.[8] Other ACE inhibitors that have shown similar liver damage are enalapril, lisinopril, and lisinopril.[2]

Contraindications

The incidence of angioedema occurring as an adverse effect is 0.1 to 0.7% due to vasodilation and plasma extravasation.[10] If patients have a history of ACE inhibitor-induced angioedema, they should avoid using fosinopril or any other agent within that class.

In cases of hepatic failure, it is crucial to avoid prescribing any ACE inhibitors. In addition, patients experiencing the adverse effect of acute liver injury from fosinopril should refrain from using other ACE inhibitors to prevent further damage.

In patients with diabetes, fosinopril should not be co-administered with aliskiren, as aliskiren may enhance the hypotensive, hyperkaliemia, and nephrotoxic effects of fosinopril.

One needs to be careful while using fosinopril with other drugs due to drug-drug interaction.

• Potassium (K+) sparing diuretics: Fosinopril may cause hyperkalemia due to the attenuation of potassium loss caused by thiazide diuretics.
• Lithium: Fosinopril causes serious lithium drug interaction. It may slow the elimination of lithium from the body, resulting in increased lithium levels.
• Antacids: Antacids may alter the absorption of fosinopril, resulting in reduced serum levels. It can further reduce the urinary excretion of fosinoprilat.
• Nonsteroidal anti-inflammatory agents: in elderly patients, co-administration of fosinopril may result in deterioration of renal function, possibly resulting in acute renal failure.

Monitoring

While on fosinopril, the patient requires monitoring for hypotension, potassium levels, renal function, and angioedema. To decrease the possibility of hypotension as an adverse effect among ACE inhibitors, the recommendation is to prescribe fosinopril at a low dose initially. During weeks 2 to 3 of usage, clinicians should note serum creatine and potassium levels and blood pressure to gauge the patient's tolerance. For instance, a patient with a history of hyperkalemia or a high potassium diet should be closely monitored to avoid exacerbating any preexisting conditions.[11]

Toxicity

If the patient is experiencing fosinopril toxicity, they will require general supportive care and should discontinue fosinopril immediately. The following case study describes a situation in which a patient suffered from the adverse effects of fosinopril.

The first documented case of a person experiencing uncommon adverse reactions due to fosinopril was a 61-year-old man who reported symptoms beginning during weeks 2 through 12 of treatment.[8] The patient reported no prior hepatobiliary disease and consuming 3 to 4 alcoholic beverages daily.[12] During the course of treatment with 20 mg fosinopril daily, he was also taking 50 mg of metoprolol twice a day and 5 mg of diazepam daily.[8] After just three weeks of using fosinopril, the patient presented with asthenia, jaundice, and pruritis. All medications were stopped once admitted to the hospital, and treatment was initiated. He received ursodiol, colestipol, and hydroxyzine to treat pruritis and cholestasis. Further examination also revealed him to have an elevated concentration of bilirubin, serum aminotransferase enzymes, and alkaline phosphatase.[8] However, other levels, such as immunoglobulins and eosinophilia, were reportedly within normal limits. During hospitalization, the patient faced complications such as renal failure, which required dialysis, duodenal ulcer bleeding, and septicemia.

Upon evaluation, the patient tested negative for hepatitis A, B, and C in addition to other autoantibody tests. Furthermore, the patient showed no signs of biliary obstruction or gallstones from an abdominal ultrasound or tomography imaging. Also, there were no other contributions to intrahepatic cholestasis. Any other medications were determined to be improbable causes of the acute liver injury he presented. A liver biopsy showed positive results for cholestasis and bile duct destruction.[12]

The patient was hospitalized for two months but continued to experience symptoms for up to 18 months after the incident. He reported having jaundice for four months, pruritis for six months, and anicteric cholestasis for 18 months. The overall recovery period lasted from 6 to 18 months, and the severity rating was 4+.[8] The risk of developing this acute liver injury due to fosinopril was categorized as a likelihood score of D. Other ACE inhibitors have shown similar risks for acute liver damage.

Enhancing Healthcare Team Outcomes

Even though fosinopril is a relatively safe and common means to treat hypertension, monitoring the treatment and reporting any adverse reactions under an interprofessional healthcare team is essential. Clinicians that tend to prescribe this class of ACE inhibitors include but are not limited to primary care clinicians, internal medicine specialists, and cardiologists. Before using fosinopril, the patient should be aware of all the possible side effects and receive instructions to avoid high potassium diets. To ensure the patient is maximizing their benefits from fosinopril, clinicians should schedule regular follow-ups and document the patient's response. A pharmacist should have involvement at the outset of therapy, verifying appropriate dosing and dose titration, checking for potential interactions, and counseling the patient on possible adverse effects. Nursing will follow up with the patient, monitor therapy progress, and answer patient questions, alerting the prescriber to any concerns. With these interprofessional strategies, fosinopril's use can achieve better patient outcomes with fewer adverse effects. [Level 5]