Continuing Education Activity

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor and is utilized for multiple indications, including hypertension and prevention of heart failure progression following a myocardial infarction (MI). Ramipril is also used to reduce the risk of MI, stroke, and mortality in patients older than 55 with a high risk of atherosclerotic disease and major adverse cardiac events. This activity provides a comprehensive review of Ramipril's indications, mechanism of action, methods of administration, significant adverse effects, contraindications, and monitoring. This activity aims to assist interprofessional team members in effectively managing hypertension and cardiovascular disease.

Objectives:

• Identify appropriate indications and contraindications for prescribing ramipril therapy in patients with hypertension and cardiovascular conditions.
• Implement ramipril therapy according to established guidelines, considering the patient's characteristics, potential drug interactions, and appropriate dosage and titration.
• Select ramipril as a suitable medication based on patient-specific factors, such as comorbidities, tolerability, and preferences.
• Coordinate patient care and monitor progress to achieve better outcomes and minimize adverse events in ramipril therapy.

Indications

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor utilized medically for various disease processes.

Approved Indications

• Hypertension: Ramipril is administered either as a monotherapy or combined with other antihypertensive agents as a dual therapy, particularly with thiazide diuretics, to achieve a target systolic and diastolic blood pressure in patients. This approach helps manage hypertension by preventing the morbidities and mortalities associated with elevated blood pressure.
• Heart failure: Ramipril is used to prevent the progression of asymptomatic heart failure with reduced ejection fraction (HFrEF) following a myocardial infarction (MI). Typically, low-dose ramipril is initiated within a few hours after confirming the MI.[1][2]
• Cardiovascular risk: Ramipril is prescribed to reduce the risk of MI, stroke, and death in patients older than 55 with a high risk of atherosclerotic disease and major adverse cardiac events.
• HFrEF: Ramipril is employed to manage symptomatic HFrEF to reduce morbidity and mortality. Goal-directed medical therapy for HFrEF includes treatment for patients with a left ventricular ejection fraction (LVEF) of less than 40%.[3]

Off-Label Indications

• ST-segment elevation MI (STEMI): According to the guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA), ramipril is recommended for the management of STEMI in hemodynamically stable patients.[4]
• Chronic kidney disease (CKD): According to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, ramipril can be used in patients with CKD, both with or without diabetes. For children with CKD who have hypertension, it is advisable to use an ACE inhibitor, such as ramipril, as the initial treatment. Ramipril has demonstrated its effectiveness in reducing proteinuria in this population.[5]
• Non-ST elevation MI (NSTEMI): According to the AHA/ACC guidelines for NSTEMI, patients with LVEF less than 40% and those with hypertension, diabetes mellitus, or stable CKD are recommended to be prescribed ACE inhibitor, such as ramipril. This medication should be continued indefinitely unless there are any contraindications.[6]

Mechanism of Action

Background Physiology

Renin-Angiotensin-Aldosterone System

The renin-angiotensin-aldosterone system (RAAS) plays a vital role in regulating blood pressure within the human body.[7][8]

• Angiotensinogen, primarily produced in the liver, is released into the bloodstream as a prohormone.
• Renin, an enzyme produced by juxtaglomerular cells located at the afferent arteriole of glomeruli, is released in response to reduced renal perfusion. This response is a direct effect of low blood pressure and serves as a signal for the juxtaglomerular cells to release renin.
• Renin interacts with angiotensinogen, released by the liver, and cleaves 10 amino acids from its structure. This process results in the formation of angiotensin I.
• Angiotensin I increases blood pressure through its vasoconstrictive effects.
• When angiotensin I passes through the lungs, it is further converted to angiotensin II by ACE, which is present in the vascular endothelial cells in the lungs.

Angiotensin II

Angiotensin II has several effects that aid in regulating blood pressure.

• Angiotensin II acts in the brain and stimulates the release of vasopressin, which improves blood pressure by reabsorbing fluids from the kidneys.
• Angiotensin II causes arteriolar vasoconstriction, leading to increased blood pressure through the elevation of total peripheral resistance.
• Angiotensin II acts on the adrenal cortex, promoting the release of aldosterone. Aldosterone further acts on the renal tubular cells, reabsorbing sodium and resulting in water reabsorption in collecting ducts.
• Angiotensin II increases adrenergic outflow from the central nervous system, resulting in elevated blood pressure.

Ramipril and its active metabolite, ramiprilat, act as ACE inhibitors, inhibiting both circulating and tissue ACE. This inhibition leads to a decrease in angiotensin II formation. As a result, sympathetic activity decreases, and there is a reduction in sodium and water reabsorption from the kidneys. Furthermore, the smooth muscles in the arterioles relax, resulting in a decrease in blood pressure. ACE also plays a role in breaking down bradykinin, a vasopressor agent. The increased levels of bradykinin caused by ACE inhibition may contribute to the therapeutic effects of ramipril. However, elevated bradykinin levels can also lead to a dry cough, a common adverse effect of ACE inhibitor.[9]

Pharmacokinetics

Absorption: Ramipril is readily available in capsule or tablet form for oral administration. Upon taking the medication, the maximum plasma concentration in the therapeutic window is typically reached within 1 hour. The bioavailability of ramipril is approximately 50% to 60%. Although concurrent meals do not significantly impact the extent of absorption of ramipril, they can slow down the absorption rate.

Distribution: Ramipril is predominantly metabolized to its active form, ramiprilat, and both substances exhibit significant plasma protein binding. The plasma protein binding of ramipril is 73%, whereas ramiprilat is 56%.

Metabolism: Removing the ester group from ramipril converts it to its active metabolite, ramiprilat. Additionally, the glucuronidation of both ramipril and ramiprilat produces inactive metabolites. Notably, ramipril is not a substrate, inhibitor, or inducer of cytochrome P450 enzymes.[10]

Excretion: The elimination of ramipril occurs in 3 phases. The initial phase involves a rapid decline in plasma concentration, characterized by distribution to tissues and plasma, with a half-life of approximately 2 to 4 hours. This phase is succeeded by apparent elimination, during which free ramiprilat is eliminated, and the half-life is approximately 9 to 18 hours. The final phase is terminal elimination, with a half-life of more than 50 hours.

Ramipril is primarily excreted from the body through urine (60%) and stool (40%). In patients with a creatinine clearance (CrCl) of less than 40 mL/min/1.73 m², the peak plasma concentration of ramiprilat is twice as high as those without kidney disorders. Similarly, the trough level tends to increase 5 times, and the area under the curve (AUC), representing drug exposure, is elevated 3 to 4 times in these patients. Individuals with liver impairment, which affects ramipril metabolism, experience an increase in plasma levels by approximately 3-fold. 

Administration

The only approved method of ramipril administration is through oral means. In the United States, ramipril is available in capsule form. Patients having trouble swallowing ramipril capsules can open the capsule and mix the contents with 120 mL of water, applesauce, or juice, if necessary, to facilitate administration.

Available Strengths

The available strengths of ramipril include 1.25 mg, 2.5 mg, 5 mg, and 10 mg.

Dosage

HFrEF: For patients with HFrEF, the recommended initial dosage of ramipril is 1.25 to 2.5 mg once daily, and the target dosage is 10 mg once daily.[3]

Hypertension: For patients not taking a diuretic, it is recommended to begin treatment with ramipril with an initial dosage of 2.5 mg, administered once daily. Adjust the dosage based on the patient's blood pressure response, ranging from 2.5 to 20 mg daily, administered in 1 or 2 equally divided doses. If the antihypertensive effect wanes at the end of the dosing interval, consider either increasing the dose or administering it twice daily. In addition, consider adding a diuretic to the treatment regimen if ramipril monotherapy does not effectively control blood pressure.[11][12]

Specific Patient Populations

Renal impairment: For patients with renal impairment, dosage adjustments for ramipril based on indications are listed below.

• Hypertension:
  • CrCl <40: Initiate dosing at 1.25 mg daily, with a maximum dosage of 5 mg daily.
  • Hemodialysis: Administer 1.25 to 5 mg daily in 1 or 2 doses, without any supplement post-dialysis.
  • Peritoneal dialysis: Administer 1.25 to 5 mg daily in 1 or 2 doses, with the supplement not specifically defined.
• All other indications:
  • CrCl <40: Decrease the usual dose by 75%.
  • Peritoneal dialysis and hemodialysis: Follow the exact dosage as provided for hypertension.

Hepatic impairment: Clinicians should exercise caution while administering ramipril to patients with hepatic impairment, specifically severe cirrhosis or ascites, as there is no defined dosage for these cases.

Pregnancy considerations: Ramipril should be avoided during pregnancy. Close monitoring of amniotic fluid and the fetus is essential if ramipril use is indicated. Studies suggest that neonatal harm, including intrauterine growth restriction, oligohydramnios, renal failure, and even death, can occur, particularly when ACE inhibitors are taken in the second and third trimesters.[13]

Breastfeeding considerations: Because no information is available on the use of ramipril during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.(LactMed^®)

Pediatric patients: Ramipril is not indicated for use in patients younger than 18.

Older patients: Refer to the sections on renal and hepatic impairment for appropriate dosage considerations and precautions required for older patients while administering ramipril.

Adverse Effects

Ramipril may cause the adverse effects listed below.

Dry cough: Dry cough occurs when ramipril inhibits the degradation of bradykinin, a substrate of ACE, in the lung tissues, leading to increased bradykinin levels in the body. Patients of Afro-Caribbean descent may experience this adverse effect more frequently than other cohorts. Typically, the dry cough develops within a few months of initiating treatment and tends to resolve within 1 month after discontinuing the medication.

Postural hypotension: Some patients may experience postural hypotension, leading to an increased risk of falls, head injuries, and bone fractures, particularly among older patients. Symptoms such as dizziness and lightheadedness can occur when patients quickly transition from sitting to lying to standing positions. Patients should receive counseling about the potential symptoms of postural hypotension during the initiation of treatment. 

Elevated serum creatinine: Ramipril may cause a transient increase in serum creatinine in approximately 1% to 2% of the patients.

Hyperkalemia: Hyperkalemia has been reported in approximately 1% to 10% of patients taking ramipril. 

Anxiety-like symptoms: Patients with anxiety or tremors should be closely monitored for these symptoms for at least a few weeks when initiating ramipril. 

Angioedema: Ramipril can lead to angioedema at any point during treatment, with a typical involvement of the intestine or head and neck region, which may pose a risk to the airway.[14]

Other rare side effects of ramipril may include hypoperfusion, movement disorders, onycholysis, and oral disorders. [British National Formulary]

Contraindications

Hypersensitivity: Ramipril should be avoided in patients with a known hypersensitivity to the drug, other ACE inhibitors, or any component of the formulation, as it is a major contraindication.  

Angioedema: Ramipril should not be used in patients with a history of hereditary or idiopathic angioedema or those who have experienced angioedema after taking an ACE inhibitor.[14]

Hyperkalemia: Aldosterone plays a critical role in potassium excretion from the kidney. Consequently, low levels of aldosterone can lead to hyperkalemia. Due to ramipril's effects on aldosterone production, the medication should be withheld or discontinued in patients who develop hyperkalemia, which is defined as potassium levels greater than 5 mEq/L.

Hyponatremia: Angiotensin II stimulates the increased release of aldosterone from the adrenal glands, leading to sodium and water reabsorption in the kidneys. Without angiotensin II, aldosterone production is reduced, which can exacerbate hyponatremia. Therefore, for patients already experiencing hyponatremia, using ramipril or other ACE inhibitors may worsen their condition.

Pregnancy: As previously mentioned in the Administration section, ramipril is contraindicated during pregnancy. Concurrent use of ACE inhibitors in pregnant patients has been associated with reports of oligohydramnios and skull defects. [British National Formulary]

Concomitant use of ramipril with aliskiren or a neprilysin inhibitor (sacubitril) is contraindicated.

The HOPE (Heart Outcome Prevention Study) study conducted in 2008 demonstrated that after administering 10 mg ramipril for 12 weeks, clinically, there was no significant change in renal function in patients with renal artery stenosis. Based on the findings from the HOPE study, ramipril can be considered safe for use in patients with renal artery stenosis.[15]

Monitoring

Renal function should be assessed before initiating ramipril. If a significant drop in the estimated glomerular filtration rate (eGFR) occurs after starting ramipril, the medication should be discontinued, and alternative treatment options should be considered.

Monitoring for signs of postural hypotension, angioedema, and hyperkalemia is recommended, especially during the initial few weeks.

If the patient has a history of collagen vascular disease or CKD, periodic monitoring of complete blood count (CBC) with differentials is recommended due to the risk of agranulocytosis.[16]

Toxicity

Ramipril overdose can lead to severe hypotension, primarily attributed to vasodilation and effective hypovolemia.

A study conducted in 2006 to investigate the effects of ramipril overdose on blood pressure concluded that, in most cases, a drop in blood pressure occurs within the first 4 to 4.5 hours after ingestion. Therefore, monitoring the patient for at least 6 hours after the overdose is essential. If the blood pressure remains stable and normal during the first 6 hours after exposure, the patient can be considered for discharge.[17]

Enhancing Healthcare Team Outcomes

The interprofessional healthcare team, consisting of physicians, specialists, advanced practice practitioners, nurses, and pharmacists, plays a crucial role in patient care. They serve as valuable sources of information for patients, guiding and educating them about their medications. By working as an interprofessional team, they can increase patient knowledge about the prescribed medicine and provide essential details about potential adverse effects to be vigilant for. This collaborative effort helps patients become more informed and compliant with their medications, leading to improved blood pressure control and overall clinical outcomes. In addition, all interprofessional team members share the responsibility for monitoring the patient's progress and identifying any potential adverse events.

Interprofessional care coordination involves establishing open communication channels, engaging in shared decision-making, and valuing the contributions of each member involved in patient care by relying on the expertise of their respective disciplines. This interprofessional approach to managing ramipril therapy and patient education fosters better outcomes with a reduced risk of adverse effects.