Continuing Education Activity

Ramipril is an ACE-inhibitor which is used for several indications. These include hypertension, prevention of heart failure progression post-myocardial infarction (MI). It is also used to reduce the risk of MI, stroke, and death in patients more than 55 years old with a high risk of atherosclerotic disease and major adverse cardiac events. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, and monitoring of ramipril which will help members of the interprofessional team in the management of patients with hypertension and cardiovascular disease.

Objectives:

• Identify the mechanism of action of ramipril.
• Summarize the various indications for initiating therapy with ramipril.
• Outline the adverse event profile and contraindications associated with ramipril.
• Explain the importance of improving care coordination among the interprofessional team to enhance the delivery of care for patients who can benefit from therapy with ramipril.

Indications

Ramipril is an ACE-i (Angiotensin Converting Enzyme inhibitor) which is used medically for following different disease processes.

• Hypertension: The most common indication in current clinical practice.
• Prevention of Heart failure progression after myocardial infarction (MI): Ramipril is used after MI to prevent the progression of asymptomatic heart failure with reduced ejection fraction. Low dose ramipril often initiated within a few hours after the confirmed myocardial infarction.[1][2]
• Risk Reduction: Ramipril is prescribed to reduce the risk of MI, stroke, and death in patients more than 55 years old with a high risk of atherosclerotic disease and major adverse cardiac events.
• Heart Failure with reduced ejection fraction (Off-label): It is used in the management of symptomatic heart failure with reduced ejection fraction to reduce morbidity and mortality. 

There may be a few other unlicensed uses in other countries. Please refer to local guidelines for more details.

Mechanism of Action

Background Physiology: Renin-Angiotensin-Aldosterone System (RAAS) is a major blood pressure regulating system in the human body.[3][4]

• Angiotensinogen is produced mainly in the liver and released in the bloodstream as a pro-hormone.
• Renin is an enzyme produced by the juxtaglomerular cells located at the afferent arteriole of glomeruli in response to reduced renal perfusion. It is a direct effect of low blood pressure and signals juxtaglomerular cells to release renin.
• Renin acts on the angiotensinogen released by the liver and cleaves ten amino acids from its structure, which leads to the formation of angiotensin I.
• Angiotensin I increases the blood pressure by vasoconstriction.
• When Angiotensin I passes through the lungs, it is further converted to angiotensin II by angiotensin-converting enzyme (ACE) which is present in the vascular endothelial cells in the lungs.

Angiotensin II: Angiotensin II has various effects that help in blood pressure optimization.

• Acts in the brain and increase the release of vasopressin, which by reabsorbing fluids from the kidneys improves blood pressure.
• It causes arteriolar vasoconstriction, which increases blood pressure by increasing total peripheral resistance.
• Acts on the adrenal cortex and promotes the release of Aldosterone. Aldosterone further acts on the renal tubular cells and result in reabsorption of sodium, which in turn causes water reabsorption in collecting ducts.
• Increases adrenergic outflow from the central nervous system, which causes blood pressure to increase.

Ramipril inhibits Angiotensin-Converting Enzyme and decreases Angiotensin II formation. As a result, sympathetic activity goes down, sodium and water reabsorption from the kidneys reduces, smooth muscles in the arterioles also relax. As a result, blood pressure decreases.

Administration

Only oral administration is licensed. In the United States, capsule form is available. Capsules can be opened to mix the contents with 120 ml of water, applesauce, or juice for the patient not able to swallow capsules. 

Available strengths: 1.25 mg, 2.5 mg, 5 mg, and 10 mg.

Ramipril is often started at the lowest dose and titrated according to blood pressure response. 

Adverse Effects

• Dry cough: In the lung tissues, Ramipril inhibits degradation of bradykinin which is a substrate of Angiotensin-converting enzyme. Higher levels of Bradykinin causes a dry cough. This side effect is more prevalent in patients from Afro-Caribbean descent than other cohorts. It usually occurs within a few months of treatment and resolves within one month after discontinuation of the medication.
• Postural hypotension: Some patients may develop postural hypotension and may also have fallen as a result, which can lead to a higher risk of head injuries and bone fractures especially in elderly patients. Dizziness and lightheadedness are related to postural hypotension when patients suddenly stand up from sitting or lying position. Patients should receive counseling regarding symptoms of postural hypotension during treatment initiation. 
• Elevated serum creatinine: Ramipril may cause a transient increase in serum creatinine in 1% to 2% of the patients.
• Hyperkalemia: In 1% to 10% of patients, hyperkalemia has been present. 
• Anxiety-like symptoms: Patients who are known to have anxiety or tremors should be watched for these symptoms for a few weeks at minimum when initiating ramipril. 
• Angioedema: Ramipril can cause angioedema at any time during treatment. It involves the head and neck (which may compromise the airway) or the intestine.[5]
• A few other rare side effects include hypoperfusion, movement disorders, onycholysis, and oral disorders. [British National Formulary]

Contraindications

• Hypersensitivity: Hypersensitivity to ramipril, other ACE-i or any component of the formulation is a major contraindication.  
• Angioedema (hereditary or idiopathic) or previous history of angioedema after treatment with an ACE inhibitor. [5]
• Hyperkalemia: Aldosterone is responsible for the excretion of potassium from the kidney. Therefore low levels of aldosterone can result in hyperkalemia. Due to its effects on aldosterone production, ramipril should be withheld or stopped in the patients who develop hyperkalemia (potassium levels greater than 5 mEq/L)
• Hyponatremia: Angiotensin II results in increased release of aldosterone from the adrenal glands. In the absence of angiotensin II, there is low production of aldosterone. Aldosterone is responsible for reabsorbing sodium and water from kidneys. Therefore if a patient is already hyponatremic, the use of ramipril and other ACE-i can worsen their hyponatremia.
• Pregnancy: Ramipril is absolutely contraindicated in pregnancy. Oligohydramnios and skull defects have been reported with concurrent use of ACE-i in pregnant ladies. [British National Formulary]
• Concomitant use with aliskiren or neprilysin inhibitor (sacubitril) is contraindicated.

The HOPE (Heart Outcome Prevention Study) study conducted in 2008 demonstrated that after administering ramipril 10mg for 12 weeks, clinically there is no significant change in renal function of patients who had renal artery stenosis. Therefore according to the HOPE study, ramipril can be safely used in patients with renal artery stenosis.[6]

Monitoring

• Renal function should be checked before starting ramipril. If there is a significant drop in the eGFR after initiation of ramipril, then the drug should be stopped, and alternative medications should be used.
• The monitoring of 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 chronic kidney disease, CBC with differentials should be monitored periodically due to the risk of agranulocytosis.[7]

Toxicity

Ramipril overdose can result in severe hypotension (due 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. Monitoring the patient for a minimum of 6 hours after taking the overdose is essential. If the blood pressure remains normal at in the first 6 hours after exposure, then the patient can be considered for discharge. [8]

Enhancing Healthcare Team Outcomes

Health care professionals including family physicians, specialists, nurses, and pharmacists are valuable sources of information for patients. The nurses, pharmacists, and clinicians should work as an interprofessional team to increase the patient's knowledge about the medication and provide them information about possible side effects to look for, helping them become more compliant with their medications, and subsequently improve their blood pressure control and overall clinical outcome. This interprofessional approach to education will lead to better outcomes. [Level 5]