Continuing Education Activity

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor used to treat hypertension and prevent heart failure progression in patients with a history of myocardial infarction. This medication is also indicated for reducing the risk of myocardial infarction, stroke, and mortality in patients older than 55 who are at high risk for atherosclerotic disease and severe adverse cardiac events. Ramipril suppresses angiotensin II synthesis, reducing sympathetic activity and sodium and water reabsorption in the kidneys. The resulting vasodilation reduces blood pressure.

This activity reviews ramipril's indications, mechanism of action, pharmacokinetics, dosing, and administration. Additionally, it highlights significant adverse effects, contraindications, monitoring parameters, and drug interactions. By enhancing clinicians' understanding of these aspects, this article improves the management of hypertension and cardiovascular disease.

Objectives:

• Identify the appropriate indications and contraindications for prescribing ramipril for patients with hypertension and cardiovascular conditions.
• Implement ramipril therapy according to established guidelines.
• Select ramipril appropriately based on patient-specific factors.
• Implement effective collaboration and communication among interprofessional team members to achieve better outcomes and treatment efficacy for patients receiving ramipril.

Indications

FDA-Approved Indications

Hypertension: Ramipril is administered as a monotherapy or combined with other antihypertensive agents, particularly thiazide diuretics, to achieve a target systolic and diastolic blood pressure. This approach aids hypertension management by preventing the morbidities and mortalities associated with elevated blood pressure.

Heart failure: Ramipril is used to prevent the progression of 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] Goal-directed medical therapy for HFrEF includes treatment for patients with a left ventricular ejection fraction (LVEF) of less than 40%.[3]

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.

Off-Label Uses

STEMI: According to the guidelines from the American College of Cardiology (ACC) and the American Heart Association (AHA), ramipril is recommended for hemodynamically stable patients with a history of ST-segment elevation MI (STEMI).[4]

NSTEMI: According to the AHA/ACC guidelines for patients with a non-ST elevation MI (NSTEMI), patients with an LVEF of less than 40% and those with hypertension, diabetes, or stable CKD should be prescribed ACE inhibitors such as ramipril. This medication should be continued indefinitely unless there are any contraindications.[5]

CKD: According to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, ramipril can treat patients with chronic kidney disease (CKD), regardless of diabetes status. For children with CKD and hypertension, an ACE inhibitor such as ramipril is recommended as the initial treatment. Ramipril has demonstrated its effectiveness in reducing proteinuria in these patients.[6]

Mechanism of Action

The renin-angiotensin-aldosterone system (RAAS) is vital for regulating blood pressure in the human body.[7][8] Below is a brief overview of RAAS and its effects.

1. Angiotensinogen is produced primarily in the liver and released into the bloodstream as a prohormone.
2. Renin, an enzyme produced by juxtaglomerular cells located at the afferent arteriole of glomeruli, is released in response to reduced renal perfusion caused by low blood pressure.
3. Renin interacts with angiotensinogen by cleaving 10 amino acids from its structure, forming angiotensin I.
4. Angiotensin I increases blood pressure through its vasoconstrictive effects.
5. When angiotensin I passes through the lungs, it is converted to angiotensin II by ACE in the pulmonary vascular endothelial cells.

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

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

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

Pharmacokinetics

Absorption: Ramipril is readily absorbed when taken orally; the maximum plasma concentration in the therapeutic window is typically reached within 1 hour. The bioavailability of ramipril is approximately 50% to 60%. Although meals do not significantly impact the extent of absorption of ramipril, taking the drug with food can slow down the absorption rate.

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

Metabolism: Removing the ester group from ramipril forms 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]

Elimination: 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 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-fold in these patients. Patients with liver impairment, which affects ramipril metabolism, may experience an increase in plasma levels by approximately 3-fold.

Administration

Available Dosage Forms and Strengths

Ramipril is available in 1.25 mg, 2.5 mg, 5 mg, and 10 mg oral capsules. Patients having trouble swallowing ramipril capsules can open the capsule and mix the contents with 120 mL of water, applesauce, or juice to facilitate administration.

Adult Dosage

HFrEF: The recommended initial ramipril dose is 1.25 to 2.5 mg once daily, gradually increasing to a target dosage of 10 mg once daily.[3]

Hypertension: Patients not taking a diuretic should begin at an initial dosage of 2.5 mg, administered once daily. This may be adjusted based on the patient's blood pressure response, ranging from 2.5 to 20 mg daily, administered in a single or 2 equally divided doses. If the antihypertensive effect wanes at the end of the dosing interval, clinicians may consider increasing the dose or administering it twice daily. Additionally, a diuretic may be added to the treatment regimen if ramipril monotherapy does not effectively control blood pressure.[11][12]

Specific Patient Populations

Renal impairment: Dosage adjustments for patients with renal impairment based on indications are listed below.

• Hypertension

  • CrCl <40: Start at 1.25 mg daily, with a maximum dosage of 5 mg daily.
  • Hemodialysis: 1.25 to 5 mg daily in 1 or 2 doses without supplement post-dialysis.
  • Peritoneal dialysis: 1.25 to 5 mg daily in 1 or 2 doses, with the supplement not explicitly defined.

• All other indications

  • CrCl <40: The standard dose is reduced by 75%.
  • Peritoneal dialysis and hemodialysis: Same as 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 patients.

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 using ramipril during breastfeeding, an alternate drug (eg, LactMed^®) may be preferred, especially while nursing a newborn or preterm infant.

Pediatric patients: Ramipril is not indicated for this patient population.

Older patients: For appropriate dosage considerations and precautions when administering ramipril to older patients, refer to the sections on renal and hepatic impairment.

Adverse Effects

The following adverse reactions have been associated with ramipril administration.

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 patient populations. The cough typically develops within a few months of initiating treatment and tends to resolve within 1 month after discontinuing the medication. Certain genetic variants and female gender are identified risk factors for dry cough.[14][15]

Postural hypotension: Some patients, particularly older adults, may experience postural hypotension, which can increase the risk of falls, head injuries, and bone fractures. Symptoms such as dizziness and lightheadedness can occur when patients quickly transition from sitting to lying to standing. 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 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 a few weeks after initiating ramipril therapy. 

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.[16]

Other rare side effects of ramipril may include hypoperfusion, movement disorders, onycholysis, and oral disorders.

Drug-Drug Interactions

Diuretics: Patients taking diuretics, particularly those who recently started diuretic therapy, may occasionally experience significant blood pressure reduction when initiating treatment with ramipril. To minimize the risk of hypotension, consider reducing or discontinuing the diuretic or increasing salt intake before starting ramipril. If these adjustments are not feasible, lowering the initial dose of ramipril is advisable.

Agents increasing serum potassium: Co-administration of medications that elevate serum potassium levels with ramipril can lead to hyperkalemia. Clinicians must monitor serum potassium levels in these patients.

Other agents affecting the renin-angiotensin system: Patients should not take RAS inhibitors in combination with ramipril. Specifically, aliskiren with ramipril should not be administered to patients with diabetes.

Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been observed in patients taking lithium with ACE inhibitors. Therefore, frequent monitoring of serum lithium levels is recommended. The risk of lithium toxicity may be further increased if a diuretic is also administered.

Gold: There are rare reports of nitritoid reactions (symptoms include nausea, vomiting, facial flushing, and hypotension) occurring in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy, including ramipril.

NSAIDs: In patients who are older, volume-depleted (such as those on diuretic therapy), or have kidney disease, the co-administration of NSAIDs (including selective COX-2 inhibitors) with ACE inhibitors like ramipril may lead to worsening renal function, potentially resulting in acute renal failure. These effects are generally reversible. Regular monitoring of renal function is recommended for patients receiving concomitant ramipril and NSAID therapy.

Agents causing angioedema: Patients taking mTOR inhibitors (eg, temsirolimus) or neprilysin inhibitors concurrently with ramipril may be at an increased risk of developing angioedema.

Contraindications

The following conditions are contraindications for ramipril administration.

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.[16]

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, 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, administering ramipril or other ACE inhibitors may worsen their condition.

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.[17]

Box Warning

Pregnancy: Ramipril is contraindicated during pregnancy. Concurrent use of ACE inhibitors in patients who are pregnant is associated with reports of oligohydramnios and skull defects.

Fetus: Medicines that act directly on RAS during the second and third trimesters of pregnancy can cause injury and death to the developing fetus. Potential adverse effects in neonates may include skull hypoplasia, anuria, hypotension, renal failure, and even death. If pregnancy is confirmed, ramipril should be discontinued immediately.

Monitoring

Baseline renal function should be assessed before initiating ramipril. If a significant drop in the estimated glomerular filtration rate (eGFR) occurs after starting ramipril, therapy 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.[18]

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 a drop in blood pressure typically 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 during the first 6 hours after administration, the patient can be considered for discharge.[19]

Enhancing Healthcare Team Outcomes

The interprofessional healthcare team, consisting of clinicians, 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. Working as an interprofessional team increases patient knowledge about prescribed medicine and provides essential details about potential adverse effects for which to be vigilant. This collaborative effort helps patients become more informed and compliant with their medications, leading to improved blood pressure control and overall clinical outcomes. Additionally, all interprofessional team members are responsible for monitoring the patient's progress and identifying 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.

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Anderson VR, Perry CM, Robinson DM. Ramipril: a review of its use in preventing cardiovascular outcomes in high-risk patients. Am J Cardiovasc Drugs. 2006;6(6):417-32. [PubMed: 17192135]

2.

Warner GT, Perry CM. Spotlight on ramipril in the prevention of cardiovascular outcomes. Am J Cardiovasc Drugs. 2003;3(2):113-6. [PubMed: 14727938]

3.

Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022 May 03;145(18):e895-e1032. [PubMed: 35363499]

4.

O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Linderbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Jan 29;61(4):e78-e140. [PubMed: 23256914]

5.

Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Ganiats TG, Holmes DR, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Smalling RW, Zieman SJ., ACC/AHA Task Force Members. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Dec 23;130(25):e344-426. [PubMed: 25249585]

6.

Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int. 2021 Mar;99(3S):S1-S87. [PubMed: 33637192]

7.

Fountain JH, Kaur J, Lappin SL. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Mar 12, 2023. Physiology, Renin Angiotensin System. [PubMed: 29261862]

8.

Thatcher SE. A Brief Introduction into the Renin-Angiotensin-Aldosterone System: New and Old Techniques. Methods Mol Biol. 2017;1614:1-19. [PubMed: 28500591]

9.

Borghi C, Cicero AF, Agnoletti D, Fiorini G. Pathophysiology of cough with angiotensin-converting enzyme inhibitors: How to explain within-class differences? Eur J Intern Med. 2023 Apr;110:10-15. [PubMed: 36628825]

10.

Hermann R, Gundlach K, Seiler D. Mechanistic Considerations About an Unexpected Ramipril Drug-Drug Interaction in the Development of a Triple Fixed-Dose Combination Product Containing Ramipril, Amlodipine, and Atorvastatin. Clin Pharmacol Drug Dev. 2021 Nov;10(11):1307-1315. [PubMed: 33773093]

11.

Soboleva MS, Loskutova EE. Analysis of Preferences in the Use of Fixed-Doses Combinations Antihypertensive Drugs in the Regions of Far-Eastern Federal District. Clinicoecon Outcomes Res. 2020;12:265-272. [PMC free article: PMC7266518] [PubMed: 32547128]

12.

Fischer K, Diec S. Once- Versus Twice-Daily Angiotensin-Converting Enzyme Inhibitors for Blood Pressure Control in Adult Patients With Hypertension. Cureus. 2021 Aug;13(8):e17331. [PMC free article: PMC8451516] [PubMed: 34567875]

13.

Buawangpong N, Teekachunhatean S, Koonrungsesomboon N. Adverse pregnancy outcomes associated with first-trimester exposure to angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers: A systematic review and meta-analysis. Pharmacol Res Perspect. 2020 Oct;8(5):e00644. [PMC free article: PMC7438312] [PubMed: 32815286]

14.

Hallberg P, Persson M, Axelsson T, Cavalli M, Norling P, Johansson HE, Yue QY, Magnusson PK, Wadelius C, Eriksson N, Wadelius M. Genetic variants associated with angiotensin-converting enzyme inhibitor-induced cough: a genome-wide association study in a Swedish population. Pharmacogenomics. 2017 Feb;18(3):201-213. [PubMed: 28084903]

15.

Mu G, Xiang Q, Zhang Z, Liu C, Zhang H, Liu Z, Pang X, Jiang J, Xie Q, Zhou S, Wang Z, Hu K, Wang Z, Jiang S, Qin X, Cui Y. PNPT1 and PCGF3 variants associated with angiotensin-converting enzyme inhibitor-induced cough: a nested case-control genome-wide study. Pharmacogenomics. 2020 Jun;21(9):601-614. [PubMed: 32397904]

16.

Krause AJ, Patel NB, Morgan J. An unusual presentation of ACE inhibitor-induced visceral angioedema. BMJ Case Rep. 2019 Sep 18;12(9) [PMC free article: PMC6754668] [PubMed: 31537593]

17.

Hobbs SD, Claridge MW, Wilmink AB, Adam DJ, Thomas ME, Bradbury AW. Effect of ramipril on renal function in patients with intermittent claudication. Vasc Health Risk Manag. 2008;4(2):471-5. [PMC free article: PMC2496985] [PubMed: 18561523]

18.

Horowitz N, Molnar M, Levy Y, Pollack S. Ramipril-induced agranulocytosis confirmed by a lymphocyte cytotoxicity test. Am J Med Sci. 2005 Jan;329(1):52-3. [PubMed: 15654181]

19.

Lucas C, Christie GA, Waring WS. Rapid onset of haemodynamic effects after angiotensin converting enzyme-inhibitor overdose: implications for initial patient triage. Emerg Med J. 2006 Nov;23(11):854-7. [PMC free article: PMC2464381] [PubMed: 17057137]

Disclosure: Munish Chauhan declares no relevant financial relationships with ineligible companies.

Disclosure: Jayesh Patel declares no relevant financial relationships with ineligible companies.

Disclosure: Faran Ahmad declares no relevant financial relationships with ineligible companies.