Ramipril


Article Author:
Munish Chauhan


Article Editor:
Faran Ahmad


Editors In Chief:
Chaddie Doerr


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Carrie Smith
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Phillip Hynes


Updated:
4/2/2019 5:35:04 PM

Indications

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

  • Hypertension: The most common use of Ramipril is in the treatment of hypertension.
  • Heart failure post-myocardial infarction(MI): Ramipril is used after MI to prevent progression of asymptomatic heart failure with reduced ejection fraction. Patients often initiate therapy on low dose ramipril within hours after the confirmed myocardial infarction.[1][2]
  • Risk Reduction: Ramipril is given 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 also used to treat symptomatic heart failure with reduced ejection fraction. It reduces 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 is a major blood pressure controlling system in the human body.[3][4]

  • Angiotensinogen is produced in the liver and released in the bloodstream as a prohormone.
  • Renin is an enzyme produced by the juxtaglomerular apparatus in the kidneys in response to a low level of perfusion. While low levels of perfusion in the kidneys indicate a low blood pressure, juxtaglomerular apparatus releases renin to increase the blood pressure and subsequently increase the perfusion in the kidneys.
  • Renin acts on the angiotensinogen released by the liver and cleaves ten amino acids, resulting in the production of angiotensin I. Angiotensin I has a role in vasoconstriction and increasing the blood pressure.
  • Angiotensin I circulates in the bloodstream, and when it passes through the lung tissues, it then further converts to angiotensin II by angiotensin-converting enzyme (ACE) which is already present in the lung tissues.

Angiotensin II: Angiotensin II has various effects which help in improving blood pressure.

  • Acts in the brain and increase the release of vasopressin, which helps in improving blood pressure by reabsorbing fluids from the kidneys.
  • Acts on the arterial and venous smooth muscles resulting in vasoconstriction, which also increases blood pressure by increasing total peripheral resistance.
  • Acts on the adrenal gland and helps in the release of Aldosterone. Aldosterone further acts on the renal tubular cells and result in reabsorption of sodium, which in turn causes water reabsorption with sodium in collecting ducts.
  • Increases adrenergic outflow from the central nervous system, which also causes blood pressure to increase.

Angiotensin-converting enzyme inhibitor medications such as ramipril suppress the mechanisms as mentioned above. 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. 

Doses can range between 1.25mg per day to 10mg per day. 

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

Adverse Effects

Dry cough: In the lung tissues, Angiotensin converting enzymes inhibitors also inhibits the degradation of bradykinin. Higher levels of Bradykinin causes a dry cough. This side effect is more prevalent in patients from Afro-Caribbean descent than other cohorts.

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 in elderly patients. Dizziness and lightheadedness are related to postural hypotension when patients suddenly stand up from sitting or lying positions. Patients should receive counsel regarding signs of postural hypotension on initiating the treatment. 

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. 

Ramipril can also cause anxiety-like symptoms including shakiness in some patient. Patients who are known to have anxiety or tremors should be watched for these symptoms for few weeks minimum when initiating ramipril. 

Angioedema, nausea, dry mouth, fatigue, erectile dysfunction have appeared in other patients.

Few other rare side effects include hypoperfusion, movement disorders, onycholysis, and oral disorders. [British National Formulary]

Contraindications

  •  Hypersensitivity: Hypersensitivity to ramipril or any other ACE-i including hereditary or idiopathic angioedema is a major contraindication.  
  • Hyperkalaemia: Aldosterone is also responsible for 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, 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 by decreasing the reabsorption of sodium in renal tubules.
  • The Afro-Caribbean patients may not be able to tolerate the ACE-i due to its side effect of a dry cough.
  • Patients who have developed hypotension due to any cause, ramipril should be stopped.
  • Other contraindications include severe vomiting, azotemia, pregnancy, deranged liver function test.
  • Angiotensin-converting enzyme inhibitors should be avoided in pregnancy. They can affect fetal blood pressure. Oligohydramnios and skull defects have been reported with concurrent use of ACE-i in pregnant ladies. [British National Formulary]

 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.[5]

Monitoring

  • Renal function should be checked before starting ramipril. If there is a significant drop in renal function after starting ramipril, then the drug should be stopped, and alternative medications should be used to control the blood pressure.
  • Patient monitoring for signs of postural hypotension, angioedema, and hyperkalemia is recommended.

Toxicity

Ramipril overdose can result in severe hypotension.

A study conducted in 2006 to investigate the effects of ramipril overdose on blood pressure concluded that in most cases, drop in blood pressure occurs within first 4-4.5 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. [6]

Enhancing Healthcare Team Outcomes

Health care professionals including family physicians, specialists, nurses, and pharmacists are valuable sources of information for patients. Increasing patient's knowledge about the medication and providing them information about possible side effects to look for, would make patients more compliant with their medications and subsequently improve their blood pressure control.


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Ramipril - Questions

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The HOPE (Heart Outcomes Prevention Evaluation) studied the use of ramipril for prevention of cardiovascular disease. Which of the following outcomes was not affected?



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Which drug was studied in the Heart Outcomes Prevention Evaluation (HOPE)?



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Ramipril - References

References

Anderson VR,Perry CM,Robinson DM, Ramipril: a review of its use in preventing cardiovascular outcomes in high-risk patients. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2006;     [PubMed]
Warner GT,Perry CM, Spotlight on ramipril in the prevention of cardiovascular outcomes. American journal of cardiovascular drugs : drugs, devices, and other interventions. 2003;     [PubMed]
Fountain JH,Lappin SL, Physiology, Renin Angiotensin System 2018 Jan;     [PubMed]
Thatcher SE, A Brief Introduction into the Renin-Angiotensin-Aldosterone System: New and Old Techniques. Methods in molecular biology (Clifton, N.J.). 2017;     [PubMed]
Hobbs SD,Claridge MW,Wilmink AB,Adam DJ,Thomas ME,Bradbury AW, Effect of ramipril on renal function in patients with intermittent claudication. Vascular health and risk management. 2008;     [PubMed]
Lucas C,Christie GA,Waring WS, Rapid onset of haemodynamic effects after angiotensin converting enzyme-inhibitor overdose: implications for initial patient triage. Emergency medicine journal : EMJ. 2006 Nov;     [PubMed]

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