Ramipril - Mechanism of Action, Indications, Dosage, and Adverse Drug Reactions

Overview

Angiotensin-converting enzyme (ACE) inhibitors like Ramipril are used to treat congestive heart failure (a chronic condition where the heart fails to pump blood efficiently) and hypertension (high blood pressure). By preventing the synthesis of angiotensin II, it lowers blood pressure. It is recommended to treat post-heart attack survival, congestive heart failure, and hypertension. The Food and Drug Administration (FDA) has approved Ramipril to treat hypertension and lower the risk of heart failure following myocardial infarction or MI (a condition where blood clots restrict blood flow to the heart). Approved for medicinal use in 1989, the patent was obtained in 1981. On February 27, 2007, the FDA authorized its usage for medicinal purposes. With over two million prescriptions in 2021, it is currently accessible as a generic and is ranked as the 201st most often prescribed drug in the United States.

Drug Group

The class of medications known as angiotensin-converting enzyme (ACE) inhibitors includes Ramipril. It functions by causing the blood vessels to relax and enlarge, facilitating easier blood flow through them. The heart has to work less to pump blood as a result. Because of this characteristic, it helps treat heart failure.

Indications

• Ramipril is approved to treat hypertension. It can be taken with Thiazide diuretics or without them.

• When a patient is 55 years of age or older and at high risk of having a serious cardiovascular incident, it is recommended to use Ramipril to lower the risk of MI, stroke (a blockage in blood supply to a part of the brain or a burst blood vessel), or passing away from heart-related conditions.

• After a myocardial infarction, stable patients who have shown clinical evidence of congestive heart failure might consider Ramipril.

Contraindications

• Angioedema (swelling under the skin) associated with ACE inhibitor therapy in the past or a history of idiopathic or hereditary angioedema.

• When using Aliskiren and Ramipril together for patients who have diabetes (high blood sugar) or renal impairment with GFR (glomerular filtration rate) less than 60 mL/min ( milliliters per minute) per 1.73 m2 (meter square)), it is not recommended.

Dosage Forms and Available Strengths

The Ramipril capsule is available in different dosages, including 1.25 mg (milligram), 2.5 mg, 5 mg, and 10 mg.

Warnings and Precautions

The following have been linked to the use of ACE inhibitors:

• Angioedema, with a higher risk in patients with a history or when paired with mTOR (mechanistic target of Rapamycin) inhibitors.

• Hyperkalemia (high potassium levels) and hypotension (low blood pressure).

• Monitoring renal function during therapy for patients experiencing renal impairment is best.

• There is a higher risk of renal damage in the presence of an additional renin-angiotensin-aldosterone system blocker.

• Hepatic failure and rare cholestatic jaundice (a condition where the liver's bile flow ceases or slows down).

• Agranulocytosis (severe neutropenia) and rare neutropenia (low neutrophil counts).

For Patients

What Is Hypertension?

High blood pressure, or hypertension, is a chronic medical disorder characterized by persistently excessive blood pressure in the arteries. The heart has to work harder due to pumping blood throughout the body. The unit to measure blood pressure is millimeters of mercury or mm Hg.

Three blood pressure classifications exist:

• Stage 1 (130 to 139 per 80 to 89 mm Hg).

• Stage 2 (140 and above or more than 90 mm Hg).

• Hypertensive emergency (greater than 180 or higher than 120 mm Hg).

• Normal (120 per 80 mm Hg).

The majority of people with high blood pressure do not experience any symptoms, but when the condition gets severe or life-threatening, some people may suffer headaches, breathlessness, and nosebleeds. High blood pressure that is left untreated raises the risk of heart attack, stroke, and other major health issues. A balanced diet, frequent exercise, and quitting smoking are lifestyle choices that can help prevent and control high blood pressure. It is imperative to undergo routine blood pressure readings, particularly if people are at risk or have a family history of hypertension.

How Does Ramipril Work?

ACE, which produces angiotensin II and aldosterone, narrows the arteries and increases blood pressure. Ramipril inhibits ACE, opening arteries, lowering blood pressure, reducing heart workload, and resolving heart failure symptoms by facilitating blood pumping and reducing the workload on the heart.

What Are the Clinical Uses of Ramipril?

Ramipril is used in several clinical settings. The clinical uses are as follows:

• Hypertension (High Blood Pressure): By blocking the synthesis of angiotensin II, a strong vasoconstrictor, Ramipril efficiently decreases blood pressure. It lessens the burden on the heart and arteries by assisting in maintaining appropriate blood pressure levels.

• Heart Failure: Ramipril is used to treat heart failure. It lessens the workload on the heart by widening blood vessels and enhancing blood flow.

• Post-Heart Attack (Myocardial Infarction): Ramipril improves survival and stops additional cardiovascular events following a heart attack. It lowers the chance of cardiovascular mortality, heart attack, and stroke.

• Kidney Damage (Nephropathy): Ramipril decreases the course of kidney damage in those with diabetes who also have albuminuria (protein in the urine).

How Is Ramipril Administered?

• Ramipril is available as an oral capsule. It can be taken with or without food, usually once or twice a day. Take Ramipril at roughly the same time each day to help with remembering. Pay close attention to the instructions on the label of the prescription, and ask the physician or pharmacist to explain anything you need help understanding. Consume Ramipril as prescribed. Never take more or less of it or more frequently than the doctor has instructed.

• People can either swallow the capsule whole or open it and sprinkle the contents over 4 ounces (approximately 120 mL) of applesauce or 4 ounces (about 120 mL) of water or apple juice. Drink or eat the entire mixture. This mixture can be made and kept in the refrigerator for 48 hours or at room temperature for 24 hours.

• Most likely, the physician will start patients on a low dosage of Ramipril and increase it gradually.

• Although it does not treat heart failure or high blood pressure, Ramipril manages these conditions. Take Ramipril as prescribed, even if patients are fine. Always consult the physician before taking Ramipril.

What Are the Side Effects of Ramipril?

Ramipril side effects are possible. If any of these symptoms are severe or persistent, let the doctor know:

• Headache.

• Lightheadedness.

• Cough.

• Stomach discomfort.

• Vomiting.

• Extreme fatigue.

• Weakness.

Certain adverse effects of Ramipril may be dangerous. Give the doctor a call right away if patients encounter any of the following symptoms:

• Swelling in the hands, feet, ankles, eyes, throat, tongue, lips, and lower limbs.

• Hoarseness.

• Breathing or swallowing difficulties.

• Skin or eye yellowing.

• Chills, sore throat, fever, and other infection-related symptoms.

• Dizziness.

• Losing consciousness.

If patients have odd side effects while taking Ramipril, contact the doctor who prescribed it.

What Are the Things to Inform the Doctor Before Taking Ramipril?

• Inform the doctor if patients have an allergy to any of the following before taking Ramipril: Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Quinapril, Trandolapril, other ACE inhibitors, any other medications, or any chemicals in Ramipril capsules.

• If patients are taking Valsartan and Sacubitril or stopped taking it in the past 36 hours, let the doctor or pharmacist know. If patients also take Sacubitril and Valsartan, the physician will likely advise against using Ramipril. Additionally, let the doctor know if patients use Aliskiren and have diabetes. If patients take Aliskiren and have diabetes, the physician will likely advise against using Ramipril.

• Inform the doctor and pharmacist about all the vitamins, nutritional supplements, herbal items, prescription and over-the-counter drugs, and vitamins used by patients. Make sure to bring up any of these: Aspirin, other NSAIDs (nonsteroidal anti-inflammatory drugs), diuretics, lithium, and potassium supplements. The physician might need to carefully monitor patients for any negative effects or adjust the dosages of the medications.

• If patients have ever experienced swelling in the hands, feet, ankles, eyes, neck, tongue, lips, face, or lower legs while taking Ramipril, let the physician know. Most likely, the physician will advise against taking Ramipril.

• Inform the doctor if patients now have or have ever had diabetes, lupus (a condition where the immune system damages its tissues), scleroderma (a disorder where excess tissue forms on the skin and in some organs), heart, liver, or kidney illness.

• Inform the doctor if patients are nursing a child.

• Inform the physician or dentist that patients are taking Ramipril if they are undergoing surgery, including dental surgery.

• Patients should be aware that vomiting, diarrhea, dehydration, and excessive sweating can lower blood pressure, which might result in dizziness and fainting.

Dietary Considerations

Consult the doctor before utilizing potassium-containing salt alternatives. If the doctor recommends a low-sodium or low-salt diet, carefully follow these guidelines.

Missed Dose

Patients should take the missed Ramipril dose as soon as they remember, but if the next dose is near, skip it and follow the usual dosage plan, never taking two doses to compensate for a missed dose.

Overdose

Single oral doses of 10 to 11 g/kg (grams per kilogram) of Ramipril in rats and mice can result in substantial mortality, but in dogs, the effects are minor gastrointestinal distress. There is a lack of information regarding overdosages in humans, and there are no laboratory tests for metabolites or blood levels. No hemodialysis technique or physiological strategy can speed up the removal of Ramipril and its metabolites. Although it is unavailable outside of research facilities, angiotensin II may function as an antagonist-antidote.

Storage and Handling

Ramipril should be stored in its original container, properly closed, and out of the reach of young children. Keep it out of the bathroom and at room temperature (77°F (degrees Fahrenheit) (25°C (degrees Celsius)), away from heat and moisture. Make sure to dispose of unnecessary Ramipril to keep it out of the reach of children, pets, and other individuals.

For Doctors

Pharmacodynamics

Ramipril gets converted into Ramiprilat in the kidneys and liver, which lowers blood pressure by acting on the renal adrenergic system (RAAS). Hemodynamics, water, and electrolyte balance are all regulated by RAAS. When sympathetic stimulation or decreased renal blood pressure occurs, the kidneys produce renin, which cleaves circulating angiotensinogen to angiotensinogen (ATI) and then to angiotensinin (ATII).

Through vasopressin, aldosterone, and arterial vasoconstriction, ATII raises blood pressure. ACE medications counteract RAAS-induced elevations in blood pressure by blocking the quick conversion of ATI to ATII. Bradykinin levels are raised by inhibiting its deactivation, which may prolong the benefits of Ramiprilat by promoting vasodilation and lowering blood pressure.

Mechanism of Action

By attaching to and inhibiting ACE, Ramipril blocks the RAAS system and stops angiotensin I from becoming angiotensin II. The G-protein coupled receptors angiotensin receptor I (AT1R) and angiotensin receptor II (AT2R) are less activated as levels of angiotensin II drop. Vasoconstriction, oxidative stress, inflammation, and fibrosis are all mediated by AT1R.

Vasoconstriction and inflammation are decreased by Ramipril's cardioprotective, renoprotective, and antihypertensive properties. To counteract, AT2R activates phosphotyrosine phosphatases, inhibits MAP kinases, prevents the opening of Ca2+ channels, and increases the generation of cGMP and nitric oxide, which causes vasodilation. The Mas receptor, triggered by Ang(1 to 7), a subtype of angiotensin generated by ACE2 from AngII or plasma esterases from AngI, shares these properties.

Pharmacokinetics

• Absorption: Food impacts the absorption of Ramipril and Ramiprilat, with bioavailabilities of 28 percent and 44 percent, respectively. After food is consumed, absorption rates drop, and the serum concentration remains unaltered after the capsules dissolve.

• Distribution: Approximately 73 percent of Ramipril and 56 percent of Ramiprilat bind to proteins. Protein binding remains constant between 0.1 μg/mL (micrograms per milliliter) and 10 μg/mL, regardless of concentration.

• Metabolism: 75 percent of the total amount of Ramipril is converted by hepatic metabolism, which produces the active metabolite Ramiprilat, whereas 100 percent of the Ramipril is converted by renal metabolism, leaving other metabolites inactive.

• Excretion: Ramipril is an oral medication excreted in urine and feces, with 40 percent of the dose ending up in the former and 60 percent in the latter. Ramiprilat has a triphasic half-life, with a fast initial decline, apparent elimination phases that last 9 to 18 hours, and terminal elimination phases that last more than 50 hours. In healthy elderly patients with normal renal function, the renal clearance of Ramipril and Ramiprilat is 7.2 and 77.4 mL/min (milliliters per minute)/1.73m2 (square meters), respectively, with a mean clearance of 10.7 and 126.8 mL/min. Patients with hepatic failure first raise their Ramipril levels, although the tmax (time to peak drug concentration) is prolonged.

Drug Interactions

• Diuretics: Following Ramipril medication, patients using diuretics may develop hypotensive symptoms. Reduce or stop using diuretics to lessen the consequences of hypotension or increase salt intake. While potassium-sparing diuretics or potassium supplements can raise the risk of hyperkalemia, Ramipril can lessen the amount of potassium lost when taking thiazide diuretics. Regularly check the patient's serum potassium levels.

• Lithium: Increased serum lithium levels and symptoms of lithium toxicity may occur in patients on ACE inhibitors during lithium therapy, requiring frequent monitoring and raising the risk if a diuretic is taken.

• Gold: There have been reports of nitritoid reactions, which include face flushing, nausea, vomiting, and hypotension.

• Non-steroidal Anti-inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors(COX-2 Inhibitors): The risk of renal impairment and loss of antihypertensive efficacy is increased when NSAIDs are used.

• mTOR Inhibitors: The use of mTOR inhibitors has been linked to an increased risk of angioedema.

Clinical Studies

As efficacious as Atenolol and other ACE inhibitors, Ramipril is a monotherapy for hypertension. It lowers blood pressure while standing and lying down without causing compensatory tachycardia. When used with thiazide diuretics, blood pressure is lowered even further. The antihypertensive impact lasts at least two years, with Hydrochlorothiazide outperforming Ramipril. The effectiveness of Ramipril is not affected by weight, sex, or age. Renal blood flow increased by 15 percent in a baseline controlled trial of ten patients with mild essential hypertension who had their blood pressure lowered. The glomerular filtration rate remained constant in volunteers in good health.

Use in Specific Populations

• Pregnancy: If pregnancy is detected, Ramipril should be discontinued.

• Breastfeeding: It is not advised for breastfeeding mothers to use Ramipril.

• Pediatric Use: Neonates with a history of Ramipril exposure should focus on blood pressure and renal perfusion, potentially requiring exchange transfusions or dialysis. Ramipril removal may be helpful, but safety and effectiveness in pediatric patients are not established.

• Geriatric Use: U.S. (United States) clinical studies on Ramipril showed no overall differences in effectiveness or safety between patients over 65 and 75. However, higher sensitivity in some older individuals may be observed, with peak ramiprilat levels and area under the plasma concentration-time curve (AUC) being higher in older patients.

• Renal Impairment: Ramipril should be started at a lower dose in patients with moderate-to-severe impairment, according to a study on hypertensive patients with renal impairment.