Ramipril

Ramipril is an ACE inhibitor used for the treatment of hypertension, Heart failure with reduced ejection fraction and reduction in risk of myocardial infarction, stroke, and death from cardiovascular causes. It is also used to treat Non–ST-elevation acute coronary syndrome, Proteinuric chronic kidney disease (diabetic or nondiabetic), and ST-elevation acute coronary syndrome.

The extent of absorption is 50-60%. Food decreases the rate of absorption from the GI tract without affecting the extent of absorption. Absolute bioavailability of Ramipril and ramiprilat are 28% and 44%, respectively, when oral administration was compared to intravenous administration.

Ramipril is available in the form of dosage forms as tablets.

Ramipril is available in India, France, Japan, and the USA.

Ramipril belonging to ACE inhibitors, acts as an Antihypertensive agent. Ramipril acts by inhibiting the Angiotensin-converting enzyme (ACE). The beneficial effects of Ramipril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system.

The onset of action is achieved in about 1 hour.

The Cmax for ramipril is 25 ng/mL.

The tmax for Ramipril is more than 50 hrs.

Ramipril is available in the form of tablets and capsules .

Ramipril tablets and capsules to be swallowed whole with water.

Ramipril comes as a tablet to be taken by mouth. It is usually taken two times a day.

Ramipril is an ACE inhibitor used for the treatment of hypertension, Heart failure with reduced ejection fraction and reduction in risk of myocardial infarction, stroke, and death from cardiovascular causes. It is also used to treat Non–ST-elevation acute coronary syndrome, Proteinuric chronic kidney disease (diabetic or nondiabetic), and ST-elevation acute coronary syndrome.

Angiotensin-converting enzyme (ACE) inhibitors are widely used in the treatment of heart failure. These agents decrease formation of angiotensin II, thereby decreasing both arteriolar and venous resistance.

Ramipril is approved for use in the following clinical indications

Hypertension

Ramipril is indicated for the treatment of hypertension. It may be used alone as the initial therapy or concomitantly with other classes of antihypertensive agents..

Heart failure

Ramipril is indicated as adjunctive therapy in the management of heart failure in patients who are not responding adequately to diuretics and digitalis.

Acute Myocardial Infraction

Ramipril is indicated for treatment of hemodynamically stable patients within 24 hours of the acute myocardial infarction, to improve survival rate. Patients should receive, as appropriate, standard recommended treatments such as thrombolytics, aspirin and beta blockers.

Ramipril is available in the form of tablets and capsules.

Ramipril is available in various dosage strengths as 1.25 mg, 2.5 mg, 5 mg, 10 mg.

Ramipril is available in the form of tablets and capsules.

Dose Adjustment in Kidney patient:

CrCl >40 mL/minute: No dosage adjustment necessary.

• CrCl <40 mL/minute: Administer 25% of normal dose.
• Heart failure with reduced ejection fraction: Initial: 1.25 mg once daily, may increase to 1.25 mg twice daily and then up to a maximum of 2.5 mg twice daily as tolerated.
• Hypertension, chronic: Initial: 1.25 mg once daily, titrated as tolerated to effect; maximum: 5 mg/day.
• Renal artery stenosis: Initial: 1.25 mg once daily; titrate as tolerated to effect.

Dose Adjustment in the pediatric patient:

Ramipril is not recommended for use in pediatrics or adolescents.

Ramipril is approved for the treatment of hypertension, Heart failure with reduced ejection fraction and reduction in risk of myocardial infarction, stroke, and death from cardiovascular causes. It is also used to treat Non–ST-elevation acute coronary syndrome; Proteinuric chronic kidney disease (diabetic or nondiabetic); ST-elevation acute coronary syndrome.

Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.

The food limitation should be tailored to the patient's needs.

Ramipril may be contraindicated in the following:

Hypersensitivity to Ramipril, other ACE inhibitors, or any component of the formulation; hereditary/idiopathic angioedema or history of angioedema related to previous treatment with an ACE inhibitor; concomitant use with aliskiren in patients with diabetes mellitus; concomitant use or within 36 hours of switching to or from a neprilysin inhibitor (eg, sacubitril).

The treating doctor must preserve pharmacovigilance as follows and continuously monitor the patient.

Concerns related to adverse effects:

• Anemia: ACE inhibitors can suppress the production of erythropoietin. This is more likely to occur in the presence of chronic kidney disease.

• Hypersensitivity reactions: Anaphylactic reaction/nonimmune anaphylaxis can occur with ACE inhibitors. Severe nonimmune anaphylaxis may be seen during hemodialysis (eg, CVVHD) with high-flux dialysis membranes (eg, AN69), and rarely, during low-density lipoprotein apheresis with dextran sulfate cellulose. Rare cases of nonimmune anaphylaxis have been reported in patients undergoing sensitization treatment with hymenoptera (bee, wasp) venom while receiving ACE inhibitors.

• Hypotension/syncope: Symptomatic hypotension with or without syncope can occur (usually with the first several doses); effects are most often observed in volume-depleted patients; correct volume depletion prior to initiation; close monitoring of patient is required especially with initial dosing and dosing increases; blood pressure must be lowered at a rate appropriate for the patient's clinical condition. Although dose reduction may be necessary, hypotension is not a reason for discontinuation of future ACE inhibitor use, especially in patients with heart failure where a reduction in systolic blood pressure is a desirable observation.

Disease-related concerns:

• Aortic stenosis: Use with caution in patients with severe aortic stenosis; may reduce coronary perfusion resulting in ischemia.

• Ascites: Generally, avoid use in patients with ascites due to cirrhosis or refractory ascites; if use cannot be avoided in patients with ascites due to cirrhosis, monitor BP and renal function carefully to avoid rapid development of renal failure.

• Cardiovascular disease: Initiation of therapy in patients with ischemic heart disease or cerebrovascular disease warrants close observation due to the potential consequences posed by falling blood pressure (eg, MI, stroke). Fluid replacement, if needed, may restore blood pressure; therapy may then be resumed. Discontinue therapy in patients whose hypotension recurs.

• Hepatic impairment: Use with caution in patients with hepatic impairment (Ramipril is primarily metabolized by hepatic esterases and these patients could develop markedly elevated plasma levels of Ramipril).

• Hypertrophic cardiomyopathy with left ventricular outflow tract obstruction: Use with caution in patients with hypertrophic cardiomyopathy and left ventricular outflow tract obstruction since reduction in afterload may worsen symptoms associated with this condition .

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment may be needed. Avoid rapid dosage escalation which may lead to further renal impairment.

Special populations:

• Race/Ethnicity: In Black patients, the BP-lowering effects of ACE inhibitors may be less pronounced. The exact mechanism is not known; differences in the renin-angiotensin-aldosterone system, low renin levels, and salt sensitivity more commonly found in Black patients may contribute.

• Surgical patients: In patients on chronic ACE inhibitor therapy, intraoperative hypotension may occur with induction and maintenance of general anesthesia; use with caution before, during, or immediately after major surgery. Cardiopulmonary bypass, intraoperative blood loss, or vasodilating anesthesia increases endogenous renin release. Use of ACE inhibitors perioperatively will blunt angiotensin II formation and may result in hypotension. However, discontinuation of therapy prior to surgery is controversial. If continued preoperatively, avoidance of hypotensive agents during surgery is prudent. Based on current research and clinical guidelines in patients undergoing non-cardiac surgery, continuing ACE inhibitors is reasonable in the perioperative period. If ACE inhibitors are held before surgery, it is reasonable to restart postoperatively as soon as clinically feasible.

Drinking alcohol while taking the Ramipril can increase drowsiness and dizziness, which in turn increase the risk of accidental injury.

Ramipril use in breast feeding patients is not recommended.

Potassium Rich Foods: Bananas, sweet potatoes, nuts, and other foods rich in potassium when taken along with Ramipril, can be led to an increase in blood potassium levels.

Pleurisy Root: Pleurisy roots are not recommended with most heart medications due to the cardiac glycoside content of the root.

The adverse reactions related to molecule Ramipril can be categorized as

• Common Adverse effects:

Insomnia, Muscle pain, Dizziness, fatigue etc.

• Less Common adverse effect:

Nervousness, Elevated liver enzymes, joint paint, edema, vivid dreams, abdominal discomfort, nausea, muscle cramps, paresthesia, bradycardia, cold extremities, hypotension, palpitations, syncope, Tachycardia, Anxiety, lethargy, diarrhea, vomiting, Impotence/reduced libido.

• Rare adverse effects:

Heart failure, tachyarrhythmia, bronchospasm, depression, decreased exercise tolerance, Raynaud's phenomenon, etc.

The clinically relevant drug interactions of Ramipril are briefly summarized here:

• May increase risk for angioedema with mammalian target of rapamycin (mTOR) inhibitors (e.g., everolimus, sirolimus, temsirolimus), dipeptidyl peptidase-4 (DPP-4) inhibitors (e.g. vildagliptin), neutral endopeptidase (NEP) inhibitor (e.g. racecadotril).
• May increase risk for hyperkalaemia with K salts, K-sparring diuretics, other drugs that increase K levels (e.g. heparin, trimethoprim/sulfamethoxazole, tacrolimus, ciclosporin).
• May increase risk of hypotension with other antihypertensive drugs (e.g., diuretics), other drugs that decrease blood pressure (e.g. anaesthetic, alfuzosin, baclofen, doxazosin, nitrates, prazosin, TCAs, tamsulosin, terazosin).
• May have decreased antihypertensive effect with vasopressor sympathomimetics and other drugs (e.g., dobutamine, dopamine, epinephrine, isoproterenol).
• May increase risk for haematologic reactions with allopurinol, cytostatics, corticosteroids, immunosuppressants, procainamide, and other drugs that alter blood cell count. May increase serum levels and toxicity of lithium. May increase risk for hypoglycaemia with antidiabetic drugs (e.g., insulin).
• Reduced antihypertensive effect, increased risk of worsening renal function and increased serum K levels with NSAIDs.
• Potentially Fatal: Increased risk of hypotension, hyperkalaemia and impaired renal function (e.g. acute renal failure) with aliskiren. Increased risk of angioedema with concomitant sacubitril/valsartan therapy. May cause severe anaphylactic reactions with dextran sulfate in LDL apheresis. Increased risk for toxicity with angiotensin II receptor blockers in patients with diabetic nephropathy.

The common side of Ramipril include the following:

Cold hands or feet, Eye irritation, upset stomach, headache, depression, dizziness, nausea, etc.

The use of Ramipril should be prudent in the following group of special populations:

Pregnancy

AU TGA pregnancy category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.

US FDA pregnancy category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks

Labor and Delivery

There is no FDA guidance on the use of Ramipril during labor and delivery.

Nursing Mothers

Since Ramipril is secreted in the human milk, nursing should not be undertaken by the mothers receiving the drug.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

There is no FDA guidance on the use of Ramipril in geriatric settings.

Symptoms: Excessive peripheral vasodilation (e.g. marked hypotension, shock), bradycardia, electrolyte disturbance, renal failure.

Management: Symptomatic and supportive treatment. May perform gastric lavage or administer adsorbents; give α₁- adrenergic agonists or angiotensin II (angiotensin amide) to restore hemodynamic stability.

Pharmacodynamics:

Like benazepril, fosinopril, and quinapril, Ramipril is an ACE inhibitor. 5 The liver, which serves as the primary site of activation, and the kidneys transform the inactive prodrug into ramiprilat. The blood pressure-lowering effects of ramiprilat are achieved by counteracting the RAAS's impact. The RAAS is a homeostatic process that controls the balance of electrolytes, water, and hemodynamics.

Pharmacokinetics:

Absorption

The extent of absorption is 50-60%. Food decreases rate of absorption from the GI tract without affecting the extent of absorption. The absolute bioavailabilities of Ramipril and ramiprilat were 28% and 44%, respectively, when oral administration was compared to intravenous administration. The serum concentration of ramiprilat was unchanged when capsules were opened and the contents dissolved in water, dissolved in apple juice, or suspended in apple sauce.

Distribution

Protein binding of Ramipril is about 73% and that of ramiprilat about 56%. Protein binding is independent of the concentration over the range of 0.1μg/mL-10μg/mL

Metabolism

Hepatic metabolism accounts for 75% of total ramipril metabolism 25% of hepatic metabolism produces the active metabolite ramiprilat via liver esterase enzymes. 100% of renal metabolism converts Ramipril to ramiprilat. Other metabolites, diketopiperazine ester, the diketopiperazine acid, and the glucuronides of Ramipril and ramiprilat, are inactive.

Elimination

Following oral administration, about 60% of the dose is eliminated in the urine as unchanged Ramipril and its metabolites. About 40% of the dose is found in the feces, representing both unabsorbed drug and drugs and metabolites eliminated via biliary excretion.

• https://www.pfizer.com/products/product-detail/altace
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022021s008lbl.pdf
• https://go.drugbank.com/drugs/DB00178