Ramipril

Overview

Ramipril (Vasotop®) is an angiotensin converting enzyme (ACE) inhibitor used in dogs and cats. It is used in the management of congestive heart failure and may be useful as adjunctive treatment for proteinuria associated with renal disease.

In dogs, ramipril is used for the treatment of congestive heart failure, often in combination with diuretics and other cardiac medications. It may also be used to treat heart failure in cats, although this use is based mainly on experience in other species, and in the management of proteinuria associated with chronic renal insufficiency, glomerular disorders, and protein-losing nephropathies.

Mechanism of Action (MOA): Ramipril is a prodrug that is converted in the liver to its active metabolite ramiprilat, which inhibits the conversion of angiotensin I to angiotensin II and inhibits the breakdown of bradykinin. This results in reduced preload and afterload through venodilation and arteriodilation, decreased aldosterone production, reduced salt and water retention, and inhibition of angiotensin-aldosterone-mediated cardiac and vascular remodeling. In the kidney, efferent arteriolar dilation may reduce intraglomerular pressure and decrease proteinuria.

Indications

Ramipril is used in dogs and cats for the management of selected cardiovascular and renal disorders.

• Congestive heart failure (dogs): Treatment of congestive heart failure of New York Heart Association (NYHA) decompensation grades II to IV in the dog, arising from chronic degenerative valvular heart disease or cardiomyopathy. It may be given with a diuretic and with digoxin or methyl-digoxin.
• Heart failure (cats): May be used in cats with heart failure, although this use is largely extrapolated from other species; it showed no significant benefit in Maine coon cats with hypertrophic cardiomyopathy without heart failure.
• Proteinuria: Management of proteinuria associated with chronic renal insufficiency, glomerular disorders, and protein-losing nephropathies.
• Systemic hypertension: May reduce blood pressure in hypertensive patients; in cats it has been used for elevated systolic blood pressure between 160 and 230 mm Hg and the clinical signs associated with it.

Dosage (Reference)

Dog

Ramipril is used for the management of heart failure. The dose may be increased after 2 weeks according to the severity of pulmonary congestion.

Cat

Ramipril has been used for the management of systemic hypertension. The dose is increased in cats whose systolic blood pressure remains above 160 mm Hg on Day 14 of treatment.

Warnings & Precautions

Ramipril may affect blood pressure, renal function, and electrolyte balance. Careful monitoring is recommended during treatment.

• Hypotension: Use cautiously in patients with hypotension. ACE inhibitors are more likely to cause or worsen prerenal azotaemia in hypotensive animals.
• Reduced renal perfusion: Use cautiously in animals with poor renal perfusion, including acute oliguric renal failure.
• Hyponatraemia: Use cautiously in patients with hyponatraemia.
• Outflow tract obstruction: Use cautiously if outflow tract obstruction is present, and do not use in haemodynamically relevant obstruction such as aortic or subaortic stenosis or obstructive hypertrophic cardiomyopathy.
• Monitoring: Regular monitoring of blood pressure, serum creatinine, urea, and electrolytes is strongly recommended during treatment. Check renal function before starting and again 7 days after starting, and repeat whenever the dose of ramipril or of a concurrent diuretic is increased.
• Heart failure patients: Monitor blood pressure, serum creatinine, and electrolytes during treatment.
• Dose adjustment: If signs of hypotension such as weakness, disorientation, apathy or ataxia develop, suspend treatment until they resolve and then continue at 50% of the original dose.
• Breeding, pregnancy, and lactation: Not recommended for breeding bitches. Avoid ramipril during pregnancy and lactation unless the maternal benefit clearly outweighs the potential risk to the offspring. ACE inhibitors cross the placenta and may cause foetal malformations or death, and ramipril is excreted in maternal milk.
• Dehydration and hypovolaemia: Use of ACE inhibitors in dehydrated or hypovolaemic patients – for example on large doses of a diuretic, or with vomiting or diarrhoea – can cause acute hypotension. Correct fluid and electrolyte status first and suspend treatment until the patient is stable. In patients at risk of hypovolaemia, the product label for dogs advises introducing the drug gradually over one week, starting at half the therapeutic dose.
• Hepatic dysfunction: Ramipril is a prodrug converted to its active form in the liver; this conversion may be reduced in patients with impaired liver function.
• Hypersensitivity: Contraindicated in patients that are hypersensitive to ramipril or to any other ACE inhibitor.
• Handling: Pregnant women should take special care to avoid accidental exposure and should wash their hands after use, because ACE inhibitors can affect the unborn child in humans.

Drug Interactions

The interactions below are reported or theoretical in humans or animals. Unless otherwise stated, concurrent use is not necessarily contraindicated, but weigh the potential risks and perform additional monitoring when appropriate.

• Potassium-sparing diuretics (e.g., spironolactone) and potassium supplements: May increase the risk of hyperkalaemia. However, spironolactone and ACE inhibitors appear safe to use concurrently in clinical practice, although the product label advises against combining ramipril with potassium-sparing diuretics; monitor serum potassium if they are used together.
• NSAIDs: May increase the risk of nephrotoxicity and reduce the clinical efficacy of ramipril when it is used as an antihypertensive. Combining an ACE inhibitor with an NSAID impairs autoregulation of glomerular blood pressure and can trigger acute renal failure.
• Diuretics: Concurrent use may increase the risk of hypotension; titrate doses carefully and avoid high diuretic doses and low-sodium diets, which potentiate the effect. The furosemide dose can be reduced when ramipril is added to achieve the same diuretic effect.
• Vasodilators (e.g., anaesthetic agents, antihypertensive agents): Concurrent use may increase the risk of hypotension.
• Negative inotropes (e.g., beta-blockers): Concurrent use may increase the risk of hypotension.
• Antacids: Aluminium-, calcium- and magnesium-containing antacids may reduce oral absorption of ramipril; separate the doses by at least 2 hours.
• Digoxin: Adding an ACE inhibitor may increase digoxin concentrations by 15% to 30%. An automatic dose reduction is not recommended, but monitor serum digoxin concentration.
• Angiotensin receptor blockers: In human medicine, combining an ACE inhibitor with an angiotensin receptor blocker such as losartan or telmisartan increases the risk of hypotension, hyperkalaemia and changes in renal function, without evidence of added benefit.
• Corticosteroids: Dexamethasone, fludrocortisone and prednisolone may reduce the antihypertensive effect of ACE inhibitors.
• Anaesthetic agents and opioids: Concurrent use with anaesthetics, or with opioids such as buprenorphine, hydrocodone and morphine, may increase the risk of hypotension.
• Other drugs that lower blood pressure: Baclofen, buspirone and cabergoline may increase or add to the risk of hypotension.
• Further drugs affecting blood pressure or glucose: Diphenhydramine, doxepin and oral glycerin may increase the risk of hypotension, and the hypoglycaemic effects of disopyramide may be enhanced.
• Cimetidine: Neurologic dysfunction has been reported in two human patients given cimetidine with an ACE inhibitor.
• Anticoagulants: Heparin and low molecular weight heparins such as dalteparin and enoxaparin may increase the risk of hyperkalaemia.
• Darbepoetin: ACE inhibitors may interfere with erythropoietin, which is relevant in chronic kidney disease patients receiving darbepoetin.
• Probenecid: Can decrease renal excretion of ramipril and may enhance both its clinical and its toxic effects.

Side Effects & Overdose

Side Effects

Although adverse-effect information for ramipril is limited, it appears well tolerated. Gastrointestinal effects are probably the most likely, while weakness, hypotension, hyperkalaemia and azotaemia are also possible.

• Hypotension: May occur during treatment.
• Hyperkalaemia: Increased serum potassium concentrations may develop.
• Azotaemia: May occur, particularly in susceptible patients.
• Gastrointestinal effects: Anorexia, vomiting, and diarrhoea have been reported rarely.
• Weakness and neurological signs: Weakness, disorientation, apathy or ataxia may be seen and may be signs of hypotension.
• Angioedema, cough and cholestatic jaundice: Angioedema and cough, caused by bradykinin accumulation, appear rare but possible in dogs. In humans, ACE inhibitors can rarely cause cholestatic jaundice that may progress to fulminant hepatic necrosis.

Overdose

• In dogs, ramipril appears quite safe; dosages as high as 1 g/kg induced only mild GI distress. In healthy young dogs, doses of up to 2.5 mg/kg – ten times the highest recommended dose of 0.25 mg/kg – have been well tolerated. No information was located on overdoses in cats.
• In overdose situations, the primary concern is hypotension; supportive treatment with volume expansion with normal saline is recommended to correct blood pressure. Because of the drug’s long duration of action, prolonged monitoring and treatment may be required.
• For a known or suspected overdose, consult a 24-hour poison consultation service specialising in veterinary information.

Key Notes

Practical points to consider when using ramipril in dogs and cats:

• Dual action on the renin-angiotensin system: Ramipril inhibits the formation of angiotensin II and reduces the breakdown of bradykinin.
• Cardiovascular effects: Reduces both preload and afterload through venodilation and arteriodilation.
• Aldosterone suppression: Reduces aldosterone production, helping decrease salt and water retention.
• Renal effects: Efferent arteriolar dilation may reduce intraglomerular pressure and decrease proteinuria.
• Cardiac and vascular remodeling: May help inhibit angiotensin-aldosterone-mediated cardiac and vascular remodeling.
• Evidence in mitral valve disease: In dogs with congestive heart failure due to myxomatous mitral valve disease, ramipril was less effective than pimobendan, and adding ramipril to pimobendan plus furosemide did not improve survival.
• Choice within the class: No ACE inhibitor has been shown to be superior to another, and ramipril has been studied less in animals than enalapril or benazepril.
• Pharmacokinetics: Ramiprilat peaks 1 to 1.5 hours after dosing and has a half-life of about 20 hours in cats; repeated doses of 0.125 mg/kg inhibited serum ACE activity by 94% at maximum and by 55% at 24 hours. Absorption is not significantly affected by food.
• Renal impairment: In dogs with moderate renal impairment, such as may accompany heart failure, there is no apparent need to adjust the ramipril dose, although renal function should still be monitored.
• Storage: Store at room temperature in a tightly closed container, protected from light.
• Client information: Give with food if vomiting or loss of appetite becomes a problem, and contact the veterinarian promptly if a rash or signs of infection such as fever develop.
• Laboratory considerations: ACE inhibitors may reversibly reduce localisation and excretion of iodohippurate sodium I123/I134 or technetium Tc99 pentetate in the affected kidney of patients with renal artery stenosis, which can confuse interpretation of the study.