Ramipril

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor, used to treat high blood pressure (hypertension) and congestive heart failure. By inhibiting an enzyme, ACE inhibitors relax the muscles around small arteries (arterioles). The arterioles expand and allow blood to flow through more easily. This reduces blood pressure.

Medical uses
Indications for its use include:
 * Hypertension; (high blood pressure)
 * Congestive heart failure;
 * Following heart attack in patients with clinical evidence of heart failure;
 * Susceptible patients over 55 years: prevention of heart attack, stroke, cardiovascular death or need of revascularization procedures.
 * Diabetic nephropathy (kidney damage due to diabetes) with microalbuminuria (protein in the urine); in low doses it is used as a prophylaxis for developing nephropathy and related secondary cardiovascular events.

Contraindications
Renovascular disease (impaired blood flow in the kidneys), severe renal impairment (especially in patients with one kidney or with bilateral renal artery stenosis), volume-depleted patients, history of angioedema while on an ACE inhibitor, pregnancy, hypotension.

Adverse effects

 * low blood sugar (in patients taking medication for diabetes), causing sweating or shakiness
 * dry cough
 * dizziness and light-headedness due to low blood pressure
 * tiredness and fatigue, especially in the early stages
 * mouth dryness in the early stages
 * nausea, vomiting, diarrhea (persistent in rare cases)
 * fainting
 * change in amount of urine
 * signs of infection (e.g., fever, chills, persistent sore throat)
 * yellowing of eyes or skin, dark urine
 * stomach or abdominal pain
 * neutropenia (low white blood cells)
 * impotence (erectile dysfunction)

Serious allergic reactions to this drug are unlikely, but immediate medical attention must be sought if they occur. Symptoms of a serious allergic reaction include, but are not limited to a rash or swelling of the face, mouth, tongue, or throat.

In extreme cases, ramipril may lead to potentially fatal liver problems.

Mechanism of action


ACE inhibitors inhibit the actions of angiotensin converting enzyme (ACE), thereby lowering the production of angiotensin II and also decreasing the breakdown of bradykinin. The decrease in angiotensin II results in relaxation of arteriole smooth muscle leading to a decrease in total peripheral resistance, reducing blood pressure as the blood is pumped through widened vessels. Its effect on bradykinin is responsible for the dry cough side effect.

Ramipril, a prodrug or precursor drug, is converted to the active metabolite ramiprilat by carboxylesterase 1 (CES1). Ramiprilat is mostly excreted by the kidneys. The half-life of ramiprilat is variable (3–16 hours), and is prolonged by heart and liver failure, as well as kidney failure.

Patent
The compound was protected by which was assigned to the German pharmaceutical company Hoechst AG (since merged into Aventis) on 29 October 1991. The patent was scheduled to expire on 29 October 2008. On 11 September 2007, in an appeal by the Indian company Lupin Ltd., the United States Court of Appeals for the Federal Circuit reversed a district court trial verdict and found that Aventis's patent on ramipril was invalid for "obviousness", opening this drug to generic manufacturers.

Ramipril is marketed in India under the brand names of Cardace, Zigpril, Ramistar and Zorem.

Clinical trials
The HOPE trial seemed to show ramipril possessed cardioprotective qualities which extended beyond its qualities as an antihypertensive. However, the HOPE trial and the interpretation of the results have been criticised.

The AIRE trial showed a 27% reduction in mortality for patients receiving ramipril for chronic heart failure following a myocardial infarction.

Ramipril was found to have similar results as telmisartan, an angiotensin II receptor blocker (ARB).

Synthesis
Although acid used to remove acetamido protecting group, base is said to give higher % yield.