Ramipril is a prodrug and nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor with antihypertensive activity. Ramipril is converted in the liver by de-esterification into its active form ramiprilat, which inhibits ACE, thereby blocking the conversion of angiotensin I to angiotensin II. This abolishes the potent vasoconstrictive actions of angiotensin II and leads to vasodilatation. This agent also causes an increase in bradykinin levels and a decrease in angiotensin II-induced aldosterone secretion by the adrenal cortex, thereby promoting diuresis and natriuresis.
Ramipril is a prodrug belonging to the angiotensin-converting enzyme (ACE) inhibitor class of medications. It is metabolized to ramiprilat in the liver and, to a lesser extent, kidneys. Ramiprilat is a potent, competitive inhibitor of ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII). ATII regulates blood pressure and is a key component of the renin-angiotensin-aldosterone system (RAAS). Ramipril is an ACE inhibitor and works by relaxing blood vessels so that blood can flow more easily.
Mechanism of action of Ramipril
There are two isoforms of ACE: the somatic isoform, which exists as a glycoprotein comprised of a single polypeptide chain of 1277; and the testicular isoform, which has a lower molecular mass and is thought to play a role in sperm maturation and binding of sperm to the oviduct epithelium. Somatic ACE has two functionally active domains, N and C, which arise from tandem gene duplication. Although the two domains have high sequence similarity, they play distinct physiological roles. The C-domain is predominantly involved in blood pressure regulation while the N-domain plays a role in hematopoietic stem cell differentiation and proliferation. Ramiprilat confers blood pressure lowing effects by antagonizing the effect of the RAAS. The RAAS is a homeostatic mechanism for regulating hemodynamics, water, and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from the granular cells of the juxtaglomerular apparatus in the kidneys. In the bloodstream, renin cleaves circulating angiotensinogen to ATI, which is subsequently cleaved to ATII by ACE. ATII increases blood pressure using a number of mechanisms. First, it stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone travels to the distal convoluted tubule (DCT) and collecting tubule of nephrons where it increases sodium and water reabsorption by increasing the number of sodium channels and sodium-potassium ATPases on cell membranes. Second, ATII stimulates the secretion of vasopressin (also known as antidiuretic hormone or ADH) from the posterior pituitary gland. ADH stimulates further water reabsorption from the kidneys via insertion of aquaporin-2 channels on the apical surface of cells of the DCT and collecting tubules. Third, ATII increases blood pressure through direct arterial vasoconstriction. Stimulation of Type 1 ATII receptor on vascular smooth muscle cells leads to a cascade of events resulting in myocyte contraction and vasoconstriction. In addition to these major effects, ATII induces the thirst response via stimulation of hypothalamic neurons. ACE inhibitors inhibit the rapid conversion of ATI to ATII and antagonize RAAS-induced increases in blood pressure. ACE (also known as kininase II) is also involved in the enzymatic deactivation of bradykinin, a vasodilator. ACE inhibitors bind to and inhibit the activity of both domains, but have the much greater affinity for an inhibitory activity against the C-domain. Ramiprilat, the principal active metabolite of ramipril, competes with ATI for binding to ACE and inhibits and enzymatic proteolysis of ATI to ATII. Decreasing ATII levels in the body decreases blood pressure by inhibiting the pressor effects of ATII as described in the Pharmacology section above. Ramipril also causes an increase in plasma renin activity likely due to a loss of feedback inhibition mediated by ATII on the release of renin and/or stimulation of reflex mechanisms via baroreceptors.
Indications of Ramipril
- High Blood Pressure
- Diabetic Kidney Disease
- Left Ventricular Dysfunction
- Cardiovascular Risk Reduction
- Heart Failure
- Diabetic Nephropathies
- Heart Failure With Reduced Ejection Fraction (HFrEF)
- Myocardial Infarction
- Strokes
- High-risk cardiovascular event
- Following the 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
- kidney damage due to diabetes with protein in the urine (In low doses it is used as a prophylaxis for developing nephropathy and related secondary cardiovascular events.
Reducing the risk of heart attack, stroke, and death due to heart disease, in people with any of the following conditions
- a history of heart disease, for example, a people who have had a heart attack, angina, or a previous surgical procedure to improve blood supply to the heart, eg heart bypass (coronary artery bypass graft – CABG), or balloon dilation of blood vessels (percutaneous transluminal coronary angioplasty – PTCA)
- a history of stroke
- poor blood circulation in the hands or feet due to hardening of the arteries (peripheral vascular disease)
- diabetes plus one or more of the following risk factors: high blood pressure, high total cholesterol levels, low HDL cholesterol levels, smoking, or protein in the urine (microalbuminuria – the beginning of diabetic kidney disease).
- Treating kidney disease or delaying worsening of kidney disease (nephropathy) in people either with or without diabetes.
For the management of mild to severe hypertension. May be used to reduce cardiovascular mortality following myocardial infarction in hemodynamically stable individuals who develop clinical signs of congestive heart failure within a few days following myocardial infarction. To reduce the rate of death, myocardial infarction and stroke in individuals at high risk of cardiovascular events. May be used to slow the progression of renal disease in individuals with hypertension, diabetes mellitus, and microalbuminuria or overt nephropathy.
Contra-Indications of Ramipril
- Low amount of sodium in the blood
- The high amount of potassium in the blood
- Inherited Disorder of Continuing Episodes of Swelling
- Decreased Neutrophils a Type of White Blood Cell
- Method of Removing Waste/Poison from Blood with Dialysis
- Renal Artery Stenosis
- Abnormally low blood pressure
- Kidney disease with the reduction in kidney function
- Systemic Lupus Erythematosus
- Scleroderma
- High Amount of Bilirubin in the Blood
- Severe Vomiting
- Severe Diarrhea
- Kidney Problems Causing a Decreased Amount of Urine to be Passed
- Azotemia
- Abnormal liver function tests
- Pregnancy
- Decreased Blood Volume
- Intestinal Angioedema
Dosage of Ramipril
Strengths : 1.25mg ,2.5mg ,5mg,10mg
Angina Pectoris
- 2.5–20 mg per day, taken by mouth in 1 or 2 divided doses per day. You may need to take 2 divided doses per day if the drug stops working before it’s time for your next dose. The starting dose is 1.25 mg taken once per day.
Hypertension
- Initial dose: 2.5 mg orally once a day for patients not taking a diuretic
- Maintenance dose: 2.5 to 20 mg/day in one or two equally divided doses
Congestive Heart Failure
- Initial dose: 2.5 mg orally twice a day
- Maintenance dose: 5 mg orally twice a day
Cardiovascular Risk Reduction
- Initial dose: 2.5 mg orally once a day for one week; 5 mg orally once a day for the next three weeks, then increase as tolerated
- Maintenance dose: 10 mg orally once a day
Diabetic Nephropathy (Off-label)
- Initial (not on the diuretic): 2.5 mg PO qDay
- Initial (with a diuretic): 1.25 mg PO qDay
- Maintenance: 2.5-20 mg PO qDay; daily dose may be either increased or divided BID if antihypertensive effect is diminished toward the end of the dosing interval
Side Effects of Ramipril
The most common
- A dry cough
- Dizziness and light-headedness due to low blood pressure
- Fatigue, especially in the early stages
- Mouth dryness in the early stages
- The most common (a burning feeling in the chest, behind the breastbone or gullet)
- Abdominal or stomach pain
- Constipation
- High blood pressure
- Nausea , vomiting,
- painful or swollen gums
- numbness or heavy feeling in the jaw
- dull, aching pain in the hip, groin, or thigh
- stomach pain,
- a headache,
- reversible hair loss or thinning, and
- fever.
Common
- chills or fever
- a headache, severe and throbbing
- joint or back pain
- muscle aching or cramping
- muscle pains or stiffness
- chest pressure or squeezing pain in the chest
- excessive sweating
- sudden drowsiness or need to sleep
- coughing up blood
- liver problems–nausea, upper stomach pain, itching, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes)
- decreased amount of urine
Rare
- Anxiety
- change in vision
- chest pain or tightness
- confusion
- a cough
- Agitation
- arm, back, or jaw pain
- blurred vision
- chest pain or discomfort
- convulsions
- extra heartbeats
- hallucinations
- a headache
- irritability
- lightheadedness
- cold and clammy skin
- fast and shallow breathing
- swelling of your feet, legs, or hands purple spot on your skin caused by internal bleeding
- fast or abnormal heart rate or palpitations
- loss of appetite
Drug Interactions of Ramipril
Ramipril may interact with following drugs, supplements, & may change the efficacy of drugs
- allopurinol
- alpha agonists (e.g., clonidine, methyldopa)
- angiotensin receptor blockers (ARBs; e.g., candesartan, irbesartan, losartan)
- azathioprine
- beta-adrenergic blockers (e.g., atenolol, propranolol, sotalol)
- calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
- cyclosporine
- diuretics (water pills; e.g., furosemide, spironolactone, )
- “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
- heparin
- insulin
- iron dextran
- monoamine oxidase inhibitors (MAOIs; e.g phenelzine, rasagiline, selegiline, )
- nitroglycerin
- nonsteroidal anti-inflammatory medications (NSAIDs; e.g., indomethacin, naproxen)
- oral diabetes medications (e.g., metformin, pioglitazone)
- pentoxifylline
- phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil)
- rituximab
- tizanidine
- trimethoprim
Pregnancy & Lactation of Ramipril
FDA Pregnancy Category D
Pregnancy
ACE inhibitors such as ramipril may cause severe harm or death to the developing baby if taken by the mother. This medication should not be used during pregnancy. If you become pregnant while taking this medication, stop taking it immediately and contact your doctor.
Lactation
This medication passes into breast milk. If you are a breast-feeding mother and are taking ramipril it may affect your baby. This medication is not recommended for breast-feeding women. Talk to your doctor about whether you should continue breast-feeding. The safety and effectiveness of using this medication have not been established for children. The use of ramipril by this age group is not recommended.
References
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