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Ramipril; Uses, Dosage, Side Effects, Interactions, Pregnancy

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.

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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

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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

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

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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.