RAMIPRIL IMPACT 2.5MG

Indications

• Hypertension
• Heart failure (as an adjunct therapy)
• Prophylaxis after myocardial infarction

Mechanism of action

Ramipril inhibits the RAAS by binding to and inhibiting ACE, preventing the conversion of angiotensin I to angiotensin II. As angiotensin II levels decrease, the activation of angiotensin receptors (AT1 and AT2) is reduced. The AT1 receptor is associated with vasoconstriction and increased blood pressure, while the AT2 receptor promotes vasodilation. Thus, by inhibiting angiotensin II production, ramipril exerts its antihypertensive and cardioprotective effects through reduced inflammation and oxidative stress.

Pharmacodynamics

Ramipril is an inactive prodrug that is metabolized to ramiprilat, the active form that exerts blood pressure-lowering effects by antagonizing the RAAS. The RAAS plays a crucial role in regulating blood pressure and fluid balance. Ramiprilat reduces blood pressure by inhibiting aldosterone secretion, leading to decreased sodium and water reabsorption in the kidneys, and by reducing the secretion of vasopressin, further promoting diuresis. This results in decreased blood volume and vascular resistance.

Pharmacokinetics

Ramipril is absorbed rapidly from the gastrointestinal tract, with peak plasma concentrations occurring about 1 hour after administration. It is extensively metabolized in the liver, with ramiprilat being the primary active metabolite. The elimination half-life of ramiprilat is approximately 13-17 hours. Renal impairment may affect the elimination of the active metabolite, necessitating dose adjustments. Ramipril and its metabolites are excreted primarily in the urine.

Adverse effects

• Back pain
• Increased risk of infection
• Insomnia
• Depression
• Dry throat
• Gastrointestinal disorders
• Generalised oedema
• Nervousness
• Proteinuria
• Transient ischaemic attack
• Vision disorders
• Balance impaired
• Glossitis
• Arthritis
• Hypersensitivity
• Jaundice
• Cholestatic
• Leucocytosis
• Pulmonary oedema
• Serositis
• Toxic epidermal necrolysis
• Vasculitis
• Necrotising

Interactions

• Diuretics
• Hepatic disorders
• Vascular stenosis

Precautions

• Caution in patients with renal impairment
• Monitor blood pressure in breastfeeding infants
• Caution in combination with diuretics

Pregnancy

Avoid use during pregnancy unless necessary due to potential harm to the fetus.

Breast-feeding

Avoid in the first few weeks after delivery, particularly in preterm infants due to the risk of profound neonatal hypotension; use only if essential in mothers breastfeeding older infants with monitoring of the infant's blood pressure.

Storage

Store in a cool, dry place, away from direct sunlight.

Formulations

• Ramipril 1.25 mg tablets
• Ramipril 2.5 mg tablets
• Ramipril 5 mg tablets
• Ramipril 10 mg tablets

Mechanism of action

Ramipril inhibits the RAAS system by binding to and inhibiting ACE thereby preventing the conversion of angiotensin I to angiotensin II. As plasma levels of angiotensin II fall, less activation of the G-protein coupled receptors angiotensin receptor I (AT₁R) and angiotensin receptor II (AT₂R) occurs. AT₁R mediates vasoconstriction, inflammation, fibrosis, and oxidative stress through a variety of signaling pathways. These include G_q coupling to the inositol triphosphate pathway, activation of phospholipases C, A₂, and D which contribute to eicosanoid production, activation of Ca²⁺-dependent and MAP kinases, G_i and G_12/13, and eventual activation of the Jak/STAT pathway leading to cell growth and production of extracellular matrix components. AT₁R activation also leads to increased activity of membrane-bound NADH/NADPH oxidase which contributes to production of reactive oxygen species. Decreased activation of this receptor mediates the renoprotective, antihypertensive, and cardioprotective effects of ramipril by reducing inflammation and vasoconstriction. AT₂R acts in opposition to the effects of AT₁R by activating phosphotyrosine phosphatases which inhibit MAP kinases, inhibiting Ca²⁺ channel opening, and stimulating cGMP and nitric oxide production leading to vasodilation. These counteracting effects are shared by the Mas receptor which is activated by Ang(1-7), a subtype of angiotensin produced by plasma esterases from AngI or by ACE2 from AngII produced through a secondary pathway by tonin and cathepsin G. Ang(1-7) also activates AT₂R although the bulk of its effect is mediated by MasR. ACE is also responsible for the breakdown of bradykinin. The resulting buildup of bradykinin due to ACE inhibition is thought to mediate the characteristic dry-cough as a side effect of ACE inhibitor medications.

Pharmacodynamics

Ramipril is an ACE inhibitor similar to benazepril, fosinopril and quinapril. It is an inactive prodrug that is converted to ramiprilat in the liver, the main site of activation, and kidneys. 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 blood stream, 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 the 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. Inhibiting the deactivation of bradykinin increases bradykinin levels and may sustain the effects of ramiprilat by causing increased vasodilation and decreased blood pressure.