AGOPRIL TABLETS

Indications

• Hypertension
• Heart failure
• Diabetic nephropathy
• Post-myocardial infarction

Dosage

Adults: Initially 12.5–25 mg twice daily, then increased if necessary up to 150 mg

Mechanism of action

Captopril competitively inhibits the activity of both the N and C domains of ACE, with a greater affinity for the C-domain, which is primarily involved in blood pressure regulation. By inhibiting the enzymatic conversion of angiotensin I (ATI) to angiotensin II (ATII), Captopril decreases ATII levels, resulting in vasodilation, decreased blood pressure, and increased plasma renin activity due to the loss of feedback inhibition. This inhibition leads to a reduction in aldosterone secretion, decreased sodium and water retention, and ultimately lower blood pressure.

Pharmacodynamics

As an ACE inhibitor, Captopril antagonizes the renin-angiotensin-aldosterone system (RAAS), which is crucial for regulating blood volume and systemic vascular resistance. By blocking the formation of angiotensin II, Captopril reduces the secretion of aldosterone and vasopressin, leading to decreased sodium and water reabsorption in the kidneys, as well as direct vasodilation of blood vessels, resulting in a decrease in blood pressure. It may also improve symptoms and outcomes in heart failure by decreasing preload and afterload on the heart.

Pharmacokinetics

Captopril is rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring approximately 1 to 2 hours after oral administration. It undergoes hepatic metabolism and is excreted primarily via the kidneys. Captopril has a half-life of approximately 2 hours, but its effects can last longer due to the pharmacodynamic effects of angiotensin II inhibition. Adjustments in dosing may be necessary in patients with renal impairment due to altered drug clearance.

Contra-indications

• Hypersensitivity to ACE inhibitors (including angioedema)
• History of angioedema associated with previous ACE inhibitor therapy
• Severe renal impairment (eGFR less than 60 mL/min/1.73 m2) when combined with aliskiren
• Diabetes mellitus when combined with aliskiren

Adverse effects

• Cough
• Dizziness
• Hyperkalemia
• Hypotension
• Angioedema
• Renal impairment
• Rash
• Cholestatic jaundice
• Hepatitis
• Fulminant hepatic necrosis

Interactions

• Potassium-sparing diuretics (increased risk of hyperkalemia)
• Other antihypertensive agents (may enhance hypotensive effect)
• NSAIDs (may reduce the antihypertensive effect)
• Lithium (increased risk of lithium toxicity)
• Aliskiren (contraindicated in patients with diabetes or renal impairment)

Precautions

• Use with caution in patients with aortic or mitral valve stenosis
• Use with caution in patients with hypertrophic cardiomyopathy
• Monitor renal function and electrolytes before and during treatment
• Elderly patients may be at increased risk of adverse effects

Pregnancy

ACE inhibitors should be avoided in pregnancy unless essential. They may adversely affect fetal and neonatal blood pressure control and renal function; skull defects and oligohydramnios have also been reported.

Breast-feeding

Information on the use of ACE inhibitors in breastfeeding is limited.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Captopril 12.5 mg tablets
• Captopril 25 mg tablets
• Captopril 50 mg tablets

Mechanism of action

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. ACE inhibitors bind to and inhibit the activity of both domains, but have much greater affinity for and inhibitory activity against the C-domain. Captopril, one of the few ACE inhibitors that is not a prodrug, 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. Captopril 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. Captopril’s affinity for ACE is approximately 30,000 times greater than that of ATI. The local role of the renin angiotensin system (RAS) was documented recently beside its conventional systemic functions. Studies showed that the effector angiotensin II (AngII) alters bone health, while inhibition of the angiotensin converting enzyme (ACE-1) preserved these effects. The newly identified Ang1-7 exerts numerous beneficial effects opposing the AngII. Thus, the current study examines the role of Ang1-7 in mediating the osteo-preservative effects of ACEI (captopril) through the G-protein coupled Mas receptor using an ovariectomized (OVX) rat model of osteoporosis. 8 weeks after the surgical procedures, captopril was administered orally (40 mg/kg/day), while the specific Mas receptor blocker (A-779) was delivered at infusion rate of 400 ng/kg/1 min for 6 weeks. Bone metabolic markers were measured in serum and urine. Minerals concentrations were quantified in serum, urine and femoral bones by inductive coupled plasma mass spectroscopy (ICP-MS). Trabecular and cortical morphometry was analyzed in the right distal femurs using micro-CT. Finally, the expressions of RAS peptides, enzymes and receptors along with the receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) were determined femurs heads. OVX animals markedly showed altered bone metabolism and mineralization along with disturbed bone micro-structure. Captopril significantly restored the metabolic bone bio-markers and corrected Ca2+ and P values in urine and bones of estrogen deficient rats. Moreover, the trabecular and cortical morphometric features were repaired by captopril in OVX groups. Captopril also improved the expressions of ACE-2, Ang1-7, Mas and OPG, while abolished OVX-induced up-regulation of ACE-1, AngII, Ang type 1 receptor (AT1R) and RANKL. Inhibition of Ang1-7 cascade by A-779 significantly eradicated captopril protective effects on bone metabolism, mineralization and micro-structure. A-779 also restored OVX effects on RANKL expression and ACE-1/AngII/AT1R cascade and down-regulated OPG expression and ACE-2/Ang1-7/Mas pathway. In line with the clinical observations of the bone-preservative properties following ACE-1 inhibition, local activation of ACE-2/Ang1-7/Mas signaling and suppressed osteoclastogenesis seem responsible for the osteo-preservative effect of captopril, which could offers a potential therapeutic value in treatment of disabling bone and skeletal muscular diseases.

Pharmacodynamics

Captopril, an ACE inhibitor, antagonizes 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 its effects by causing increased vasodilation and decreased blood pressure.