化合物信息

Drug Groups

approved; investigational

Description

Lisinopril is a potent, competitive inhibitor of angiotensin-converting enzyme (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). Lisinopril may be used to treat hypertension and symptomatic congestive heart failure, to improve survival in certain individuals following myocardial infarction, and to prevent progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy.

Indication

For the treatment of hypertension and symptomatic congestive heart failure. May be used in conjunction with thrombolytic agents, aspirin and/or β-blockers to improve survival in hemodynamically stable individuals following myocardial infarction. May be used to slow the progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy.

Pharmacology

Lisinopril is an orally active ACE inhibitor that 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 further sustain the effects of lisinopril by causing increased vasodilation and decreased blood pressure.

Toxicity

Symptoms of overdose include severe hypotension, electrolyte disturbances, and renal failure. LD₅₀= 2000 mg/kg(orally in rat). Most frequent adverse effects include headache, dizziness, cough, fatigue and diarrhea.

Affected Organisms

Biotransformation

Does not undergo metabolism, excreted unchanged in urine.

Absorption

Approximately 25%, but widely variable between individuals (6 to 60%) in all doses tested (5-80 mg); absorption is unaffected by food

Half Life

Effective half life of accumulation following multiple dosing is 12 hours.

Protein Binding

Lisinopril does not appear to be bound to serum proteins other than ACE.

Elimination

Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine.

Clearance

* 10 L/h [child weighting 30 kg receiving doses of 0.1 to 0.2 mg/kg]

References

External Links