Indications
Valsartan is primarily prescribed for the treatment of hypertension, aimed at reducing the risk of both fatal and nonfatal cardiovascular events, such as strokes and myocardial infarctions. Additionally, it serves as a therapeutic option for heart failure classified by the New York Heart Association as class II-IV, as well as for patients experiencing left ventricular dysfunction or failure subsequent to a myocardial infarction, particularly when the use of an angiotensin-converting enzyme inhibitor (ACEI) is deemed inappropriate. Valsartan is also utilized in combination with sacubitril for enhanced therapeutic effect.
Pharmacodynamics
Valsartan functions by inhibiting the pressor effects of angiotensin II, with an oral dose of 80 mg reducing these effects by approximately 80% at peak levels, with about 30% inhibition persisting for 24 hours. This inhibition leads to a 2- to 3-fold increase in plasma renin and consequently in angiotensin II plasma concentration in hypertensive patients. Minimal alterations in plasma aldosterone levels have been noted post-administration. In multiple-dose trials involving hypertensive patients, valsartan exhibited negligible influence on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid. Incidents of excessive hypotension were rare and primarily occurred in patients with an activated renin-angiotensin system. Caution is advised when initiating the treatment in patients with heart failure, as some reduction in blood pressure is common. Renal function should be monitored regularly due to potential impairment, and the risk of hyperkalemia, especially in patients with pre-existing renal impairments, should also be considered.
Absorption
Upon oral administration, valsartan begins its antihypertensive activity within approximately two hours and reaches peak efficacy within four to six hours in most patients. The presence of food can decrease the exposure to valsartan by around 40% and the peak plasma concentration by about 50%. The area under the curve (AUC) and maximum concentration (Cmax) values of valsartan typically increase linearly with dose increments across the therapeutic range. Notably, valsartan does not accumulate significantly in plasma following repeated administration.
Metabolism
Valsartan undergoes minimal liver metabolism, with only about 20% of a single dose being metabolized. The primary metabolite, valeryl 4-hydroxy valsartan, accounts for roughly 9% of the dose. In vitro studies with recombinant CYP 450 enzymes indicate that CYP 2C9 is responsible for the formation of this metabolite. Valsartan does not significantly inhibit CYP 450 isozymes at clinically applicable concentrations, making drug interactions mediated by this pathway unlikely.
Mechanism of Action
Valsartan functions as an antagonist of angiotensin II receptors and is classified within the angiotensin II receptor blocker (ARB) family of medications. It specifically targets the angiotensin receptor 1 (AT1), effectively inhibiting the binding of angiotensin II and preventing its hypertensive effects, which include vasoconstriction, and synthesis of aldosterone and antidiuretic hormone, along with cardiac stimulation and enhanced renal sodium reabsorption. Consequently, valsartan diminishes blood pressure levels, reduces aldosterone concentration, decreases cardiac workload, and promotes sodium excretion.
