Indications
Iloprost, administered through inhalation, is specifically indicated for the management of pulmonary arterial hypertension (PAH) classified under WHO Group 1. Its primary objective is to enhance exercise tolerance, alleviate symptoms as categorized by the New York Heart Association (NYHA) Class, and prevent clinical deterioration. Clinical trials substantiating its efficacy predominantly involved patients diagnosed with NYHA Functional Class III-IV symptoms, with a significant percentage having idiopathic or heritable PAH (65%) or PAH associated with connective tissue diseases (23%). Additionally, intravenous iloprost is prescribed for treating severe frostbite in adults, aiming to minimize the risk of digital amputations, with effectiveness demonstrated in young, healthy individuals affected by frostbite at high altitudes.
Pharmacodynamics
Iloprost acts as a synthetic analogue of prostacyclin PGI2, effectively dilating both systemic and pulmonary arterial vascular beds. It exists in two diastereoisomeric forms, with the 4S isomer demonstrating greater potency in vasodilation compared to the 4R isomer. In patients suffering from primary pulmonary hypertension, iloprost significantly reduces pulmonary vascular resistance and arterial pressure. It also inhibits platelet aggregation, although the extent to which this contributes to its vasodilatory activity remains unclear. Furthermore, iloprost has shown potential in mitigating ischemia-induced tissue damage, exhibiting cytoprotective properties in patients with conditions like critical leg ischemia and during delayed amputation processes.
Absorption
Upon inhaling a 5 mcg dose of iloprost, patients with pulmonary hypertension reach peak plasma concentrations of approximately 150 pg/mL. Iloprost concentrations generally become undetectable in plasma 30 minutes to one hour post-inhalation. The absolute bioavailability of inhaled iloprost, however, has not been definitively established. For intravenous administration at a rate of 2 ng/kg/min, a steady-state plasma concentration of 85 ng/L is achieved.
Metabolism
In vitro investigations indicate that cytochrome P450-dependent pathways are minimally involved in the metabolic processing of iloprost. Its primary metabolic pathway is β-oxidation of the carboxyl side chain, resulting mainly in the formation of tetranor-iloprost, a compound identified as pharmacologically inactive in animal studies. Additionally, dinor-iloprost has been detected as a metabolite of iloprost in rabbits.
Mechanism of Action
Iloprost is a pharmacological agent that mirrors the biological functions of prostacyclin, a potent and transient vasodilator derived predominantly from the vascular endothelium. In the context of pulmonary arterial hypertension, it is recognized for its ability to influence endothelial vasoactive mediators, such as nitric oxide and prostacyclin, which play a pivotal role in vasoconstriction. Although the precise mechanisms by which iloprost exerts its cytoprotective effects are not completely understood, it is hypothesized to reduce catecholamine release from sympathetic nerve endings, maintain mitochondrial integrity, and diminish oxidative stress. Additionally, iloprost is thought to contribute to decreased neutrophil accumulation and stabilization of cell membranes.
