Summary
Synopsis
Iloprost is an analogue of epoprostenol (prostacyclin; PGI2; a potent but short-lived prostanoid mainly produced in the vascular endothelium) and mimics the pharmacodynamic properties of this compound, namely: inhibition of platelet aggregation, vasodilatation and, as yet ill-defined, cytoprotection. Improved metabolic and, in particular, chemical stability enhance the clinical utility of iloprost.
When administered as an intermittent intravenous infusion at ⩽ 2 ng/kg/min for 2 to 4 weeks, iloprost reduced rest pain and improved ulcer healing in 40 to 60% of patients with critical leg ischaemia, including diabetic patients, and delayed amputation in the majority of responding individuals. Similar benefits have been seen in thromboangiitis obliterans and, in patients with severe Raynaud’s phenomenon, shorter courses of therapy reduced the frequency, intensity and duration of ischaemic episodes for at least 6 weeks. The very few comparative trials reported to date (i.e. vs nifedipine in Raynaud’s phenomenon; vs low-dose aspirin in thromboangiitis obliterans) have favoured iloprost, but comparisons with more established agents are needed to assess this drug’s value in less severe forms of peripheral ischaemia, such as intermittent claudication. At present, iloprost is administered intravenously and this is a limitation to treatment.
The potent, rapidly reversible antiplatelet activity of iloprost suits it for use in extracorporeal circulation and for the intraoperative management of heparin-induced platelet activation. Although results in animal models of ischaemic myocardial injury are encouraging, preliminary clinical experience in patients with myocardial ischaemia or infarction has been disappointing.
Most patients tolerate iloprost infusion rates of up to 2 ng/kg/min. Headache and flushing are extremely common and are the suggested end-point of dose titration, as higher doses are associated with a significant incidence of gastrointestinal distress and, ultimately, hypotension.
Thus, iloprost provides a pharmacotherapeutic option for patients with severe peripheral vascular disease, a condition for which few alternative drug therapies exist. Its potent but short-lived effects make it well-suited to certain therapeutic niches such as the management of intraoperative platelet activation. Prostanoid analogues have far-reaching therapeutic potential and further experience with iloprost will no doubt help to define its clinical applications.
Pharmacodynamic Properties
The pharmacodynamic profile of the synthetic epoprostenol analogue, iloprost, mimics that of the endogenous prostanoid, epoprostenol (PGI2; prostacyclin). Both are universal and potent inhibitors of platelet activation. Aggregation and release reactions stimulated by exposure to aggregating agents such as arachidonic acid, collagen or epinephrine (adrenaline) in vitro are essentially abolished by nanomolar concentrations of iloprost. There is significant inhibition of platelet aggregation (as measured ex vivo) during infusion of iloprost up to 2 ng/kg/min in healthy individuals and patients with peripheral vascular or myocardial ischaemic disease, but these effects decline rapidly once treatment is stopped. In contrast to results in healthy volunteers, plasma levels of platelet specific proteins are not decreased by infusion of iloprost in clinical settings associated with platelet activation. Studies in animal models of bleeding and vascular injury confirm a dose-related decrease in thrombogenesis similar to that of epoprostenol.
The putative mechanism for the antiaggregatory effect of iloprost involves platelet receptor-mediated activation of adenyl cyclase which increases levels of cyclic adenosine monophosphate (cAMP), thereby affecting phospholipase activity and cytosolic calcium levels. A decrease in epoprostenol receptor binding capacity, but not in receptor affinity, has been documented in human platelets exposed to iloprost over a prolonged period in vitro or in vivo. There are a few reports of increased aggregability during iloprost therapy or post-infusion (i.e. ‘rebound’ hyperreactivity). The mechanism for this effect has not been clarified; altered receptor status may be involved, but iloprost may also influence the activity of endogenous proaggregatory agents, such as thromboxane A2.
With regard to other components of haemostasis, iloprost appears to have some fibrinolytic activity and to decrease neutrophil adhesion and chemotaxis, but evidence of a substantial effect on blood fluidity is tenuous.
Iloprost is an arterial vasodilator. The ratio of antiaggregatory: vasodilatory potency in vivo is in the order of 2–7: 1 and this increases its therapeutic value for systemic administration — hypotension is a limitation of therapy with epoprostenol. As in platelets, the mechanism of action in vascular preparations may involve an increase in smooth muscle cAMP secondary to receptor activation, but this is controversial. Iloprost inhibits constriction induced in various human and animal artery preparations by arachidonic acid, the thromboxane A2 analogue U 46619, angiotensin II, phenylephrine and transmural neural stimulation.
In humans, iloprost decreases peripheral vascular resistance and mean arterial blood pressure with a mild increase in heart rate and cardiac index. Iloprost increases renal blood flow, but has a natriuretic effect which is independent of the haemodynamic change. Interestingly, it has been difficult to consistently demonstrate improved perfusion in the affected limb of patients with symptomatic peripheral ischaemia.
An important but less well-characterised aspect of iloprost’s pharmacodynamic profile is its cytoprotective action. The drug appears to preserve myocardial function in isolated heart preparations and in intact animals after ischaemia-reperfusion injury. Putative mechanisms include prevention of catecholamine outflow from sympathetic nerve terminals with preservation of sympathetic nerve responses, preservation of mitochondrial function and Superoxide dismutase activity with reduced ‘oxidative stress’, decreased neutrophil accumulation, and membrane stabilisation as assessed, for example, by phospholipid loss and levels of cathepsin D and creatine phosphokinase. A membrane stabilising action is also suggested by the protective effect in rats subjected to carbon tetrachloride-induced hepatic injury or traumatic shock. Iloprost demonstrates some antiarrhythmic activity in isolated and intact animal models of reperfusion arrhythmias.
Preliminary investigation in animal models suggest that iloprost improves the preservation of donor organs and may be useful in conjunction with cyclosporin after transplantation. When applied topically in solution or incorporated into sutures, iloprost prevented the occlusion of small vessel anastomoses (rat femoral vessels).
Pharmacokinetic Properties
Iloprost is most commonly administered by intravenous infusion, achieving steady-state plasma concentrations of 85 ng/L when infused at a rate of 2 ng/kg/min in healthy volunteers. Plasma concentrations are linearly related to dose. It is very rapidly absorbed after oral administration but undergoes extensive biotransformation in the gut wall and liver such that <20% reaches the systemic circulation. The apparent volume of distribution of iloprost during the terminal phase is approximately 0.7 L/kg. In rats, maximum CNS levels of the drug (<10% of simultaneous plasma concentrations) are reached within 5 minutes. Distribution into other tissues has not been reported.
Iloprost is completely metabolised by β-oxidation with predominantly (70%) renal excretion of the metabolites. Faecal excretion accounts for another 12 to 17%. Elimination is biphasic with an initial half-life of distribution of 4 min and elimination half-life of approximately 30 min. In normal individuals, the total body clearance is 20 ml/min/kg, but was decreased to 16 ml/min/ kg in a group of patients with critical leg ischaemia. Patients with severe hepatic disease or renal disease requiring maintenance haemodialysis have a 2-to 3-fold reduction in iloprost clearance and a substantial elevation of plasma drug concentrations.
Therapeutic Use
Most clinical experience with iloprost has been gained in the treatment of peripheral vascular disease. In patients with critical leg ischaemia secondary to peripheral atherosclerotic obliterative disease (PAOD) or diabetic angiopathy or with thromboangiitis obliterans, intermittent intravenous infusion of iloprost, usually ⩽2 ng/kg/min for 14 to 28 days, was superior to placebo and, in the latter indication, to low-dose aspirin in relieving rest pain and improving ulcer healing. The initial response rate in critical leg ischaemia was 40 to 60% and the majority of these patients had sustained improvement during 6 months to 1 year of follow-up. Successful therapy with iloprost tended to at least delay the need for amputation, e.g. 36% of ‘responders’ with diabetes deteriorated or required amputation during 1 year of follow-up as compared with 75% of ‘non-responding’ PAOD patients who required amputation within 4 months. Thus, in patients whose disease is not amenable to surgical revascularisation, iloprost is one of very few pharmacotherapy options and may improve the patients’ functional level and quality of life.
In preliminary studies, short courses of iloprost produced significant increases for up to 60 days in the time to claudication during treadmill testing in patients with intermittent claudication, but the intravenous route of administration may be a limiting factor. The very interesting question of whether prostanoid therapy, with its presumed ‘physiological’ mechanisms of action, impacts on the progression of ischaemia has not been addressed.
Severe Raynaud’s phenomenon secondary to systemic sclerosis is also amenable to iloprost therapy. In crossover comparisons with placebo, iloprost < 2 or 3 ng/kg/min for 6 h/day for 3 days was more effective in decreasing the intensity, duration and severity of ischaemic episodes. Digital lesions also healed with the overall clinical improvement lasting for at least 6 weeks. A similar dosage of iloprost with one repeat infusion after 8 weeks was as effective as oral nifedipine 10 to 20mg 3 times daily for 16 weeks in a small comparative trial.
Experience with iloprost in myocardial ischaemia and infarction is very limited as yet. Preliminary studies suggest that, during infusion of 2 to 6 ng/kg/min, exercise tolerance is improved in patients with exertional angina — albeit to a variable degree — but that a substantial proportion of patients (10 to 20% of those tested) experience ischaemia at rest, probably due to iloprost-induced coronary ‘steal’. Variant angina (assessed in only 5 patients) did not improve in response to intermittent infusion of the drug.
Iloprost produced a beneficial haemodynamic change in 1 study of 14 patients with acute myocardial infarction. Whether concurrent intravenous iloprost administration may enhance or reduce the activity of recombinant tissue plasminogen activator (rt-PA) is undetermined.
A situation in which the potent antiplatelet activity of iloprost appears to be very useful is extracorporeal circulation. When administered during cardiopulmonary bypass at a rate of 10 ng/ kg/min, iloprost significantly decreased platelet deposition within the circuit, resulting in higher postoperative platelet counts. This result was not confirmed in another study, however, and it remains to be seen whether iloprost significantly improves the postoperative course of these patients. High doses (⩽24 ng/kg/min) successfully prevented platelet activation in patients at risk for thrombotic complications due to heparin-induced platelet aggregation and serotonin release, who required heparinisation during vascular surgery. Despite the more pronounced hypotensive effect of iloprost at these dosages, the risk: benefit ratio appears to favour the prophylactic use of iloprost.
Data regarding use of iloprost in haemodialysis are inconclusive. It does not appear to be ‘heparin-sparing’; moreover, haemodialysis patients are more likely to experience hypotension and, possibly, unreliable anticoagulation due to variable interaction between heparin, platelets and iloprost.
Tolerability
Minor vascular reactions (flushing and headache) are very common during infusion with iloprost (70% incidence). Gastrointestinal reactions, including nausea, vomiting, abdominal cramping and diarrhoea are also common. There is considerable variation in tolerability of iloprost among patients, but adverse effects are dose-related and, within an individual, gastrointestinal distress and hypotension can usually be avoided with careful upward titration of the dose until the appearance of mild headache and flushing. Drug-induced reactions resolve rapidly once iloprost is discontinued.
The incidence of clinically significant hypotension appears to be quite low in patients with peripheral vascular disease treated with intermittent infusions of iloprost ⩽2 ng/kg/min, although symptomatic hypotension has been reported. Intraoperative hypotension, which may be substantial at the dosages used during extracorporeal circulation, responds to phenylephrine and resolves rapidly postoperatively.
Dosage and Administration
For the treatment of peripheral vascular disease iloprost has generally been administered intravenously as intermittent infusions of ⩽2 ng/kg/min for 5 to 12 hours for 3 to 6 (Raynaud’s phenomenon) or 14 to 28 (critical leg ischaemia) consecutive days. The optimal total dose is not established. Treatment should be initiated at 0.5 ng/kg/min (possibly lower in patients with severe renal or hepatic dysfunction) and increased in increments of 0.5 ng/kg/min until the appearance of mild headache and flushing. Tapering the rate of administration is recommended prior to discontinuing the drug.
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Various sections of the manuscript reviewed by: C.D. de Langen, Department of Pharmacology/Clinical Pharmacology, Gröningen, The Netherlands; J.A. Dormandy, Vascular Surgery Department, St George’s Hospital, London, England; J.-N. Fiessinger, Service de Médicine Vasculaire, Hôpital Broussais, Paris, France; E.J. Kraenzler, Cleveland Clinic Foundation, Cleveland, Ohio, USA; J.L. Mehta, Division of Cardiovascular Medicine, University of Florida, Gainesville, Florida, USA; S. Nicosia, Istituto di Scienzi Farmacologiche, Facoltà di Farmacia, University of Milan, Milan, Italy; F. Numano, Department of Internal Medicine, Tokyo Medical and Dental University, Bunkyo-Ku, Tokyo, Japan; T. Ohta, Department of Surgery, Aichi Medical University, Aichi-Ken, Japan; R. Paoletti, Istituto di Scienzi Farmacologiche, Facoltà di Farmacia, University of Milan, Milan, Italy; J.R. Parratt, Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland; K. Schrör, Institutes für Pharmakologie, University of Düsseldorf, Düsseldorf, Federal Republic of Germany; R.K. Türker, Department of Pharmacology, Medical Faculty of Ankara University, Ankara, Turkey; R. Verhaeghe, Universitaire Ziekenhuizen, Leuven, Belgium; H. Vapaatalo, Department of Biomedical Sciences, University of Tampere, Tampere, Finland.
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Grant, S.M., Goa, K.L. Iloprost. Drugs 43, 889–924 (1992). https://doi.org/10.2165/00003495-199243060-00008
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DOI: https://doi.org/10.2165/00003495-199243060-00008