Molecule
Drug
Alpha benzopyrones
Coumarins
Gama benzopyrones
Diosmin (micronized purified flavonoid fraction – MPFF)
Rutin, rutosides
Saponins
Aescin (horse chestnut seed extract)
Ruscus extract
Other plant extracts
Anthocyanins
Extract of Ginkgo
Synthetic
Calcium dobesilate
Benzarone
Naftazone
Mode of Action of VAD
VAD improve venous tone by acting through the noradrenaline pathway. Micronized purified flavonoid fraction (MPFF) prolongs noradrenergic activity. Hydroxyethyl rutosides block the inactivation of noradrenaline. Ruscus extract is an agonist of α 1 adrenergic receptors [1].
Capillary resistance is increased and filtration reduced [1].
Lymphatic system: Coumarins are used in the treatment of lymphedema. MPFF is known to improve lymph flow and increase the number of lymphatics. Calcium dobesilate can increase lymphatic clearance [1].
Hemorheological changes: Increased viscosity due to plasma volume reduction and increased fibrinogen content is a common finding in CVI. Another common feature is red cell aggregation. MPFF and calcium dobesilate reduce viscosity. RBC aggregation is inhibited by Ginkgo extract. MPFF improves RBC velocity [1].
Anti-inflammatory action: Venous hypertension induces an inflammatory response in the veins, capillaries, and skin. Experimental induction of venous hypertension in animals by venous occlusion, A-V fistula, and venous ligation confirmed the release of several inflammatory mediators. More importantly, priming these animals by administering MPFF considerably reduced the harmful effects induced by these inflammatory mediators [3]. Only MPFF is known to possess such anti-inflammatory action.
Indications for the Use of VAD
For symptomatic improvement. Several RCTs have confirmed that pain, cramps, restless legs, heaviness, and edema are all relieved by the use of VAD [1]. As per the outcome measures, MPFF and Rutosides offer strong benefit, while the other agents have only moderate impact.
For healing of venous leg ulcers as an adjunct to compression therapy and local treatment, MPFF has been recommended [2].
Daflon: Micronized Purified Flavonoid Fraction (Diosmin 450 mg and Hesperidin 50 mg)
This has been in clinical use for quite some time. Several trials have reported significant symptomatic improvement and better healing of ulcers with the use of this drug [2, 4]. The dosage recommended is 1,000 mg daily for 2 months [5]. The drug is reported to be effective in blocking the inflammatory cascade in CVI [4]. It has been reported that MPFF might be a useful adjunct to conventional therapy in large and long-standing ulcers that heal slowly [2].
Calcium Dobesilate
This is a synthetic preparation. Meta-analysis has shown improvement of symptoms of night cramps, paresthesia, pain, heaviness, and malleolar swelling in a dosage of 1,000 mg daily in comparison to placebo. The improvement was better in patients with the more severe forms of the disease [6]. Another trial has demonstrated that the improvement in symptoms is independent of the concomitant use of stockings [7].
Side Effects of VAD
These drugs have no serious adverse events. Hepatotoxicity has been reported with coumarins, rutin, and benzarone. Transient agranulocytosis is reported with the use of calcium dobesilate [1].
Hemorheological Agents – Pentoxifylline
Pentoxifylline is extensively used in the treatment of peripheral arterial diseases. Its use has been extended to the management of CVI. It inhibits cytokine-mediated neutrophil action. It also reduces white cell adhesion to endothelium and the release of superoxide free radicals [2]. The current opinion indicates that pentoxifylline in a dose of 1,200–2,400 mg could be an effective adjunct to compression therapy for treating leg ulcers [1, 3]. It can also heal ulcers on its own without compression but the level of evidence is much lower [3].
Antiplatelet Agents
Aspirin 300 mg daily had no impact in the healing of leg ulcers [8]. Ifetroban is a thromboxane A2 receptor antagonist. It inhibits platelet activation. Oral administration of this drug showed no effect on venous ulcer healing [2, 5].
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