CHAPTER 14 Venoactive Drugs

Introduction

Venoactive drugs (VAD) are a heterogeneous group of medicinal products, of plant or synthetic origin, which have effects on edema (C3) and on symptoms related to chronic venous disease (CVD, classes C0s–C6s according to the CEAP classification).^1,² A specific ‘pain-killer’ effect has been suggested, as VAD are active on venous pain, which does not respond to anti-inflammatory drugs.¹^–⁵

VAD have no demonstrated effect on varicose veins or in varicose vein prevention. Flavonoids may be an adjuvant factor to leg ulcer healing.

Many names have been used to describe VAD: edema-protective agents, phlebotonics, venotonics, vasoprotectors, phlebotropics, and venotropics. These names should be discarded, as a standardization of appellations is highly desirable.

The main mechanisms of action of VAD are:

• increasing venous tone (this results in restoration of normal blood flow, dispersion of red cell aggregates, and better oxygenation)

• improving capillary hyperpermeability and lymph flow (thus protecting the microcirculation and decreasing the risk of edema)

• inhibiting the leukocyte adhesion to endothelial cells and the transmigration of leukocytes into the venous wall (presently demonstrated only for micronized purified flavonoid fraction (MPFF))

• improving fibrinolysis and blood rheology.¹^–¹⁴

As a consequence of lack of interest in CVD, publications devoted to VAD are scattered in journals of different languages, which are not always indexed in PubMed.

Although most authors are certainly perfectly honest, it must be emphasized that one group has been accused of fraudulent behavior. As their studies have already been published, they are, unfortunately, still available in reviews and meta-analyses.

Effectiveness of VAD has been regularly discussed, mostly by pharmacologists. Some of them have a poor knowledge of phlebology and VAD; their assertions are debatable. Others are not aware of the difficulty of assessing the activity of VAD.¹³ Symptoms are subjective, although they can be correctly quantified. Clinical signs such as edema are not easy to measure, owing to significant daily variations in each individual. Efficacy of VAD on edema and venous symptoms may currently be considered as correctly established. However, there is a need for further randomized, controlled clinical trials with greater attention paid to methodological quality.¹³^–¹⁵

Classification of VAD

The various classes of VAD are shown in Table 14.1.¹^–³

Table 14.1 Classification of the main venoactive drugs

In this chapter, we shall distinguish VDA as:

• benzopyrones

• saponins

• other plant extracts

• synthetic drugs.

Benzopyrones

This large group of medicines contains many substances, which are often closely related and endowed with multiple pharmacologic properties. Benzopyrones (alpha-pyrones and gamma-pyrones) are obtained from many indigenous and exotic plants, often used in traditional medicine. They belong to the family of phytophenols, and are related to resveratrol, which is currently undergoing a wide range of studies to assess its possible preventative and therapeutic value in atherosclerosis.¹⁶

Alpha-benzopyrones

Coumarin (1,2-benzopyrone; 5,6-benzo-alpha-pyrone) has been used either alone (mainly for the treatment of lymphedema) or in low doses in combination with oxerutin.

Esculetin (6,7-dihydroxycoumarin) and umbelliferone (7-hydroxycoumarin) are coumarin derivatives. Dicoumarols (dimers of 4-hydroxycoumarins) are powerful oral anticoagulants (acenocoumarol, phenprocoumon, warfarin). Their therapeutic properties thus differ fundamentally from those of VAD, despite their chemical similarities.

Coumarin is quickly absorbed and has a short half-life of 1 hour. Both it and its metabolites are excreted via the kidney.

Coumarin induces proteolysis of high-molecular-weight proteins present in lymphedema. Small-size protein fragments can then be more easily drained via the lymphatics. The oncotic pressure drops and edema lessens. However, effectiveness is debatable.¹⁷ Although coumarin and its derivatives have an antiedematous effect, they do not modify the coagulation of blood, in contrast to dicoumarols. Alongside its therapeutic properties, the aromatic properties of coumarin are extensively used in spices for cooking, cosmetology (soap, perfumes) and the tobacco industry.

Several cases of drug-related hepatitis have been reported after taking high doses of coumarin or dicoumarols as an anticoagulant. Coumarin has been withdrawn from the market for this reason, except in brands associating low doses of coumarin and troxerutin.¹⁸

Gamma-benzopyrones (flavonoids)

These have been previously defined as ‘vitamin P’ or factor P (permeability), as flavonoid deficiency results in capillary fragility and increased vessel wall permeability in the animal. These appellations are obsolete.

Many plant pigments belong to this group. They are used in the form of plant extracts, in semisynthetic or synthetic preparations. The main distinction is between:

• flavone and its derivatives, flavonols (kaempferol, diosmetin, diosmin, hidrosmin, quercetin, rutin (rutoside, oxerutin))

• flavanes (or flavonones): hesperitin, hesperidin and its derivatives, Pycnogenol, procyanidolic oligomers, etc.

Substances mostly used therapeutically in CVD are described below.

Diosmin and Micronized Purified Flavonoid Fraction

Diosmin (3′,5,7-trihydroxy-4′-methoxyflavone-7-rhamnoglucoside) is extracted from plants (rutaceae) or obtained by synthesis (as another bioflavonoid, hidrosmin).¹⁹ The half-life of diosmin is 8 to 12 hours, with its elimination being renal (65%) and biliary (35%).

Micronization enables a decrease in particle size of the flavone fraction from 20 to 2 µM (MPFF ²⁰^–⁴⁵), thereby increasing the intestinal absorption and bioavailability of the substance, as has been demonstrated in two clinical trials.²²^–²⁷

Diosmin and MPFF act:

• On venous tone, indirectly, by inhibiting the breakdown of norepinephrine (noradrenaline) by COMT (catechol-O-methyltransferase). Noradrenergic activity is thereby prolonged and venous tone increased. The degree of this effect varies in linear relation to the dose administered.

• On lymphatic drainage: decrease in the diameter of lymphatic vessels and intralymphatic pressure, increased number of functional lymphatics, and lymphatic flow and peristalsis, as well as capillary hematocrit and red cell velocity.

• On the microcirculation: protection of microvascular permeability via inhibition of adhesion of leukocytes, their intratissue migration, the release of inflammatory mediators and the expression of certain leukocyte (L-selectin) and endothelial (ICAM-1, VCAM-1) adhesion substances initiating the inflammatory events leading to raised microcirculatory venous pressure.

MPFF is indicated in the treatment of edema and of symptoms related to venous insufficiency (edema, heavy legs, discomfort, pruritus, night cramps, pain, swelling), pelvic congestion syndrome,⁴² venous surgery (decrease in postoperative pain and more rapid recovery^43,⁴⁴) as well as lymphedema, including filarial.⁴⁵ Its other indications are gynecological (tense painful breasts, IUD-related bleeding) and proctological.

All of these effects have been confirmed in double-blind clinical trials,²⁰^–⁴⁴ which also showed a significant improvement in the quality of life of patients suffering from (chronic venous insufficiency) CVI. According to five clinical trials joined in a meta-analysis, MPFF may hasten the healing of leg ulcers.⁴¹

Rutosides and Oxerutin

A standard mixture of several flavonoid derivatives is obtained by hydroxyethylation of a natural substance, rutin. Troxerutin is a fraction of oxerutine. Absorbed by the digestive tract, oxerutine has a half-life of 24 hours and is principally excreted in bile. A large number of pharmacological and clinical studies ⁴⁶^–⁵⁸ have provided evidence of its influence on disturbances of capillary permeability, effects on erythrocyte deformation and aggregation, antiedematous actions, and inhibition of prostaglandin synthesis. Its diffusion and accumulation in the venous wall have been demonstrated.⁵⁴

Rutosides are indicated as an antiedematous agent in venous disorders, in proctology (hemorrhoids) and in ophthalmology (retinopathy). Following topical application, oxerutine is absorbed and its action on cutaneous capillary fragility has been demonstrated.

Saponins

Escin

Escin is a mixture extracted from horse-chestnut seed (HCSE) containing many compounds, such as protoescigenin, barringtogenol, alpha- and beta-escin, cryptoescin, and benzopyrones.

HCSE compounds are poorly absorbed in the digestive tract (12.5%). Maximum activity of the preparation occurs 16 hours after ingestion. Escin and its metabolites are eliminated via the kidney and gallbladder; its percutaneous absorption has also been demonstrated.

Escin increases venous wall tone and has a well-demonstrated antiedematous effect.⁵⁹^–⁶⁴ The HSCE extracts have been evaluated in one Cochrane study, curiously excluding other VADs.¹²

Ruscus

Extracts of ruscus (butcher’s broom) contain saponins and flavonoids. The precise composition of these extracts is poorly understood. Venotonic and antiedematous actions have been well demonstrated in open and randomized controlled trial (RCT) studies and are associated with a reduction of symptoms in patients suffering from CVD.⁶⁵^–⁷⁴

Other plant extracts

Extracts of Ginkgo biloba⁷⁵^–⁷⁸ contain terpens and flavonoids. Antagonists of platelet activating factor (PAF), they have an action on platelet aggregation, blood viscosity, and edema. Extracts of Centella asiatica^79,⁸⁰ are believed to enhance collagen synthesis in connective tissue.

Many other plants are used in the treatment of symptoms of CVD. All of them contain flavonoids among other active substances: procyanidolic oligomers (anthocyans in bilberry extracts; proanthocyanidols in white grape pit, Vitis vinifera,^81,⁸² maritime pine (Pycnogenol)⁸³^–⁸⁵).

Synthetic drugs

Calcium dobesilate

This synthetic substance (dihydroxy-2,5-benzene-calcium sulfonate) is well absorbed after oral administration. Plasma levels are maximal 6 hours after ingestion. The half-life is short (5 hours).

The drug is eliminated principally in the urine, without being metabolized. It is absorbed following topical application.

Calcium dobesilate decreases capillary permeability and blood viscosity, and improves lymphatic drainage.⁸⁶^–⁹⁶ The antiedematous effect persists for about 2 months after treatment is stopped.

Benzarone

Benzarone, or (2-ethyl-1-benzofuran-3-yl)-(4-hydroxyphenyl)methanone is well absorbed following oral administration. Its half-life is about 10 hours. It is eliminated with its metabolites by the kidney. Benzarone has fibrinolytic properties and inhibits platelet aggregation.

Several cases of severe hepatitis have been reported.⁹⁷ Photosensitization may occur during treatment.

Naftazone

Beta-naphtoquinone monosemicarbazone or naftazone ^98,⁹⁹ is rapidly absorbed from the digestive tract. Its half-life is short (1.5 hours) and its metabolites are eliminated in urine.

A venoconstrictor effect and lowering of serum beta-glucuronidase levels have been demonstrated following the administration of 30 mg a day of naftazone. This substance might act on vessel wall permeability and on abnormalities of endothelial cells seen in CVD.

Tribenoside

Ethyl-3,5,6-tri-O-benzyl-D-glucofuranoside or tribenoside is a glucose derivative.¹ It is well absorbed following oral administration and is believed to have a half-life of about 24 hours. Its metabolites are excreted in the urine. Tribenoside can also be used by topical application.

Tribenoside decreases capillary permeability and has anti-inflammatory and analgesic actions. The usefulness of this preparation is limited by the frequency of its adverse effects: digestive and, above all, cutaneous (up to 7.2%). Presently it has been abandoned.