Venoactive Drugs

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CHAPTER 14 Venoactive Drugs

Albert-Adrien Ramelet

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

image

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 (MPFF20–45), 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 recovery43,44) 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 studies46–58 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 asiatica79,80 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).

Phytotherapy

Plant extracts used in phytotherapy are often poorly standardized and controlled. Their active substance content may vary according to plant genetics, as well as to climatic factors, quality of the ground in which the plants were grown, the time of harvesting, and the extraction methods. Flavonoids may be at least partially responsible for their pharmacologic effects, but other glycosides might also be active.

Nutritional supplement

Nutritional supplements are a new trend. Some brands have been introduced in countries where VAD are not available, or as a new commercial over-the-counter (OTC) channel. They contain vegetal derivatives, mostly polyphenols, and antioxidants in order to relieve the symptoms of CVD.

Other preparations used in the past

Dihydroergotamine and dihydroergocristine (rye ergot extract)1 are no longer used in CVD treatment.

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 naftazone98,99 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.

Principal Mode of Action of VAD

VAD have a demonstrated positive action on:

• edema: decrease in capillary permeability, improved lymphatic drainage
• venous tone
• microcirculation: inhibition of leukocyte adhesion and migration, inhibition of inflammatory mediator release and prostaglandin synthesis, antioxidant effects (anti-free radicals), decrease in blood viscosity
• erythrocytes: inhibition of aggregation, decrease in erythrocytic deformation.

Administration, Dosage, Limits

VAD are mainly administered orally. The drug substances of plant origin are frequently poorly absorbed. Absorption may be enhanced by various chemical devices, hydroxyethylation of rutosides or micronization (MPFF).

Usual dosages are mentioned in Table 14.1. Low VAD doses should not be prescribed, as they are ineffective.1,2 Combinations of different preparations, whose value has not been validated by clinical trials, is to be avoided.2

Duration of treatment

A course of VAD treatment generally lasts 1 month. It is not appropriate to prescribe a VAD for more than 3 months except in the event of re-emergence of the symptoms after treatment discontinuation.2

Premenstrual syndrome

A particular dosage regimen (intake restricted to the last 2 weeks of the menstrual cycle) has been recommended for women presenting with premenstrual syndrome with pain and edema of the legs.100–102

Pregnancy and lactation

Some VAD have been used without any problems during the second and third trimester of pregnancy to relieve edema and symptoms of CVD and have been effective.103–105 They are indicated in Table 14.1. The pharmaceutical companies do not advise administration during pregnancy, however, and generally recommend that VAD should not be administered during breastfeeding.

Topical application

Topical VAD preparations are also available (rutosides, diosmin, escin, calcium dobesilate, among others). Absorption of the active drug has been demonstrated to have a degree of efficacy in a few double-blind studies.106,107

Adverse effects

Safety is in general good. Adverse effects occur in about 5% of the patients treated (Table 14.2). The side effects are rarely severe and comprise:

• dizziness, headache
• minor gastrointestinal disorders: ‘heavy’ stomach, flatulence, rarely nausea and vomiting, constipation and diarrhea
• rare skin rashes.

Table 14.2 Adverse effects of venoactive drugs

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However, the intake of benzarone or of high doses of coumarin (400 mg/day) has been associated with hepatitis. Prescription of these drugs is debatable. Coumarin has been withdrawn from most occidental countries. Low doses of coumarin combined with rutosides, marketed in certain countries, do not appear to induce such complications.

Several cases of agranulocytosis were associated with calcium dobesilate (but with a possible causal relationship in only some cases). Nine of these cases were reported in Spain since the product was first marketed over 35 years ago. Currently to the best of our knowledge, the incidence of agranulocytosis with calcium dobesilate treatment is less than the spontaneous prevalence in the overall population.

Scientifically Recognized Indications

Main indications of VAD

These are:

• edema
• subjective symptoms related to varicose veins or attributed to CVD (heavy legs, ‘heaviness’, ‘discomfort’, pruritus, pain along varicose vein paths)
• minor specific but frequently associated symptoms (paresthesia, night-time cramps, or restless leg syndrome).

Leg ulcer

Double-blind studies using MPFF29,40 and one meta-analysis41 have demonstrated an adjuvant effect on healing of leg ulcers when larger than 5 cm2 and existing for more than 6 months. Pain was relieved in all treated patients.

Long-term administration of rutosides did not prevent leg ulcer relapses in one study.46

Other indications

These include:

• prophylaxis of edema following long flights
• premenstrual syndrome
• pelvic congestion syndrome42
• prevention of pain after venous surgery.43,44

However, the indications vary depending on the country. Venoactive drugs may also have been registered for other indications such as episodes of hemorrhoids or diabetic retinopathy.

Combination with compression

Elastic compression is considered as the first-line treatment of CVD; VAD may:

• accentuate the effect of compression47,52,55
• be prescribed instead of compression when compression is contraindicated (arterial insufficiency, sensitive neuropathies) or poorly tolerated (individual reactions, summer heat).3,60

Results

The evaluation of VAD is complex since:

• the objective assessment of edema and of the attenuation of symptoms is difficult and subject to criticism.
• the placebo effect is marked even though the drug substance effect is statistically greater. Thus, the overall score of the assessments range from 54% to 76% for the drug substance and 18% to 46% for the placebo groups.
• the articles were frequently published in phlebological journals that are not indexed.
• university departments have little interest in CVD and scarcely contribute to the international studies.
• some pharmacologists reject VAD without being sufficiently aware of the dossiers on those drugs.

Demonstrated therapeutic effect

More than 130 RCTs or meta-analyses have been published to validate the clinical effectiveness of VAD.17–107 These publications have been evaluated in Cochrane reviews,13,64 in other reviews,15 and in consensus meetings, as in Paphos4 and Siena.3

Recommendations according to three levels of evidence – A, B, and C – may be suggested after a critical review of the different papers devoted to VAD (Table 14.3):

• Grade A: RCT with large sample sizes, valid meta-analyses
• Grade B: RCT with small sample size
• Grade C: Other controlled trials, no RCTs.

Table 14.3 Levels of evidence and grades of recommendations

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Guidelines

Scientific societies have published guidelines with the purpose of developing double-blind trials whose parameters are incontestable.14

The American Venous Forum in its Guidelines suggests the use of VAD (as MPFF and rutosides) in hot climates when the wearing of stockings is less acceptable. MPFF might be a useful adjunct to conventional therapy in large and long-standing ulcers which might otherwise be expected to heal slowly.108

In patients with persistent venous ulcers, the American College of Chest Physicians suggest that MPFF administered orally be added to local care and compression.109

Conclusions

Although not available in the United States, VAD are widely used in the world in the interest of patients.

They have no demonstrable effect on varicose veins or in varicose vein prevention, but they are effective on edema (C3) and on symptoms related to CVD (C0s–C6s), or as an adjuvant factor to leg ulcer healing. A specific ‘pain-killer’ effect has been suggested, as VAD are active on venous pain, which does not respond to anti-inflammatory drugs.

Successful treatment of venous symptoms is cost-effective. Renouncement of the use of VAD may induce an augmentation of health budget in the mid term, as demonstrated by Allegra.110 If patients do not present early for symptoms of CVD, the complications from venous disorders will surmount, inducing higher expenses: nonsteroidal anti-inflammatory drugs may be prescribed for venous pain, with expensive side effects; days off work may increase, among other effects of insufficient and late treatment of CVD, including alteration to quality of life.

While it is not acceptable for ineffective medications to be sold, it is no more acceptable for drug substances that have long been in use, and whose efficacy has been demonstrated, to be sacrificed for political reasons.

Further clinical RCTs are desirable, with greater attention paid to methodological quality, in order to establish more accurately the place of VAD in the treatment of CVD.

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